RESUMEN
The developmental origins of healthy and disease (DOHaD) concept has demonstrated a higher rate of chronic diseases in the adult population of individuals whose mothers experienced severe maternal protein restriction (MPR). Using proteomic and in silico analyses, we investigated the lung proteomic profile of young and aged rats exposed to MPR during pregnancy and lactation. Our results demonstrated that MPR lead to structural and immune system pathways changes, and this outcome is coupled with a rise in the PI3k-AKT-mTOR signaling pathway, with increased MMP-2 activity, and CD8 expression in the early life, with long-term effects with aging. This led to the identification of commonly or inversely differentially expressed targets in early life and aging, revealing dysregulated pathways related to the immune system, stress, muscle contraction, tight junctions, and hemostasis. We identified three miRNAs (miR-378a-3p, miR-378a-5p, let-7a-5p) that regulate four proteins (ACTN4, PPIA, HSPA5, CALM1) as probable epigenetic lung marks generated by MPR. In conclusion, MPR impacts the lungs early in life, increasing the possibility of long-lasting negative outcomes for respiratory disorders in the offspring.
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Pulmón , MicroARNs , Proteómica , Animales , Femenino , Pulmón/metabolismo , Masculino , Proteómica/métodos , Embarazo , MicroARNs/genética , MicroARNs/metabolismo , Ratas , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/genética , Dieta con Restricción de Proteínas , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/genética , Longevidad/genética , Ratas Wistar , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteoma/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Envejecimiento/metabolismo , Envejecimiento/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/genéticaRESUMEN
Current stage of proteomic research in the field of biology, medicine, development of new drugs, population screening, or personalized approaches to therapy dictates the need to analyze large sets of samples within the reasonable experimental time. Until recently, mass spectrometry measurements in proteomics were characterized as unique in identifying and quantifying cellular protein composition, but low throughput, requiring many hours to analyze a single sample. This was in conflict with the dynamics of changes in biological systems at the whole cellular proteome level upon the influence of external and internal factors. Thus, low speed of the whole proteome analysis has become the main factor limiting developments in functional proteomics, where it is necessary to annotate intracellular processes not only in a wide range of conditions, but also over a long period of time. Enormous level of heterogeneity of tissue cells or tumors, even of the same type, dictates the need to analyze biological systems at the level of individual cells. These studies involve obtaining molecular characteristics for tens, if not hundreds of thousands of individual cells, including their whole proteome profiles. Development of mass spectrometry technologies providing high resolution and mass measurement accuracy, predictive chromatography, new methods for peptide separation by ion mobility and processing of proteomic data based on artificial intelligence algorithms have opened a way for significant, if not radical, increase in the throughput of whole proteome analysis and led to implementation of the novel concept of ultrafast proteomics. Work done just in the last few years has demonstrated the proteome-wide analysis throughput of several hundred samples per day at a depth of several thousand proteins, levels unimaginable three or four years ago. The review examines background of these developments, as well as modern methods and approaches that implement ultrafast analysis of the entire proteome.
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Espectrometría de Masas , Proteómica , Proteómica/métodos , Humanos , Proteoma/análisis , Proteoma/metabolismoRESUMEN
In recent years, advancements in deep learning techniques have significantly expanded the structural coverage of the human proteome. GalaxySagittarius-AF translates these achievements in structure prediction into target prediction for druglike compounds by incorporating predicted structures. This web server searches the database of human protein structures using both similarity- and structure-based approaches, suggesting potential targets for a given druglike compound. In comparison to its predecessor, GalaxySagittarius, GalaxySagittarius-AF utilizes an enlarged structure database, incorporating curated AlphaFold model structures alongside their binding sites and ligands, predicted using an updated version of GalaxySite. GalaxySagittarius-AF covers a large human protein space compared to many other available computational target screening methods. The structure-based prediction method enhances the use of expanded structural information, differentiating it from other target prediction servers that rely on ligand-based methods. Additionally, the web server has undergone enhancements, operating two to three times faster than its predecessor. The updated report page provides comprehensive information on the sequence and structure of the predicted protein targets. GalaxySagittarius-AF is accessible at https://galaxy.seoklab.org/sagittarius_af without the need for registration.
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Proteoma , Humanos , Proteoma/química , Proteoma/metabolismo , Ligandos , Bases de Datos de Proteínas , Sitios de Unión , Programas Informáticos , Biología Computacional/métodos , Conformación Proteica , Aprendizaje Profundo , Descubrimiento de Drogas/métodos , Modelos Moleculares , Proteínas/química , Proteínas/metabolismoRESUMEN
Kidney Stone Disease (KSD) constitutes a multifaceted disorder, emerging from a confluence of environmental and genetic determinants, and is characterized by a high frequency of occurrence and recurrence. Our objective is to elucidate potential causative proteins and identify prospective pharmacological targets within the context of KSD. This investigation harnessed the unparalleled breadth of plasma protein and KSD pooled genome-wide association study (GWAS) data, sourced from the United Kingdom Biobank Pharma Proteomics Project (UKBPPP) and the FinnGen database version R10. Through Mendelian randomization analysis, proteins exhibiting a causal influence on KSD were pinpointed. Subsequent co-localization analyses affirmed the stability of these findings, while enrichment analyses evaluated their potential for pharmacological intervention. Culminating the study, a phenome-wide association study (PheWAS) was executed, encompassing all phenotypes (2408 phenotypes) catalogued in the FinnGen database version R10. Our MR analysis identified a significant association between elevated plasma levels of proteins FKBPL, ITIH3, and SERPINC1 and increased risk of KSD based on genetic predictors. Conversely, proteins CACYBP, DAG1, ITIH1, and SEMA6C showed a protective effect against KSD, documented with statistical significance (PFDR<0.05). Co-localization analysis confirmed these seven proteins share genetic variants with KSD, signaling a shared genetic basis (PPH3 + PPH4 > 0.8). Enrichment analysis revealed key pathways including hyaluronan metabolism, collagen-rich extracellular matrix, and serine-type endopeptidase inhibition. Additionally, our PheWAS connected the associated proteins with 356 distinct diseases (PFDR<0.05), highlighting intricate disease interrelations. In conclusion, our research elucidated a causal nexus between seven plasma proteins and KSD, enriching our grasp of prospective therapeutic targets.
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Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Proteoma , Humanos , Nefrolitiasis/genética , Nefrolitiasis/sangre , Nefrolitiasis/metabolismo , Fenotipo , ProteómicaRESUMEN
BACKGROUND: Trypanosoma cruzi is transmitted to humans by hematophagous bugs belonging to the Triatominae subfamily. Its intra-vectorial cycle is complex and occurs exclusively in the insect's midgut. Dissecting the elements involved in the cross-talk between the parasite and its vector within the digestive tract should provide novel targets for interrupting the parasitic life cycle and affecting vectorial competence. These interactions are shaped by the strategies that parasites use to infect and exploit their hosts, and the host's responses that are designed to detect and eliminate parasites. The objective of the current study is to characterize the impact of T. cruzi establishment within its vector on the dynamics of its midgut. METHODS: In this study, we evaluated the impact of T. cruzi infection on protein expression within the anterior midgut of the model insect Rhodnius prolixus at 6 and 24 h post-infection (hpi) using high-throughput quantitative proteomics. RESULTS: Shortly after its ingestion, the parasite modulates the proteome of the digestive epithelium by upregulating 218 proteins and negatively affecting the expression of 11 proteins involved in a wide array of cellular functions, many of which are pivotal due to their instrumental roles in cellular metabolism and homeostasis. This swift response underscores the intricate manipulation of the vector's cellular machinery by the parasite. Moreover, a more in-depth analysis of proteins immediately induced by the parasite reveals a pronounced predominance of mitochondrial proteins, thereby altering the sub-proteomic landscape of this organelle. This includes various complexes of the respiratory chain involved in ATP generation. In addition to mitochondrial metabolic dysregulation, a significant number of detoxifying proteins, such as antioxidant enzymes and P450 cytochromes, were immediately induced by the parasite, highlighting a stress response. CONCLUSIONS: This study is the first to illustrate the response of the digestive epithelium upon contact with T. cruzi, as well as the alteration of mitochondrial sub-proteome by the parasite. This manipulation of the vector's physiology is attributable to the cascade activation of a signaling pathway by the parasite. Understanding the elements of this response, as well as its triggers, could be the foundation for innovative strategies to control the transmission of American trypanosomiasis, such as the development of targeted interventions aimed at disrupting parasite proliferation and transmission within the triatomine vector.
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Enfermedad de Chagas , Insectos Vectores , Mitocondrias , Rhodnius , Trypanosoma cruzi , Animales , Rhodnius/parasitología , Rhodnius/metabolismo , Trypanosoma cruzi/fisiología , Trypanosoma cruzi/metabolismo , Insectos Vectores/parasitología , Mitocondrias/metabolismo , Enfermedad de Chagas/transmisión , Enfermedad de Chagas/parasitología , Tracto Gastrointestinal/parasitología , Proteómica , Interacciones Huésped-Parásitos , ProteomaRESUMEN
Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) is the leading cause of childhood chronic kidney failure and a significant cause of chronic kidney disease in adults. Genetic and environmental factors are known to influence CAKUT development, but the currently known disease mechanism remains incomplete. Our goal is to identify affected pathways and networks in CAKUT, and thereby aid in getting a better understanding of its pathophysiology. With this goal, the miRNome, peptidome, and proteome of over 30 amniotic fluid samples of patients with non-severe CAKUT was compared to patients with severe CAKUT. These omics data sets were made findable, accessible, interoperable, and reusable (FAIR) to facilitate their integration with external data resources. Furthermore, we analysed and integrated the omics data sets using three different bioinformatics strategies: integrative analysis with mixOmics, joint dimensionality reduction and pathway analysis. The three bioinformatics analyses provided complementary features, but all pointed towards an important role for collagen in CAKUT development and the PI3K-AKT signalling pathway. Additionally, several key genes (CSF1, IGF2, ITGB1, and RAC1) and microRNAs were identified. We published the three analysis strategies as containerized workflows. These workflows can be applied to other FAIR data sets and help gaining knowledge on other rare diseases.
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Colágeno , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Colágeno/metabolismo , Colágeno/genética , Biología Computacional/métodos , MicroARNs/genética , MicroARNs/metabolismo , Reflujo Vesicoureteral/genética , Reflujo Vesicoureteral/metabolismo , Femenino , Proteoma/metabolismo , Líquido Amniótico/metabolismo , Sistema Urinario/metabolismo , Multiómica , Anomalías UrogenitalesRESUMEN
Although helminth parasites have different life cycles, their hosts share similar immune responses involving Th2 cell-type. Here, we extracted proteins from the larvae of Anisakis simplex complex and Trichinella spiralis to identify common and specific antigens (or allergens) associated with the Th2 immune response. We performed two-dimensional electrophoresis analysis and Matrix-assisted laser desorption ionization-time of flight/time of flight (MALDI-TOF/TOF) experiments. We found 13 potentially immunogenic proteins, which included 5 spots specific to T. spiralis and 8 common to T. spiralis and A. simplex, by tandem mass spectrometry. These molecules were identified structurally as actin, tropomyosin, col cuticle N domain-containing protein, and heat shock proteins. We also identified molecules related to parasite-host immune modulation and interactions. Our results may contribute to reveal potential roles of immunological proteins in parasite-derived immune modulation.
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Anisakis , Proteínas del Helminto , Proteoma , Trichinella spiralis , Animales , Proteoma/inmunología , Proteínas del Helminto/inmunología , Trichinella spiralis/inmunología , Anisakis/inmunología , Antígenos Helmínticos/inmunología , Antígenos Helmínticos/análisis , Electroforesis en Gel Bidimensional , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Interacciones Huésped-Parásitos/inmunología , Larva/inmunología , Espectrometría de Masas en TándemRESUMEN
Clinical expression of coronavirus disease 2019 (COVID-19) infectionis widely variable including fatal cases and patients with mild symptoms and a rapid resolution. We studied saliva from 63 hospitalized COVID-19 patients and from 30 healthy controls by integrating large-scale proteomics, peptidomics and targeted metabolomics to assess the biochemical alterations following the infection and to obtain a set of putative biomarkers useful for noninvasive diagnosis. We used an untargeted approach by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for proteomics and peptidomics analysis and targeted LC-multiple reaction monitoring/MS for the analysis of amino acids. The levels of 77 proteins were significantly different in COVID-19 patients. Among these, seven proteins were found only in saliva from patients with COVID-19, four were up-regulated and three were down-regulated at least five-folds in saliva from COVID-19 patients in comparison to controls. The analysis of proteins revealed a complex balance between pro-inflammatory and anti-inflammatory proteins and a reduced amount of several proteins with immune activity that possibly favours the spreading of the virus. Such reduction could be related to the enhanced activity of endopeptidases induced by the infection that in turn caused an altered balance of free peptides. In fact, on a total of 28 peptides, 22 (80%) were differently expressed in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and control subjects. The multivariate analysis of such peptides permits to obtain a diagnostic algorithm that discriminate the two populations with a high diagnostic efficiency. Among amino acids, only threonine resulted significantly different between COVID-19 patients and controls, while alanine levels were significantly different between COVID-19 patients with different severity. In conclusion, the present study defined a set of molecules to be detected with a quick and easy method based on mass spectrometry tandem useful to reveal biochemical alterations involved in the pathogenesis of such a complex disease. Data are available via ProteomeXchange with identifier PXD045612.
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Biomarcadores , COVID-19 , Metabolómica , Proteómica , SARS-CoV-2 , Saliva , Espectrometría de Masas en Tándem , Humanos , COVID-19/virología , COVID-19/metabolismo , Saliva/química , Saliva/virología , Espectrometría de Masas en Tándem/métodos , Masculino , Femenino , Proteómica/métodos , Persona de Mediana Edad , Metabolómica/métodos , Biomarcadores/análisis , Biomarcadores/metabolismo , Adulto , Anciano , Cromatografía Liquida/métodos , Estudios de Casos y Controles , Proteoma/análisis , Proteoma/metabolismoRESUMEN
Trypanosoma evansi is a unicellular protozoan responsible for causing a disease known as "surra," which is found in different regions of the world and primarily affects horses and camels. Few information is known about virulence factors released from the parasite within the animals. The organism can secrete extracellular vesicles (EVs), which transport a variety of molecules, including proteins. Before being considered exclusively as a means for eliminating unwanted substances, extracellular vesicles (EVs) have emerged as key players in intercellular communication, facilitating interactions between cells, host cells, and parasites, and even between parasites themselves. Thus, they may be used as potential biomarkers. This study aimed to assess the induction of EVs production by Ca+2, conduct a proteomic analysis of the EVs released by T. evansi, and identify epitopes that could serve as biomarkers. The findings indicated that Ca+2 is not an effective promoter of vesiculation in T. evansi. Furthermore, the proteomic analysis has identified multiple proteins that have been investigated as biomarkers or vaccine antigens, previously. A total of 442 proteins were identified, with 7 of them specifically recognizing 9 epitopes that are unique to T. evansi. At least one of these epitopes of TevSTIB805.9.11580 have been previously identified, which increases the possibility of further investigating its potential as a biomarker.
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Vesículas Extracelulares , Proteómica , Proteínas Protozoarias , Trypanosoma , Trypanosoma/metabolismo , Trypanosoma/genética , Vesículas Extracelulares/metabolismo , Proteínas Protozoarias/genética , Proteínas Protozoarias/metabolismo , Animales , Calcio/metabolismo , Biomarcadores , Tripanosomiasis/parasitología , Proteoma , Epítopos/inmunologíaRESUMEN
Shortening of telomere length (TL) is correlated with many age-related disorders and is a hallmark of biological aging. This study used proteome-wide Mendelian randomization to identify the protein biomarkers associated with telomere length. Protein quantitative trait loci (pQTL) were derived from two studies, the deCODE Health study (4907 plasma proteins) and the UK Biobank Pharma Proteomics Project (2923 plasma proteins). Summary data from genome-wide association studies (GWAS) for TL were obtained from the UK Biobank (472,174 cases) and GWAS Catalog (418,401 cases). The association between proteins and TL was further assessed using colocalization and summary data-based Mendelian randomization (SMR) analyses. The protein-protein network, druggability assessment, and phenome-wide MR were used to further evaluate the potential biological effects, druggability, and safety of the target proteins. Proteome-wide MR analysis identified 22 plasma proteins that were causally associated with telomere length. Five of these proteins (APOE, SPRED2, MAX, RALY, and PSMB1) had the highest evidence of association with TL and should be prioritized. This study revealed telomere length-related protein biomarkers, providing new insights into the development of new treatment targets for chronic diseases and anti-aging intervention strategies.
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Biomarcadores , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Proteómica , Sitios de Carácter Cuantitativo , Humanos , Biomarcadores/sangre , Proteómica/métodos , Homeostasis del Telómero , Telómero/metabolismo , Telómero/genética , Proteoma/metabolismo , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Acortamiento del TelómeroRESUMEN
Limited knowledge exists on the quality of polyclonal antibody responses generated following Marburg virus (MARV) infection and its evolution in survivors. In this study, we evaluate MARV proteome-wide antibody repertoire longitudinally in convalescent phase approximately every six months for five years following MARV infection in ten human survivors. Differential kinetics were observed for IgM vs IgG vs IgA epitope diversity, antibody binding, antibody affinity maturation and Fc-receptor interaction to MARV proteins. Durability of MARV-neutralizing antibodies is low in survivors. MARV infection induces a diverse epitope repertoire with predominance against GP, VP40, VP30 and VP24 that persisted up to 5 years post-exposure. However, the IgM and IgA repertoire declines over time. Within MARV-GP, IgG recognize antigenic sites predominantly in the amino-terminus, wing domain and GP2-heptad repeat. Interestingly, MARV infection generates robust durable FcɣRI, FcɣRIIA and FcɣRIIIA IgG-Fc receptor interactions. Immunization with immunodominant MARV epitopes reveals conserved wing region between GP1 and GP2, induces neutralizing antibodies against MARV. These findings demonstrate that MARV infection generates a diverse, long-lasting, non-neutralizing, IgG antibody repertoire that perturbs disease by FcɣR activity. This information, along with discovery of neutralizing immunogen in wing domain, could aid in development of effective therapeutics and vaccines against Marburg virus.
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Anticuerpos Neutralizantes , Anticuerpos Antivirales , Enfermedad del Virus de Marburg , Marburgvirus , Proteoma , Marburgvirus/inmunología , Humanos , Enfermedad del Virus de Marburg/inmunología , Enfermedad del Virus de Marburg/virología , Anticuerpos Antivirales/inmunología , Anticuerpos Neutralizantes/inmunología , Proteoma/inmunología , Femenino , Vacunas Virales/inmunología , Inmunoglobulina G/inmunología , Masculino , Epítopos/inmunología , Adulto , Inmunoglobulina M/inmunología , Persona de Mediana Edad , Estudios Longitudinales , Inmunoglobulina A/inmunología , Desarrollo de Vacunas , Proteínas del Envoltorio Viral/inmunologíaRESUMEN
BACKGROUND: Osteoarthritis (OA) is a degenerative osteoarticular disease, involving genetic predisposition. How the risk variants confer the risk of OA through their effects on proteins remains largely unknown. Therefore, we aimed to discover new and effective drug targets for OA and its subtypes. METHODS: A proteome-wide association study (PWAS) was performed based on OA and its subtypes genome-wide association studies (GWAS) summary datasets and the protein quantitative trait loci (pQTL) data. Subsequently, Mendelian randomization (MR) and colocalization analysis was conducted to estimate the associations between protein and OA risk. The replication analysis was performed in an independent dataset of human plasma pQTL data. RESULTS: The abundance of seven proteins was causally related to OA, two proteins to knee OA and six proteins to hip OA, respectively. We replicated 2 of these proteins using an independent pQTL dataset. With the further support of colocalization, and higher ECM1 level was causally associated with a higher risk of OA and hip OA. Higher PCSK1 level was causally associated with a lower risk of OA. And higher levels of ITIH1, EFEMP1, and ERLEC1 were associated with decreased risk of hip OA. CONCLUSION: Our study provides new insights into the genetic component of protein abundance in OA and a promising therapeutic target for future drug development.
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Estudio de Asociación del Genoma Completo , Proteoma , Sitios de Carácter Cuantitativo , Humanos , Osteoartritis/genética , Osteoartritis/sangre , Osteoartritis de la Rodilla/genética , Osteoartritis de la Rodilla/sangre , Predisposición Genética a la Enfermedad/genética , Osteoartritis de la Cadera/genética , Osteoartritis de la Cadera/sangre , Análisis de la Aleatorización Mendeliana , Masculino , Femenino , Terapia Molecular Dirigida/métodosRESUMEN
OBJECTIVES: The Ishikawa cell line is the most widely used model system for investigating implantation and endometrial cancer. Understanding the biology of this cell line is essential for developing effective interventional strategies. To gain a deeper understanding of its cellular protein profile, we extracted cellular proteins from Ishikawa cells and analyzed the peptides using mass spectrometry. Our goal was to create a proteomic resource specifically tailored for Ishikawa cells. This data set is of particular significance in the realm of targeted drug delivery. Liposomes are synthetic spherical vesicles composed of hydrophobic bilayer phospholipids and have received immense recognition as highly effective carriers for the delivery of pharmaceutical drugs and essential nutrients to the endometrium. Phosphatidylcholine and phosphatidylethanolamine are often combined to create functional liposomal systems. To discern any potential interfering effects originating from the liposome backbone, our investigation involved direct effects of phospholipid liposomes on endometrial epithelial cells. DATA DESCRIPTION: The data set includes peptide spectra derived from the intracellular proteomes of Ishikawa endometrial cancer cell isolates and their phospholipid-treated counterparts. Representing a proteome-wide profile, this dataset aims to contribute to a broader understanding of the physiology of endometrial epithelial cells. Proteomic analysis identified key proteins involved in the intricate regulation of cellular metabolism, cell cycle progression, and signaling. Between-group analysis revealed no differentially expressed proteins after adjusting for multiple testing using the applied thresholds (p-value < 0.05 and |logFC| > 1). Data are available via ProteomeXchange with identifier PXD050871.
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Neoplasias Endometriales , Liposomas , Proteómica , Femenino , Humanos , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/patología , Proteómica/métodos , Línea Celular Tumoral , Proteoma/metabolismo , Fosfatidiletanolaminas/metabolismo , Fosfatidilcolinas/metabolismoRESUMEN
Analyses of mitochondrial adaptations in human skeletal muscle have mostly used whole-muscle samples, where results may be confounded by the presence of a mixture of type I and II muscle fibres. Using our adapted mass spectrometry-based proteomics workflow, we provide insights into fibre-specific mitochondrial differences in the human skeletal muscle of men before and after training. Our findings challenge previous conclusions regarding the extent of fibre-type-specific remodelling of the mitochondrial proteome and suggest that most baseline differences in mitochondrial protein abundances between fibre types reported by us, and others, might be due to differences in total mitochondrial content or a consequence of adaptations to habitual physical activity (or inactivity). Most training-induced changes in different mitochondrial functional groups, in both fibre types, were no longer significant in our study when normalised to changes in markers of mitochondrial content.
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Ejercicio Físico , Proteínas Mitocondriales , Humanos , Masculino , Proteínas Mitocondriales/metabolismo , Adulto , Ejercicio Físico/fisiología , Proteómica/métodos , Músculo Esquelético/metabolismo , Mitocondrias Musculares/metabolismo , Adulto Joven , Fibras Musculares Esqueléticas/metabolismo , Descanso/fisiología , Mitocondrias/metabolismo , Proteoma/metabolismo , Adaptación FisiológicaRESUMEN
Introduction: SARS-CoV-2 variants are defined by specific genome-wide mutations compared to the Wuhan genome. However, non-clade-defining mutations may also impact protein structure and function, potentially leading to reduced vaccine effectiveness. Our objective is to identify mutations across the entire viral genome rather than focus on individual mutations that may be associated with vaccine failure and to examine the physicochemical properties of the resulting amino acid changes. Materials and methods: Whole-genome consensus sequences of SARS-CoV-2 from COVID-19 patients were retrieved from the GISAID database. Analysis focused on Dataset_1 (7,154 genomes from Italy) and Dataset_2 (8,819 sequences from Spain). Bioinformatic tools identified amino acid changes resulting from codon mutations with frequencies of 10% or higher, and sequences were organized into sets based on identical amino acid combinations. Results: Non-defining mutations in SARS-CoV-2 genomes belonging to clades 21 L (Omicron), 22B/22E (Omicron), 22F/23A (Omicron) and 21J (Delta) were associated with vaccine failure. Four sets of sequences from Dataset_1 were significantly linked to low vaccine coverage: one from clade 21L with mutations L3201F (ORF1a), A27- (S) and G30- (N); two sets shared by clades 22B and 22E with changes A27- (S), I68- (S), R346T (S) and G30- (N); and one set shared by clades 22F and 23A containing changes A27- (S), F486P (S) and G30- (N). Booster doses showed a slight improvement in protection against Omicron clades. Regarding 21J (Delta) two sets of sequences from Dataset_2 exhibited the combination of non-clade mutations P2046L (ORF1a), P2287S (ORF1a), L829I (ORF1b), T95I (S), Y145H (S), R158- (S) and Q9L (N), that was associated with vaccine failure. Discussion: Vaccine coverage associations appear to be influenced by the mutations harbored by marketed vaccines. An analysis of the physicochemical properties of amino acid revealed that primarily hydrophobic and polar amino acid substitutions occurred. Our results suggest that non-defining mutations across the proteome of SARS-CoV-2 variants could affect the extent of protection of the COVID-19 vaccine. In addition, alteration of the physicochemical characteristics of viral amino acids could potentially disrupt protein structure or function or both.
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Vacunas contra la COVID-19 , COVID-19 , Mutación , Proteoma , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , SARS-CoV-2/inmunología , COVID-19/prevención & control , Vacunas contra la COVID-19/genética , Vacunas contra la COVID-19/inmunología , Genoma Viral/genética , Eficacia de las Vacunas , España , ItaliaRESUMEN
Zinc (Zn) deficiency is a significant nutritional limitation to crop yield globally, particularly in calcareous soil environments. Tree peony of Peaonia ostii 'Fengdan' is regarded as an oil crop due to its seeds rich in alpha-linolenic acid, a beneficial compound for health promotion. However, low seed yield remains a primary challenge in attaining sufficient seed oil from tree peony. In this study, Zn fertilization was applied to soil or foliage of P. ostii 'Fengdan' in the growth period before fruit development. Our findings reveal that foliar Zn-spraying, as opposed to soil application, proves to be a more effective method for augmenting seed yield, Zn accumulation and photosynthetic capacity in 'Fengdan'. Comparative analyses of the leaf proteome of 'Fengdan' using iTRAQ profiling under foliar Zn-spraying identified 115 differentially expressed proteins (DEPs), including 36 upregulated proteins, which likely contribute to the observed increase in seed yields of 'Fengdan' caused by foliage Zn-spraying. Specifically, Zn2+ stimulation of phosphatidylinositol signaling initiates a cascade of metabolic regulations. Firstly, ATP synthesis promotes leaf photosynthetic capacity, facilitated by improved sucrose metabolism through upregulated pullulanase and 1,4-alpha-glucan-branching enzyme. Furthermore, lipid synthesis and transport are facilitated by upregulated lipoyl synthase and plastid lipid-associated proteins. Additionally, DEPs involved in secondary metabolism are upregulated in the production of various metabolites conducive to 'Fengdan' growth. Overall, our results demonstrate that foliage Zn-spraying enhances seed yield in P. ostii 'Fengdan' by elevating Zn content and secondary metabolite synthesis in leaves, thereby augmenting leaf photosynthetic capacity and lipid synthesis. This study provides an effective way to increase seed yield of tree peony by exogenous Zn application.
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Fotosíntesis , Proteínas de Plantas , Proteoma , Semillas , Zinc , Fotosíntesis/efectos de los fármacos , Zinc/metabolismo , Semillas/metabolismo , Semillas/efectos de los fármacos , Semillas/crecimiento & desarrollo , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Proteoma/metabolismo , Hojas de la Planta/metabolismo , Hojas de la Planta/efectos de los fármacos , Proteómica/métodosRESUMEN
The integration of proteomics data with constraint-based reconstruction and analysis (COBRA) models plays a pivotal role in understanding the relationship between genotype and phenotype and bridges the gap between genome-level phenomena and functional adaptations. Integrating a generic genome-scale model with information on proteins enables generation of a context-specific metabolic model which improves the accuracy of model prediction. This review explores methodologies for incorporating proteomics data into genome-scale models. Available methods are grouped into four distinct categories based on their approach to integrate proteomics data and their depth of modeling. Within each category section various methods are introduced in chronological order of publication demonstrating the progress of this field. Furthermore, challenges and potential solutions to further progress are outlined, including the limited availability of appropriate in vitro data, experimental enzyme turnover rates, and the trade-off between model accuracy, computational tractability, and data scarcity. In conclusion, methods employing simpler approaches demand fewer kinetic and omics data, consequently leading to a less complex mathematical problem and reduced computational expenses. On the other hand, approaches that delve deeper into cellular mechanisms and aim to create detailed mathematical models necessitate more extensive kinetic and omics data, resulting in a more complex and computationally demanding problem. However, in some cases, this increased cost can be justified by the potential for more precise predictions.
Asunto(s)
Modelos Biológicos , Proteómica , Proteómica/métodos , Genoma , Humanos , Proteoma/metabolismo , Proteoma/genética , Proteoma/análisisRESUMEN
Predicting the binding of ligands to the human proteome via reverse-docking methods enables the understanding of ligand's interactions with potential protein targets in the human body, thereby facilitating drug repositioning and the evaluation of potential off-target effects or toxic side effects of drugs. In this study, we constructed 11 reverse docking pipelines by integrating site prediction tools (PointSite and SiteMap), docking programs (Glide and AutoDock Vina), and scoring functions (Glide, Autodock Vina, RTMScore, DeepRMSD, and OnionNet-SFCT), and then thoroughly benchmarked their predictive capabilities. The results show that the Glide_SFCT (PS) pipeline exhibited the best target prediction performance based on the atomic structure models in AlphaFold2 human proteome. It achieved a success rate of 27.8% when considering the top 100 ranked prediction. This pipeline effectively narrows the range of potential targets within the human proteome, laying a foundation for drug target prediction, off-target assessment, and toxicity prediction, ultimately boosting drug development. By facilitating these critical aspects of drug discovery and development, our work has the potential to ultimately accelerate the identification of new therapeutic agents and improve drug safety.
Asunto(s)
Simulación del Acoplamiento Molecular , Proteoma , Humanos , Proteoma/química , Proteoma/metabolismo , Benchmarking , Programas Informáticos , Ligandos , Unión Proteica , Conformación ProteicaRESUMEN
Herbicide exposure can pose a considerable threat to non-target aquatic animals. We aimed to study changes in the liver proteome of a model cyprinid fish species, zebrafish Danio rerio, to provide a molecular basis for the adverse effects of environmentally relevant concentrations of glyphosate (100 µg/L), its breakdown product aminomethylphosphonic acid (AMPA; 100 µg/L), and a mixture of both (50 + 50 µg/L) in the presence of humic acid (20 mg/L), which simulated a component of natural organic matter in the aquatic environment. Proteomic analysis was performed by means of high-performance liquid chromatography-tandem mass spectrometry employing a label-free quantification approach. The results present molecular evidence of the stress responses and disturbance of primary metabolic processes such as immune response, dysregulation in DNA repair, necroptosis and apoptosis signaling pathways, oxidative phosphorylation, cholesterol, lipoprotein, and carbohydrate metabolism. We registered the synergistic effect of the glyphosate and AMPA co-exposure, which was expressed in a substantial increase in the number of dysregulated proteins compared to the solo treatments. Humic acid alleviated the effects of glyphosate and its mixture with AMPA and aggravated the impact of AMPA exposure. RuvB-like 2, a protein taking part in DNA repair, and EIF2S1, involved in the regulation of stress-induced gene expression, were downregulated in the liver of zebrafish from all treatments.
Asunto(s)
Glicina , Glifosato , Herbicidas , Sustancias Húmicas , Hígado , Proteoma , Pez Cebra , Animales , Pez Cebra/metabolismo , Glicina/análogos & derivados , Glicina/toxicidad , Hígado/efectos de los fármacos , Hígado/metabolismo , Proteoma/metabolismo , Proteoma/efectos de los fármacos , Herbicidas/toxicidad , Organofosfonatos/toxicidad , Contaminantes Químicos del Agua/toxicidadRESUMEN
Whether differences in lifestyle between co-twins are reflected in differences in their internal or external exposome profiles remains largely underexplored. We therefore investigated whether within-pair differences in lifestyle were associated with within-pair differences in exposome profiles across four domains: the external exposome, proteome, metabolome and epigenetic age acceleration (EAA). For each domain, we assessed the similarity of co-twin profiles using Gaussian similarities in up to 257 young adult same-sex twin pairs (54% monozygotic). We additionally tested whether similarity in one domain translated into greater similarity in another. Results suggest that a lower degree of similarity in co-twins' exposome profiles was associated with greater differences in their behavior and substance use. The strongest association was identified between excessive drinking behavior and the external exposome. Overall, our study demonstrates how social behavior and especially substance use are connected to the internal and external exposomes, while controlling for familial confounders.