From the publisher: "Background: The introduction of whole new foods in a population may lead to sensitization and food allergy. This constitutes a potential public health problem and a challenge to risk assessors and managers as the existing understanding of the pathophysiological processes and the currently available biological tools for prediction of the risk for food allergy development and the severity of the reaction are not sufficient. There is a substantial body of in vivo and in vitro data describing molecular and cellular events potentially involved in food sensitization. However, these events have not been organized in a sequence of related events that is plausible to result in sensitization, and useful to challenge current hypotheses. The aim of this manuscript was to collect and structure the current mechanistic understanding of sensitization induction to food proteins by applying the concept of adverse outcome pathway (AOP). Main body: The proposed AOP for food sensitization is based on information on molecular and cellular mechanisms and pathways evidenced to be involved in sensitization by food and food proteins and uses the AOPs for chemical skin sensitization and respiratory sensitization induction as templates. Available mechanistic data on protein respiratory sensitization were included to fill out gaps in the understanding of how proteins may affect cells, cell-cell interactions and tissue homeostasis. Analysis revealed several key events (KE) and biomarkers that may have potential use in testing and assessment of proteins for their sensitizing potential. Conclusion: The application of the AOP concept to structure mechanistic in vivo and in vitro knowledge has made it possible to identify a number of methods, each addressing a specific KE, that provide information about the food allergenic potential of new proteins. When applied in the context of an integrated strategy these methods may reduce, if not replace, current animal testing approaches. The proposed AOP will be shared at the www.aopwiki.org platform to expand the mechanistic data, improve the confidence in each of the proposed KE and key event relations (KERs), and allow for the identification of new, or refinement of established KE and KERs." Authors: Jolanda H. M. van BilsenEmail author, Edyta Sienkiewicz-Szłapka, Daniel Lozano-Ojalvo, Linette E. M. Willemsen, Celia M. Antunes, Elena Molina, Joost J. Smit, Barbara Wróblewska, Harry J. Wichers, Edward F. Knol, Gregory S. Ladics, Raymond H. H. Pieters, Sandra Denery-Papini, Yvonne M. Vissers, Simona L. Bavaro, Colette Larré, Kitty C. M. Verhoeckx and Erwin L. Roggen
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Introduction: Strenuous physical stress induces a range of physiological responses, the extent depending, among others, on the nature and severity of the exercise, a person’s training level and overall physical resilience. This principle can also be used in an experimental set-up by measuring time-dependent changes in biomarkers for physiological processes. In a previous report, we described the effects of workload delivered on a bicycle ergometer on intestinal functionality. As a follow-up, we here describe an analysis of the kinetics of various other biomarkers. Aim: To analyse the time-dependent changes of 34 markers for different metabolic and immunological processes, comparing four different exercise protocols and a rest protocol. Methods: After determining individual maximum workloads, 15 healthy male participants (20–35 years) started with a rest protocol and subsequently performed (in a cross-over design with 1-week wash-out) four exercise protocols of 1-h duration at different intensities: 70% Wmax in a hydrated and a mildly dehydrated state, 50% Wmax and intermittent 85/55% Wmax in blocks of 2 min. Perceived exertion was monitored using the Borg’ Rating of Perceived Exertion scale. Blood samples were collected both before and during exercise, and at various timepoints up to 24 h afterward. Data was analyzed using a multilevel mixed linear model with multiple test correction. Results: Kinetic changes of various biomarkers were exercise-intensity-dependent. Biomarkers included parameters indicative of metabolic activity (e.g., creatinine, bicarbonate), immunological and hematological functionality (e.g., leukocytes, hemoglobin) and intestinal physiology (citrulline, intestinal fatty acid-binding protein, and zonulin). In general, responses to high intensity exercise of 70% Wmax and intermittent exercise i.e., 55/85% Wmax were more pronounced compared to exercise at 50% Wmax. Conclusion: High (70 and 55/85% Wmax) and moderate (50% Wmax) intensity exercise in a bicycle ergometer test produce different time-dependent changes in a broad range of parameters indicative of metabolic activity, immunological and hematological functionality and intestinal physiology. These parameters may be considered biomarkers of homeostatic resilience. Mild dehydration intensifies these time-related changes. Moderate intensity exercise of 50% Wmax shows sufficient physiological and immunological responses and can be employed to test the health condition of less fit individuals.
In this review, we present the growing scientific evidence showing the importance of protein and amino acid provision in nutritional support and their impact on preservation of muscle mass and patient outcomes.
Chemo-enzymatic peptide synthesis is unique in enabling the fast and sustainable synthesis of cyclic peptides, complex peptides and functionalized mini-proteins. The starting materials are routinely obtained by solid-phase peptide synthesis. One of the starting materials requires an oxo-ester functionality for recognition by the enzymes active site. The SPPS-based synthesis of the oxo-ester functionality still suffers from significant byproduct formation and low overall synthesis yields. The solution to this is introduction of the oxo-ester functionality at the end of the SPPS via a so-called Passerini reaction. Such a process does not only result in a more efficient production of cyclic or long peptides, but also expand the scope towards proteins derived from biological synthesis (i.e. recombinant proteins). To highlight the relevance of this proposed methodology, we will demonstrate a site-selective modification of the pharmaceutically important drug insulin.
Pre-eclampsia (PE) is a common and severe pregnancy complication and is associated with substantial perinatal morbidity and mortality in mothers and infants. The disease is often characterized by a non-specific presentation which makes it challenging for physician to diagnose PE during regular pregnancy check-ups. To date, there are no diagnostic tests on the market for detection of PE early in pregnancy (first trimester). In this project, we will develop a platform to sensitively analyse calcium-binding proteins (CBPs) which will unlock the full potential of CBPs as predictive PE markers. The technology will also be applicable for other diseases (e.g., dementia and cancer) where CBPs are also known to play a key role in disease pathophysiology. We will develop with phage display antibodies that can recognize calcium binding to specific motifs in proteins. To this end we will synthesize peptide motifs with and without calcium to select antibodies that are specific for calcium bound proteins. These antibodies will be validated for their clinical use. For this goal we will use serum samples from the Improved studie (EU subsidised study) to determine if we can recognize pre-eclampsia in a very early stage. This knowledge can lead to a better treatment of pregnant women suffering from this disease and also will probably increase the well-being for the baby born and the development further in life.
Treatment of crops with insecticides remains essential because globally more than 75 billion dollars is lost through crop destruction by invasive insects. However it is accompanied by severe disadvantages including i. increasing resistance of the target insects against insecticides and ii. the undesired lethality of beneficial insects such as bees and other pollinator species. The significant reduction of insect species during the last years, at least partly caused by the presently available insecticides has also effects on insect-eating species. Last but not least the presence of residual amount of insecticides in the environment (soil and plants), because of poor (bio)degradation, is another distinct disadvantage. Therefore, the overall aim of this proposal is to design and synthesize peptide based biopesticides. This should lead to Nature inspired green alternatives for insect control because "Peptides" are the small equivalents of "proteins", that are biomolecules, which are universally present in all organisms and subject to their natural biodegradation mechanisms, as well as also chemically degraded in the soil (water, heat, UV, oxygen). Design and synthesis of these environmentally benign compounds will eventually take place in a founded company called "INNOVAPEPLINE". Evaluation of candidate peptide based biopesticides can be carried out in collaboration with a recently founded company (spin-out of the University of Glasgow) called "SOLASTA BIO" (founders professors Shireen Davies, Julian Dow and Rob Liskamp) and/or with other (third) parties such as the University of Wageningen. Upon recent identification of promising candidate compounds ("leads"), chemical optimization studies of leads will take place, followed by evaluation in field trials. In this proposal design, synthesis and chemical optimization of the biological activity of new peptides and development of methods to monitor their biodegradation rate will take place. Thereby expanding the repertoire of peptide based biopesticides. (292 words)
