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PubMed2026

The mechanism by which long-term exposure to TDCIPP promotes cognitive impairment in 3 ×Tg-AD mice: Insights from multi-omics studies.

Tri(1,3-dichloro-2-propyl) phosphate (TDCIPP) is a commonly used organophosphate ester that has the potential to adversely affect human health. Although previous studies have closely associated TDCIPP with cognitive impairment, the underlying mechanisms remain unclear. To elucidate the neurotoxic effects of TDCIPP and its mechanistic contribution to cognitive impairment in 3 ×Tg-AD mice, a multi-omics approach incorporating proteomics, untargeted metabolomics, and 16S ribosomal RNA (rRNA) gene sequencing was employed to evaluate the impact of TDCIPP exposure on neurobehavioral function. TDCIPP exposure promoted cognitive impairment in 3 ×Tg-AD mice. Proteomic analyses revealed that this promotion is associated with disturbances in the hippocampal mitochondrial autophagy pathway. Furthermore, TDCIPP may interfere with the PINK1/Parkin-mediated mitophagy pathway at the functional level, without altering PINK1 protein abundance. Untargeted metabolomic analysis of urine samples demonstrated that TDCIPP exposure altered the metabolic profile of 3 ×Tg-AD mice, with 58 metabolites upregulated and 11 downregulated. Additionally, 16S rRNA sequencing revealed substantial modifications in gut microbiome composition following exposure to TDCIPP. Notably, significant correlations were identified between the perturbed bacterial genera and the differential metabolites. In conclusion, exposure to TDCIPP promotes cognitive impairment in 3 ×Tg-AD mice, which is associated with the interference with the PINK1/Parkin-mediated mitophagy pathway, as well as alterations in the urinary metabolome and gut microbiota. These findings suggest the potential to mitigate such cognitive impairment by targeting the microbiota-gut-brain axis.

Animals↗
PubMed2005

Synapse proteomics of multiprotein complexes: en route from genes to nervous system diseases.

Proteomic experiments have produced a draft profile of the overall molecular composition of the mammalian neuronal synapse. It appears that synapses have over 1000 protein components and the mapping of their interactions, organization and functions will lead to a global view of the role of synapses in physiology and disease. A major functional subcomponent of the synaptic machinery is a multiprotein complex of glutamate receptors and adhesion proteins with associated adaptor and signalling enzymes totally 185 proteins known as the N-methyl-d-aspartate receptor complex/MAGUK associated signalling complex (NRC/MASC). Here, we review the proteomic studies and functions of NRC/MASC and specifically report on the role of its component genes in human diseases. Using a systematic literature search protocol, we identified reports of mutations or polymorphisms in 47 genes associated with 183 disorders, of which 54 were nervous system disorders. A similar number of genes are important in mouse synaptic plasticity and behaviour, where the NRC/MASC acts as a signalling complex with multiple functions provided by its individual protein components and their interactions. The individual gene mutations suggest not only an important role for the NRC/MASC in human diseases but that these diseases may be functionally connected by their common link to the NRC/MASC. The NRC/MASC is a rich source of genetic variation and provides a platform for understanding relationships of disease phenotype amenable to systematic studies such as the Genes to Cognition research consortium (www.genes2cognition.org) that links human and mouse genetics with proteomic studies.

Humans↗
PubMed2003

Is proteomics heading in the wrong direction?

Proteomics is now considered to be one of the most important 'post-genome' approaches to help us understand gene function. In fact, several genomics companies have launched large-scale proteomics projects, and have started to annotate the entire human proteome. The 'holistic view' painted by a human proteome project is seductive, but is it realistic?

Animals↗
PubMed2026

Reassessing Semen Analysis: Clinical Insights Beyond Sperm Count and Motility.

BACKGROUND: Semen analysis (SA), recognized by the World Health Organization (WHO) as the cornerstone of male infertility evaluation, remains indispensable in reproductive medicine. However, advances in assisted reproductive technology (ART) and artificial intelligence (AI) have highlighted the limitations of relying solely on conventional semen parameters. OBJECTIVE: To critically review the evolving clinical role of SA by integrating conventional assessment with emerging functional, molecular, and computational approaches that improve diagnostic accuracy and individualized patient care. METHODS: A narrative review of contemporary evidence was conducted, focusing on conventional semen parameters, biofunctional sperm testing, omics technologies, AI-assisted analysis, and broader clinical applications of SA. RESULTS: Conventional parameters, including sperm concentration, motility, and morphology, remain essential but inadequately reflect fertilizing capacity. Adjunctive assessments, including oxidative stress biomarkers and sperm DNA fragmentation, provide valuable insights into sperm function and reproductive potential. Omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, deepen mechanistic understanding, while AI enhances diagnostic precision, reproducibility, and standardization. Beyond infertility evaluation, SA also supports male contraceptive assessment, natural conception, ART, and patient counseling. CONCLUSIONS: Integrating conventional SA with functional, molecular, and AI-driven diagnostics provides a comprehensive framework for evaluating male fertility, advancing precision reproductive medicine and personalized clinical management.

cryopreservation↗
PubMed2026

Proteomic signatures of adipocyte recruitment in breast cancer.

The tumor microenvironment (TME) is increasingly recognized as a dynamic regulator of breast cancer progression, with adipocytes functioning as active contributors rather than passive bystanders. Here, we investigated the proteomic and morphologic reprogramming of breast cancer-associated adipocytes (BrCAAs) in response to triple-negative breast cancer (TNBC). Using conditioned medium from HCC1143 cells, we established an in vitro BrCAA model and performed mass spectrometry-based proteomics. Comparative profiling revealed 256 differentially expressed proteins, enriched for pathways including fatty acid degradation, carbon metabolism, and glycogen turnover, consistent with a metabolic shift from energy storage to energy supply. Gene ontology and protein-protein interaction analyses further identified cytoskeletal remodeling, adhesion dynamics, and secretory pathway activation, supporting BrCAA-driven microenvironmental remodeling. In the MMTV-PyMT mouse model, morphometric analysis demonstrated progressive size reduction and increased contour irregularity of adipocytes adjacent to tumors, correlating with proteomic evidence of metabolic stress. Importantly, BrCAAs localized at tumor interfaces were associated with increased microvessel density and CD105+ endothelial activation compared to desmoplastic zones. Proteomic enrichment highlighted pro-angiogenic remodeling, with validation of basigin (BSG), integrin αV (ITGAV), and 2,4-dienoyl-CoA reductase 1 (DECR1). Collectively, our findings establish BrCAAs as metabolically and structurally reprogrammed stromal components that promote tumor metabolism and localized angiogenesis, representing potential therapeutic targets in aggressive breast cancer.

Female↗
PubMed2004

[Development of novel DDS technologies for pharmacoproteomic-based drug discovery and development].

With the success of the Human Genome Project, the focus of life science research has shifted to the functional and structural analyses of proteins, such as proteomics and structural genomics. These novel approaches to the analysis of proteins, including newly identified ones, are expected to help in the identification and development of protein therapies for various diseases. Thus pharmacoproteomic-based drug discovery currently has a very high profile. Nevertheless, the use of bioactive proteins in the clinical setting is not straightforward because in vivo these proteins have low stability and pleiotropic action. To promote pharmacoproteomic-based drug discovery and development, we have attempted to establish a system for creating functional mutant proteins (muteins) with the desired properties and to develop a site-specific bioconjugation system for further improving their therapeutic potency. These innovative protein-drug systems are discussed in this review.

Drug Delivery Systems↗
PubMed2004

S-nitrosoprotein formation and localization in endothelial cells.

Protein S-nitrosation represents a recently described form of post-translational modification that is rapid and reversible. However, the analysis of protein S-nitrosation in situ has been difficult because of the absence of specific probes and the instability of cellular protein S-nitrosothiols. We developed a rapid and specific method for detecting endothelial S-nitrosoproteins patterned after the biotin switch method that involves thiol alkylation followed by reductive generation of thiols from S-nitrosothiols, which are then labeled with either a biotin- or Texas red-derivative of methanethiosulfonate. When we used this methodology, we found that S-nitrosated proteins can form within endothelial cells from an exogenous S-nitrosothiol donor or from endogenous production of NO by endothelial NO synthase. When we used confocal microscopy, we found that these S-nitrosoproteins exist mainly in the mitochondria and peri-mitochondrial compartment, and that their half-life is approximately 1 h. Cellular S-nitrosated protein abundance changed as expected, with changes in activity of NO synthase, and with impairment of mitochondrial function and scavenging of peroxynitrite. We used a proteomic approach involving two-dimensional gel electrophoresis and mass spectrometry, and found that a limited number of S-nitrosoproteins exist in endothelial cells (S-nitrosoproteome) and identified GAPDH, vimentin, beta-galactosidase, peroxiredoxin 1, beta-actin, and ubiquitin-conjugating enzyme E2 among them. The most abundant S-nitrosated protein in the resting endothelial cell is GAPDH, suggesting a regulatory function for NO in glycolysis. These data offer methods and insights into identifying the protein targets of S-nitrosation reactions and their potential role in cell function and phenotype.

Animals↗
PubMed2006

Tissue microarrays as a platform for proteomic investigation.

Tissue microarrays have become an essential tool in translational pathology. They are used to confirm results from other experimental platforms, such as expression microarrays, as well as a primary tool to explore the expression profile of proteins by immunohistochemical analysis. Tissue microarrays are routinely used molecular epidemiology, drug development and determining the diagnostic, prognostic and predictive value of new biomarkers. By applying traditional protein based assays, as well as novel assays to the platform, tissue microarrays have gained a new utility as a proteomic tool for both basic science as well as clinical investigation. This article will explore the new approaches that are being applied to tissue microarrays to, characterize the human proteome, and new technologies that allow tissue microarrays to function as a protein array.

Animals↗
PubMed2006

Proteomics of the peroxisome.

Genomes provide us with a blue print for the potential of a cell. However, the activity of a cell is expressed in its proteome. Full understanding of the complexity of cells demands a comprehensive view of the proteome; its interactions, activity states and organization. Comprehensive proteomic approaches applied to peroxisomes have yielded new insights into the organelle and its dynamic interplay with other cellular structures. As technologies and methodologies improve, proteomics hold the promise for new discoveries of peroxisome function and a full description of this dynamic organelle.

Arabidopsis↗
PubMed2005

Development and application of proteomics technologies in Saccharomyces cerevisiae.

Proteomics research focuses on the identification and quantification of "all" proteins present in cells, organisms or tissue. Proteomics is technically complicated because it encompasses the characterization and functional analysis of all proteins that are expressed by a genome. Moreover, because the expression levels of proteins strongly depend on complex regulatory systems, the proteome is highly dynamic. This review focuses on the two major proteomics methodologies, one based on 2D gel electrophoresis and the other based on liquid chromatography coupled to mass spectrometry. The recent developments of these methodologies and their application to quantitative proteomics are described. The model system Saccharomyces cerevisiae is considered to be the optimal vehicle for proteomics and we review studies investigating yeast adaptation to changes in (nutritional) environment.

Chromatography, Liquid↗
PubMed2003

Genome-wide analyses of carboxyl-terminal sequences.

Sequence motifs at the protein carboxyl termini in linear polypeptides are uniquely positioned and functionally capable of serving as recognition signatures for a variety of cellular and biochemical processes. At the proteome level, it is unknown whether and what carboxyl-terminal sequences might be particularly conserved, which may be directly related to specific biological functions shared among certain groups of proteins. To investigate this question, we analyzed the terminal sequences of reported yeast open reading frames, which presumably constitute the predicted, entire proteome of Saccharomyces cerevisiae. The results show that there are both known and novel terminal sequences. They are conserved at a frequency similar to that of functionally important, experimentally confirmed signals such as the HDEL sequence that mediates the endoplasmic reticulum retention and/or retrieval. The findings support the notion that there may be additional carboxyl-terminal signals, and the conserved motifs could be experimentally tested for currently unknown biological functions. Similar analyses were also applied to the limited proteome databases of other organisms with overall consistent findings. Therefore, indexing a proteome according to its carboxyl-terminal sequences may provide a means for functional classification and determination of proteins.

Amino Acid Motifs↗
PubMed2003

Protein and peptide identification: the rôle of mass spectrometry in proteomics.

Proteomics encompasses several disciplines in the quest to unravel the science of life. Mass spectrometry plays a key rôle in proteomics-associated analyses and this review describes that function in terms of the instrumentation used, the results generated, data interpretation and the advances in analytical techniques being made to deal with the production of highly specific, high throughput data. The review has 151 references.

Mass Spectrometry↗
PubMed2001

Functional genomic research of alpha 1-adrenoceptors.

The Human Genome Project is now almost completed, and we are about to move into the post-genome sequence era of functional genomics. The advent of genome science has markedly changed the way life science research including pharmacological study is conducted; thus, systematic and integrated 'genome-wide' survey is feasible. The stream of 'Genome-->Transcriptome--> Proteomics' is logical and, in each aspect, approaches for functional genomics are now pursued at a high pace. We have recently developed a standardized technical platform (in various levels, such as transcription, cell and whole animal levels, etc.), and applied these techniques to the study of functional genomics of G-protein-coupled receptors, particularly alpha1-adrenoceptors as a model. Combining the genome information and technology, future pharmacological studies would become the genome-based search and research.

Animals↗
PubMed2026

Single-organ proteomics in Drosophila melanogaster larva.

The combination of genetic accessibility, organ complexity, evolutionary conservation, and cost-efficiency makes Drosophila melanogaster (Dm) a well-known model system for biomedical and fundamental biological research. Proteomic analysis of single organs enables the identification and quantification of proteins expressed in specific organs. This will help to uncover specific biological functions and unique protein profiles that are not detectable in whole-organism analyses. In this study we have isolated single organs form Dm larvae, and we have performed a deep proteomics mapping by following a minimal manipulation preparation procedure. The combined dataset across all organs comprised 9132 identified proteins. As anticipated, principal component analysis (PCA) revealed clear separation between the proteomes of most organs, confirming distinct protein profiles. These findings demonstrate the applicability of the sample preparation strategy for high-resolution proteomic characterization of individual organs in Drosophila. Given the extensive genetic tools available for this model organism, our approach has the potential to open new avenues for proteomic studies in Drosophila melanogaster and any other biological systems where the sample amount is limiting. SIGNIFICANCE STATEMENT: Drosophila melanogaster is a well-known model system for biomedical and fundamental biological research that serves as a valuable in vivo model organism due to its high degree of evolutionary conservation with higher vertebrates, tractable genetics, and logistical efficiency. However, the proteome of Drosophila at single organ level has been elusive to date, due to several factors like low sensitivity of previous generation mass spectrometers and sample preparation procedures, difficult isolation of some organs. In this study we have applied a compilation of advanced methods including minimal sample manipulation together with simple, straightforward and efficient protein extraction and digestion methods. Obtained peptides were minimally handled to be analyzed by applying specific and sensitive nLC methods coupled on-line to state-of-the-art MS/MS system. Altogether, the applied strategy allowed us to get the first single organ study to date for this animal. These datasets represent a significative resource for future genomic, transcriptomic and proteomic studies in Drosophila, as multi-omic integration requires deep proteomics to translate data into functional biochemistry, and serves as a critical bridge and an indispensable standalone resource across the genomic, transcriptomic, and proteomic landscapes.

Animals↗
PubMed2006

Starvation induces phase-specific changes in the proteome of mouse small intestine.

Food deprivation results in metabolic, structural, and functional changes in the small intestine that influences gut mucosal integrity, epithelial cell proliferation, mucin synthesis, and other processes. The underlying mechanisms are still unclear, which lead to the study of molecular effects of short-term and long-term starvation in the intestine of mice. A comparative proteomics approach, combining two-dimensional gel electrophoresis with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, was used to identify intestinal proteins whose expression is changed under different starvation conditions (0, 12, 24, and 72 h). In total, the expression levels of 80 protein spots changed significantly between the different groups. The results demonstrate that after 12 h of starvation, mainly proteins involved in glycolysis and energy metabolism show decreased expression levels. Starvation for 24 h results in a down-regulation of proteins involved in protein synthesis and amino acid metabolism. Simultaneously, proteins with a protective role, e.g., reg I and II, glutathione peroxidase 3, and carbonic anhydrase 3, are clearly up-regulated. The last starvation phase (72 h) is characterized by increased ezrin expression, which may enhance villus morphogenesis critical for survival. Together, these results provide novel insights in the intestinal starvation response and may contribute to improved nutritional support during conditions characterized by malnutrition.

Animals↗
PubMed2001

New technologies for biomarker analysis of prostate cancer progression: Laser capture microdissection and tissue proteomics.

The widespread use of serum markers during cancer screenings has led to the belief that there may be tumor markers yet to be discovered that offer better specificity and sensitivity than prostate-specific antigen (PSA). Proteomics, the analysis and characterization of global protein modifications, will add to our understanding of gene function and aid in biomarker and/or therapeutic target discovery. In the past, most proteomic studies were either performed using tumor cell lines or homogenized bulk tissue. Unfortunately, these approaches may not accurately reflect molecular events that take place in the actual ductal epithelium that change as a consequence of the malignant process. This report describes alternative proteomic-based approaches aimed at the identification of protein markers in the actual premalignant and frankly malignant epithelium.

Biomarkers, Tumor↗
PubMed2001

An evaluation of the use of two-dimensional gel electrophoresis in proteomics.

With whole genomes being sequenced almost routinely, the next logical step towards a better understanding of cellular mechanisms lies in studying the functional units of gene expression-proteins. One of the fundamental approaches in proteomics is the use of two-dimensional gel electrophoresis as a mode of separation and visualization of complex protein mixtures. Despite several limitations of the method, its ability to separate large numbers of proteins, including their post-translationally modified forms, ensures that it will continue to be popular in several well-defined areas of proteomics. In this article, we discuss the merits and drawbacks of two-dimensional gels and compare them with alternative systems such as one-dimensional gels and liquid chromatography-based separation methods. In the wake of recent advances in mass spectrometry and related areas, we outline areas where two-dimensional gels can best be utilized as the preferred separation method in proteomic strategies.

Electrophoresis, Gel, Two-Dimensional↗
PubMed2003

Protein family classification and functional annotation.

With the accelerated accumulation of genomic sequence data, there is a pressing need to develop computational methods and advanced bioinformatics infrastructure for reliable and large-scale protein annotation and biological knowledge discovery. The Protein Information Resource (PIR) provides an integrated public resource of protein informatics to support genomic and proteomic research. PIR produces the Protein Sequence Database of functionally annotated protein sequences. The annotation problems are addressed by a classification-driven and rule-based method with evidence attribution, coupled with an integrated knowledge base system being developed. The approach allows sensitive identification, consistent and rich annotation, and systematic detection of annotation errors, as well as distinction of experimentally verified and computationally predicted features. The knowledge base consists of two new databases, sequence analysis tools, and graphical interfaces. PIR-NREF, a non-redundant reference database, provides a timely and comprehensive collection of all protein sequences, totaling more than 1,000,000 entries. iProClass, an integrated database of protein family, function, and structure information, provides extensive value-added features for about 830,000 proteins with rich links to over 50 molecular databases. This paper describes our approach to protein functional annotation with case studies and examines common identification errors. It also illustrates that data integration in PIR supports exploration of protein relationships and may reveal protein functional associations beyond sequence homology.

Amino Acid Motifs↗