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PubMed2026

Elucidating the In Vitro Adverse Effect of Functionalized Single-Walled Carbon Nanotubes Against Breast Cancer Cells at the Proteomics Level.

The tremendous therapeutic potential of carbon-based nanomaterials (CNMs) has been limited by inconsistent data regarding the nanotoxicity assessment. Although a bulk of studies have been performed to assess the in vitro cytotoxicity mechanism of CNMs, the exact factors responsible for the cytotoxicity of CNMs have not been fully understood. With the rapid advancement of mass spectrometry technologies, proteomics has emerged as a powerful strategy for systematically investigating the molecular and cellular mechanisms underlying toxicity induced by nanomaterials. This study examined the in vitro cytotoxicity of single-walled carbon nanotubes (SWCNTs) in human MCF-7 breast cancer cells by conducting a comparative proteome-level analysis using mass spectrometry. Initially, the characterized SWCNTs were incubated with MCF-7 cells for 3, 6, and 24 h. Proteins were subsequently extracted from each treatment group and subjected to nano-liquid chromatography-tandem mass spectrometry (nLC-MS/MS) analysis. The relative abundance of the identified proteins was determined by comparison with the control group, and differential expression patterns, including upregulated and downregulated proteins, were assessed. A total of 3482 unique protein groups were identified across all exposure periods. Among these, 3466 protein groups were detected following 3 h of exposure, 3469 following 6 h of exposure, and 3480 following 24 h of exposure. Compared with the control group, the identified differentially expressed proteins exhibited fold changes ranging from 2-fold to 20-fold across the incubation periods. In total, 70 proteins were found to be significantly regulated following SWCNT exposure. Of the differentially expressed proteins, 45 were significantly upregulated, whereas 25 were significantly downregulated. Visualization of these regulations over time was shown in a heatmap of log2-transformed fold-change values to explore time-specific proteomic alterations. Functional enrichment analysis of these proteins also showed that the regulated proteins were significantly associated with Reactome pathways, including ER-to-Golgi anterograde transport, Golgi-to-ER retrograde transport, COPI-mediated vesicle trafficking, regulation of insulin-like growth factor transport and uptake by insulin-like growth factor-binding proteins, protein metabolism, and posttranslational protein modification. Furthermore, a systematic comparison of previous studies within the present findings was provided to situate our study within the broader context of understanding CNT-induced cellular toxicity. Collectively, these findings provided an important proteomic evidence of the adverse effects of SWCNTs on MCF-7 cells. Furthermore, this study showed a comprehensive proteomic landscape of cellular responses to SWCNT exposure, contributing to a better understanding of the molecular mechanisms underlying SWCNT-induced cytotoxicity and bridging the gap between protein regulation and the resulting cellular responses. In this study, we characterized the proteomic landscape of MCF-7 cells following SWCNT exposure, revealing molecular mechanisms associated with cellular responses and cytotoxicity. The identified differentially expressed proteins established a link between altered protein regulation and SWCNT-induced cellular effects. Moreover, these proteins need to be further validated in different cell models and would potentially represent promising candidates for the identification of novel molecular targets involved in SWCNT-induced cytotoxicity.

MCF‐7 cells↗
PubMed2002

In vivo-applied functional RNAs as tools in proteomics and genomics research.

Non-natural, functional RNA molecules, such as short interfering (si) RNAs, aptazymes, maxizymes and intramers, allow modulation of gene function at the mRNA or protein level. This review discusses recent advances made in the expression and application of these functional RNAs and illustrates how engineered, intracellularly active RNAs can serve as promising tools for understanding the function of genes and their protein products or as potential therapeutic agents.

Animals↗
PubMed2005

Discovery metabolite profiling--forging functional connections between the proteome and metabolome.

Of primary interest for every enzyme is the identification of its physiological substrates. However, the vast structural diversity of endogenous metabolites, coupled with the overlapping activities of numerous enzymes, makes it difficult to deduce the identity of natural substrates for a given enzyme based on in vitro experiments. To address this challenge, we recently introduced an LC-MS based analytical method termed discovery metabolite profiling (DMP) to evaluate the global metabolic effects of enzyme inactivation in vivo. We have applied DMP to study mice lacking the enzyme fatty acid amide hydrolase (FAAH), which degrades the endocannabinoid family of signaling lipids. DMP identified several previously uncharacterized FAAH substrates, including a structurally novel class of brain lipids that represent conjugates of very long chain fatty acids with the amino acid derivative taurine [N-acyl taurines (NATs)]. These findings show that DMP can establish direct connections between the proteome and metabolome and thus offers a powerful strategy to assign physiological functions to enzymes in the post-genomic era.

Amidohydrolases↗
PubMed2001

The phagosome proteome: insight into phagosome functions.

Phagosomes are key organelles for the innate ability of macrophages to participate in tissue remodeling, clear apoptotic cells, and restrict the spread of intracellular pathogens. To understand the functions of phagosomes, we initiated the systematic identification of their proteins. Using a proteomic approach, we identified >140 proteins associated with latex bead-containing phagosomes. Among these were hydrolases, proton pump ATPase subunits, and proteins of the fusion machinery, validating our approach. A series of unexpected proteins not previously described along the endocytic/phagocytic pathways were also identified, including the apoptotic proteins galectin3, Alix, and TRAIL, the anti-apoptotic protein 14-3-3, the lipid raft-enriched flotillin-1, the anti-microbial molecule lactadherin, and the small GTPase rab14. In addition, 24 spots from which the peptide masses could not be matched to entries in any database potentially represent new phagosomal proteins. The elaboration of a two-dimensional gel database of >160 identified spots allowed us to analyze how phagosome composition is modulated during phagolysosome biogenesis. Remarkably, during this process, hydrolases are not delivered in bulk to phagosomes, but are instead acquired sequentially. The systematic characterization of phagosome proteins provided new insights into phagosome functions and the protein or groups of proteins involved in and regulating these functions.

Animals↗
PubMed2000

The ATCG of drug discovery.

The publication of human and microbial genomic sequences has resulted in the availability of large amounts of data that are directly relevant to the discovery of novel and useful drug targets. The elucidation of the function of new genes is not a simple matter and human genetic studies have been among the most useful in identifying genes implicated in disease, although homologs, or orthologs, of human genes in mouse, worm, fly and yeast genomes have also been useful in deciphering gene function. The advent of genomics has led into the study of protein structure and function under the rubric of proteomics. Proteins function in a cell mostly by interacting with other proteins, and protein interaction maps of cellular circuits are now available. Screening strategies to address protein-protein interactions are being developed, and many drug targets in the future are expected to be directed towards these interactions. In addition to using genetic and analytical approaches for finding new drug targets, chemical libraries can be used to inhibit the activity of new proteins, and thus reveal function. The combination of high-throughput screening with testing compounds for ADME (absorption, distribution, metabolism and excretion) and toxicity will help in the early clarification of clinical utility of both new drug targets, as well as drug candidates.

Animals↗
PubMed2002

Functional post-translational proteomics approach to study the role of N-glycans in the development of Caenorhabditis elegans.

Glycosylation is one of the most common post-translational protein modifications. Carbohydrate-mediated interactions between cells and their environment are important in differentiation, embryogenesis, inflammation, cancer and metastasis and other processes. Humans and mice with mutations that prevent normal N-glycosylation show multi-systemic defects in embryogenesis, thereby proving that these molecules are essential for normal development; however, a large number of proteins undergo defective glycosylation in these human and mouse mutants, and it is therefore difficult to determine the precise molecular roles of specific N-glycans on individual proteins. We describe here a 'functional post-translational proteomics' approach that is designed to determine the role of N-glycans on individual glycoproteins in the development of Caenorhabditis elegans.

Animals↗
PubMed2026

Proteomic Profiling of Pulmonary Function and Cardiovascular Disease Risk in the Atherosclerosis Risk in Communities Study.

BACKGROUND: Pulmonary function is linked to cardiovascular disease risk; however, the underlying mechanisms remain unclear. We aimed to identify protein biomarkers associated with pulmonary function and examine their impact on incident chronic obstructive pulmonary disease, coronary heart disease, heart failure, and all-cause mortality. METHODS: Data from White and Black Americans in the Atherosclerosis Risk in Communities study (visit 2: N=11&#x2009;354, mean age=57 years; visit 5: N=3517, mean age=75 years), a prospective cohort, were analyzed. Linear regression assessed associations between protein levels and pulmonary function measures, including forced expiratory volume in 1 second and forced vital capacity. The impact of the identified proteins on incident chronic obstructive pulmonary disease, coronary heart disease, heart failure, and mortality was estimated using logistic regression and Cox proportional hazards models. Pathway enrichment and Mendelian randomization explored underlying biological functions and causal effects. RESULTS: Of 4766 proteins analyzed, 364 were cross-sectionally associated with forced expiratory volume in 1 second (and forced vital capacity (false discovery rate<0.05). Ninety-four and 270 proteins had concordant positive and negative effects, respectively. Five pathways related to pulmonary and cardiac function were enriched. Of the 364 proteins, 112 were linked to all 4 outcomes, where 86 were associated with increased risk (odds ratio/hazard ratio [OR/HR], 1.05-1.42) and 26 with reduced risk (OR/HR, 0.69-0.96). Six proteins (STAT3 [signal transducer and activator of transcription 3], MIC-1 [growth differentiation factor 15], apoA-II [apolipoprotein A-II], TPST1 [protein-tyrosine sulfotransferase 1], integrin a1b1 [integrin alpha-I: beta-1 complex], and BLC [C-X-C motif chemokine 13]) showed potential inverse causal effects on with forced expiratory volume in 1 second and forced vital capacity, and integrin a1b1 demonstrated consistent inverse associations with chronic obstructive pulmonary disease, coronary heart disease, and heart failure risks. CONCLUSIONS: Proteins associated with pulmonary function may influence CVD risk. Six proteins, including integrin a1b1, represent promising targets for future interventions.

Aged↗
PubMed2004

Functional genomics studied by proteomics.

The human genome contains about 30,000 genes, each creating several transcripts per gene. Transcript structures and expression are studied by high-throughput transcriptomic techniques using microarrays. Generally, transcripts are not directly operating molecules, but are translated into functional proteins, post-translationally modified by proteolysis, glycosylation, phosphorylation, etc., sometimes with great functional impact. Proteins need to be analyzed by proteomic techniques, less suited for high-throughput. Two-dimensional polyacrylamide gel electrophoresis (2D-PAGE), separating thousands of proteins has developed slowly over the past quarter of a century. This technique is now quite reproducible and suitable for differential proteomics, comparing normal and diseased cells/tissues revealing differentially regulated proteins. 2D-PAGE is combined with protein-identification methods, currently mass spectrometry (MS), which has been significantly improved over the last decade. Other proteomic techniques studying protein-protein interactions are now either established or still being developed, such as peptide or protein arrays, phage display, and the yeast two-hybrid system. The strengths and weaknesses of these techniques are discussed.

Databases, Factual↗
PubMed2006

Gene functional similarity search tool (GFSST).

BACKGROUND: With the completion of the genome sequences of human, mouse, and other species and the advent of high throughput functional genomic research technologies such as biomicroarray chips, more and more genes and their products have been discovered and their functions have begun to be understood. Increasing amounts of data about genes, gene products and their functions have been stored in databases. To facilitate selection of candidate genes for gene-disease research, genetic association studies, biomarker and drug target selection, and animal models of human diseases, it is essential to have search engines that can retrieve genes by their functions from proteome databases. In recent years, the development of Gene Ontology (GO) has established structured, controlled vocabularies describing gene functions, which makes it possible to develop novel tools to search genes by functional similarity. RESULTS: By using a statistical model to measure the functional similarity of genes based on the Gene Ontology directed acyclic graph, we developed a novel Gene Functional Similarity Search Tool (GFSST) to identify genes with related functions from annotated proteome databases. This search engine lets users design their search targets by gene functions. CONCLUSION: An implementation of GFSST which works on the UniProt (Universal Protein Resource) for the human and mouse proteomes is available at GFSST Web Server. GFSST provides functions not only for similar gene retrieval but also for gene search by one or more GO terms. This represents a powerful new approach for selecting similar genes and gene products from proteome databases according to their functions.

Chromosome Mapping↗
PubMed2006

Modeling a whole organ using proteomics: the avian bursa of Fabricius.

While advances in proteomics have improved proteome coverage and enhanced biological modeling, modeling function in multicellular organisms requires understanding how cells interact. Here we used the chicken bursa of Fabricius, a common experimental system for B cell function, to model organ function from proteomics data. The bursa has two major functional cell types: B cells and the supporting stromal cells. We used differential detergent fractionation-multidimensional protein identification technology (DDF-MudPIT) to identify 5198 proteins from all cellular compartments. Of these, 1753 were B cell specific, 1972 were stroma specific and 1473 were shared between the two. By modeling programmed cell death (PCD), cell differentiation and proliferation, and transcriptional activation, we have improved functional annotation of chicken proteins and placed chicken-specific death receptors into the PCD process using phylogenetics. We have identified 114 transcription factors (TFs); 42 of the bursal B cell TFs have not been reported before in any B cells. We have also improved the structural annotation of a newly sequenced genome by confirming the in vivo expression of 4006 "predicted", and 6623 ab initio, ORFs. Finally, we have developed a novel method for facilitating structural annotation, "expressed peptide sequence tags" (ePSTs) and demonstrate its utility by identifying 521 potential novel proteins from the chicken "unassigned chromosome".

Amino Acid Sequence↗
PubMed2004

Using models of the myocyte for functional interpretation of cardiac proteomic data.

There has been significant progress towards the development of highly integrative computational models of the cardiac myocyte over the past decade. Models now incorporate descriptions of voltage-gated ionic currents and membrane transporters, mechanisms of calcium-induced calcium release and intracellular calcium cycling, mitochondrial ATP production and its coupling to energy-requiring membrane transport processes and mechanisms of force generation. There is an extensive literature documenting both the reconstructive and predictive abilities of these models and there is no question that an interplay between quantitative modelling and experimental investigation has become a central component of modern cardiovascular research. As data regarding the cardiovascular proteome in both health and disease emerge, integrative models of the myocyte are becoming useful tools for interpreting the functional significance of changes in protein expression and post-translational modifications (PTMs). Data of particular importance include information on: (a) changes of expressed protein level, (b) changes of protein PTMs, (c) protein localization, and (d) protein-protein interactions, as it is often possible to incorporate and interpret the functional significance of such findings using computational models. We provide two examples of how models may be used in this fashion. In the first example, we show how information on altered expression of the sarcoplasmic reticulum Ca2+-ATPase, when interpreted through the use of a computational model, has provided key insights into fundamental mechanisms regulating cardiac action potential duration. In the second example, we show how information on the effects of phosphorylation of L-type Ca2+ channels, when interpreted through the use of a model, provides insights on how this post-translational modification alters the properties of excitation-contraction coupling and risk for arrhythmia.

Animals↗
PubMed2026

TNF&#x3b1;-induced endothelial extracellular vesicles regulate astrocyte function: an integrated transcriptomic and proteomic study.

Endothelial cells and astrocytes are critical structural and functional components of the blood-brain barrier. In many neuroinflammatory diseases, endothelial cells are among the first to respond to inflammatory stimuli and release extracellular vesicles (EVs). However, whether inflammatory stimulation alters EV RNA cargo and subsequently regulates astrocyte function remains unclear. In this study, we performed integrated RNA sequencing and proteomic analyses to investigate the effects of TNF&#x3b1;-stimulated endothelial EVs on astrocytes. RNA profiling revealed significant alterations in EV cargo after TNF&#x3b1; stimulation, including 867 upregulated and 577 downregulated mRNAs, 317 upregulated and 15 downregulated lncRNAs, and 88 upregulated and 62 downregulated miRNAs. The results of functional enrichment analysis suggested that altered EV RNAs may primarily promote inflammatory responses, cell migration, and RNA splicing in astrocytes while reducing their regulatory effects on neuronal projection and calcium homeostasis. Further integrative analysis of EV RNAs and astrocytic proteomics revealed key overlapping targets, including upregulated expression of ICAM1, SOD2, TFPI2, and TNFAIP8, whereas NFKBIA expression was consistently decreased. Network analysis revealed NF-&#x3ba;B as the central regulatory node. Reduced levels of EV-derived NFKBIA mRNA were associated with decreased I&#x3ba;B&#x3b1; protein levels in astrocytes, which promoted NF-&#x3ba;B activation and inflammatory cytokine release. Finally, overexpression of I&#x3ba;B&#x3b1; in astrocytes significantly attenuated TNF&#x3b1; EV-induced IL-1&#x3b2; and IL-6 secretion. Collectively, these findings demonstrate that TNF&#x3b1;-stimulated endothelial EVs coordinately regulate astrocyte function through mRNA, lncRNA, and miRNA cargo and that the I&#x3ba;B&#x3b1;/NF-&#x3ba;B axis may be a key mechanism underlying endothelial EV-mediated inflammatory disruption of the blood-brain barrier.

Astrocytes↗
PubMed2026

Big data analytics for CLEC5A dynamics based on single cell genomics and proteomics reveal its diverse functions in human diseases.

BACKGROUND: CLEC5A (C-type lectin domain family 5 member A) is an innate immune receptor implicated in inflammatory signaling, contributing to hyperinflammatory responses in infections and sterile inflammation. However, CLEC5A dynamics in human diseases remain to be identified. Here, we systematically characterized CLEC5A dynamics in humans across cells, tissues, and disease states, and to explore the functional significance of CLEC5A in macrophage activation based on single-cell genomics. METHODS: With multi-omics (scRNA-seq, proteomics and big data analytics), we analyzed extensive human transcriptomic datasets (>42,000 samples) to profile CLEC5A expression by cell type, tissue, and disease. Single-nucleus RNA-seq (snRNA-seq) from pediatric congenital heart disease and a virtual CLEC5A gene knockout were also performed to characterize CLEC5A dynamics in humans. RESULTS: CLEC5A is highly enriched in innate immune cells, particularly in macrophages and neutrophils. Baseline CLEC5A in most tissues is low, but it is markedly upregulated in inflammatory and infectious diseases. CLEC5A expression has sex-specific differences in certain organs. Single-cell analysis showed that CLEC5A can be considered novel marker of proinflammatory macrophages with elevated cytokine production, antigen presentation, and impaired phagocytosis. Virtual CLEC5A knockout analysis identified coordinated perturbation of immune-regulatory pathways and overlapping genes linking CLEC5A to macrophage activation networks. CONCLUSION: CLEC5A is predominantly expressed in myeloid cells and acts as a key amplifier of inflammation in human diseases. Our findings highlight CLEC5A as a potential biomarker and therapeutic target in myeloid-driven hyperinflammatory conditions, warranting further experimental and translational validation.

Humans↗
PubMed2003

Functional profiling of the proteome with affinity labels.

The analysis of proteomic samples with affinity labels has been firmly established as a tool for the post-genomic researcher. Recent examples highlight the advantages of profiling functionally active members of specific protein families to identify therapeutically relevant protein targets that have escaped normal physiological regulation leading to increased or decreased activity. This dysregulation may result from any number of biological changes that modulate a protein's activity; for example, post-translational modifications of the protein or an imbalance between the protein and its endogenous inhibitor(s). By providing a direct measure of a protein's functional activity, affinity probe analysis identifies these changes and allows investigators to focus their research efforts upon those proteins that are most likely to be responsible for the biological changes under evaluation.

Affinity Labels↗
PubMed2006

Prion infection-impaired functional blocks identified by proteomics enlighten the targets and the curing pathways of an anti-prion drug.

Prion-induced neurodegeneration results from multiple cellular alterations among which the accumulation of a modified form of the host protein PrP is but a hallmark. Drug treatments need understanding of underlying mechanisms. Proteomics allows getting a comprehensive view of perturbations leading to neuronal death. Heparan sulfate mimetics has proved to be efficient to clear scrapie protein in cultured cells and in animals. To investigate the mechanisms of drug attack, protein profiles of the neuronal cell line GT1 and its chronically Chandler strain infected counterpart were compared, either in steady state cultures or after a 4-day drug treatment. Differentially expressed proteins were associated into functional blocks relevant to neurodegenerative diseases. Protein structure repair and modification, proteolysis, cell shape and energy/oxidation players were affected by infection, in agreement with prion biology. Unexpectedly, novel affected blocks related to translation, nucleus structure and DNA replication were unravelled displaying commonalities with proliferative processes. The drug had a double action in infected cells by reversing protein levels back to normal in some blocks and by heightening survival functions in others. This study emphasizes the interest of a proteomic approach to unravel novel networks involved in prion infection and curing.

Animals↗
PubMed2000

Mass spectrometry in viral proteomics.

Mass spectrometry is a valuable tool in structural and functional viral proteomics, where it has been used to identify viral capsid proteins, viral mutants, and posttranslational modifications. Further, mass-based approaches combined with time-resolved proteolysis (mass mapping) have revealed the dynamic nature of viral particles in solution; this method is contributing to an understanding of the dynamic domains of the viral capsid which may have significant value in developing new approaches for viral inactivation. As a result of these experiments, and by comparison with complementary data from X-ray crystallography, a new dimension to viral protein structure and function is emerging.

Mass Spectrometry↗
PubMed2025

Venomics of the Arabian saw-scaled viper (Echis coloratus) through transcriptome-guided proteomics and in vitro functional profiling.

The Arabian saw-scaled viper (Echis coloratus) is among the snakes of highest medical relevance in the Middle East and North Africa. However, to date, its venom has been investigated in a very limited number of studies, and much remains unknown regarding its compositional and functional properties. By integrating proteotranscriptomics with bioactivity profiling, we present a comprehensive transcriptome-level catalogue of E. coloratus venom components and their associated biological activities. Our analysis identified 183 venom components belonging to 17 distinct protein families. Relative toxin abundances revealed that 92% of the venom proteome is composed of C-type lectin and C-type lectin-related protein (CTL), L-amino acid oxidase (LAAO), phospholipase A2 (PLA2), snake venom serine protease (SVSP), and snake venom metalloproteinase (SVMP), with CTL and PLA2 alone accounting for 73% of the total composition. Bioassays targeting key aspects of viperid envenomation demonstrated potent protease and PLA2 activity in a concentration-dependent manner. In contrast, Factor Xa-like, plasmin-like, and haemolytic activities were negligible. Marked cytotoxicity was observed at the highest concentration tested (i.e., 25 &#x3bc;g/ml) in the mammalian cell lines MDCK II and Calu-3, whereas cytotoxic effects were minimal at lower concentrations. These findings highlight the complexity and potency of E. coloratus venom, and provide a valuable foundation for improving our understanding of envenomation caused by this species.

Animals↗