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Julius Mugweru, Gaelle Makafe, Yuanyuan Cao, Yang Zhang, Bangxing Wang, Shaobo Huang, Moses Njire, Chiranjibi Chhotaray, Yaoju Tan, Xinjie Li, Jianxiong Liu, Shouyong Tan, Jiaoyu Deng, Tianyu Zhang
The genetic manipulation of Mycobacterium tuberculosis genome is limited by the availability of selection markers. Spontaneous resistance mutation rate of M. tuberculosis to the widely used kanamycin is relatively high which often leads to some false positive transformants. Due to the few available markers, we have created a cassette containing thiostrepton resistance gene (tsr) for selection in M. tuberculosis and M. bovis BCG, and gentamicin resistance gene (aacC1) for Escherichia coli and M. smegmatis mc(2)155, flanked with dif sequences recognized by the Xer system of mycobacteria...
2017: Frontiers in Microbiology
Raquel Azevedo, Marija Markovic, Marta Machado, Blandine Franke-Fayard, António M Mendes, Miguel Prudêncio
The sporogonic stage of the life cycle of Plasmodium spp., the causative agents of malaria, occurs inside the parasite's mosquito vector, where a process of fertilization, meiosis and mitotic divisions culminates in the generation of large numbers of mammalian-infective sporozoites. Efforts to cultivate Plasmodium mosquito stages in vitro have proved challenging and yielded only moderate success. Here, we describe a methodology that simplifies the in vitro screening of much-needed transmission blocking (TB) compounds employing a bioluminescence-based method to monitor the in vitro development of sporogonic stages of the rodent malaria parasite, P...
March 27, 2017: Antimicrobial Agents and Chemotherapy
Sofia M E Weiler, Federico Pinna, Thomas Wolf, Teresa Lutz, Aman Geldiyev, Carsten Sticht, Maria Knaub, Stefan Thomann, Michaela Bissinger, Shan Wan, Stephanie Rössler, Diana Becker, Norbert Gretz, Hauke Lang, Frank Bergmann, Vladimir Ustiyan, Tatiana V Kalin, Stephan Singer, Ju-Seog Lee, Jens U Marquardt, Peter Schirmacher, Vladimir V Kalinichenko, Kai Breuhahn
BACKGROUND & AIMS: Many different types of cancer cells have chromosome instability. The hippo pathway leads to phosphorylation of the transcriptional activator yes associated protein 1 (YAP1, YAP), which regulates proliferation and has been associated with development of liver cancer. We investigated the effects of hippo signaling via YAP on chromosome stability and hepatocarcinogenesis in humans and mice. METHODS: We analyzed transcriptome data from 242 patients with hepatocellular carcinoma (HCC) to search for gene signatures associated with chromosomal instability; we investigated associations with overall survival time and cancer recurrence using Kaplan-Meier curves...
February 26, 2017: Gastroenterology
Wan-Xin Peng, Xiu Han, Chun-Li Zhang, Lu Ge, Feng-Yi Du, Jie Jin, Ai-Hua Gong
Although methylguanine-DNA-methyltransferase (MGMT) plays an important role in resistance to temozolomide (TMZ) in glioma, 40% of gliomas with MGMT inactivation are still resistant to TMZ. The underlying mechanism is not clear. Here, we report that forkhead box M1 (FoxM1) transcriptionally activates the expression of DNA repair gene replication factor C5 (RFC5) to promote TMZ resistance in glioma cells independent of MGMT activation. We showed that RFC5 expression is positively correlated with FoxM1 expression in human glioma cells and FoxM1 is able to transcriptionally activate RFC expression by interaction with the RFC5 promoter...
February 9, 2017: Cell Biology and Toxicology
Pavel Kudrin, Vallo Varik, Sofia Raquel Alves Oliveira, Jelena Beljantseva, Teresa Del Peso Santos, Ievgen Dzhygyr, Dominik Rejman, Felipe Cava, Tanel Tenson, Vasili Hauryliuk
The nucleotide (p)ppGpp is a key regulator of bacterial metabolism, growth, stress tolerance, and virulence. During amino acid starvation, the Escherichia coli (p)ppGpp synthetase RelA is activated by deacylated tRNA in the ribosomal A-site. An increase in (p)ppGpp is believed to drive the formation of antibiotic-tolerant persister cells, prompting the development of strategies to inhibit (p)ppGpp synthesis. We show that in a biochemical system from purified E. coli components, the antibiotic thiostrepton efficiently inhibits RelA activation by the A-site tRNA...
April 2017: Antimicrobial Agents and Chemotherapy
N Yang, C Wang, Z Wang, S Zona, S-X Lin, X Wang, M Yan, F-M Zheng, S-S Li, B Xu, L Bella, J-S Yong, E W-F Lam, Q Liu
Substantial evidence suggests that breast cancer initiation, recurrence and drug resistance is supported by breast cancer stem cells (BCSCs). Recently, we reported a novel role of Aurora kinase A (AURKA) in BCSCs, as a transactivating co-factor in the induction of the c-Myc oncoprotein. However, the mode of action and transcriptional network of nuclear AURKA in BCSCs remain unknown. Here, we report that nuclear AURKA can be recruited by Forkhead box subclass M1 (FOXM1) as a co-factor to transactivate FOXM1 target genes in a kinase-independent manner...
January 23, 2017: Oncogene
Donghyun Lee, Adel R Moawad, Tania Morielli, Maria C Fernandez, Cristian O'Flaherty
STUDY QUESTION: Do peroxiredoxins (PRDXs) control reactive oxygen species (ROS) levels during human sperm capacitation? SUMMARY ANSWER: PRDXs are necessary to control the levels of ROS generated during capacitation allowing spermatozoa to achieve fertilizing ability. WHAT IS KNOWN ALREADY: Sperm capacitation is an oxidative event that requires low and controlled amounts of ROS to trigger phosphorylation events. PRDXs are antioxidant enzymes that not only act as scavengers but also control ROS action in somatic cells...
February 10, 2017: Molecular Human Reproduction
Qingfei Zheng, Shoufeng Wang, Panpan Duan, Rijing Liao, Dandan Chen, Wen Liu
Thiostrepton (TSR), an archetypal bimacrocyclic thiopeptide antibiotic that arises from complex posttranslational modifications of a genetically encoded precursor peptide, possesses a quinaldic acid (QA) moiety within the side-ring system of a thiopeptide-characteristic framework. Focusing on selective engineering of the QA moiety, i.e., by fluorination or methylation, we have recently designed and biosynthesized biologically more active TSR analogs. Using these analogs as chemical probes, we uncovered an unusual indirect mechanism of TSR-type thiopeptides, which are able to act against intracellular pathogens through host autophagy induction in addition to direct targeting of bacterial ribosome...
December 13, 2016: Proceedings of the National Academy of Sciences of the United States of America
Qingfei Zheng, Shoufeng Wang, Rijing Liao, Wen Liu
Side-ring-modified thiostrepton (TSR) derivatives that vary in their quinaldic acid (QA) substitution possess more potent biological activities and better pharmaceutical properties than the parent compound. In this work, we sought to introduce fluorine onto C-7' or C-8' of the TSR QA moiety via precursor-directed mutational biosynthesis to obtain new TSR variants. Unexpectedly, instead of the target product, the exogenous chemical feeding of 7-F-QA into the ΔtsrT mutant strain resulted in a unique TSR analog with an incomplete side-ring structure and an unoxidized QA moiety (1)...
October 21, 2016: ACS Chemical Biology
Noemí Bahamontes-Rosa, María G Gomez-Lorenzo, Joël Lelièvre, Ane Rodriguez Alejandre, María Jesus Almela, Sonia Lozano, Esperanza Herreros, Francisco-Javier Gamo
BACKGROUND: Drugs that kill or inhibit Plasmodium gametocytes in the human host could potentially synergize the impact of other chemotherapeutic interventions by blocking transmission. To develop such agents, reliable methods are needed to study the in vitro activity of compounds against gametocytes. This study describes a novel assay for characterizing the activity of anti-malarial drugs against the later stages of Plasmodium falciparum gametocyte development using real-time PCR (qPCR)...
July 22, 2016: Malaria Journal
Akira Maekawa, Kenichi Kohashi, Masaaki Kuda, Kunio Iura, Takeaki Ishii, Makoto Endo, Tetsuya Nakatsura, Yukihide Iwamoto, Yoshinao Oda
BACKGROUND: Synovial sarcoma (SS) is a soft tissue sarcoma of unknown histogenesis. Most metastatic or unresectable cases are incurable. Novel antitumor agents and precise prognostication are needed for SS patients. The protein forkhead box M1 (FOXM1), which belongs to the FOX family of transcription factors, is considered to be an independent predictor of poor survival in many cancers and sarcomas, but the prognostic implications and oncogenic roles of FOXM1 in SS are poorly understood...
2016: BMC Cancer
Katsumi Doi, Yasuhiro Fujino, Yuko Nagayoshi, Toshihisa Ohshima, Seiya Ogata
Streptomyces laurentii ATCC 31255 produces thiostrepton, a thiopeptide class antibiotic. Here, we report the complete genome sequence for this strain, which contains a total of 8,032,664 bp, 7,452 predicted coding sequences, and a G+C content of 72.3%.
2016: Genome Announcements
Takamichi Ito, Kenichi Kohashi, Yuichi Yamada, Takeshi Iwasaki, Akira Maekawa, Masaaki Kuda, Daichi Hoshina, Riichiro Abe, Masutaka Furue, Yoshinao Oda
BACKGROUND: The prognosis of angiosarcoma is poor and a novel treatment option for the disease is desired. The aim of this study was to investigate the prognostic significance of Forkhead box M1 (FOXM1), a transcription factor that regulates cell-cycle progression and various crucial processes in tumor progression, and its potential as a new therapeutic target. METHODS: We investigated 125 angiosarcoma clinical samples (94 primary lesions and 31 metastatic lesions in 94 patients) and a human angiosarcoma cell line (HAMON) using immunohistochemical staining and molecular biological approaches...
2016: Journal of Cancer
Na Yang, Tai-Cheng Zhou, Xiu-xia Lei, Chang Wang, Min Yan, Zi-Feng Wang, Wei Liu, Jian Wang, Kai-Hua Ming, Bi-Cheng Wang, Bang-Lao Xu, Quentin Liu
BACKGROUND/AIM: Triple-negative breast cancer (TNBC) represents a particular clinical challenge because these cancers do not respond to endocrine therapy or other available targeted agents. The lack of effective agents and obvious targets are major challenges in treating TNBC. In this study we explored the cytostatic effect of thiazole ring containing antibiotic drug thiostrepton on TNBC cell lines and investigated the molecular mechanism. METHODS: Cell viability was measured by MTT assay...
2016: Cellular Physiology and Biochemistry
Anthony J Blaszczyk, Alexey Silakov, Bo Zhang, Stephanie J Maiocco, Nicholas D Lanz, Wendy L Kelly, Sean J Elliott, Carsten Krebs, Squire J Booker
TsrM, an annotated radical S-adenosylmethionine (SAM) enzyme, catalyzes the methylation of carbon 2 of the indole ring of L-tryptophan. Its reaction is the first step in the biosynthesis of the unique quinaldic acid moiety of thiostrepton A, a thiopeptide antibiotic. The appended methyl group derives from SAM; however, the enzyme also requires cobalamin and iron-sulfur cluster cofactors for turnover. In this work we report the overproduction and purification of TsrM and the characterization of its metallocofactors by UV-visible, electron paramagnetic resonance, hyperfine sublevel correlation (HYSCORE), and Mössbauer spectroscopies as well as protein-film electrochemistry (PFE)...
March 16, 2016: Journal of the American Chemical Society
Feifei Zhang, Chaoxuan Li, Wendy L Kelly
The thiopeptides are a family of ribosomally synthesized and post-translationally modified peptide metabolites, and the vast majority of thiopeptides characterized to date possess one highly modified macrocycle. A few members, including thiostrepton A, harbor a second macrocycle that incorporates a quinaldic acid moiety and the four N-terminal residues of the peptide. The antibacterial properties of thiostrepton A are well established, and its recently discovered ability to inhibit the proteasome has additional implications for the development of antimalarial and anticancer therapeutics...
February 19, 2016: ACS Chemical Biology
Takamichi Ito, Kenichi Kohashi, Yuichi Yamada, Akira Maekawa, Masaaki Kuda, Masutaka Furue, Yoshinao Oda
AIMS: Forkhead box M1 (FoxM1) is a transcription factor that regulates cell-cycle progression and tumour progression, but limited information is available regarding its clinical significance in melanoma. The aim of this study was to investigate the potency of FoxM1 as a therapeutic target in melanoma. METHODS AND RESULTS: We investigated 60 melanoma clinical samples and a melanoma WM266-4 cell line using immunohistochemical staining and molecular biological approaches...
July 2016: Histopathology
Akira Maekawa, Kenichi Kohashi, Nokitaka Setsu, Masaaki Kuda, Kunio Iura, Takeaki Ishii, Tomoya Matsunobu, Tetsuya Nakatsura, Yukihide Iwamoto, Yoshinao Oda
Leiomyosarcoma (LMS) of soft tissue is a sarcoma with smooth-muscle differentiation, and conventional chemotherapy does not improve its outcome. The application of novel antitumor agents and precise prognostication has been demanded. The expression of the protein Forkhead box M1 (FOXM1), a member of the FOX family, is considered an independent predictor of poor survival in many cancers and sarcomas. However, the expression status of FOXM1 in LMS is poorly understood. The purposes of this study were to examine the correlation between the expression of FOXM1 and clinicopathologic or prognostic factors and to clarify the efficacy of FOXM1 target therapy in LMS...
January 2016: Cancer Science
Kengo Sakihara, Jumpei Maeda, Kosuke Tashiro, Yasuhiro Fujino, Satoru Kuhara, Toshihisa Ohshima, Seiya Ogata, Katsumi Doi
Streptomyces azureus ATCC 14921 belongs to the Streptomyces cyaneus cluster and is known to be a thiostrepton producer. Here, we report a draft genome sequence for this strain, consisting of 350 contigs containing a total of 8,790,525 bp, 8,164 predicted coding sequences, and a G+C content of 70.9%.
2015: Genome Announcements
Alhosna Benjdia, Stéphane Pierre, Carmen Gherasim, Alain Guillot, Manon Carmona, Patricia Amara, Ruma Banerjee, Olivier Berteau
Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a novel class of natural products including several antibiotics and bacterial toxins. In countless RiPP biosynthetic pathways, cobalamin-dependent radical SAM (B12/rSAM) enzymes play a pivotal role. In the biosynthetic pathway of the antibiotic and anti-cancer agent thiostrepton A, TsrM, a B12/rSAM enzyme, catalyses the transfer of a methyl group to an electrophilic carbon atom of tryptophan. Here we show that methylcob(III)alamin is the probable physiological enzyme cofactor, and cob(II)alamin rather than cob(I)alamin is a key reaction intermediate...
October 12, 2015: Nature Communications
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