Nanomedicine encompasses usage of materials smaller than 100 nm for diagnosis, monitoring and treatment of disease. A frequent application of these materials is in reformulation of active drugs, ...which were previously approved for clinical use. As illustrated with chemotherapeutics, delivery of a drug within a nanocarrier can represent a clear clinical benefit as it can increase its targeted uptake and reduce the off-target toxicity. Matching nanomedicine treatments with patient-specific biomarkers provides an exciting prospect for moving the filed towards precision medicine. In parallel, a strong potential for personalized treatments comes from employing nanomaterials for the delivery of patient-tailored biologically active molecules. Recent research and clinical data have highlighted mRNA and siRNA molecules, as well as short peptides, as powerful new drug classes that can be designed according to patient profiles and effectively delivered within nanoparticles. Particles used for therapeutic delivery are based on biodegradable and safe materials, frequently lipids and polymers, which can be further functionalized into more complex forms. Currently, there is a strong interest in developing specific nanocarrier formulations which can achieve optimal delivery of active molecules to targeted cells while reducing unwanted side-effects. Here, we discuss recent developments and future perspectives in the nanomedicine field and specifically highlight innovative approaches for the personalized patient treatments.
Protein kinases are essential for signal transduction and control of most cellular processes, including metabolism, membrane transport, motility, and cell cycle. Despite the critical role of kinases ...in cells and their strong association with diseases, good coverage of their interactions is available for only a fraction of the 535 human kinases. Here, we present a comprehensive mass-spectrometry-based analysis of a human kinase interaction network covering more than 300 kinases. The interaction dataset is a high-quality resource with more than 5,000 previously unreported interactions. We extensively characterized the obtained network and were able to identify previously described, as well as predict new, kinase functional associations, including those of the less well-studied kinases PIM3 and protein O-mannose kinase (POMK). Importantly, the presented interaction map is a valuable resource for assisting biomedical studies. We uncover dozens of kinase-disease associations spanning from genetic disorders to complex diseases, including cancer.
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•AP-MS confirms over 1,300 known and reveals over 5,000 kinase protein interactions•Functional contexts and regulatory circuits for poorly studied kinases•Kinases are biochemically linked to a broad range of Mendelian disease modules•Biochemical context for kinase complexes containing human cancer proteins
In this issue of Molecular Cell, Buljan et al. present a comprehensive account of human kinase complexes for inferring new kinase functions, kinase signaling modules, and kinase complexes linked to genetic diseases.
Deterioration of biomolecules in clinical tissues is an inevitable pre-analytical process, which affects molecular measurements and thus potentially confounds conclusions from cohort analyses. Here, ...we investigate the degradation of mRNA and protein in 68 pairs of adjacent prostate tissue samples using RNA-Seq and SWATH mass spectrometry, respectively. To objectively quantify the extent of protein degradation, we develop a numerical score, the Proteome Integrity Number (PIN), that faithfully measures the degree of protein degradation. Our results indicate that protein degradation only affects 5.9% of the samples tested and shows negligible correlation with mRNA degradation in the adjacent samples. These findings are confirmed by independent analyses on additional clinical sample cohorts and across different mass spectrometric methods. Overall, the data show that the majority of samples tested are not compromised by protein degradation, and establish the PIN score as a generic and accurate indicator of sample quality for proteomic analyses.
Down syndrome (DS) is mostly caused by a trisomy of the entire Chromosome 21 (Trisomy 21, T21). Here, we use SWATH mass spectrometry to quantify protein abundance and protein turnover in fibroblasts ...from a monozygotic twin pair discordant for T21, and to profile protein expression in 11 unrelated DS individuals and matched controls. The integration of the steady-state and turnover proteomic data indicates that protein-specific degradation of members of stoichiometric complexes is a major determinant of T21 gene dosage outcome, both within and between individuals. This effect is not apparent from genomic and transcriptomic data. The data also reveal that T21 results in extensive proteome remodeling, affecting proteins encoded by all chromosomes. Finally, we find broad, organelle-specific post-transcriptional effects such as significant downregulation of the mitochondrial proteome contributing to T21 hallmarks. Overall, we provide a valuable proteomic resource to understand the origin of DS phenotypic manifestations.
Nucleophosmin (NPM1) is a multifunctional phospho-protein with critical roles in ribosome biogenesis, tumor suppression, and nucleolar stress response. Here we show that the N-terminal ...oligomerization domain of NPM1 (Npm-N) exhibits structural polymorphism by populating conformational states ranging from a highly ordered, folded pentamer to a highly disordered monomer. The monomer–pentamer equilibrium is modulated by posttranslational modification and protein binding. Phosphorylation drives the equilibrium in favor of monomeric forms, and this effect can be reversed by Npm-N binding to its interaction partners. We have identified a short, arginine-rich linear motif in NPM1 binding partners that mediates Npm-N oligomerization. We propose that the diverse functional repertoire associated with NPM1 is controlled through a regulated unfolding mechanism signaled through posttranslational modifications and intermolecular interactions.
Protein domains are the common currency of protein structure and function. Over 10,000 such protein families have now been collected in the Pfam database. Using these data along with animal gene ...phylogenies from TreeFam allowed us to investigate the gain and loss of protein domains. Most gains and losses of domains occur at protein termini. We show that the nature of changes is similar after speciation or duplication events. However, changes in domain architecture happen at a higher frequency after gene duplication. We suggest that the bias towards protein termini is largely because insertion and deletion of domains at most positions in a protein are likely to disrupt the structure of existing domains. We can also use Pfam to trace the evolution of specific families. For example, the immunoglobulin superfamily can be traced over 500 million years during its expansion into one of the largest families in the human genome. It can be shown that this protein family has its origins in basic animals such as the poriferan sponges where it is found in cell-surface-receptor proteins. We can trace how the structure and sequence of this family diverged during vertebrate evolution into constant and variable domains that are found in the antibodies of our immune system as well as in neural and muscle proteins.
Iron-carbohydrate complexes are widely used to treat iron deficiencies. Macrophages play a crucial role in the uptake and fate of these nanomedicines, however, how complexed iron carbohydrates are ...taken up and metabolized by macrophages is still not fully understood. Using a (phospho-)proteomics approach, we assessed differences in protein expression and phosphorylation in M2 macrophages triggered by iron sucrose (IS). Our results show that IS alters the expression of multiple receptors, indicative of a complex entry mechanism. Besides, IS induced an increase in intracellular ferritin, the loss of M2 polarization, protective mechanisms against ferroptosis, and an autophagic response. These data indicate that macrophages can use IS as a source of iron for its storage and later release, however, the excess of iron can cause oxidative stress, which can be successfully regulated by the cells. When comparing IS with ferric carboxymaltose (FCM) and iron isomaltoside-1000 (IIM), complexes with a higher carbohydrate ligand stability, we observed that FCM and IIM are metabolized at a slower rate, and trigger M2 polarization loss to a lower extent. These results indicate that the surface characteristics of the iron-carbohydrate complexes may influence the cell responses. Our data show that the application of (phospho-)proteomics can lead to a better understanding of metabolic processes, including the uptake, biodegradation and bioavailability of nanomedicines.
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•Proteomics can unravel molecular response and mode of action of nanomedicines.•Iron-carbohydrate complexes can enter macrophages as complete nanoparticles.•Macrophages use them as a source of iron for storage and later release.•Complexes with a more dynamic interaction are internalized and biodegraded faster.•Macrophages can successfully adapt to oxidative stress, preventing ferroptosis.
The purpose of this study was to examine the possible association between cheilitis and allergic reactions, and to use allergy skin tests to identify the allergens that induce allergic reactions in ...cheilitis patients (type I and type IV). We included SO patients with recurrent cheilitis (reversible cheilitis) who were dermatologically examined and agreed to undergo allergy skin tests, i.e., patch test and prick test. Additionally, clinical pictures and patient mental stress levels were examined using the Perceived Stress Scale (PSS). Positive prick tests (atopy) were recorded in 84% of patients with cheilitis. The most frequently found allergens were contact allergens (54%) (cobalt chloride, nickel sulfate and thimerosal) and inhalant allergens (46%). The patch test positive subjects who used cosmetic, hygiene, and decorative products were significantly more likely to have swollen and red lips than the patch test negative subjects. Also, low stress levels were recorded less frequently in patients with confirmed allergies than in non-allergic patients. The results indicated a higher incidence of cheilitis in the people prone to allergies (atopics) and confirmed an association between cheilitis and allergies. To our knowledge, this is the first study in patients with cheilitis, which simultaneously analyzed allergies, their clinical features and PSS in the same patients. Key words: Cheilitis; Lip inflammation; Allergy; Allergens; Mental stress Svrha ovoga rada bila je istraziti mogucu povezanost izmedu upale usnica (heilitisa) i alergijskih reakcija te pomocu alergoloskih testova utvrditi najcesce alergene koji uzrokuju alergijske reakcije u bolesnika s upalom usnica (tip I. i tip IV.). Ukupno je 50 ispitanika s reverzibilnim heilitisom bilo podvrgnuto dermatoloskom pregledu te u konacnici pristalo na alergoloska testiranja koze, patch test i prick test. Zatim su zabiljezeni simptomi koji se pojavljuju nakon primjene raznih proizvoda za usnice. Takoder, ispitanici su ispunili upitnik kojim se utvrduje razina psihickog stresa, Perceived Stress Scale (PSS). U 84% ispitanika s heilitisom bio je pozitivan barem jedan alergen iz prick testa (atopija). Najcesce utvrdeni alergeni bili su alergeni patch testa (54%, kobalt klorid, nikal sulfat i timerosal) te inhalacijski alergeni (46%). Ispitanici koji su bili pozitivni na kontaktne alergene (alergene patch testa) nakon uporabe kozmetickih, higijenskih i dekorativnih proizvoda cesce su imali otecene i crvene usnice nego ispitanici koji nisu imali niti jedan pozitivan kontaktni alergen. Takoder, u bolesnika u kojihje utvrdena alergija, niska razina stresa uocena je rjede nego u ne-alergicara. Rezultati ovoga istrazivanja pokazuju visu incidenciju heilitisa u bolesnika sklonih alergijama (atopicari) te potvrduju povezanost heilitisa i alergija. Prema nasim spoznajama, ovo je prvo istrazivanje u kojem su u bolesnika s upalom usnica istodobno analizirane alergijske reakcije, simptomi i klinicka slika te razina stresa. Kljucne rijeci: Heilitis; Upala usnica; Alergija; Alergeni; Psihicki stres
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