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PubMed1999

Signaling pathways activated by interferons.

Interferons are pleiotropic cytokines that exhibit negative regulatory effects on the growth of normal and malignant hematopoietic cells in vitro and in vivo. There are two different classes of interferons, Type I (alpha, beta, and omega) and Type II (gamma) interferons. Although the precise mechanisms by which these cytokines exhibit their potent effects on hematopoiesis remain unknown, there has been considerable progress in our understanding of the cellular changes that occur upon engagement of interferon receptors. It is now well established that Type I interferons activate multiple signaling pathways in hematopoietic cells, a finding consistent with their pleiotropic biological effects. One major pathway in Type I IFN signaling involves activation of Stat- proteins and formation of complexes that translocate to the nucleus and bind to specific elements to regulate gene transcription. The activation of this pathway (Jak-Stat pathway) is apparently regulated by members of the Jak-family of kinases, which are constitutively associated with the Type I IFN receptor. In addition to the Jak-Stat pathway, multiple other Jak-kinase-dependent signaling cascades are activated, including the IRS-PI 3'-kinase pathway, a pathway involving the vav proto-oncogene product, and a pathway involving adaptor proteins of the Crk-family (CrkL and CrkII). The only Type II interferon, IFNgamma, also activates multiple Jak-kinase-dependent signaling cascades, including the Stat and Crk pathways. Recent evidence suggests that non-Stat pathways play a critical role in the generation of signals for both Type I and Type II interferons and may be the primary mediators of their growth inhibitory effects on hematopoietic cells.

Animals↗
PubMed2004

Closed-loop learning control of bio-networks.

A general goal of systems biology is to acquire a detailed quantitative understanding of the life-sustaining interactions between genes and proteins. There arises an interesting question of whether these network dynamics can be controlled externally. In the open-loop approach to experimental biology, a control design would be chosen based on a desired target response and modeling with all the available knowledge about the system. If the system is not completely understood or disturbances occur, then unexpected deviations from the desired response can arise. A means to circumvent this difficulty is to optimize the controls in a closed-loop operation by modifying successive input controls based on the performance of previous controls. This paper presents a simulation of closed-loop learning control applied to biological systems in order to generate a desired response. The most powerful advantage of this technique is that the controls are deduced based on experimental results and the process can operate without a model for the underlying biochemical network. This feature eliminates the problem of faulty predictions as well as the need for a detailed understanding of the underlying molecular pathways, suggesting that biological systems can be controlled even before the post-systems biology era.

Artificial Intelligence↗
PubMed2025

Psychological Resilience and Mental Wellbeing Mitigate the Risk of Irritable Bowel Syndrome.

INTRODUCTION: Comorbidities between mental disorders and irritable bowel syndrome (IBS) have been widely reported, yet associations between mental wellbeing and IBS, particularly regarding underlying genetic modification and proteomic signatures, remain underexplored. METHODS: This prospective cohort study analyzed 75,842 IBS-free participants aiming to investigate the prospective association between mental wellbeing and the risk of IBS in UK Biobank. Mental wellbeing was assessed through life satisfaction, positive affect, neuroticism, and depressive/anxiety symptoms. Cox models evaluate the hazard ratio (HR) for mental wellbeing and plasma proteome in relation to incident IBS during follow-up. Proteomic profiling identified mental wellbeing-associated proteins, with pathway enrichment analysis revealing biological mechanisms. Mediation and Mendelian randomization analyses further examine intermediate pathways and causality. RESULTS: With a 12.4-year follow-up period, 1,400 cases of incident IBS were documented. Better mental wellbeing mitigated IBS risk dose-dependently (low risk group: HR, 0.37; 95% confidence interval [CI]: 0.31-0.43). Higher life satisfaction (HR, 0.41; 95% CI: 0.30-0.56) and positive affect (HR, 0.50; 95% CI: 0.41-0.62) were inversely associated with IBS risk, whereas neuroticism (HR, 2.35; 95% CI: 1.92-2.88) and depressive/anxiety symptoms (HR, 3.09; 95% CI: 2.17-4.42) increased the risk. Findings remained consistent in across prevalent IBS and IBS subtypes. Mental wellbeing effects were independent of genetic predisposition. Mediation analyses revealed about 27% of protective effect of mental wellbeing were mediated through reduced depression and anxiety. Mendelian randomization supports causal protective effects of positive mental wellbeing on IBS. Proteomic profiling identified mental wellbeing-associated proteins mainly enriched in cytokine-cytokine receptor interactions. Chromogranin A and gastrin emerged as key protein biomarkers, showing significant associations with both mental wellbeing components and IBS risk. DISCUSSION: Our study demonstrates that enhanced mental wellbeing confers substantial protection against IBS development, highlighting psychological interventions as potential primary prevention strategies.

Humans↗
PubMed1982

The mucopolysaccharidoses: a synergism between clinical and basic investigation.

The mucopolysaccharidoses are a family of genetic diseases involving faulty degradation of one or more type of mucopolysaccharide or glycosaminoglycan. These conditions are characterized by skeletal, connective tissue, and intellectual manifestations. Biochemical investigations over the past 10-20 yr have enhanced our understanding of the clinical conditions and advanced our knowledge of catabolic pathways for complex biological structures. Identification of stored and excreted materials as partially degraded glycosaminoglycans allowed classification of these conditions on clinical and chemical criteria. The development of a cell culture model for studying the mucopolysaccharidoses lead to the identification of a variety of lysosomal sulfatases and glycosidases as deficient enzymes. This stimulated the identification of several new conditions. Knowledge of primary biochemical defects improved genetic services by providing accurate diagnosis, facilitating carrier identification and improving prenatal diagnosis. Glycosaminoglycan excretion patterns associated with individual enzyme defects suggested sequential degradative pathways for GAGs and related macromolecules. Attempts at enzyme replacement revealed a complex system of recognition markers and membrane receptors for the uptake of extracellular proteins. Multiple enzyme deficiencies are providing information on lysosomal enzyme synthesis and processing. The mucopolysaccharide storage diseases offer an excellent example of a productive synergism between basic biology and clinical medicine.

Chemical Phenomena↗
PubMed2004

C-kit expression and mutational analysis in medulloblastoma.

The proto-oncogene c-kit is a receptor tyrosine kinase recognized to initiate essential signal transduction pathways that transmit biological signals for cellular proliferation, differentiation, and metastasis. Aberrant expression or mutation of c-kit has been shown to be involved in the pathogenesis of many cancers. Studies using imatinib mesylate (STI 571, Gleevec, Novartis, East Hannover, NJ, USA), an inhibitor of the tyrosine kinases brc-abl, c-kit, and PDGFR, have shown significant response in patients with chronic myelogenous leukemia and gastrointestinal stromal tumor. With the aim of identifying additional groups of tumors that may use the stem cell factor/c-kit pathway and, secondarily, may be responsive to imatinib mesylate treatment, we looked at the expression of c-kit in medulloblastoma. Medulloblastoma, a highly invasive primitive neuroectodermal tumor of the cerebellum, is the most common, malignant central nervous system tumor of childhood. Histologic features of medulloblastoma have failed to provide an accurate prediction of the clinical-biological behavior of these tumors. Characterizing the genetic events that play a role in the biology of these tumors may allow for molecular sub-typing and could lead to the development of novel therapeutic strategies. This study evaluated c-kit expression and mutational status in 10 medulloblastoma tumor samples. All 10 medulloblastoma tumors expressed c-kit by reverse transcriptase-polymerase chain reaction and 9 by immunohistochemical analysis. All tumor samples were screened for mutations in exons 9, 11, and 13 of the c-kit gene by direct sequencing. No sequence abnormalities were detected in these exons. These experiments lead us to the conclusion that c-kit activation in medulloblastoma is independent of mutation.

Adolescent↗
PubMed2003

Methods for the study of protein-protein interactions in cancer cell biology.

Development of sensitive methods to monitor and quantitatively assess the expression levels of endogenous genes and the association-interaction of proteins in living cells and whole organisms is a complex and challenging problem. In this chapter, we have described basic methods for investigating protein-protein interactions which include immunoprecipitation, GST pull-down assays, peptide bead pull-down assays, chemical crosslinking and photoaffinity labeling. These methods should provide important tools to dissect crosstalk between proteins and the direct implications of this crosstalk in signaling pathways and cancer biology.

Cell Membrane↗
PubMed2006

Vascular endothelial growth factor receptors: molecular mechanisms of activation and therapeutic potentials.

Angiogenesis-associated eye diseases are among the most common cause of blindness in the United States and worldwide. Recent advances in the development of angiogenesis-based therapies for treatment of angiogenesis-associated diseases have provided new hope in a wide variety of human diseases ranging from eye diseases to cancer. One group of growth factor receptors critically implicated in angiogenesis is vascular endothelial growth factor receptors (VEGFR), a subfamily of receptor tyrosine kinases (RTKs). VEGFR-1 and VEGFR-2 are closely related receptor tyrosine kinases and have both common and specific ligands. VEGFR-1 is a kinase-impaired RTK and its kinase activity is suppressed by a single amino acid substitution in its kinase domain and by its carboxyl terminus. VEGFR-2 is highly active kinase, stimulates a variety of signaling pathways and broad biological responses in endothelial cells. The mechanisms that govern VEGFR-2 activation, its ability to recruit signaling proteins and to undergo downregulation are highly regulated by phosphorylation activation loop tyrosines and its carboxyl terminus. Despite their differential potentials to undergo tyrosine phosphorylation and kinase activation, both VEGFR-1 and VEGFR-2 are required for normal embryonic development and pathological angiogenesis. VEGFR-1 regulates angiogenesis by mechanisms that involve ligand trapping, receptor homodimerization and heterodimerization. This review highlights recent insights into the mechanism of activation of VEGFR-1 and VEGFR-2, and focuses on the signaling pathways employed by VEGFR-1 and VEGFR-2 that regulate angiogenesis and their therapeutic potentials in angiogenesis-associated diseases.

Animals↗
PubMed2000

Ectopic expression of Rsu-1 results in elevation of p21CIP and inhibits anchorage-independent growth of MCF7 breast cancer cells.

Signal transduction from tyrosine kinase receptors mediates growth regulation of breast cancer cells in part through the GTPase Ras and downstream kinases. Rsu-1 is a cDNA previously identified as an inhibitor of Ras-induced transformation. An HA-epitope tagged Rsu-1 cDNA was introduced into the MCF7 breast carcinoma cell line. Stable transfectants were selected and used for analysis of Rsu-1 expression on growth control and Ras-dependent kinase pathways. Assessment of biological activity of HA-Rsu-1 transfectants revealed that HA-Rsu-1 clones showed slower anchorage dependent growth rates than control MCF7 cell lines and a significant reduction in anchorage independent growth. Analysis of cell cycle regulatory proteins required for transit through G1 revealed that HA-Rsu-1 transfectant cell lines expressed elevated levels of p21CIP CDK inhibitor. Perturbations in signal transduction pathways which can be activated by Ras were detected in the Ha-Rsu-1 transfectants. Exposure of serum-starved cells to EGF revealed that expression of HA-Rsu-1 increased ERK-2 kinase activation, decreased activation of Jun kinase and inhibited Rho-dependent Rho-alpha kinase (ROK) activity compared to control cells. While serum starvation reduced AKT activity to undetectable levels in HA-Rsu-1 transfectants but not in control MCF7 cells, activation of AKT kinase by serum was unaffected by HA-Rsu-1 expression. Finally, the level of c-myc transcription in HA-Rsu-1 transfectants reached only 60% of the MCF7 control cell line following serum stimulation of starved cells while Fos RNA levels were similar to control cells. These results demonstrate that increased Rsu-1 expression critically altered cell cycle regulation and growth of MCF7 cells as well as signaling pathways in MCF7 cells required for malignant growth.

Blotting, Northern↗
PubMed1986

Interpretation of biological ion channel flux data--reaction-rate versus continuum theory.

Although the reaction-rate theory may provide a useful mathematical description of the channel flux, it presents a misleading physical picture of the channel structure. There is a tendency to regard the barriers in the model as actual physical structures, whereas they are actually only mathematical artifacts that allow one to reduce a complicated differential equation with an infinite number of states to a finite difference equation with a minimum number of states. I argue that the energy profile in the permeation pathway of most biological channels should vary relatively smoothly with only a few localized energy barriers or wells. In these smoothly varying regions, the resistance to ion movement is similar to bulk diffusion and cannot be accurately modeled by one or two energy barriers. For the one-ion channel, the continuum approach is as general and at least as simple as the reaction-rate theory and may provide a more physical interpretation of the data. Thus for the SR K+ channel, the structure suggested by the reaction-rate theory seems inconsistent with some experimental data, while the continuum-theory model is not only consistent with, but complements, the structure suggested by other data. Multi-ion channels have such complicated kinetics that one can only expect the theories to provide a qualitative description of the experimental data. They can be modeled by either the reaction-rate model or a finite difference approximation to the continuum model.

Animals↗
PubMed2004

PathAligner: metabolic pathway retrieval and alignment.

MOTIVATION: Analysis of metabolic pathways is a central topic in understanding the relationship between genotype and phenotype. The rapid accumulation of biological data provides the possibility of studying metabolic pathways at both the genomic and the metabolic levels. Retrieving metabolic pathways from current biological data sources, reconstructing metabolic pathways from rudimentary pathway components, and aligning metabolic pathways with each other are major tasks. Our motivation was to develop a conceptual framework and computational system that allows the retrieval of metabolic pathway information and the processing of alignments to reveal the similarities between metabolic pathways. RESULTS: PathAligner extracts metabolic information from biological databases via the Internet and builds metabolic pathways with data sources of genes, sequences, enzymes, metabolites etc. It provides an easy-to-use interface to retrieve, display and manipulate metabolic information. PathAligner also provides an alignment method to compare the similarity between metabolic pathways. AVAILABILITY: PathAligner is available at http://bibiserv.techfak.uni-bielefeld.de/pathaligner.

Algorithms↗
PubMed2005

Systems-ADME/Tox: resources and network approaches.

The increasing cost of drug development is partially due to our failure to identify undesirable compounds at an early enough stage of development. The application of higher throughput screening methods have resulted in the generation of very large datasets from cells in vitro or from in vivo experiments following the treatment with drugs or known toxins. In recent years the development of systems biology, databases and pathway software has enabled the analysis of the high-throughput data in the context of the whole cell. One of the latest technology paradigms to be applied alongside the existing in vitro and computational models for absorption, distribution, metabolism, excretion and toxicology (ADME/Tox) involves the integration of complex multidimensional datasets, termed toxicogenomics. The goal is to provide a more complete understanding of the effects a molecule might have on the entire biological system. However, due to the sheer complexity of this data it may be necessary to apply one or more different types of computational approaches that have as yet not been fully utilized in this field. The present review describes the data generated currently and introduces computational approaches as a component of ADME/Tox. These methods include network algorithms and manually curated databases of interactions that have been separately classified under systems biology methods. The integration of these disparate tools will result in systems-ADME/Tox and it is important to understand exactly what data resources and technologies are available and applicable. Examples of networks derived with important drug transporters and drug metabolizing enzymes are provided to demonstrate the network technologies.

ATP Binding Cassette Transporter 1↗
PubMed1997

Signal transduction from multiple Ras effectors.

Ras proteins activate a signaling cascade through direct binding of the serine/threonine kinase Raf. They also activate additional signaling pathways that are essential for full biological activity. Candidate effectors for these pathways include RalGDS and phosphatidyl inositol 3' kinase, as well as several other Ras binding proteins the biochemical and biological properties of which are poorly understood.

Animals↗
PubMedDate not supplied

Potential and challenges of a human cytome project.

BACKGROUND: The elucidation of the molecular pathways from the 20-40.000 genes of the sequenced human genome via investigation of genetic networks and molecular pathways up to the cellular and organismal phenotypes is highly complex and time consuming. STRATEGY AND GOALS: The proposed upside-down research strategy of a human cytome project accesses the expressed molecular cell phenotypes by differential screening, for example of diseased versus healthy, or undifferentiated versus differentiated cells to obtain information on disease or differentiation related molecular hotspots at the single cell level. The genome serves as inventory of the biomolecular capacities of organisms while the mechanisms of genome realisation are initially entirely bypassed. Detected molecular hotspots are further investigated by backward directed systems biology, including molecular pathway modelling to elucidate disease related molecular pathways. New drug targets may be identified to specifically influence such pathways. Differential screening provides, in addition, individualized disease course predictions for everyday medicine, in form of "predictive medicine by cytomics." The early recognition of future disease complications enables an immediate application of preventive therapies. This is likely to lower disease related irreversible tissue destruction and adverse drug reactions and will allow to individually optimize patient therapy. OUTLOOK: Immediate medical use, facilitated access to the detection of new drug targets, increased research speed and the stimulation for advanced technological developments represent major driving forces for the efforts to establish a human cytome project.

Cell Biology↗
PubMed1995

Molecular biology of angiotensin II biosynthesis and receptors.

In vitro data suggest that there are complex pathways of angiotensin production and that multiple receptor subtypes mediate the actions of this peptide. These observations may have important in vivo physiological and pharmacological implications. This paper reviews the current state of knowledge of angiotensin II (Ang II) biosynthetic pathways and the molecular biology of angiotensin receptors. The similarities and differences between inhibiting angiotensin-converting enzyme activity and blocking Ang II receptors with regard to their clinical application in the treatment of hypertension are discussed.

Angiotensin II↗
PubMed1990

P1 gene expression in Drosophila larval fat body: induction by various ecdysteroids.

Using the developmental mutant ecd1, the biological activity of 20-hydroxyecdysone (20E) and 20E metabolites 3-dehydro-20-hydroxyecdysone (3D20E), 3-epi-20-hydroxyecdysone (3D20E), 3-epi-20-hydroxyecdysone-3-phosphate (20E'3P), 20,26-dihydroxyecdysone (20,26E), and 20-hydroxyecdysonoic acid (20Eoic) was tested for their ability to induce the transcription of the steroid-inducible gene P1 in the Drosophila larval fat body. 3D20E was the most efficient ecdysteroid in the initiation of P1 gene transcription therefore the formation of 3D20E and the 3-epimer could not be regarded as an inactivation pathway in Drosophila larvae. Formation of 20,26E and 20Eoic may be an inactivation pathway in this biological model.

Adipose Tissue↗
PubMed2002

Cyclooxygenase, lipoxygenase and tumor angiogenesis.

Arachidonic acid metabolism through cyclooxygenase (COX) and lipoxygenase (LOX) pathways generates various biologically active lipids that play important roles in inflammation, thrombosis and tumor progression. Angiogenesis, the formation of new capillary vessels from preexisting ones, underpins a number of physiological processes and participates in the development of several pathological conditions such as arthritis, cancer and various eye diseases. The formation of new capillary vessels is a multistep process that involves endothelial cell proliferation, migration and tube formation. In the present review, we survey the literature on the regulation of angiogenesis by arachidonate metabolites, especially those from the COX and 12-LOX pathways in the context of tumor growth, and put forward some unanswered but important questions for future studies.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1990

Genetic and mutational analysis of the T-cell antigen receptor.

The studies reviewed here exploit the fact that the TCR is a multisubunit complex whose perturbation initiates an assortment of biochemical pathways and diverse biological responses. The creation and analysis of T cells bearing aberrant TCRs has led to a number of important conclusions and provided a framework for some educated speculation about T-cell biology. The assembly of the TCR is a highly regulated process in which the majority of the synthesized material is rapidly degraded. Partial complexes, which potentially might interfere with ligand binding by, or the function of, complete receptor molecules, are not tolerated; this "architectural editing" is performed in a compartment(s) associated with the ER or, in some cases, lysosomes. The individual chains of the TCR can be separated into subgroups that are, perhaps, functionally autonomous. The disulfide-linked variable chains bind ligand. The zeta eta heterodimer appears to be largely responsible for coupling receptor occupancy to PI hydrolysis, the zeta 2 heterodimer may couple to tyrosine kinase activation and/or other signaling pathways. The zeta 2-containing receptors are fully capable of transducing signals leading to IL-2 production and growth inhibition, while the presence of the zeta eta heterodimer is associated with the autolytic response of T-cell hybridomas to activation. Finally, an intact and functional TCR must be present for optimal expression of some, although not all, manifestations of activation that are initiated via independent cell-surface molecules such as Thy-1, Ly-6, and CD2. Future experiments in which TCR chains that incorporate site-directed mutations are transfected into T and non-T cells are certain to enhance our appreciation of how the structure of this receptor determines its many biological attributes.

Animals↗
PubMed2005

Secretoneurin: a new player in angiogenesis and chemotaxis linking nerves, blood vessels and the immune system.

Secretoneurin (SN) represents a 33 amino acid neuropeptide, which is highly conserved between mammals, reptiles, birds, amphibians and fish. It is specifically expressed in endocrine, neuroendocrine and neuronal tissues. In brain, the pattern of SN expression is widespread and unique, partially overlapping with established neurotransmitters. ProSN, the precursor protein, also named secretogranin II, belongs to a class of proteins collectively called chromogranins. Changes in ProSN mRNA, which is significantly regulated by cell depolarisation, represent a useful marker for both rapid and long-lasting changes (positive and negative) of neuronal activity. Under pathophysiological conditions, especially following cellular hypoxia, SN expression can be induced in non-endocrine tissues like muscle cells, pneumocytes or tumor epithelial cells. Several biological effects were attributed to SN. SN releases dopamine from rat striatal slices in a dose dependent manner and influences neurite outgrowth in the developing cerebellum. It potently and specifically attracts monocytes, eosinophils and endothelial cells towards a concentration gradient and acts as an angiogenic cytokine comparable in potency to VEGF. Thus, SN contributes to neurogenic inflammation and might play a role in the (hypoxia-driven) induction of neo-vascularisation in ischemic diseases like peripheral or coronary artery disease, diabetic retinopathia, cerebral ischemia or in solid tumors. The signalling pathways of various biological effects have not been identified in detail, but most data point to a G-protein coupled receptor structure with respective associated intracellular events.

Animals↗