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Lehao Ren, Wanju Zhang, Peng Han, Jiaxiang Zhang, Yong Zhu, Xiaoxiao Meng, Jing Zhang, Yunwen Hu, Zhigang Yi, Ruilan Wang
Virus reprogramming of host cellular function is a critical strategy for viral survival and replication. A better understanding of virus-host interaction may provide new potential avenues for the treatment of viral diseases. It has been reported that hypoxia-inducible factor-1 (HIF-1) pathway is activated by a range of pathogens via different mechanisms, but the impact of Influenza A virus on HIF-1 signaling is still unclear. In this study, we observed H1N1 infection stabilized HIF-1α under normoxic conditions...
February 11, 2019: Virology
Guohua An, Daryl J Murry, Kiran Gajurel, Thanh Bach, Greg Deye, Larissa V Stebounova, Ellen E Codd, John Horton, Armando E Gonzalez, Hector H Garcia, Dilek Ince, Denice Hodgson-Zingman, Effie Y H Nomicos, Thomas Conrad, Jessie Kennedy, Walt Jones, Robert H Gilman, Patricia Winokur
Cysticercosis is a parasitic disease that frequently involves the human central nervous system (CNS) and current treatment options are limited. Oxfendazole, a veterinary medicine belonging to the benzimidazole family of anthelmintic drugs, has demonstrated substantial activity against the tissue stages of Taenia solium and has potential to be developed as an effective therapy for neurocysticercosis. To accelerate the transition of oxfendazole from veterinary to human use, the pharmacokinetics, safety and tolerability of oxfendazole were evaluated in healthy volunteers in this Phase 1 first-in-human (FIH) study...
February 11, 2019: Antimicrobial Agents and Chemotherapy
Iljin Kim, Seung-Hyun Shin, Jae Eun Lee, Jong-Wan Park
Oxygen is an indispensable element for cell survival and maintenance. Eukaryotic cells are equipped with a series of signaling pathways that cope with hypoxia. The dioxygenase factor inhibiting HIF (FIH) is an oxygen sensor that regulates the transcriptional activity of hypoxia-inducible factor (HIF) through asparaginyl hydroxylation. Given that HACE1 was detected as an FIH-interacting protein in a previous proteomics study, we tested whether the E3 ubiquitin ligase HACE1 is a substrate for FIH. FIH interacted with HACE1, in cells and in vitro, and was determined to hydroxylate HACE1 at the N191 residue within the ankyrin repeat domain...
January 18, 2019: Oncogene
Tal Burt, Le Thuy Vuong, Elizabeth Baker, Graeme C Young, A Daniel McCartt, Mats Bergstrom, Yuichi Sugiyama, Robert Combes
Phase 0 approaches, including microdosing, involve the use of sub-therapeutic exposures to the tested drugs, thus enabling safer, more-relevant, quicker and cheaper first-in-human (FIH) testing. These approaches also have considerable potential to limit the use of animals in human drug development. Recent years have witnessed progress in applications, methodology, operations, and drug development culture. Advances in applications saw an expansion in therapeutic areas, developmental scenarios and scientific objectives, in, for example, protein drug development and paediatric drug development...
December 2018: Alternatives to Laboratory Animals: ATLA
Jianshuang Wang, Michael Van Parys, Lin Pan, Yuan Chen, Dorothy Cheung, Janine McKnight, Dennis Milanowski, Xiao Ding, Brian Dean
A specific and robust LC-MS/MS method was developed and validated for the quantitative determination of GDC-3280 in human plasma and urine. The nonspecific binding associated with urine samples was overcome by the addition of CHAPS. The sample volume was 25 μL for either matrix, and supported liquid extraction was employed for analyte extraction. d6-GDC-3280 was used as the internal standard. Linear standard curves (R2 >0.9956) were established from 5.00 to 5000 ng/mL in both matrices with quantitation extended to 50,000 ng/mL through dilution...
January 7, 2019: Biomedical Chromatography: BMC
Xiu Feng, Xiaomu Yu, Meixia Pang, Jingou Tong
Factor-inhibiting HIF-1 (FIH-1) is an asparagine hydroxylase that interacts with hypoxia-inducible factor 1α (HIF-1α) to regulate transcriptional activity of HIF-1. Few studies of fish FIH-1 have been reported to date. In this study, the cDNA of FIH-1 gene was cloned and characterized for bighead carp, Aristichthys nobilis (AnFIH-1). The AnFIH-1 cDNA is 2065 bp in length, encoding a protein of 357 amino acid (aa) residues, which contains a JmjC homology region of the jumonji transcription factors. AnFIH-1 shares high identities with other vertebrate FIH-1 (79...
January 3, 2019: Fish Physiology and Biochemistry
Yuanyuan Meng, Fujun Yang, Wei Long, Wenqing Xu
The radiation-induced damage to the human body is primarily caused by excessive reactive oxygen species (ROS) production after irradiation. Therefore, the removal of the increase of ROS caused by ionizing radiation (IR) has been the focus of research on radiation damage protective agents. Hypoxia inducible factor (HIF) is a transcription factor in human and plays an important role in regulating the body metabolism. Factor inhibiting HIF (FIH) is an endogenous inhibitor factor of HIF protein under normoxia conditions...
December 21, 2018: International Journal of Molecular Sciences
Brian P Hobbs, Pedro C Barata, Yada Kanjanapan, Channing J Paller, Jane Perlmutter, Gregory R Pond, Tatiana M Prowell, Eric H Rubin, Lesley K Seymour, Nolan A Wages, Timothy A Yap, David Feltquate, Elizabeth Garrett-Mayer, William Grossman, David S Hong, S Percy Ivy, Lillian L Siu, Steven A Reeves, Gary L Rosner
Traditionally, drug development has evaluated dose, safety, activity, and comparative benefit in a sequence of phases using trial designs and endpoints specifically devised for each phase. Innovations in drug development seek to consolidate the phases and rapidly expand accrual with "seamless" trial designs. Although consolidation and rapid accrual may yield efficiencies, widespread use of seamless first-in-human (FiH) trials without careful consideration of objectives, statistical analysis plans, or trial oversight raises concerns...
December 17, 2018: Journal of the National Cancer Institute
Juliana Kretsinger, Neha Frantz, Scott A Hart, Wayne P Kelley, Bob Kitchen, Shawn Novick, Barbara Rellahan, Daniela Stranges, Corné J M Stroop, Ping Yin, Martin H Gastens
Early phase specifications are established to ensure that materials used in clinical studies have appropriate product quality, reducing the risk of harm to patients. Currently, guidance is available for specification setting practices at commercial phase. With very limited data and manufacturing experience available, it is not possible to fully align to these expectations at the start of clinical trials. A survey was performed among 19 biopharmaceutical companies to gather information about the current practices for setting specifications in early phase development...
December 6, 2018: Journal of Pharmaceutical Sciences
Susan Reijntjes, Muna Albayaty, James Bush, Joseph Cheriyan, Anthea Cromie, Annelize Koch, Michael Hammond, Stuart Mair, Peter Scholes, Ulrike Lorch, Steffan Stringer, Jorg Taubel, Timothy C Hardman
The Association for Human Pharmacology in the Pharmaceutical Industry (AHPPI) annual meeting focused on the changing face of early phase drug development and opened with a keynote speech concerning the revolution in pharmaceutical medicine over the last 30 years and the impact this has had on the way patients are treated. Examples were presented of how translational pharmaceutics is being used to tackle the high drug candidate failure rate and is improving productivity when moving drug candidates from the laboratory through to clinical proof of concept...
2018: Frontiers in Pharmacology
Yihua Wang, Shan Zhong, Christopher J Schofield, Peter J Ratcliffe, Xin Lu
Hypoxia plays a crucial role at cellular and physiological levels in all animals. The responses to chronic hypoxia are, at least substantially, orchestrated by activation of the hypoxia inducible transcription factors (HIFs), whose stability and subsequent transcriptional activation are regulated by HIF hydroxylases. Factor inhibiting HIF (FIH), initially isolated as a HIFα interacting protein following a yeast two-hybrid screen, is an asparaginyl hydroxylase that negatively regulates transcriptional activation by HIF...
November 19, 2018: Journal of Cell Science
Vanessa D Chaplin, John A Hangasky, Hsin-Ting Huang, Ran Duan, Michael J Maroney, Michael J Knapp
α-Ketoglutarate (αKG) dependent oxygenases comprise a large superfamily of enzymes that activate O2 for varied reactions. While most of these enzymes contain a nonheme Fe bound by a His2 (Asp/Glu) facial triad, a small number of αKG-dependent halogenases require only the two His ligands to bind Fe and activate O2 . The enzyme "factor inhibiting HIF" (FIH) contains a His2 Asp facial triad and selectively hydroxylates polypeptides; however, removal of the Asp ligand in the Asp201→Gly variant leads to a highly active enzyme, seemingly without a complete facial triad...
October 15, 2018: Inorganic Chemistry
Jengmin Kang, Yang-Sook Chun, June Huh, Jong-Wan Park
The N-terminal acetyltransferase A (NatA) complex, which is composed of NAA10 and NAA15, catalyzes N-terminal acetylation of many proteins in a co-translational manner. Structurally, the catalytic subunit NAA10 was believed to have no activity toward an internal lysine residue because the gate of its catalytic pocket is too narrow. However, several studies have demonstrated that the monomeric NAA10 can acetylate the internal lysine residues of several substrates including hypoxia-inducible factor 1α (HIF-1α)...
October 2018: Redox Biology
Shyam R Iyer, Vanessa D Chaplin, Michael J Knapp, Edward I Solomon
FIH [factor inhibiting HIF (hypoxia inducible factor)] is an α-ketoglutarate (αKG)-dependent nonheme iron enzyme that catalyzes the hydroxylation of the C-terminal transactivation domain (CAD) asparagine residue in HIF-1α to regulate cellular oxygen levels. The role of the facial triad carboxylate ligand in O2 activation and catalysis was evaluated by replacing the Asp201 residue with Gly (D201G), Ala (D201A), and Glu (D201E). Magnetic circular dichroism (MCD) spectroscopy showed that the (FeII )FIH variants were all 6-coordinate (6C) and the αKG plus CAD bound FIH variants were all 5-coordinate (5C), mirroring the behavior of the wild-type ( wt) enzyme...
September 19, 2018: Journal of the American Chemical Society
Xiaolian Cai, Dawei Zhang, Jing Wang, Xing Liu, Gang Ouyang, Wuhan Xiao
Many aerobic organisms have developed molecular mechanism to tolerate hypoxia, but the specifics of these mechanisms remain poorly understood. It is important to develop genetic methods that confer increased hypoxia tolerance to intensively farmed aquatic species, as these are maintained in environments with limited available oxygen. As an asparaginyl hydroxylase of hypoxia-inducible factors (HIFs), factor inhibiting HIF (FIH) inhibits transcriptional activation of hypoxia-inducible genes by blocking the association of HIFs with the transcriptional coactivators CREB-binding protein (CBP) and p300...
October 5, 2018: Journal of Biological Chemistry
Jie Shen, Brandon Swift, Richard Mamelok, Samuel Pine, John Sinclair, Mayssa Attar
A milestone step in translational science to transform basic scientific discoveries into therapeutic applications is the advancement of a drug candidate from preclinical studies to initial human testing. First-in-human (FIH) trials serve as the link to advance new promising drug candidates and are conducted primarily to determine the safe dose range for further clinical development. Cross-functional collaboration is essential to ensure efficient and successful FIH trials. The aim of this publication is to serve as a tutorial for conducting FIH trials for both small molecule and biological drug candidates with topics covering regulatory requirements, preclinical safety testing, study design considerations, safety monitoring, biomarker assessment, and global considerations...
July 26, 2018: Clinical and Translational Science
Frank R Brennan, Laura Andrews, Antonio R Arulanandam, Jorg Blumel, Jim Fikes, Christine Grimaldi, Janice Lansita, Lise I Loberg, Tim MacLachlan, Mark Milton, Suezanne Parker, Jay Tibbitts, Jayanthi Wolf, Krishna P Allamneni
Nonclinical safety testing of biopharmaceuticals can present significant challenges to human risk assessment with these innovative and often complex drugs. Emerging topics in this field were discussed recently at the 2016 Annual US BioSafe General Membership meeting. The presentations and subsequent discussions from the main sessions are summarized. The topics covered included: (i) specialty biologics (oncolytic virus, gene therapy, and gene editing-based technologies), (ii) the value of non-human primates (NHPs) for safety assessment, (iii) challenges in the safety assessment of immuno-oncology drugs (T cell-dependent bispecifics, checkpoint inhibitors, and costimulatory agonists), (iv) emerging therapeutic approaches and modalities focused on microbiome, oligonucleotide, messenger ribonucleic acid (mRNA) therapeutics, (v) first in human (FIH) dose selection and the minimum anticipated biological effect level (MABEL), (vi) an update on current regulatory guidelines, International Council for Harmonization (ICH) S1, S3a, S5, S9 and S11 and (vii) breakout sessions that focused on bioanalytical and PK/PD challenges with bispecific antibodies, cytokine release in nonclinical studies, determining adversity and NOAEL for biologics, the value of second species for toxicology assessment and what to do if there is no relevant toxicology species...
July 17, 2018: Regulatory Toxicology and Pharmacology: RTP
Biying Zhu, Xiuye Cao, Wenqiang Zhang, Guoping Pan, Qing Yi, Wenbin Zhong, Daoguang Yan
The enhanced expression of miR-31 has been observed in many human malignancies including lung cancer, and this microRNA regulates several aspects of oncogenesis. However, the role of miR-31-5p in energy metabolism remains elusive. Here, we confirm that H1299 and A549 cells, 2 lung cancer cell lines, relay on aerobic glycolysis as main source of ATP. Inhibition of miR-31-5p leads to decreased glycolysis and ATP production, while miR-31-5p overexpression increases them. Hypoxia inducible factor 1 (HIF-1) up-regulates the expression of glycolytic enzymes, and the HIF-1α inhibitor (FIH) inhibits HIF-1 activity...
July 13, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
(no author information available yet)
No abstract text is available yet for this article.
July 1, 2018: Cancer Research
Priyanshu Bhargava, Anjani Kumari, Jayarani F Putri, Yoshiyuki Ishida, Keiji Terao, Sunil C Kaul, Durai Sundar, Renu Wadhwa
Honeybee propolis and its bioactive component, caffeic acid phenethyl ester (CAPE), are known for a variety of therapeutic potentials. By recruiting a cell-based reporter assay for screening of hypoxia-modulating natural drugs, we identified CAPE as a pro-hypoxia factor. In silico studies were used to probe the capacity of CAPE to interact with potential hypoxia-responsive proteins. CAPE could not dock into hypoxia inducing factor (HIF-1), the master regulator of hypoxia response pathway. On the other hand, it was predicted to bind to factor inhibiting HIF (FIH-1)...
September 2018: Cell Stress & Chaperones
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