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Key determinants for the development of an allergic response to an otherwise ‘harmless’ food protein involve different factors like the predisposition of the individual, the timing, the dose, the route of exposure, the intrinsic properties of the allergen, the food matrix (e.g. lipids) and the allergen modification by food processing. Various physicochemical parameters can have an impact on the allergenicity of animal proteins. Following our previous review on how physicochemical parameters shape plant protein allergenicity, the same analysis was proceeded here for animal allergens. We found that each parameter can have variable effects, ranging on an axis from allergenicity enhancement to resolution, depending on its nature and the allergen. While glycosylation and phosphorylation are common, both are not universal traits of animal allergens. High molecular structures can favour allergenicity, but structural loss and uncovering hidden epitopes can also have a similar impact. We discovered that there are important knowledge gaps in regard to physicochemical parameters shaping protein allergenicity both from animal and plant origin, mainly because the comparability of the data is poor. Future biomolecular studies of exhaustive, standardised design together with strong validation part in the clinical context, together with data integration model systems will be needed to unravel causal relationships between physicochemical properties and the basis of protein allergenicity.

Allergy is an overreaction by the immune system to a previously encountered, ordinarily harmless substance —typically proteins—resulting in skin rash, swelling of mucous membranes, sneezing or wheezing, or other abnormal conditions. The use of modified proteins is increasingly widespread: their presence in food, commercial products, such as washing powder, and medical therapeutics and diagnostics, makes predicting and identifying potential allergens a crucial societal issue. The prediction of allergens has been explored widely using bioinformatics, with many tools being developed in the last decade; many of these are freely available online. Here, we report a set of novel models for allergen prediction utilizing amino acid E -descriptors, auto- and cross-covariance transformation, and several machine learning methods for classification, including logistic regression (LR), decision tree (DT), naïve Bayes (NB), random forest (RF), multilayer perceptron (MLP) and k nearest neighbours ( k NN). The best performing method was k NN with 85.3 % accuracy at 5-fold cross-validation. The resulting model has been implemented in a revised version of the AllerTOP server ( http://www.ddg-pharmfac.net/AllerTOP ). Figure ᅟ

This review searched for published evidence that could explain how different physicochemical properties impact on the allergenicity of food proteins and if their effects would follow specific patterns among distinct protein families. Owing to the amount and complexity of the collected information, this literature overview was divided in two articles, the current one dedicated to protein families of plant allergens and a second one focused on animal allergens. Our extensive analysis of the available literature revealed that physicochemical characteristics had consistent effects on protein allergenicity for allergens belonging to the same protein family. For example, protein aggregation contributes to increased allergenicity of 2S albumins, while for legumins and cereal prolamins, the same phenomenon leads to a reduction. Molecular stability, related to structural resistance to heat and proteolysis, was identified as the most common feature promoting plant protein allergenicity, although it fails to explain the potency of some unstable allergens (e.g. pollen-related food allergens). Furthermore, data on physicochemical characteristics translating into clinical effects are limited, mainly because most studies are focused on in vitro IgE binding. Clinical data assessing how these parameters affect the development and clinical manifestation of allergies is minimal, with only few reports evaluating the sensitising capacity of modified proteins (addressing different physicochemical properties) in murine allergy models. In vivo testing of modified pure proteins by SPT or DBPCFC is scarce. At this stage, a systematic approach to link the physicochemical properties with clinical plant allergenicity in real-life scenarios is still missing.

Insects of the order Hymenoptera have a defensive substance that contains many biologically active compounds. Specifically, venom from honeybees (Apis mellifera) contains many enzymes and peptides that are effective against various diseases. Different research papers stated the possibility of using bee venom (a direct bee sting or in an injectable form) in treating several complications; either in vivo or in vitro. Other reports used the active fractions of bee venom clinically or at labratory scale. Many reports and publications have stated that bee venom and its constituents have multiple biological activities including anti-microbial, anti-protozoan, anti-cancer, anti-inflammatory, and anti-arthritic properties. The present review aims to refer to the use of bee venom itself or its fractions in treating several diseases and counteracting drug toxicities as an alternative protocol of therapy. The updated molecular mechanisms of actions of bee venom and its components are discussed in light of the previous updated publications. The review also summarizes the potential of venom loaded on nanoparticles as a drug delivery vehicle and its molecular mechanisms. Finally, the products of bee venom available in markets are also demonstrated.

Background Allergy is a form of hypersensitivity to normally innocuous substances, such as dust, pollen, foods or drugs. Allergens are small antigens that commonly provoke an IgE antibody response. There are two types of bioinformatics-based allergen prediction. The first approach follows FAO/WHO Codex alimentarius guidelines and searches for sequence similarity. The second approach is based on identifying conserved allergenicity-related linear motifs. Both approaches assume that allergenicity is a linearly coded property. In the present study, we applied ACC pre-processing to sets of known allergens, developing alignment-independent models for allergen recognition based on the main chemical properties of amino acid sequences. Results A set of 684 food, 1,156 inhalant and 555 toxin allergens was collected from several databases. A set of non-allergens from the same species were selected to mirror the allergen set. The amino acids in the protein sequences were described by three z -descriptors ( z 1 , z 2 and z 3 ) and by auto- and cross-covariance (ACC) transformation were converted into uniform vectors. Each protein was presented as a vector of 45 variables. Five machine learning methods for classification were applied in the study to derive models for allergen prediction. The methods were: discriminant analysis by partial least squares (DA-PLS), logistic regression (LR), decision tree (DT), naïve Bayes (NB) and k nearest neighbours ( k NN). The best performing model was derived by k NN at k = 3. It was optimized, cross-validated and implemented in a server named AllerTOP, freely accessible at http://www.pharmfac.net/allertop . AllerTOP also predicts the most probable route of exposure. In comparison to other servers for allergen prediction, AllerTOP outperforms them with 94% sensitivity. Conclusions AllerTOP is the first alignment-free server for in silico prediction of allergens based on the main physicochemical properties of proteins. Significantly, as well allergenicity AllerTOP is able to predict the route of allergen exposure: food, inhalant or toxin.

Mite allergen plays tricks House dust mites ( Dermatophagoides spp.) are a common cause of allergy, known to trigger asthma attacks. The main dust-mite allergen, Der p 2, is found in high concentrations in mite faecal pellets. Der p 2 has structural homology with a component of the Toll-like-receptor signalling complex, and now that homology has been implicated in the mechanism by which such a strong allergic response is provoked. Der p 2 is shown to mimic the function of a Toll-like receptor complex protein, acting as an 'auto-adjuvant' and in effect tricking the immune system into believing that it is facing a bacterial infection. The common dust mite allergen Der p 2 is shown to replace MD-2 as the lipopolysaccharide-binding component and facilitates signalling through TLR4. It is suggested that Der p 2 tends to be targeted by adaptive immune responses because of its auto-adjuvant properties. Aeroallergy results from maladaptive immune responses to ubiquitous, otherwise innocuous environmental proteins 1 . Although the proteins targeted by aeroallergic responses represent a tiny fraction of the airborne proteins humans are exposed to, allergenicity is a quite public phenomenon—the same proteins typically behave as aeroallergens across the human population. Why particular proteins tend to act as allergens in susceptible hosts is a fundamental mechanistic question that remains largely unanswered. The main house-dust-mite allergen, Der p 2, has structural homology with MD-2 (also known as LY96), the lipopolysaccharide (LPS)-binding component of the Toll-like receptor (TLR) 4 signalling complex 2 , 3 , 4 . Here we show that Der p 2 also has functional homology, facilitating signalling through direct interactions with the TLR4 complex, and reconstituting LPS-driven TLR4 signalling in the absence of MD-2. Mirroring this, airway sensitization and challenge with Der p 2 led to experimental allergic asthma in wild type and MD-2-deficient, but not TLR4-deficient, mice. Our results indicate that Der p 2 tends to be targeted by adaptive immune responses because of its auto-adjuvant properties. The fact that other members of the MD-2-like lipid-binding family are allergens, and that most defined major allergens are thought to be lipid-binding proteins 5 , suggests that intrinsic adjuvant activity by such proteins and their accompanying lipid cargo may have some generality as a mechanism underlying the phenomenon of allergenicity.

Mitochondrial calcium uptake has a central role in cell physiology by stimulating ATP production, shaping cytosolic calcium transients and regulating cell death. The biophysical properties of mitochondrial calcium uptake have been studied in detail, but the underlying proteins remain elusive. Here we use an integrative strategy to predict human genes involved in mitochondrial calcium entry based on clues from comparative physiology, evolutionary genomics and organelle proteomics. RNA interference against 13 top candidates highlighted one gene, CBARA1, that we call hereafter mitochondrial calcium uptake 1 (MICU1). Silencing MICU1 does not disrupt mitochondrial respiration or membrane potential but abolishes mitochondrial calcium entry in intact and permeabilized cells, and attenuates the metabolic coupling between cytosolic calcium transients and activation of matrix dehydrogenases. MICU1 is associated with the mitochondrial inner membrane and has two canonical EF hands that are essential for its activity, indicating a role in calcium sensing. MICU1 represents the founding member of a set of proteins required for high-capacity mitochondrial calcium uptake. Its discovery may lead to the complete molecular characterization of mitochondrial calcium uptake pathways, and offers genetic strategies for understanding their contribution to normal physiology and disease.

Almond (Prunus dulcis) is a tree nut with high nutritional value that is widely cultivated and consumed globally. Prudu6, an 11S globulin, is one of the main allergens in almond, which can trigger a series of severe allergic reactions. To our knowledge, its correlation with Glym6, another 11S globulin, in terms of allergenicity has not yet been studied. In this study, natural Prudu6 was obtained by the optimized column chromatography method. Its structure was studied by the CD spectra, ultraviolet spectra and bioinformatics method. Then, WB and ELISA were performed to analyze the cross-reactivity. Prudu6 of high purity (>85%) was obtained by one-step chromatography. Strong cross-reactivity was found between Prudu6 and Glym6, which were also the main actors in the cross-reactivity between almond and soybean. For IgE in sera from almond-allergic patients, Glym6 demonstrated considerable affinity compared with Prudu6, while Prudu6 could hardly inhibit Glym6 in the soybean group. Three groups of epitope structures were found to be common in both proteins. These similar epitopes were regarded as the core structures causing the cross-reactivity between Prudu6 and Glym6.

The detection of molecules belonging to the pathogenesis-related protein-4 (PR-4) family as a cause of allergic reactions towards the pomegranate fruit has already been suggested, although information regarding their isolation and characterization is not available in the literature. The objective of this study was the purification and description of some features of a pomegranate PR-4 protein. This protein, named punein, was purified by classical biochemical methods, identified by direct protein sequencing and mass spectrometry and analyzed by bioinformatic tools. Biochemical characterization shows that punein has a molecular mass of 13.29 kDa by mass spectrometry and about 14 kDa on SDS-PAGE, and it displays a blocked N-terminus. Bioinformatic analysis highlights that its primary structure shows similarity with the allergens prohevein (containing the strong allergen Hev b 6) and Bra r 2, from latex and turnip, respectively. In particular, punein could be aligned with the C-terminal region of prohevein, which shows IgE epitope regions, the amino acid sequences of which are partially conserved in the two molecules. However, further investigations are needed to understand the clinical relevance of this PR-4 food protein and the factors affecting the concentration of specific proteins, including punein, that are recognized by the immune systems of patients sensitized to pomegranate.

Ingestion is one of the main exposure routes of humans and animals to microplastics (MPs). During digestion, MPs can interact with both gastrointestinal enzymes and food proteins. This study investigated the adsorption of trypsin onto polypropylene (PP) and polyethylene terephthalate (PET) MPs, the influence of MPs on trypsin structure and activity, and the in vitro trypsin digestibility of bovine meat extract (BME) sarcoplasmic proteins and BME α-Gal-carrying allergens (α-GalA) in the presence of PP and PET MPs. Trypsin, BME and α-GalA proteins interact with MPs, resulting in the formation of a soft (SC) and hard (HC) corona. This interaction is dynamic, leading to the adsorption and desorption of protein through time. Trypsin adsorption onto MPs results in slight structural changes in the SC and bulk solution, while a trypsin fraction residing in the HC loses most of its specific activity. The presence of MPs slightly slows down the digestibility of proteins with a mass of 38 kDa, while it does not affect the digestion of α-GalA. According to our results, it is unlikely that realistic concentrations of MPs in the intestine would have significant effects on meat extract proteins’ and allergens’ digestibility by trypsin. We confirmed that during trypsin digestion, the corona on PP and PET MP is composed of BME sarcoplasmic proteins and allergenic α-Gal-carrying proteins.