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PubMed2005

Integrating cell-level kinetic modeling into the design of engineered protein therapeutics.

Functional genomics and proteomics are identifying many potential drug targets for novel therapeutic proteins, and both rational and combinatorial protein engineering methods are available for creating drug candidates. A central challenge is the definition of the most appropriate design criteria, which will benefit critically from computational kinetic models that incorporate integration from the molecular level to the whole systems level. Interpretation of these processes will require mathematical models that are refined in combination with relevant data derived from quantitative assays, to correctly set biophysical objectives for protein design.

Cell Physiological Phenomena↗

PubMedDate not supplied

Gas chromatographic-mass spectrometric urinary metabolome analysis to study mutations of inborn errors of metabolism.

Urine contains numerous metabolites, and can provide evidence for the screening or molecular diagnosis of many inborn errors of metabolism (IEMs). The metabolomic analysis of urine by the combined use of urease pretreatment, stable-isotope dilution, and capillary gas chromatography/mass spectrometry offers reliable and quantitative data for the simultaneous screening or molecular diagnosis of more than 130 IEMs. Those IEMs include hyperammonemias and lactic acidemias, and the IEMs of amino acids, pyrimidines, purines, carbohydrates, and others including primary hyperoxalurias, hereditary fructose intolerance, propionic acidemia, and methylmalonic acidemia. Metabolite analysis is comprehensive for mutant genotypes. Enzyme dysfunction-either by the abnormal structure of an enzyme/apoenzyme, the reduced quantity of a normal enzyme/apoenzyme, or the lack of a coenzyme-is involved. Enzyme dysfunction-either by an abnormal regulatory gene, abnormal sub-cellular localization, or by abnormal post-transcriptional or post-translational modification-is included. Mutations-either known or unknown, common or uncommon-are involved. If the urine metabolome approach can accurately observe quantitative abnormality for hundreds of metabolites, reflecting 100 different disease-causing reactions in a body, then it is possible to simultaneously detect different mutant genotypes of far more than tens of thousands.

DNA Mutational Analysis↗

PubMed2006

Comparative serum glycoproteomics using lectin selected sialic acid glycoproteins with mass spectrometric analysis: application to pancreatic cancer serum.

A strategy is developed in this study for identifying sialylated glycoprotein markers in human cancer serum. This method consists of three steps: lectin affinity selection, a liquid separation and characterization of the glycoprotein markers using mass spectrometry. In this work, we use three different lectins (Wheat Germ Agglutinin, (WGA) Elderberry lectin,(SNA), Maackia amurensis lectin, (MAL)) to extract sialylated glycoproteins from normal and cancer serum. Twelve highly abundant proteins are depleted from the serum using an IgY-12 antibody column. The use of the different lectin columns allows one to monitor the distribution of alpha(2,3) and alpha(2,6) linkage type sialylation in cancer serum vs that in normal samples. Extracted glycoproteins are fractionated using NPS-RP-HPLC followed by SDS-PAGE. Target glycoproteins are characterized further using mass spectrometry to elucidate the carbohydrate structure and glycosylation site. We applied this approach to the analysis of sialylated glycoproteins in pancreatic cancer serum. Approximately 130 sialylated glycoproteins are identified using microLC-MS/MS. Sialylated plasma protease C1 inhibitor is identified to be down-regulated in cancer serum. Changes in glycosylation sites in cancer serum are also observed by glycopeptide mapping using microLC-ESI-TOF-MS where the N83 glycosylation of alpha1-antitrypsin is down regulated. In addition, the glycan structures of the altered proteins are assigned using MALDI-QIT-MS. This strategy offers the ability to quantitatively analyze changes in glycoprotein abundance and detect the extent of glycosylation alteration as well as the carbohydrate structure that correlate with cancer.

Case-Control Studies↗

PubMed2001

Protein profiling comes of age.

Ever since DNA microarrays were first applied to the quantitation of RNA levels, there has been considerable interest in generating a protein homolog that can be used to assay cellular protein expression. A recent paper describes the first microarray that can be used for such protein profiling.

Gene Expression Profiling↗

PubMed2004

Preparation of human heart for laser microdissection and proteomics.

Proteomics generates information on expressed proteins, and laser microdissection (LMD) is a method that allows enrichment of specific cell types from complex heterogeneous tissue. Together they provide a powerful tool for functional genomic research. Here, we have investigated (i) the effects of fixation and staining on cardiac proteins separated by two-dimensional gel electrophoresis (2-DE) and (ii) feasibility of using LMD to separately prepare myocytes and blood vessels for 2-DE gel analysis. This is the first such study of human heart. The effect of fixation (ethanol or acetone), staining with haematoxylin and eosin in the presence and absence of xylene, and antibody staining was investigated. Proteins were separated by 2-DE and spots detected by silver staining. Quantitative spot analysis showed that contractile proteins were preserved under all conditions, and no significant differences were found when the groups studied were compared with the control group. However, there were differences in the visual quality of the gel patterns. LMD provided enough protein from blood vessels and myocytes to run one large-format (18 x 24 cm) 2-D gel for each subset of cells. Collection of this material took 70 h (approximately 2800 blood vessels and 17,000 myocytes) and resulted in tissue-specific gel patterns for these two structures. In conclusion, the use of haematoxylin and eosin staining without xylene provided the best morphology and did not significantly affect protein spot number.

Cells, Cultured↗

PubMed2026

Proteome-wide Mendelian randomisation of lung function to identify potential therapeutic targets for respiratory disease.

BACKGROUND: Despite multiple clinical trials, disease-modifying treatments for COPD are currently limited. Since many drugs target proteins, identifying causality between proteins and lung function informs understanding of COPD pathophysiology and may suggest novel targets. We used Mendelian randomisation (MR) to prioritise proteins as potentially causal for imparied lung function. For prioritised proteins, we explored their potential suitability as drug targets by predicting their effects on a range of clinical outcomes. METHODS: We used genome-wide association study (GWAS) data on 2923 proteins (n=48 195, UK Biobank) to identify single genetic variants (protein quantitative trait loci (cis-pQTLs)) associated with protein levels (p≤5×10-9, variant ≤100 kb of a transcription start site). We performed cis-pQTL-MR analyses of four spirometric traits (n=149 166, 36 independent cohorts). Sensitivity analyses included colocalisation and reverse direction MR. We report associations between cis-pQTLs for prioritised proteins and multiple clinical respiratory outcomes, and use phenome-wide analysis to explore potential adverse effects or drug repurposing opportunities. FINDINGS: 1841 proteins had a suitable cis-pQTL. We implicated 16 proteins as potentially causal for lung function (p<1.71×10-5): seven proteins have not been implicated by previous lung function GWAS or MR (CCND2, DTD1, PILRA, PTPRK, TDRKH, GRHPR, NUDT5), and we provide corroborative evidence for 10 proteins. We add to the literature identifying surfactant protein D (SFTPD) as a candidate, yet predict that integrin subunit alpha V (ITGAV) inhibition could impair some lung function measures, mimicking adverse results from a recent trial. INTERPRETATION: Our approach identifies proteins (some novel) that are potentially therapeutic targets for respiratory disease, and which warrant follow-up for utility and safety.

Journal Article↗

PubMed2026

Multi-omics identification of therapeutic targets of compound sappan decoction in hepatocellular carcinoma.

BACKGROUND: Compound sappan decoction (CSD) is a multi-herbal traditional Chinese medicine formulation with clinical relevance in hepatocellular carcinoma (HCC). However, its therapeutic mechanisms remain unclear. METHODS: Bioactive compounds of CSD were identified and standardized using pharmacological and chemical databases. Potential targets were predicted via multiple target inference platforms. HCC-related genes were curated from comprehensive disease databases. Summary-data-based Mendelian randomization (SMR) was conducted to infer causal relationships between compound targets and HCC risk using large-scale quantitative trait loci (QTL) datasets and HCC genome-wide association study data. Colocalization analysis, protein-protein interaction (PPI) network construction, and GO/KEGG enrichment were performed on SMR-identified targets. Molecular docking evaluated binding affinities of representative compounds to prioritized targets. RESULTS: A total of 784 overlapping genes between predicted CSD targets and HCC-related genes were subjected to SMR analysis. Among these, 22 targets were significantly associated with HCC risk based on transcriptomic or proteomic QTLs and showed colocalization evidence. Notably, four targets (ADRB2, APOE, SYK, and PGF) were supported by both replication in an independent cohort and strong colocalization. These 22 targets were enriched in apoptosis, PI3K-Akt signaling, redox metabolism, and detoxification pathways. PPI analysis revealed central hubs including MMP9, BCL2, CASP1, and MCL1. Molecular docking demonstrated strong binding of APOE to quercetin, PGF to luteolin-7-olate, and SYK to kaempferol. CONCLUSIONS: CSD may exert therapeutic effects on HCC through modulation of genetically validated targets involved in tumor progression, inflammation, and metabolic reprogramming, supporting its potential clinical utility as an adjunctive treatment strategy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s12672-026-04740-8.

Caesalpinia↗

PubMed2026

Plasma proteins are integral to cross-tissue gene regulatory networks implicated in cardiometabolic disorders and coronary artery disease.

The plasma proteome has demonstrated promise for identifying diagnostic markers for cardiometabolic disorders (CMDs) and coronary artery disease (CAD). However, identifying the organ of origin for these biomarkers is critical for establishing biological relevance. We performed a multi-omic integrative analysis across multiple tissues from the STARNET study by profiling 974 plasma proteins in 532 CAD patients, integrating RNA sequencing (RNA-seq) data from the arterial wall, major metabolic organs, and blood. We identified 144 cis-protein quantitative trait loci in plasma, colocalizing with tissue cis-expression quantitative trait loci. Additionally, by mapping tissue mRNA "seed genes," we traced 262 plasma proteins to their source organs, primarily the liver. Crucially, we found that 851 plasma proteins are associated with the activity of cross-tissue gene regulatory networks (GRNs), including GRNs implicated in CMD and CAD development. Our findings demonstrate that plasma proteins are integral components of GRNs, with potential for developing reliable diagnostics and precise therapeutic targets. A record of this paper's transparent peer review process is included in the supplemental information.

cardiometabolic disorders↗

PubMed2003

Absolute systems biology--measuring dynamics of protein modifications.

Mass spectrometry is already established as the method of choice for protein identification. Hitherto, a major limitation of mass spectrometry was the inability to quantitate protein levels. With the development of novel methods, such as the AQUA method by Gerber et al., this hurdle has finally been overcome, unleashing the power of mass spectrometry to study protein dynamics in cells.

Isotope Labeling↗

PubMed2005

A microarray data-based semi-kinetic method for predicting quantitative dynamics of genetic networks.

BACKGROUND: Elucidating the dynamic behaviour of genetic regulatory networks is one of the most significant challenges in systems biology. However, conventional quantitative predictions have been limited to small networks because publicly available transcriptome data has not been extensively applied to dynamic simulation. RESULTS: We present a microarray data-based semi-kinetic (MASK) method which facilitates the prediction of regulatory dynamics of genetic networks composed of recurrently appearing network motifs with reasonable accuracy. The MASK method allows the determination of model parameters representing the contribution of regulators to transcription rate from time-series microarray data. Using a virtual regulatory network and a Saccharomyces cerevisiae ribosomal protein gene module, we confirmed that a MASK model can predict expression profiles for various conditions as accurately as a conventional kinetic model. CONCLUSION: We have demonstrated the MASK method for the construction of dynamic simulation models of genetic networks from time-series microarray data, initial mRNA copy number and first-order degradation constants of mRNA. The quantitative accuracy of the MASK models has been confirmed, and the results indicated that this method enables the prediction of quantitative dynamics in genetic networks composed of commonly used network motifs, which cover considerable fraction of the whole network.

Amino Acid Motifs↗

PubMed2003

Proteomic changes during disturbance of cholesterol metabolism by azacoprostane treatment in Caenorhabditis elegans.

Although nematodes like Caenorhabditis elegans are incapable of de novo cholesterol biosynthesis, they can utilize nonfunctional sterols by converting them into cholesterol and other sterols for cellular function. The results reported previously and presented here suggest that blocking of sterol conversion to cholesterol in C. elegans by 25-azacoprostane-HCl (azacoprostane) treatment causes a serious defect in germ cell development, growth, cuticle development, and motility behavior. To establish a biochemical basis for these physiological abnormalities, we performed proteomic analysis of mixed stage worms that had been treated with the drug. Our results from a differential display proteomic analysis revealed significant decreases in the levels of proteins involved in collagen and cytoskeleton organization such as protein disulfide isomerase (6.7-fold), beta-tubulin (5.41-fold), and NEX-1 protein (>30-fold). Also reduced were enzymes involved in energy production such as phosphoglycerate kinase (4.8-fold) and phosphoenolpyruvate carboxykinase (8.5-fold), a target for antifilarial drugs such as azacoprostane. In particular, reductions in the expression of lipoprotein families such as vitellogenin-2 (7.7-fold) and vitellogenin-6 (5.4-fold) were prominent in the drug-treated worms, indicating that sterol metabolism disturbance caused by azacoprostane treatment is tightly coupled with suppression of the lipid transfer-related proteins at the protein level. However, competitive quantitative reverse transcriptase polymerase chain reaction showed that the transcriptional levels of vit-2, vit-6, and their receptors (e.g. rme-2 and lrp-1) in drug-treated worms were 3- to 5-fold higher than those in the untreated group, suggesting a presence of a sterol regulatory element-binding protein (SREBP)-like pathway in these genes. In fact, multiple predicted sterol regulatory elements or related regulatory sequences responding to sterols were found to be located at the 5'-flanking regions in vit-2 and lrp-1 genes, and their transcriptional activities fluctuated highly in response to changes in sterol concentration. Thus, many physiological abnormalities caused by azacoprostane-mediated sterol metabolism disturbance appear to be exerted at least in part through SREBP pathway in C. elegans.

Animals↗

PubMed2003

Global characterization of disulfide stress in Bacillus subtilis.

We used DNA macroarray and proteome analysis to analyze the regulatory networks in Bacillus subtilis that are affected by disulfide stress. To induce disulfide stress, we used the specific thiol oxidant diamide. After addition of 1 mM diamide to an exponentially growing culture, cell growth stopped until the medium was cleared of diamide. Global analysis of the mRNA expression pattern during growth arrest revealed 350 genes that were induced by disulfide stress by greater than threefold. Strongly induced genes included known oxidative stress genes that are under the control of the global repressor PerR and heat shock genes controlled by the global repressor CtsR. Other genes that were strongly induced encode putative regulators of gene expression and proteins protecting against toxic elements and heavy metals. Many genes were substantially repressed by disulfide stress, among them most of the genes belonging to the negative stringent response. Two-dimensional gels of radioactively labeled protein extracts allowed us to visualize and quantitate the massive changes in the protein expression pattern that occurred in response to disulfide stress. The observed dramatic alteration in the protein pattern reflected the changes found in the transcriptome experiments. The response to disulfide stress seems to be a complex combination of different regulatory networks, indicating that redox-sensing cysteines play a key role in different signaling pathways sensing oxidative stress, heat stress, toxic element stress, and growth inhibition.

Bacillus subtilis↗

PubMed2005

Proteomic analysis of hypothalamic proteins of high and low egg production strains of chickens.

Two slow-growth local chicken strains, derived from a common base population, were bi-directionally selected over twenty generations for carcass traits (B strain) and egg production (L2 strain). The objective of the present study was to identify hypothalamic proteins associated with high egg production (by taking advantage of the similar genetic background of these two strains). Prior to and during egg laying, hypothalamic proteins of B and L2 hens were analyzed with two-dimensional gel electrophoresis (2-DE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Approximately 430 well-resolved spots, ranging from 10 to 40 kDa, pH 5-9, were quantified by image processing. Eight protein spots differed in quantity between B and L2 strains at either stage. Using LC-MS/MS, we identified six of eight protein spots, including proteins known for regulating gene expression, signal transduction and lipid metabolism. The mRNA expression levels of these six proteins were then evaluated by quantitative RT-PCR in five strains of hens, including B, L2 and another three commercial strains; heterogeneous nuclear ribonucleoprotein H3 (HNRPH3) was higher in L2 than in the B strain (consistent with the findings in 2-DE). Increased levels of HNRPH3 mRNA were also present in the hypothalamus of high-egg-yield White Leghorn layers, but were absent in other domestic commercial strains with low egg production rates. In conclusion, the expression level of HNRPH3 may be a new molecular marker to screen for high egg production in slow-growth local chickens.

Animals↗

PubMed2006

Slide-based cytometry for cytomics--a minireview.

In the postgenomic era, to gain the most detailed quantitative data from biological specimens has become increasingly important in the emerging new fields of high-content and high-throughput single-cell analysis for systems biology and cytomics. Areas of research and diagnosis with the demand to virtually measure "anything" in the cell include immunophenotyping, rare cell detection and characterization in the case of stem cells and residual tumor cells, tissue analysis, and drug discovery. Systemic analysis is also a prerequisite for predictive medicine by genomics, proteomics, and cytomics. This issue of Cytometry Part A is dedicated to innovative concepts of system wide single cells analysis and manipulation, new technologies, data analysis and display, and, finally, quality assessment. The manuscripts to these chapters are provided by cutting edge experts in the fields. This overview will briefly highlight the most important aspects of this continuously developing field.

Animals↗

PubMed2006

Application of immunoproteomics to rapid cytokine detection.

Cytokines are pivotal to a balanced innate or cell-mediated immune response, and can be indicative of disease progression and/or resolution. Methods to measure key cytokines rapidly with accuracy, precision, and sensitivity are consequently important. The current assay technologies, which are based on RT-PCR, immunoassays, or bioassays, are limited in their use in the clinic, in particular because of the long time (1-3 h) required to carry out the assays. An alternative, semi-quantitative approach described here, uses an immunological capture step and a mass spectral readout. The goal of the assay is speed rather than sensitivity or precision.

Animals↗

PubMed2001

Recent developments in computational proteomics.

The mapping of the human genome was completed earlier this year and efforts are underway to understand the role of gene products (i.e. proteins) in biological pathways and human disease and to exploit their functional roles to derive protein therapeutics and protein-based drugs. A key component to the next revolution in the 'post-genomic' era will be the increasingly widespread use of protein structure in rational experimental design. Improvements in quality, availability and utility of large-scale three- and four-dimensional protein structural information are enabling a revolution in rational design, having particular impact on drug discovery and optimization. New computational methodologies now yield modeled structures that are, in many cases, quantitatively comparable with crystal structures, at a fraction of the cost.

Journal Article↗

PubMed2006

Isobaric tags for relative and absolute quantitation (iTRAQ) reproducibility: Implication of multiple injections.

We analyzed 10 isobaric tags for relative and absolute quantitation (iTRAQ) experiments using three different model organisms across the domains of life: Saccharomyces cerevisiae KAY446, Sulfolobussolfataricus P2, and Synechocystis sp. PCC6803. A double database search strategy was employed to minimize the rate of false positives to less than 3% for all organisms. The reliability of proteins with single-peptide identification was also assessed using the search strategy, coupled with multiple analyses of samples into LC-MS/MS. The outcomes of the three LC-MS/MS analyses provided higher proteome coverage with an average increment in total proteins identified of 6%, 33%, and 50% found in S. cerevisiae, S. solfataricus, and Synechocystis sp., respectively. The iTRAQ quantification values were found to be highly reproducible across the injections, with an average coefficient of variation (CV) of 0.09 (scattering from 0.14 to 0.04) calculated based on log mean average ratio for all three organisms. Hence, we recommend multiple analyses of iTRAQ samples for greater proteome coverage and precise quantification.

Amino Acid Sequence↗

PubMed2004

Cadmium and health in the 21st century--historical remarks and trends for the future.

The first health effect of cadmium (Cd) was lung damage, reported in workers already in the 1930's, while bone effects and proteinuria were reported in the 1940's. After World War II, a bone disease with fractures and severe pain, the itai-itai disease, a form of Cd-induced renal osteomalacia, was identified in Japan. Subsequently, the toxicokinetics and toxicodynamics of Cd were described including its binding to the protein metallothionein. International warnings of health risks from cadmium pollution were issued in the 1970's. WHO, 1992, identified renal dysfunction as the critical effect and a crude quantitative evaluation was presented. In the 1990's population groups in China exposed to Cd via rice were studied and new information on skeletal, renal and reproductive toxicity of Cd was obtained in the ChinaCad project. There was a decrease in Bone Mineral Density (BMD), an increased prevalence of fractures and an increased urinary content of marker proteins of renal dysfunction among persons with long term exposure to Cd. The development of such biomarkers can be seen as a result of applied 'proteomics' research. Variation in metallothionein gene expression was related to development of renal dysfunction, supporting the usefulness of this 'genomic' approach. The ongoing rapid development of 'genomics' and 'proteomics' technologies will improve possibilities for molecular epidemiology studies in the future, providing an even better basis for preventive action. In many countries, Cd exposures are now under better control than in the past. The target for the 21st century is to achieve a totally acceptable exposure situation without adverse health effects from Cd.

Animals↗