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PubMed2026

Large-Scale Plasma Proteomics Reveals Preclinical Biomarkers of Incident Severe Liver Disease.

The absence of robust biomarkers for early detection of severe liver disease (SLD) highlights the critical need for high-throughput proteomics-driven discovery. In this prospective cohort study, we aimed to identify plasma protein signatures associated with incident SLD and assess their clinical utility. Using the large-scale Olink Explore 1536 platform, we quantified 1461 plasma proteins in 46951 participants from the UK Biobank community-based cohort without baseline liver disease. Over a median follow-up of 14.1 years, we identified 490 proteins significantly associated with incident SLD risk. Growth differentiation factor 15 (GDF15) emerged as the strongest predictor, achieving a C-index of 0.80 and outperforming conventional clinical indices (LiverRisk score: 0.75; FIB-4: 0.68; APRI: 0.68). Temporal trajectories revealed that GDF15 levels began increasing up to 10 years before diagnosis, with progressive elevation as the diagnosis timepoint approached. Mendelian randomization analysis supported genetic associations linking higher protein levels of GDF15, FABP1, SPON2, CHI3L1, and PIGR with SLD risk. Our large-scale proteome-wide study not only reveals significant proteomic changes preceding SLD diagnosis but also establishes GDF15 as both a promising preclinical biomarker, opening new avenues for early intervention in at-risk individuals.

Humans↗

PubMed2003

Topological proteomics, toponomics, MELK-technology.

MELK is an ultrasensitive topological proteomics technology analysing proteins on the single cell level (Multi-Epitope-Ligand-'Kartographie'). It can trace out large scale protein patterns with subcellular resolution, mapping the topological position of many proteins simultaneously in a cell. Thereby, it addresses higher level order in a proteome, referred to as the toponome, coding cell functions by topologically and timely determined webs of interacting proteins. The resulting cellular protein maps provide new structures in the proteome: single combinatorial protein patterns (s-CPP), and combinatorial protein pattern motifs (CPP-motifs), bound to superior units. They are images of functional protein networks, which are specific signatures of tissues, cell types, cell states and diseases. The technology unravels hierarchies of proteins related to particular cell functions or dysfunctions, thus identifying and prioritising key proteins within cell and tissue protein networks. Interlocking MELK with the drug screening machinery provides new clues related to the selection of target proteins, and functionally relevant hits and drug leads. The present chapter summarizes the steps that have contributed to the establishment of the technology.

Humans↗

PubMed2025

Application of Proteomic Methods in Oomycete Biology.

The biochemical makeup of any organism provides insight into key factors regarding its biological functions. These factors can be explored using proteomics, which allows us to obtain a snapshot of the protein content and abundance in an organism, cell type or sub-cellular compartment. Here, we describe proteomic methodologies that can be used to dissect the biochemical mechanism of phytopathogenicity in oomycetes. These methodologies include protein extraction, purification, subsequent processing, mass spectrometry analysis, and qualitative and quantitative data processing of oomycete proteomes for comparative studies. Additionally, the use of mass spectra to assist in gene validation and modelling in unfinished oomycete genomes is also described.

Oomycetes↗

PubMed2003

Proteomic approaches to the diagnosis, treatment, and monitoring of cancer.

The field of proteomics holds promise for the discovery of new biomarkers for the early detection and diagnosis of disease, molecular targets for therapy and markers for therapeutic efficacy and toxicity. A variety of proteomics approaches may be used to address these goals. Two-dimensional gel electrophoresis (2D-PAGE) is the cornerstone of many discovery-based proteomics studies. Technologies such as laser capture microdissection (LCM) and highly sensitive MS methods are currently being used together to identify greater numbers of lower abundance proteins that are differentially expressed between defined cell populations. Newer technologies such as reverse phase protein arrays will enable the identification and profiling of target pathways in small biopsy specimens. Surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) analysis enables the high throughput characterization of lysates from very few tumor cells or body fluids and may be best suited for diagnosis and monitoring of disease. Such technologies are expected to supplement our arsenal of mRNA-based assays, and we believe that in the future, entire cellular networks and not just a single deregulated protein will be the target of therapeutics and that we will soon be able to monitor the status of these pathways in diseased cells before, during and after therapy.

Biomarkers, Tumor↗

PubMed2026

Tissue origins of the plasma proteomic response to glucose ingestion in humans.

AIMS/HYPOTHESIS: Circulating proteins act as important hormonal signals of nutrient intake. We aimed to systematically characterise the time-resolved proteomic response to glucose ingestion in humans, and to assess its robustness following prolonged complete caloric restriction. METHODS: We conducted oral glucose tolerance tests (OGTTs) in 11 healthy volunteers before and after 7 days of complete caloric restriction and measured the response of >2900 targets through high-resolution plasma protein profiling. RESULTS: We identified a signature of 44 proteins that changed significantly following glucose ingestion, which was reproducible after 7 days without food, and was strongly (20-fold) enriched for 'stomach-specific' proteins. We report that annexin A10 (ANXA10) shows the most significant post-glucose change observed, similar to the trajectories of secreted hormones. We present observational human evidence from multiple sources suggesting that ANXA10 is secreted upon sensing an increase in gastric pH, with the stomach as the major contributing tissue. Despite a profound metabolic shift after 7 days of complete caloric restriction, characterised by delayed insulin secretion and postprandial hyperglycaemia, only four proteins showed robust evidence for a differential trajectory during both OGTTs. This included plasma levels of tryptophanyl-tRNA synthetase 1 (WARS), for which we found a genetic association with glucose homeostasis and coronary artery disease. CONCLUSIONS/INTERPRETATION: Our exploratory study identifies the proteomic response to glucose ingestion and demonstrates its reproducibility despite major shifts in glucose homeostasis. We characterise the gastrointestinal origin of these changes, and hypothesise a hitherto under-recognised role for sensing of changes in gastric pH on the plasma proteome.

Humans↗

PubMed2002

Genomes, proteomes, and dynamic networks in the cell nucleus.

Post-genome era experimental strategies seek to understand cellular pathways globally rather than through examination of individual components. Genomics and proteomics provide the experimental tools to establish the framework of gene and protein pathways present in a cell. These methods are complemented by emerging in vivo microscopy approaches, which permit placement of pathways within the architectural context of the cell. Analysis of dynamic live cell microscopy data combined with computational analyses finally allows the quantitative, mechanistic description of protein properties and pathways operating in living cells. Here we discuss how genomics and proteomics are changing the study of the cell nucleus and how in vivo microscopy methods have contributed to our changing conceptual and mechanistic understanding of nuclear architecture and function. Mapping of gene loci and genome regions are beginning to reveal organizational principles of the genome within the cell nucleus, proteomic analysis of subnuclear compartments and the gene expression machinery is providing insights into the molecular nature of nuclear events, and in vivo microscopy is illuminating the dynamic nature of nuclear organization. Initial findings from these efforts make clear that nuclear and cellular behavior can not be described by linear pathways. New tools such as computational modeling are providing evidence that emerging concepts such as network organizations and stochastic interactions are crucially important for cellular function and organization. These insights are changing our view of the nucleus and the cell as a whole.

Animals↗

PubMed2006

Proteomic based investigation of rhamnolipid production by Pseudomonas chlororaphis strain NRRL B-30761.

We recently reported that a strain of the non-pathogenic bacterial species Pseudomonas chlororaphis was capable of producing the biosurfactant molecule, rhamnolipids. Previous to this report the organisms known to produce rhamnolipids were almost exclusively pathogens. The newly described P. chlororaphis strain produced rhamnolipids at room temperature in static minimal media, as opposed to previous reports of rhamnolipid production which occurred at elevated temperatures with mechanical agitation. The non-pathogenic nature and energy conserving production conditions make the P. chlororaphis strain an attractive candidate for commercial rhamnolipid production. However, little characterization of molecular/biochemical processes in P. chlororaphis have been reported. In order to achieve a greater understanding of the process by which P. chlororaphis produces rhamnolipids, a survey of proteins differentially expressed during rhamnolipid production was performed. Separation and measurement of the bacteria's proteome was achieved using Beckman Coulter's Proteome Lab PF2D packed column-based protein fractionation system. Statistical analysis of the data identified differentially expressed proteins and known orthologues of those proteins were identified using an AB 4700 Proteomics Analyzer mass spectrometer system. A list of proteins differentially expressed by P. chlororaphis strain NRRL B-30761 during rhamnolipid production was generated, and confirmed through a repetition of the entire separation process.

Bacterial Proteins↗

PubMed2026

Identification of intranasal oxytocin plasma proteome signatures.

BACKGROUND: The hypothalamic peptide oxytocin regulates a range of central and peripheral activities, ranging from uterine contractions to energy homeostasis. Oxytocin-based therapeutics are under investigation for neuropsychiatric and metabolic disease, including obesity. The mechanisms underlying oxytocin effects are poorly understood. This study profiles 4725 serum proteins in 19 healthy men across the adiposity spectrum (9 normal-weight, BMI < 25 kg/m2; 10 overweight/obese, BMI ≥ kg/m2) following exogenous, intranasal oxytocin administration to identify markers of pharmacodynamic effect. METHODS: In a double-blind, randomized controlled crossover design, 25 men were exposed to a single dose of 24 IU intranasal oxytocin vs. placebo. Fasting blood was drawn immediately prior and at 15, 30, and 55 min after oxytocin/placebo administration for proteomic analysis (SOMA Scan, Soma Logic, Inc.). RESULTS: As previously reported in the parent study, intranasal oxytocin reduced caloric intake at the test meal; here, we examined proteomic predictors of this behavioral effect. Proteomic data was available for 19 men. We identified 198 differentially expressed proteins in response to intranasal oxytocin in fasting men across the adiposity spectrum. The pathways identified are involved in intracellular signaling pathways, as well as immune regulation and inflammation. Oxytocin modulated a cluster of proteins that was associated with subsequent caloric intake at the test meal. CONCLUSIONS: These data provide insights into mechanisms underlying pharmacologic oxytocin effects on human physiology and a framework for future investigations.

Humans↗

PubMed2006

Contributions of advanced proteomics technologies to cancer diagnosis.

The ability of Medicine to effectively treat and cure cancer is directly dependent on their capability to detect cancers at their earliest stages. The advent of proteomics has brought with it the hope of discovering novel biomarkers in the early phases of tumorigenesis that can be used to diagnose diseases, predict susceptibility, and monitor progression. This discipline incorporates technologies that can be applied to complex biosystems such as serum and tissue in order to characterize the content of, and changes in, the proteome induced by physiological changes, benign or pathologic. These tools include 2-DE, 2D-DIGE, ICAT, protein arrays, MudPIT and mass spectrometries including SELDI-TOF. The application of these tools has assisted to uncover molecular mechanisms associated with cancer at the global level and may lead to new diagnostic tests and improvements in therapeutics. In this review these approaches are evaluated in the context of their contribution to cancer biomarker discovery. Particular attention is paid to the promising contribution of the ProteinChip/SELDI-TOF platform as a revolutionary approach in proteomic patterns analysis that can be applied at the bedside for discovering protein profiles that distinguish disease and disease-free states with high sensitivity and specificity. Understanding the basic concepts and tools used will illustrate how best to apply these technologies for patient benefit for the early cancer detection and improved patient care.

Biomarkers, Tumor↗

PubMed2026

Proteomic characterization of the acquired enamel pellicle under acidic challenges at early and mature formation stages.

OBJECTIVES: This study aimed to characterize acquired enamel pellicle (AEP) proteomic changes after exposure to citric acid (CA) and hydrochloric acid (HCl) under different pellicle formation times (3 and 120 min) in the same volunteers. DESIGN: Nine healthy volunteers participated in this randomized crossover in vivo study. The AEP was allowed to form for 3 or 120 min and subsequently exposed for 10 s to deionized water (control), 1% CA (pH 2.5), or 0.01 M HCl (pH 2.0). Pellicle samples were collected, followed by protein extraction, tryptic digestion, and analysis by nanoliquid chromatography (nanoLC) coupled to mass spectrometry (MS) with MSE (data-independent acquisition; nanoLC-MSᴱ). Label-free quantitative proteomics were performed for relative quantification using t-test (p < 0.05). RESULTS: At 120 min, CA exposure markedly reduced several typical AEP proteins, especially acidic proline-rich proteins (PRPs). Conversely, basic PRPs were upregulated, suggesting acid-resistance protein signature. At 3 min, basal-layer proteins (PRPs, cystatins, histatins and mucins) were more abundant. Hemoglobins increased 6-8-fold (up to 150-fold in 3 min control), suggesting association with early pellicle formation and an acid-resistant protein signature. CA exposures for 120 min also upregulated typical AEP proteins (PRPs, mucins, cystatins, immunoglobulins), while HCl exposure depleted albumins and lactotransferrin. CONCLUSION: Intrinsic and extrinsic acids induce distinct proteomic signatures in the AEP. Hemoglobin and PRPs appear consistently enriched in the early pellicle layer, reflecting an initial acid-resistant protein signature. These findings provide new insights into the molecular remodeling of the AEP following intrinsic and extrinsic acid exposure, highlighting proteins potentially involved in early-stage pellicle formation.

Humans↗

PubMed2006

In vivo proteomic analysis of the intracellular bacterial pathogen, Francisella tularensis, isolated from mouse spleen.

Understanding the pathogenesis of infectious diseases requires comprehensive knowledge of the proteins expressed by the pathogen during in vivo growth in the host. Proteomics provides the tools for such analyses but the protocols required to purify sufficient quantities of the pathogen from the host organism are currently lacking. Here, we present a rapid immunomagnetic protocol for the separation of Francisella tularensis, a highly virulent bacterium and potential biowarfare agent, from the spleens of infected mice. In less than one hour, bacteria can be isolated in quantities sufficient to carry out meaningful proteomic comparisons with in vitro grown bacteria. Furthermore, the isolates are virtually free from contaminating host proteins. Two-dimensional gel analysis revealed a host induced proteome in which 78 proteins were differentially expressed in comparison to in vitro grown controls. The results obtained clearly demonstrate the complexity of the adaptive response of F. tularensis to the host environment, and the difficulty of mimicking such behavior in vitro.

Animals↗

PubMed2006

Differential serum proteomic analysis in a model of metabolic disease.

Protein profiling would aid in better understanding the pathophysiology of metabolic disease. Here, we report on differential proteomic analysis using an animal model of diabetes mellitus and associated metabolic disorders (Otsuka Long-Evans Tokushima Fatty rat). Serum was analyzed by a new two-dimensional liquid chromatography system which separated proteins by chromatofocusing and subsequent reversed-phase chromatography. This is the first application of this approach to differential serum proteomics. Differentially expressed proteins, identified with MALDI-TOF mass spectrometry, included apolipoproteins and alpha2-HS-glycoprotein. These findings add to our understanding of the underlying pathophysiology. This new proteomic analysis is a promising tool to elucidate disease mechanisms.

Animals↗

PubMed2006

Inner ear proteomics: a fad or hear to stay.

Proteomics, the large-scale analysis of the structure and function of proteins, as well as of protein-protein interactions, has evolved into a major component of 'systems analysis'. This requires the integration of information from different sources and at multiple levels, and involves two distinct parameters, (1) high-throughput protein separation, identification, and characterization, and (2) the extension of the obtained analytical data for the determination of the physiological function. The inner ear poses exceptional challenges to the study of proteomics because of its minute size, poor accessibility, association with complex fluid spaces, and diversity of cell types. Various approaches to the study of proteomics of the inner ear are presented, and success stories, noteworthy failures and what lies ahead, will be discussed.

Animals↗

PubMed2006

Multidimensional capillary array liquid chromatography and matrix-assisted laser desorption/ionization tandem mass spectrometry for high-throughput proteomic analysis.

A two-dimensional capillary array liquid chromatography system coupled with matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) was developed for high-throughput comprehensive proteomic analysis, in which one strong cation-exchange (SCX) capillary chromatographic column was used as the first separation dimension and 10 parallel reversed-phase liquid chromatographic (RPLC) capillary columns were used as the second separation dimension. A novel multi-channel interface was designed and fabricated for on-line coupling of the SCX to RPLC column array system. Besides the high resolution based on the combination of SCX and RPLC separation, the developed new system provided the most rapid two-dimensional liquid chromatography (2D-LC) separation. Ten three-way micro-splitter valves used as stop-and-flow switches in transferring SCX fractions onto RPLC columns. In addition, the three-way valves also acted as mixing chambers of RPLC effluent with matrix. The system enables on-line mixing of the LC array effluents with matrix solution during the elution and directly depositing the analyte/matrix mixtures on MALDI plates from the tenplexed channels in parallel through an array of capillary tips. With the novel system, thousands of peptides were well separated and deposited on MALDI plates only in 150min for a complex proteome sample. Compared with common 2D-LC system, the parallel 2D-LC system showed about 10-times faster analytical procedure. In combination with a high throughput tandem time of flight mass spectrometry, the system was proven to be very effective for proteome analysis by analyzing a complicated sample, soluble proteins extracted from a liver cancer tissue, in which over 1202 proteins were identified.

Chromatography, Liquid↗

PubMed2004

Genomic and proteomic technologies for individualisation and improvement of cancer treatment.

The development of microarray-based technologies for characterising tumours, both at the genomic and proteomic levels, has had a significant impact on the field of oncology. Gene expression profiling of various human tumour tissues has led to the identification of expression patterns related to disease outcome and drug resistance, as well as to the discovery of new therapeutic targets and insights into disease pathogenesis. Protein microarray technologies, such as reverse-phase protein arrays, provide the unique opportunity to profile tissues and assess the activity of signalling pathways within isolated cell populations. This technology can be used to identify patients likely to benefit from specific treatment modalities and also to monitor therapeutic response in samples obtained during and after treatment. Routine application of genomic and proteomic microarray technologies in clinical practice will require significant efforts to standardise the techniques, controls and reference standards, and analytical tools used. Extensive, independent validation using large, statistically-powered datasets will also be necessary. Inclusion of concomitant genomic and proteomic-based molecular profiling techniques into clinical trial protocols will bring us closer to the reality of patient-tailored therapy.

Gene Expression Profiling↗

PubMed2006

Oxidative stress in Alzheimer's disease brain: new insights from redox proteomics.

Alzheimer's disease, an age-related neurodegenerative disorder, is characterized clinically by a progressive loss of memory and cognitive functions. Neuropathologically, Alzheimer's disease is defined by the accumulation of extracellular amyloid protein deposited senile plaques and intracellular neurofibrillary tangles made of abnormal and hyperphosphorylated tau protein, regionalized neuronal death, and loss of synaptic connections within selective brain regions. Evidence has suggested a critical role for amyloid-beta peptide metabolism and oxidative stress in Alzheimer's disease pathogenesis and progression. Among the other indices of oxidative stress in Alzheimer's disease brain are protein carbonyls and 3-nitrotyrosine, which are the markers of protein oxidation. Thus, in this review, we discuss the application of redox proteomics for the identification of oxidatively modified proteins in Alzheimer's disease brain and also discuss the functions associated with the identified oxidized proteins in relation to Alzheimer's disease pathology. The information obtained from proteomics may be helpful in understanding the molecular mechanisms involved in the development and progression of Alzheimer's disease as well as of other neurodegenerative disorders. Further, redox proteomics may provide potential targets for drug therapy in Alzheimer's disease.

Actins↗

PubMed2005

Mitochondrial proteomics in free radical research.

The importance of mitochondrial dysfunction in numerous diseases has long been appreciated. The impact of oxidative and nitrosative stress on mitochondrial function is complex; however, recent progress in the field using proteomics technologies has begun to shed light on the molecular defects responsible for mitochondrial and cellular dysfunction. This review focuses on the state-of-the-art technologies being used and current research endeavors in the field of mitochondrial proteomics with emphasis on those advancements being made in the field of free radical biology to identify the importance of alterations to the mitochondrial proteome in the development of disease.

Alcohols↗

PubMed2006

Study of proteins associated with the Eimeria tenella refractile body by a proteomic approach.

Refractile bodies (RB), whose function is still unknown, are specific structures of Eimeriidae parasites. In order to study their proteome, RB were purified from Eimeria tenella sporozoites by a new procedure using a reversible fixation followed by centrifugation. RB proteins were resolved by two-dimensional electrophoresis. Around 76 and 89 spots were detected on RB two-dimensional gels using gradients in the 3-10 and 4-7 range, respectively. RB proteins were located mainly between pH 5 and 7. RB gels were then compared with previously established maps of the entire sporozoite proteome. Proteins appearing in new spots were identified by mass spectrometry. Thirty protein isoforms were located in RB. Added to the already known RB proteins such as Eimepsin and SO7', the new RB proteins were defined as haloacid dehalogenase, hydrolase, subtilase, lactacte dehydrogenase or ubiquitin family proteins. The RB proteome analysis confirmed the hypothesis that this structure is a reservoir for proteins necessary to invasion but also suggests that RB have energetic and metabolic functions.

Animals↗