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PubMed2005

Synthetic modular systems--reverse engineering of signal transduction.

During the last decades, biology has decomposed cellular systems into genetic, functional and molecular networks. It has become evident that these networks consist of components with specific functions (e.g., proteins and genes). This has generated a considerable amount of knowledge and hypotheses concerning cellular organization. The idea discussed here is to test the extent of this knowledge by reconstructing, or reverse engineering, new synthetic biological systems from known components. We will discuss how integration of computational methods with proteomics and engineering concepts might lead us to a deeper and more abstract understanding of signal transduction systems. Designing and successfully introducing synthetic proteins into cellular pathways would provide us with a powerful research tool with many applications, such as development of biosensors, protein drugs and rewiring of biological pathways.

Animals↗

PubMed2026

Research on identification of key genes and immune-metabolic mechanisms in atrial fibrillation through integrated multi-cohort transcriptomic analysis and machine learning.

This study aimed to integrate multiple datasets for the identification of atrial fibrillation (AF)-related differentially expressed genes (DEGs), analyze their underlying mechanisms through functional enrichment and machine learning, construct diagnostic models, and explore immune-metabolic interactions to provide novel biomarkers and theoretical foundations. Gene expression datasets were integrated and normalized, with batch effects removed using principal component analysis. Differential expression analysis, functional enrichment analysis (Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways), and machine learning-based feature gene selection and model construction were performed. Shapley additive explanations analysis was utilized to interpret the constructed models, while gene set enrichment analysis, gene set variation analysis, and immune cell infiltration analysis were conducted to investigate the associations between feature genes and immune infiltration. After integrating and normalizing gene expression data and eliminating batch effects via principal component analysis, 6 DEGs were identified, including 4 upregulated and 2 down-regulated ones. Functional enrichment analysis showed these DEGs were significantly enriched in neuro-related biological processes and pathways, indicating their key roles in AF pathogenesis. Five key feature genes were selected using LASSO, random forest, and support vector machine-recursive feature elimination algorithms. They had significant expression differences between the AF and control groups (P < .001) and were located on distinct chromosomes. The constructed random forest and support vector machine models performed excellently (area under the curve ≥ 0.85). Shapley additive explanations analysis revealed TNNI1 contributed most to model prediction, with its expression significantly positively correlated with immune cell infiltration. Gene set enrichment analysis and gene set variation analysis analyses further showed feature genes participated in AF pathogenesis by regulating immune modulation, metabolic pathways, and autophagy. Immune cell infiltration analysis found altered proportions of T-cell subsets and M0 macrophages in the AF group, along with complex links between feature gene expression and immune cell function. This study systematically elucidated the unique gene expression patterns and key regulatory pathways associated with AF, clarifying the crucial roles of feature genes in immune regulation, metabolic imbalance, and cellular dysfunction. These findings provide a theoretical basis and potential therapeutic targets for understanding AF pathogenesis and developing targeted treatment strategies.

Atrial Fibrillation↗

PubMed2006

Role of FLAP and PDE4D in myocardial infarction and stroke: target discovery and future treatment options.

Biomarkers such as C-reactive protein (CRP) and myeloperoxidase (MPO) are elevated in patients with coronary artery disease and confer risk of acute cardiovascular events, such as myocardial infarction (MI) and stroke. More recently, variants in the 5-lipoxygenase-activating protein (FLAP) gene were shown to confer risk to both MI and stroke, effects that appear to be mediated through elevated LTB(4), a chemoattractant mediator shown to be upregulated in patients with MI. Another gene in the leukotriene (LT) pathway, LTA(4) hydrolase, was subsequently found to confer increased risk to MI, effects that were ethnicity-specific with an approximately threefold higher risk in African Americans than in whites. In another study, markers in the phosphodiesterase (PDE) 4D gene were found to confer risk to large-vessel occlusive and cardiogenic stroke. Interestingly, there is a cross-link between the 5-LO and the PDE4D pathways with converging biology. To address the role of an inhibitor of FLAP on biomarkers of MI risk, a randomized placebo-controlled phase II trial was conducted in patients with MI. This trial showed that LTB(4) and MPO production was reduced in whole blood leukocytes that were stimulated with ionomycin and the effects of the inhibitor were dose dependent. Serum CRP and plasma MPO were also reduced at the highest dose, which was well tolerated. These data suggest that LTB(4) is a risk factor of MI and that inhibition of FLAP and the LT pathway produces suppression of biomarkers that are associated with MI risk, including but not limited to LTB(4), MPO, and CRP, supporting the notion that the LTB(4) arm of the LT pathway may play a fundamental role in heart attacks and stroke.

Journal Article↗

PubMed2026

Resurrection biology: Melatonin as a modulator of anastasis (Review).

Although apoptosis is regarded as an irreversible and terminal process, recent research has identified anastasis as a cellular mechanism that enables cell recovery even after the activation of executioner caspases. While important in supporting tissue homeostasis following mild or transient injury, anastasis presents significant challenges in oncology, as cancer cells may exploit this phenomenon to evade chemotherapy, subsequently acquiring aggressive traits such as genomic instability, stem‑like properties, and increased metastatic capacity. N‑acetyl‑5‑methoxytryptamine (melatonin), recognized for its antioxidant activity and role as a mitochondrial regulator, has been associated with several biological processes that overlap with pathways involved in anastasis, including mitochondrial bioenergetics, redox homeostasis, and DNA repair mechanisms. However, direct evidence supporting a role for melatonin in regulating anastasis remains limited. The present review consolidated current insights into the molecular regulation of anastasis, examining its biphasic transcriptional profile and oncogenic consequences, while exploring the mechanistic links between melatonin biology and pathways relevant to apoptotic recovery and evaluating the therapeutic prospects of melatonin in targeting anastasis as a strategy to mitigate tumor recurrence and improve clinical outcomes.

Melatonin↗

PubMed2006

Interleukin-1alpha enhances the aggressive behavior of pancreatic cancer cells by regulating the alpha6beta1-integrin and urokinase plasminogen activator receptor expression.

BACKGROUND: In human pancreatic cancer progression, the alpha6beta1-integrin is expressed on cancer cell surface during invasion and metastasis formation. In this study, we investigated whether interleukin (IL)-1alpha induces the alterations of integrin subunits and urokinase plasminogen activator/urokinase plasminogen activator receptor (uPA/uPAR) expression in pancreatic cancer cells. We hypothesize that the alterations of integrin subunits and uPA/uPAR expression make an important role in signaling pathways responsible for biological behavior of pancreatic cancer cells. RESULTS: IL-1alpha upregulated the expression of alpha6 and beta1 integrins without any alterations of alpha5 and alphav integrins expression. IL-1alpha also induced enhancement in the expression of uPA/uPAR in pancreatic cancer cells. IL-1alpha enhanced the proliferation, adhesion, and migration in pancreatic cancer cells, and IL-1alpha-induced alterations of uPA/uPAR expression correlated with the increased the migration of pancreatic cancer cells. Upregulation of alpha6 integrin subunit and uPA/uPAR correlated with the activation of Ras and downstream extracellular signal-regulated kinase (ERK) pathways. IL-1alpha-induced activation of Ras and downstream ERK can be inhibited by using inhibitory antibodies against alpha6 and beta1 integrin and uPAR, consistent with the inhibition of proliferation, adhesion and migration of pancreatic cancer cells. Immunohistochemical analysis demonstrated a significant association between strong expressions of alpha6 integrin with uPAR in pancreatic cancer specimens. Furthermore, the strong expression of alpha6 integrin and uPAR was found to be independent prognosticator in pancreatic cancer patients. CONCLUSION: Based on these findings, we conclude that IL-1alpha can induce selective upregulation of alpha6beta1-integrin and uPA/uPAR in pancreatic cancer cells and these changes may modulate the aggressive functions of pancreatic cancer.

Aged↗

PubMed1999

Reconstitution of protein transport across the vacuolar membrane in Plasmodium falciparum-infected permeabilized erythrocytes.

The parasite Plasmodium falciparum induces morphological and biochemical alterations of its host erythrocyte. Some of these changes are mediated by parasite proteins that are transported to specific destinations within the erythrocyte or to the erythrocyte plasma membrane. The pathways underlying this transport are still unknown. We anticipate that at least some aspects of these pathways may be biologically unique and therefore potential targets for chemotherapeutic intervention. We have utilized bacterial pore-forming proteins to establish an experimental system that allows selective permeabilization of the erythrocyte plasma membrane, without affecting the integrity of the vacuolar membrane and the parasite plasma membrane, in order to study protein transport from the parasite into the host erythrocyte. Physiological properties of the parasite within permeabilized erythrocytes, such as the ability to synthesize proteins, will be described. The permeabilization of infected erythrocytes has allowed the dissection of individual steps in protein transport from the parasite surface across the vacuolar membrane. Possible pathways involved in the trafficking of parasite proteins within the erythrocyte cytosol, i.e. in a cell that normally has no need to transport proteins, will be discussed.

Animals↗

PubMedDate not supplied

Prognostic and biological role of neurotrophin-receptor TrkA and TrkB in neuroblastoma.

Expression of different neurotrophin receptors of the tyrosine kinase (Trk) family plays an important role in the biology and clinical behavior of neuroblastomas (NB). Observations from several independent studies suggest that high expression of TrkA is present in NB with favorable biological features and highly correlated with patient survival, whereas TrkB is mainly expressed on unfavorable, aggressive NB with MYCN-amplification. To determine expression of Trk receptors and ligands in primary NB, we developed a reliable semiquantitative duplex RT-PCR protocol, that requires only 1 microgram RNA per tumor sample. Activation of TrkA by its ligand nerve growth factor (NGF) initiates a cascade of signaling events and promotes neuronal differentiation in vitro. Activation of TrkB by its ligand brain derived neurotrophic factor (BDNF) has been associated with proliferation and survival of NB cells. To study Trk signal transduction pathways and their biological effects in NB, we stably expressed TrkA and TrkB cDNA in the human NB cell line SH-SY5Y. Introduction of TrkA and TrkB restored responsiveness of SH-SY5Y cells to the ligands NGF and BDNF, respectively, and resulted in morphological differentiation. Expression of TrkA resulted in growth inhibition of the transfectants compared to parental cells, whereas TrkB transfectants demonstrated an increased proliferation rate. Further insight into the differences of TrkA and TrkB signaling may suggest new options for the treatment of NB. As expression of TrkA is a strong prognostic factor especially in MYCN non-amplified NB, a prospective study of Trk receptor expression using RT-PCR should be performed for German neuroblastoma patients.

Biomarkers, Tumor↗

PubMed2005

Temporal properties in masking biological motion.

The perception of biological motion using point light animation techniques was investigated in several experiments. Animations simulating walking were presented with additional masking dots. The temporal properties of the walking motion or the temporal relationship between the walking and masking motions were systematically manipulated. Results showed that (1) perception of biological motion was sensitive to even small temporal perturbation within the walker, (2) the effectiveness of a mask depended upon the temporal phase difference between the mask and point light walker, (3) relatively small temporal differences between the mask and point light walker decreased the effectiveness of the mask, and (4) these effects were not due simply to observers detecting the phase offsets in the display. Temporal properties of the motion are important in perceiving the human form in action, just as in other types of figure-ground segregation. This information may be processed by both motion and form pathways for processing biological motion.

Humans↗

PubMed2001

Kinetic modelling approaches to in vivo imaging.

The ability to visualize protein dynamics and biological processes by in vivo microscopy is revolutionizing many areas of biology. These methods generate large, kinetically complex data sets, which often cannot be intuitively interpreted. The combination of dynamic imaging and computational modelling is emerging as a powerful tool for the quantitation of biophysical properties of molecules and processes. The new discipline of computational cell biology will be essential in uncovering the pathways, mechanisms and controls of biological processes and systems as they occur in vivo.

Animals↗

PubMed1994

Alternative processing pathways for MHC class I-restricted epitope presentation to CD8+ cytotoxic T lymphocytes.

CD8+ cytotoxic T lymphocytes (CTL) mediate protective immunity against many intracellular pathogens. New generation vaccines that exploit the potential of recombinant protein technology have to meet the challenge to identify immunodominant antigen systems of the pathogen of interest, to produce these antigens in recombinant form, and to find ways to selectively deliver them to the compartments of the specific immune system that mediate the protective responses. Immunization with soluble protein antigens usually primers CD4+ T cells but not CD8+ T cells because of the stringent requirements for 'endogenous processing' for major histocompatibility complex (MHC) class I-restricted epitope presentation to CD8+ CTL. This rule is not absolute because priming of class I-restricted CTL by soluble, recombinant viral protein antigens injected without adjuvants has been reported in various antigen systems. An understanding of the cell biology of alternative pathways of protein antigen processing for MHC class I-restricted epitope presentation is emerging. We describe subcellular sites, alternative peptide transport mechanisms, and alternative modes of MHC class I molecule recycling that allow different modes of peptide loading of class I molecules. Experimental evidence for some of these novel pathways of 'endogenous' processing for class I-restricted epitope presentation is discussed. Some pathways are still hypothetical. The issue of alternative modes of 'endogenous' processing for class I-restricted antigen presentation is of theoretical and practical relevance. Immunologists are interested in the question from which source protein antigens are derived that are potentially accessible to specific recognition by different T cell subsets.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2002

JAK/STAT signaling pathways and cancer. Janus kinases/signal transducers and activators of transcription.

Recent highlights in understanding molecular nature of signaling pathways that mediate biological effects of various external stimuli and control number of normal physiological processes of cells such as growth, differentiation, senescence and apoptosis, defined three major groups of proteins which apparently play an essential role in transmitting external signals from surface membrane to target genes in the nucleus. These include Janus kinases (JAKs), signal transducers and activators of transcription (STATs) and their endogenous inhibitors of SOCS family. Their inappropriate functioning and defective cross-talking associate with several human disorders including cancer. There is an increasing evidence that perturbances in STAT proteins are involved in the pathogenesis of some human malignancies. Moreover, cancer-related defective JAK/STAT/SOCS pathways may negatively affect tumor response to the cytokine-based immunotherapy. This article provides an overview of the current knowledge about JAK/STAT/SOCS intracellular signaling cascades with special emphasis on their abnormalities in cancer.

Carrier Proteins↗

PubMed1992

Further aspects of IL-1 beta secretion revealed by transfected monkey kidney cells.

Because the cytokine interleukin-1 beta (IL-1 beta) lacks a classical hydrophobic signal sequence, it has been unclear how it is released from cells, and whether release proceeds via a novel mechanism or through non-specific leakage. To address this issue, we have examined the secretion of the recombinant forms of human IL-1 beta from COS monkey kidney cells, which express low levels of endogenous IL-1 beta. Four proteins were expressed: precursor and mature IL-1 beta and precursor and mature IL-1 beta fused to an amino terminal hydrophobic signal sequence from human tissue plasminogen activator. By monitoring the appearance of a known cytosolic protein (ATP citrate lyase) in the medium, we find that the unmodified IL-1 beta s are non-specifically released in very small quantities from the cytosol. On the other hand, the signal sequence-modified IL-1 beta s are glycosylated and efficiently secreted by the ER/Golgi pathway. The secreted, modified-mature protein is also biologically active, suggesting that this pathway has been bypassed for reasons other than maintaining the structural integrity of IL-1 beta. More likely the alternative pathway is a critical aspect of IL-1 biology. The differences in kinetics and quantity of IL-1 beta release from monocytic and COS cells suggest that COS cells lack critical components for the rapid release seen in monocytes.

Animals↗

PubMed2006

Bystander effect: biological endpoints and microarray analysis.

In cell populations exposed to ionizing radiation, the biological effects occur in a much larger proportion of cells than are estimated to be traversed by radiation. It has been suggested that irradiated cells are capable of providing signals to the neighboring unirradiated cells resulting in damage to these cells. This phenomenon is termed the bystander effect. The bystander effect induces persistent, long-term, transmissible changes that result in delayed death and neoplastic transformation. Because the bystander effect is relevant to carcinogenesis, it could have significant implications for risk estimation for radiation exposure. The nature of the bystander effect signal and how it impacts the unirradiated cells remains to be elucidated. Examination of the changes in gene expression could provide clues to understanding the bystander effect and could define the signaling pathways involved in sustaining damage to these cells. The microarray technology serves as a tool to gain insight into the molecular pathways leading to bystander effect. Using medium from irradiated normal human diploid lung fibroblasts as a model system we examined gene expression alterations in bystander cells. The microarray data revealed that the radiation-induced gene expression profile in irradiated cells is different from unirradiated bystander cells suggesting that the pathways leading to biological effects in the bystander cells are different from the directly irradiated cells. The genes known to be responsive to ionizing radiation were observed in irradiated cells. Several genes were upregulated in cells receiving media from irradiated cells. Surprisingly no genes were found to be downregulated in these cells. A number of genes belonging to extracellular signaling, growth factors and several receptors were identified in bystander cells. Interestingly 15 genes involved in the cell communication processes were found to be upregulated. The induction of receptors and the cell communication processes in bystander cells receiving media from irradiated cells supports the active involvement of these processes in inducing bystander effect.

Apoptosis↗

PubMed2004

Stereospecific regulation of tyrosine hydroxylase and proenkephalin genes by short-chain fatty acids in rat PC12 cells.

Circulating short-chain fatty acids (SCFAs) are primarily derived from bacterial fermentation of carbohydrates in the colon where they function as physiologic modulators of epithelial cell maturation. Butyrate has been shown to induce tyrosine hydroxylase, the rate-limiting enzyme of catecholamine synthesis, and enkephalin neuropeptide gene transcription, suggesting a role in perinatal sympathoadrenal stress-adaptation. We sought to determine whether there were SCFA structural requirements for this effect. Nine biologically relevant SCFAs and butyrate derivatives were tested in an in vitro model (PC12, rat pheochromocytoma cells) for their ability to regulate neurotransmitter-related gene expression. Our results revealed that among all the studied SCFAs, only propionate and butyrate increased tyrosine hydroxylase and proenkephalin mRNA levels. The functional activity was selective to the carbon atom chain length and associated with the presence of an ethyl moiety in the carbon atom backbone chain. Modifications or absence of this domain affected the gene induction response, suggesting a receptor-mediated mechanism(s). Moreover, propionate, butyrate, and the drug 4-phenylbutyrate were each shown to regulate transmitter genes via at least three independent mechanisms: histone hyperacetylation, cAMP signaling, or peroxisome proliferator-activated receptor gamma-mediated pathways. Thus, the biologic impact of SCFAs on catecholaminergic and opioid systems depend on the activation of SCFA-specific, dose-specific, and gene-specific molecular mechanisms. We speculate that 1) circulating levels of SCFAs may influence sympathoadrenal transmitter biosynthesis and hence whole animal stress-adaptive responsiveness after birth, and 2) the adverse effects of antibiotics on delayed acquisition of postnatal gut flora may affect this apparent evolutionary advantage of gut colonization.

Acetylation↗

PubMed2002

Draft sequencing and comparative genomics of Xylella fastidiosa strains reveal novel biological insights.

Draft sequencing is a rapid and efficient method for determining the near-complete sequence of microbial genomes. Here we report a comparative analysis of one complete and two draft genome sequences of the phytopathogenic bacterium, Xylella fastidiosa, which causes serious disease in plants, including citrus, almond, and oleander. We present highlights of an in silico analysis based on a comparison of reconstructions of core biological subsystems. Cellular pathway reconstructions have been used to identify a small number of genes, which are likely to reside within the draft genomes but are not captured in the draft assembly. These represented only a small fraction of all genes and were predominantly large and small ribosomal subunit protein components. By using this approach, some of the inherent limitations of draft sequence can be significantly reduced. Despite the incomplete nature of the draft genomes, it is possible to identify several phage-related genes, which appear to be absent from the draft genomes and not the result of insufficient sequence sampling. This region may therefore identify potential host-specific functions. Based on this first functional reconstruction of a phytopathogenic microbe, we spotlight an unusual respiration machinery as a potential target for biological control. We also predicted and developed a new defined growth medium for Xylella.

Attachment Sites, Microbiological↗

PubMed2005

Immunoglobulins can utilize riboflavin (Vitamin B2) to activate the antibody-catalyzed water oxidation pathway.

We have recently discovered a reaction that all antibodies, regardless of source or antigenic specificity can catalyze, that is the reaction between singlet dioxygen ((1)O(2)(*)) and H(2)O to generate H(2)O(2). We have named this process the antibody-catalyzed water oxidation pathway (ACWOP). As part of our ongoing investigations into the possible biological role of this pathway, we have studied whether isoalloxazine-containing cofactors, that are known to be endogenous photosensitizers via Type-II pathways to generate (1)O(2)(*), such as riboflavin (RF, Vitamin B2) can trigger the ACWOP. Herein we show that regardless of the antigenic specificity or heavy and light chain composition, all antibodies and their fragments are able to intercept the (1)O(2)(*) generated by photo-oxidation of RF in the presence of oxygen (ambient aerobic conditions) to activate the ACWOP. The initial rate of HOOH generation by a panel of murine antibodies ranges from 0.218 to 0.998 microM/min. The initial rate of antibody-catalyzed HOOH production is accelerated in D(2)O and is quenched in NaN(3), highlighting the key intermediacy of (1)O(2)(*) in the process. Critically, the ACWOP is photo-activated at physiologically relevant concentrations of RF (<50 nM) suggesting that this pathway may be relevant in an in vivo setting. Finally, when activated by RF the ACWOP generates oxidants that accelerate the hemolysis of sheep RBCs hinting at a pathophysiological effect of this RF-induced photo-oxidation pathway.

Animals↗

PubMed2003

Mitochondrial lipids as apoptosis regulators.

Mitochondria are key players in fundamental processes such as energy production and adaptive responses to cellular stress, including apoptosis. Mitochondrial membranes may undergo permeabilization when perturbed by a number of intracellular stress mediators, and consequently may allow the release of intramitochondrial proteins. This event triggers and amplifies the cellular apoptotic program, provided sufficient energy is available. Mitochondrial membranes are therefore both targets and regulators of intracellular pathways controlling cell fate. Evidence is emerging that the integration and biological outcome of these pathways might be critically dependent on the unique lipid composition of mitochondrial membranes.

Animals↗

PubMed1999

Insulin signalling: metabolic pathways and mechanisms for specificity.

Biological actions of insulin are mediated by the insulin receptor, a member of a large family of receptor tyrosine kinases (RTK). Signal transduction by the insulin receptor follows a paradigm for RTK signalling. Many intracellular signalling molecules contain multiple modular domains that mediate protein-protein interactions and participate in the formation of signalling complexes. Phosphorylation cascades are also a prominent feature of RTK signalling. Distal pathways are difficult to dissect because branching paths emerge from downstream effectors and several upstream inputs converge upon single branch points. Thus, insulin action is determined by complicated signalling networks rather than simple linear pathways. Interestingly, many signalling molecules downstream from the insulin receptor are also activated by a plethora of RTKs. Therefore, mechanisms that generate specificity are required. In this review we discuss recent advances in the elucidation of specific metabolic insulin signalling pathways related to glucose transport, one of the most distinctive biological actions of insulin. We also present examples of potential mechanisms underlying specificity in insulin signalling including interactions between multiple branching pathways, subcellular compartmentalization, tissue-specific expression of key effectors and modulation of signal frequency and amplitude.

Animals↗