scholarly journals The Triphenylethylenes, a Novel Class of Antifungals

mBio ◽  
2014 ◽  
Vol 5 (3) ◽  
Author(s):  
Audrey R. Odom
Keyword(s):  
Mechanism Of Action ◽  
Fungal Infections ◽  
Disease Model ◽  
Drug Repurposing ◽  
Animal Disease ◽  
Fungal Burden ◽  
Animal Disease Model ◽  
Life Threatening ◽  
Preclinical Efficacy ◽  
Estrogen Receptor Antagonists

ABSTRACT New antifungals are needed, particularly in the developing world, to treat life-threatening fungal infections, such as cryptococcosis. Drug repurposing is one strategy to identify new drug-like compounds, but it is often difficult to identify a mechanism of action. Here we discuss the outstanding effort by Butts et al. to identify calmodulin as an antifungal target of repurposed estrogen receptor antagonists [A. Butts, K. Koselny, Y. Chabrier-Roselló, C. P. Semighini, Y. C. S. Brown, et al., mBio 5(1):e00765-13, 2014, doi:10.1128/mBio.00765-13]. The authors show that these compounds bind to and directly inhibit fungal calmodulin and also reduce fungal burden in an animal disease model. These studies thus establish both the key preclinical efficacy and the antifungal mechanism of action, which will allow these compounds to progress toward development of novel antifungal therapies.

scholarly journals Exosome TDP-43 profile in canine model of ALS: A preliminary study in developing surrogate biomarker

2021 ◽  
Author(s):  
Penelope Pfeiffer ◽  
Joan R Coates ◽  
Andrew Kennedy ◽  
Kyleigh Getchell ◽  
Edina Kosa ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Nervous System ◽  
Disease Model ◽  
Canine Model ◽  
Biological Processes ◽  
Animal Disease ◽  
Animal Disease Model ◽  
Preliminary Study ◽  
Degenerative Myelopathy

Blood-based biomarkers are much-needed diagnostic and prognostic tools for ALS. Canine degenerative myelopathy (DM) is recognized animal disease model to study the biology of human ALS. Serum derived exosomes are potential carrier that transport intercellular hormone-like messengers, together with their stability as carrier of proteins and RNA, make them ideal as biomarkers for a variety of diseases and biological processes. We study exosomal TDP-43 pattern as a surrogate biomarker that reflects biochemical changes in central nervous system. We isolated exosomes from canine serum using commercial exosome isolation reagents. TDP-43 and SOD1 profile in spinal cord homogenate lysate and that of serum-derived exosomes were found elevated in dogs with DM. We conclude levels of spinal cord TDP-43 and serum-derived exomes were similar in TDP-43 profiling, which warrant further investigation of disease sensitivity and specificity for establishing as a blood-based biomarker in canine DM.

scholarly journals Candidate Animal Disease Model of Elizabethkingia Spp. Infection in Humans, Based on the Systematic Pathology and Oxidative Damage Caused by E. miricola in Pelophylax nigromaculatus

2019 ◽  
Vol 2019 ◽  
pp. 1-13
Author(s):  
Xiaoli Huang ◽  
Yang Feng ◽  
Hong Tang ◽  
Guanqing Xiong ◽  
Liangyu Li ◽  
...  
Keyword(s):  
Oxidative Damage ◽  
Neurological Diseases ◽  
Disease Model ◽  
Infection Model ◽  
Animal Disease ◽  
Animal Disease Model ◽  
Brain Abscesses ◽  
Oxidative System ◽  
Pelophylax Nigromaculatus ◽  
Host Brain

Most species of the genus Elizabethkingia are pathogenic to humans and animals, most commonly causing meningitis. However, our understanding of the pathogenic mechanisms involved is poor and there have been few pathological studies of Elizabethkingia spp. in animals. To understand the host injury induced by Elizabethkingia spp., we established a model of E. miricola infection in the black-spotted frog (Pelophylax nigromaculatus). The systematic pathology in and oxidative damage in the infection model were investigated. Our results show that recently isolated E. miricola is a bacterium that mainly parasitizes the host brain and that neurogenic organs are the predominant sites of damage. Infection mainly manifested as severe brain abscesses, meningoencephalitis, necrotic spondylitis, and necrotic retinitis. The liver, spleen, kidney, gastrointestinal tract, and lung were also affected to varying degrees, with bacterial necrotic inflammation. P. nigromaculatus also suffered enormous damage to its oxidative system during E. miricola infection, which may have further aggravated its disease state. Our results provide a preliminary reference for the study and treatment of Elizabethkingia spp.-induced neurological diseases in animals.

scholarly journals A hierarchical 3D-motion learning framework for animal spontaneous behavior mapping

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Kang Huang ◽  
Yaning Han ◽  
Ke Chen ◽  
Hongli Pan ◽  
Gaoyang Zhao ◽  
...  
Keyword(s):  
Low Cost ◽  
Disease Model ◽  
Quantitative Description ◽  
Feature Space ◽  
Transgenic Animal ◽  
Neural System ◽  
Animal Disease ◽  
Animal Disease Model ◽  
Wide Range ◽  
Spontaneous Behavior

AbstractAnimal behavior usually has a hierarchical structure and dynamics. Therefore, to understand how the neural system coordinates with behaviors, neuroscientists need a quantitative description of the hierarchical dynamics of different behaviors. However, the recent end-to-end machine-learning-based methods for behavior analysis mostly focus on recognizing behavioral identities on a static timescale or based on limited observations. These approaches usually lose rich dynamic information on cross-scale behaviors. Here, inspired by the natural structure of animal behaviors, we address this challenge by proposing a parallel and multi-layered framework to learn the hierarchical dynamics and generate an objective metric to map the behavior into the feature space. In addition, we characterize the animal 3D kinematics with our low-cost and efficient multi-view 3D animal motion-capture system. Finally, we demonstrate that this framework can monitor spontaneous behavior and automatically identify the behavioral phenotypes of the transgenic animal disease model. The extensive experiment results suggest that our framework has a wide range of applications, including animal disease model phenotyping and the relationships modeling between the neural circuits and behavior.

scholarly journals Exosome TDP-43 Profile in Canine Model of ALS: A Preliminary Study in Developing Surrogate Biomarker

2021 ◽  
Author(s):  
Penelope Pfeiffer ◽  
Joan R. Coates ◽  
Andrew Kennedy ◽  
Kyleigh Getchell ◽  
Edina Kosa ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Nervous System ◽  
Disease Model ◽  
Canine Model ◽  
Biological Processes ◽  
Animal Disease ◽  
Animal Disease Model ◽  
Preliminary Study ◽  
Degenerative Myelopathy

Blood-based biomarkers are much-needed diagnostic and prognostic tools for ALS. Canine degenerative myelopathy (DM) is recognized animal disease model to study the biology of human ALS. Serum derived exosomes are potential carrier that transport intercellular hormone-like messengers, together with their stability as carrier of proteins and RNA, make them ideal as biomarkers for a variety of diseases and biological processes. We study exosomal TDP-43 pattern as a surrogate biomarker that reflects biochemical changes in central nervous system. We isolated exosomes from canine serum using commercial exosome isolation reagents. TDP-43 and SOD1 profile in spinal cord homogenate lysate and that of serum-derived exosomes were found elevated in dogs with DM. We conclude levels of spinal cord TDP-43 and serum-derived exomes were similar in TDP-43 profiling, which warrant further investigation of disease sensitivity and specificity for establishing as a blood-based biomarker in canine DM.

scholarly journals Therapeutic potential of Fosmanogepix (APX001) for intra-abdominal candidiasis: from lesion penetration to efficacy in a mouse model

2021 ◽  
Author(s):  
Annie Lee ◽  
Ning Wang ◽  
Claire L. Carter ◽  
Matthew Zimmerman ◽  
Véronique Dartois ◽  
...  
Keyword(s):  
Mouse Model ◽  
Therapeutic Potential ◽  
Fungal Infections ◽  
Ionization Mass ◽  
Drug Penetration ◽  
Fungal Burden ◽  
Life Threatening ◽  
Infected Liver ◽  
Repeated Dosing ◽  
Abdominal Candidiasis

Intra-abdominal candidiasis (IAC) is one of the most common yet underappreciated form of invasive candidiasis. IAC is difficult to treat, and therapeutic failure and drug resistant breakthrough infections are common in some institutions despite the use of echinocandins as first line agents. Fosmanogepix (FMGX, formerly APX001) is a first-in-class antifungal prodrug that can be administered both intravenously and orally. FMGX is currently in Phase 2 clinical development for the treatment of life-threatening invasive fungal infections. To explore the pharmacological property and therapeutic potential of FMGX for IAC, we evaluated both drug penetration and efficacy of the active moiety manogepix (MGX, formerly APX001A) in infected liver tissues in a clinically relevant IAC mouse model due to C. albicans. Matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) and laser capture microdissection (LCM)-directed absolute drug quantitation were employed to evaluate drug penetration into liver abscess lesions both spatially and quantitatively. The partitioning of MGX into lesions occurred slowly after a single dose; however robust accumulation in the lesion was achieved after 3 days of repeated dosing. Associated with this drug penetration pattern, reduction in fungal burden and clearance in the liver were observed in mice receiving the multi-day FMGX regimen. In comparison, administration of micafungin resulted in marginal reduction in fungal burden at the end of 4 days of treatment. These results suggest that FMGX is a promising candidate for the treatment of IAC.

scholarly journals Towards the evaluation in an animal disease model: Fluorinated 17β-HSD1 inhibitors showing strong activity towards both the human and the rat enzyme

2015 ◽  
Vol 103 ◽  
pp. 56-68 ◽  
Author(s):  
Ahmed S. Abdelsamie ◽  
Emmanuel Bey ◽  
Emanuele M. Gargano ◽  
Chris J. van Koppen ◽  
Martin Empting ◽  
...  
Keyword(s):  
Disease Model ◽  
Animal Disease ◽  
Strong Activity ◽  
Animal Disease Model
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