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Ekanayaka E.A.P.,Michigan State University | Ekanayaka E.A.P.,MPI Research | Celiz M.D.,Michigan State University | Jones A.D.,Michigan State University
Plant Physiology | Year: 2015

The rapid identification of novel plant metabolites and assignments of newly discovered substances to natural product classes present the main bottlenecks to defining plant specialized phenotypes. Although mass spectrometry provides powerful support for metabolite discovery by measuring molecular masses, ambiguities in elemental formulas often fail to reveal the biosynthetic origins of specialized metabolites detected using liquid chromatography-mass spectrometry. A promising approach for mining liquid chromatography-mass spectrometry metabolite profiling data for specific metabolite classes is achieved by calculating relative mass defects (RMDs) from molecular and fragment ions. This strategy enabled the rapid recognition of an extensive range of terpenoid metabolites in complex plant tissue extracts and is independent of retention time, abundance, and elemental formula. Using RMD filtering and tandem mass spectrometry data analysis, 24 novel elemental formulas corresponding to glycosylated sesquiterpenoid metabolites were identified in extracts of the wild tomato Solanum habrochaites LA1777 trichomes. Extensive isomerism was revealed by ultra-high-performance liquid chromatography, leading to evidence of more than 200 distinct sesquiterpenoid metabolites. RMD filtering led to the recognition of the presence of glycosides of two unusual sesquiterpenoid cores that bear limited similarity to known sesquiterpenes in the genus Solanum. In addition, RMD filtering is readily applied to existing metabolomics databases and correctly classified the annotated terpenoid metabolites in the public metabolome database for Catharanthus roseus. © 2014 American Society of Plant Biologists. All Rights Reserved.


Zhu Y.,CAS Shanghai Institute of Materia Medica | Zhang Z.,CAS Shanghai Institute of Materia Medica | Zhang M.,CAS Shanghai Institute of Materia Medica | Mais D.E.,MPI Research | Wang M.-W.,CAS Shanghai Institute of Materia Medica
Combinatorial Chemistry and High Throughput Screening | Year: 2010

Throughout the centuries, traditional Chinese medicine has been a rich resource in the development of new drugs. Modern drug discovery, which relies increasingly on automated high throughput screening and quick hit-to-lead development, however, is confronted with the challenges of the chemical complexity associated with natural products. New technologies for biological screening as well as library building are in great demand in order to meet the requirements. Here we review the developments in these techniques under the perspective of their applicability in natural product drug discovery. Methods in library construction, component characterization, biological evaluation, and other screening approaches including NMR and X-ray diffraction are discussed. © 2010 Bentham Science Publishers Ltd.


Mansueto V.,University of Palermo | Cangialosi M.V.,University of Palermo | Faqi A.S.,MPI Research
Caryologia | Year: 2011

In the present study we have determined the effects of endocrine disrupting chemicals such as Tributyltin (TBT) and Bisphenol-A (BPA) in juvenile Ciona intestinalis (Ascidiacea, Urochordata). The interest in Urochordata is due to its close phylogenetic relation to vertebrates. Moreover, in the juvenile the organs of a form similar to the adult form are present and they can easily be studied for the eventual morphological alterations that can be induced under stress conditions. Juvenile Ciona intestinalis of 4 days post fertilization were incubated for 1 h at increasing concentrations of either TBT or BPA solutions (0.1, 1 and 10 μM). The morphology of several organs was altered in a concentration-dependent manner in both TBT and BPA treated animals. BPA seems to be more toxic than TBT, destroying the tunic, the gonad cells and inhibiting the rhythmic body contractions. The TBT and BPA induced toxicity on the gonads is in agreement with previous data demonstrating that many chemicals can endanger the reproductive system leading to reproductive failure and consequently a population decline. These results suggest that the juvenile Ciona intestinalis can be used as an alternative or supplemental model for toxicological studies regarding the effects of toxicants not only on organs but also on metamorphosis and on reproductive, defense and nervous systems.


Chow C.P.,Cleveland BioLabs Inc. | Faqi A.S.,MPI Research
Reproductive Toxicology | Year: 2014

CBLB502 is a derivative of a microbial protein that binds to Toll-like receptor 5. It is demonstrated to reduce inflammatory response from acute stresses, such as radiation in animal models. We determined the potential developmental toxicity of CBLB502 in rats. Four groups of 25 time-mated female Wistar rats/group received subcutaneously 0, 30, 100, or 300. μg/kg/day of CBLB502 from Gestation Days (GD) 6 to 17 at a dose volume of 1.0. mL/kg. Toxicokinetic evaluation was performed on GD 6 and 17. On GD 20 C-section was performed for uterine evaluation and blood samples collected from each dam for immunogenicity assay.Significant decrease in gestation body weight, weight changes and food consumption indicative of maternal toxicity were observed in all dose groups. Also adjusted body weight and weight changes were seen at 300. μg/kg/day. No external, visceral and skeletal abnormalities were observed. The NOAEL for developmental toxicity was estimated to be ≥300. μg/kg/day. © 2014.


Faqi A.S.,MPI Research
Systems Biology in Reproductive Medicine | Year: 2012

The nonhuman primates (NHPs) are used in many areas of biomedical research where their similarities to humans make them exclusively valuable animal models. The use of NHPs in pre-clinical testing is expected to increase due to the increase in the development of biological compounds for therapeutic uses. The regulatory agencies around the world including Food and Drug Administration (FDA) generally requires developmental and reproductive toxicity (DART) testing of all new drugs to be used by women of childbearing age or men of reproductive potential. NHPs are most frequently used for DART testing when commonly used rodents and/or rabbits are not pharmacologically relevant species. Animal studies are unique in that assessment of reproduction and development as DART studies are not performed in controlled clinical trials; therefore, pre-clinical safety assessment forms the basis for risk assessment for marketed drug products. This paper provides a critical evaluation of developmental and reproductive toxicity studies in NHPs. The manuscript will focus on species selection, limitation of International Conference for Harmonization stages (A-F) using NHPs as a test system, study designs, logistical/technical challenges, and strength, and limitations. It will also pinpoint confounding factors inherent to the test system that may complicate the interpretation of the NHP DART data. © 2012 Informa Healthcare USA, Inc.


Abernathy M.M.,MPI Research
Handbook of Experimental Pharmacology | Year: 2015

Safety pharmacology satisfies a key requirement in the process of drug development. Safety pharmacology studies are required to assess the impact of a new chemical entity (NCE) or biotechnology-derived product for human use on vital systems, such as those subserving auditory function. Safety pharmacology studies accordingly are defined as those studies that investigate the potential undesirable effects of a substance on auditory functions in relation to exposure in and above the therapeutic range. Auditory safety studies should be designed with the primary objective of determining how administration of a compound influences normal hearing. If an effect on hearing is identified, then it is necessary to determine through histopathology the underlying mechanism for the observed hearing loss. Since the auditory system contains a heterogeneous mixture of structural and cellular components that are organized in a very complex and integrated manner, it is necessary to clearly identify the underlying primary mechanism or target of the new chemical entity that produced the hearing loss. This chapter will highlight major components of auditory function with regard to potential opportunities for drug interaction. Aspects of designing ototoxicity studies will be discussed with an emphasis on standards deemed necessary by the US Food and Drug Administration. Additionally, classes of ototoxic compounds and their proposed mechanisms of action are described in depth. © Springer-Verlag Berlin Heidelberg 2015


Blakemore W.R.,Celtic Colloids Inc | Kwok S.K.,MPI Research | Harding N.I.,Previously with MPI Research
Food Additives and Contaminants - Part A Chemistry, Analysis, Control, Exposure and Risk Assessment | Year: 2014

An LC-MS/MS method was validated in accordance with 21CFR Part 58 Good Laboratory Practice for Non-clinical Laboratory Studies to measure the concentration of carrageenan in dose formulations used in a 28-day piglet dietary feeding study of swine-adapted infant formulations stabilised with carrageenan. Carrageenan concentrations in the test formulations were 0, 300, 1000 and 2250 mg kg–1 formula. The method for the measurement of carrageenan was LC-MS/MS coupled with ESI in negative-ion mode for detection. Linearity was established over the range 1.00–7.50 µg ml–1. Carrageenan dose formulation samples ranging from 0 to 2250 mg kg–1 of carrageenan were diluted to within the linearity range for measurement. © 2014, © 2014 Taylor & Francis.


Hanlon P.R.,Abbott Laboratories | Thorsrud B.A.,MPI Research
Food and Chemical Toxicology | Year: 2014

One of the most abundant oligosaccharides found in human milk is 2'-fucosyllactose, a trisaccharide composed of fucose and lactose, and multiple studies have demonstrated a health benefit to this compound. Recent advances have allowed for the large-scale production of oligosaccharides via fermentation, including 2'-fucosyllactose. A neonatal piglet model was used to evaluate the tolerability of 2'-fucosyllactose, produced through this process, in order to demonstrate the suitability of this compound for human infants under 12 weeks of age. Crossbred farm piglets, at lactation day 2, were assigned to one of four treatment groups receiving a liquid diet containing 0, 200, 500 or 2000 mg/L of 2'-fucosyllactose. The calculated consumption of 2'-fucosyllactose corresponded to dose levels of 29.37, 72.22 and 291.74 mg/kg/day, respectively, in males and 29.30, 74.31, and 298.99 mg/kg/day, respectively in females. Piglets were administered diet for 3 weeks; and there were no test article-related effects on growth and development (clinical observations, body weight and food consumption), clinical pathology parameters (hematology, clinical chemistry, coagulation and urinalysis), or any histopathologic changes. Therefore, dietary exposure to 2'-fucosyllactose at concentrations up to 2000 mg/L was well tolerated by neonatal farm piglets and did not result in adverse health effects or impact piglet growth. © 2014 Elsevier Ltd.


Produce and other non-certified foods may be provided to laboratory animals for enrichment, but this practice can generate scientific concerns, particularly if these food items contain nutrients that are pharmacologically active or affect animals' consumption of the basal diet. The author reviews information on potential for a number of nutritional components of food items to affect study data. On the basis of published effect levels, he proposes an upper limit for the consumption of each component in enrichment items relative to the amount present in a standard basal diet. He then assesses the amounts of these nutritional components in a broad range of food enrichment items and proposes a maximum serving size for each item for several common laboratory animals. Total caloric content and sugar content are the limiting components for many enrichment food items, but most items may be used as enrichment for laboratory animals without affecting study results, as long as the amounts of the items provided are managed. © 2015 Nature America, Inc.


One enrichment strategy for laboratory animals is the provision of food variety and foraging opportunities. Fresh agricultural items, including produce or packaged human food items, provide variation in palatability, texture and complexity and can therefore be used as enrichment for lab animals. But concerns are often raised that these food items might sometimes carry contaminants that could affect research subjects and confound experimental results. The author discusses the potential for agriculturally sourced foods used as enrichment for lab animals to be contaminated with mycotoxins, microorganisms and pesticide residues and the effects these contaminants might have on lab animals. He also suggests strategies for reducing the risk of contamination. © 2015 Nature America, Inc. All rights reserved.

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