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Perfluorooctane sulfonate (PFOS) is a ubiquitous pollutant in global aquatic ecosystems with increasing concern for its toxicity to aquatic wildlife through inadvertent exposures. To assess the likely adverse effects of PFOS exposure on aquatic wildlife inhabiting polluted ecosystems, there is a need to identify biomarkers of its exposure and toxicity. We used an integrated systems toxicological framework to identify physiologically relevant biomarkers of PFOS toxicity in fish. An in silico stoichiometric metabolism model of zebrafish (Danio rerio) was used to integrate available (published by other authors) metabolomics and transcriptomics datasets from in vivo toxicological studies with 5 days post fertilized embryo-larval life stage of zebrafish. The experimentally derived omics datasets were used as constraints to parameterize an in silico mathematical model of zebrafish metabolism. In silico simulations using flux balance analysis (FBA) and its extensions showed prominent effects of PFOS exposure on the carnitine shuttle and fatty acid oxidation. Further analysis of metabolites comprising the impacted metabolic reactions indicated carnitine to be the most highly represented cofactor metabolite. Flux simulations also showed a near dose-responsive increase in the pools for fatty acids and acyl-CoAs under PFOS exposure. Taken together, our integrative in silico results showed dyslipidemia effects under PFOS exposure and uniquely identified carnitine as a candidate metabolite biomarker. The verification of this prediction was sought in a subsequent in vivo environmental monitoring study by the authors which showed carnitine to be a modal biomarker of PFOS exposure in wild-caught fish and marine mammals sampled from the northern Gulf of Mexico. Therefore, we highlight the efficacy of FBA to study the properties of large-scale metabolic networks and to identify biomarkers of pollutant exposure in aquatic wildlife. [ABSTRACT FROM AUTHOR]

The human nose harbors various microbes that decisively influence the wellbeing and health of their host. Among the most threatening pathogens in this habitat is Staphylococcus aureus. Multiple epidemiological studies identify Dolosigranulum pigrum as a likely beneficial bacterium based on its positive association with health, including negative associations with S. aureus. Carefully curated GEMs are available for both bacterial species that reliably simulate their growth behavior in isolation. To unravel the mutual effects among bacteria, building community models for simulating co-culture growth is necessary. However, modeling microbial communities remains challenging. This article illustrates how applying the NCMW fosters our understanding of two microbes' joint growth conditions in the nasal habitat and their intricate interplay from a metabolic modeling perspective. The resulting community model combines the latest available curated GEMs of D. pigrum and S. aureus. This uses case illustrates how to incorporate genuine GEM of participating microorganisms and creates a basic community model mimicking the human nasal environment. Our analysis supports the role of negative microbe-microbe interactions involving D. pigrum examined experimentally in the lab. By this, we identify and characterize metabolic exchange factors involved in a specific interaction between D. pigrum and S. aureus as an in silico candidate factor for a deep insight into the associated species. This method may serve as a blueprint for developing more complex microbial interaction models. Its direct application suggests new ways to prevent disease-causing infections by inhibiting the growth of pathogens such as S. aureus through microbe-microbe interactions. [ABSTRACT FROM AUTHOR]

The influence of metabolism on signaling, epigenetic markers, and transcription is highly complex yet important for understanding cancer physiology. Despite the development of high-resolution multi-omics technologies, it is difficult to infer metabolic activity from these indirect measurements. Fortunately, genome-scale metabolic models and constraint-based modeling provide a systems biology framework to investigate the metabolic states and define the genotype-phenotype associations by integrations of multi-omics data. Constraint-Based Reconstruction and Analysis (COBRA) methods are used to build and simulate metabolic networks using mathematical representations of biochemical reactions, gene-protein reaction associations, and physiological and biochemical constraints. These methods have led to advancements in metabolic reconstruction, network analysis, perturbation studies as well as prediction of metabolic state. Most computational tools for performing these analyses are written for MATLAB, a proprietary software. In order to increase accessibility and handle more complex datasets and models, community efforts have started to develop similar open-source tools in Python. To date there is a comprehensive set of tools in Python to perform various flux analyses and visualizations; however, there are still missing algorithms in some key areas. This review summarizes the availability of Python software for several components of COBRA methods and their applications in cancer metabolism. These tools are evolving rapidly and should offer a readily accessible, versatile way to model the intricacies of cancer metabolism for identifying cancer-specific metabolic features that constitute potential drug targets. [ABSTRACT FROM AUTHOR]

Genome-scale metabolic network models are of great Importance In systems biology research, as they are used in metabolic activity dynamics studies and provide the metabolic level representation in multi-omic investigations. Especially for human, accurate metabolic network reconstruction is important in biomedical research and drug discovery. Today, there exist many instances of the human metabolic network as a whole and in its tissue-specific versions. Some are improved updates of models reconstructed from the same research team, while others are combinations of models from various teams, in an effort to include all available information from genome annotation and omic datasets. A major challenge regarding the human stoichiometric models in particular is the standardization of the reconstruction methods, representation formats and model repositories. Stoichiometric model standardization will enable the educated selection of the model that better fits the goals of a study, the direct comparison of results from various flux analysis studies and the identification of model sections that require reconsideration and updating with respect to the annotation of the human genome and proteome. Standardized human metabolic models aligned to the human genome will be a very useful tool in multi-omic studies, enabling the direct and consistent integration of the metabolic with the gene regulation and protein interaction networks. In this work, we provide a thorough overview of the current collection of human metabolic stoichiometric models, describe the current issues regarding their direct comparison and alignment in the context of the various model repositories, exposing the standardization needs, and propose potential solutions. [ABSTRACT FROM AUTHOR]

Astrocytes play an important role in various processes in the brain, including pathological conditions such as neurodegenerative diseases. Recent studies have shown that the increase in saturated fatty acids such as palmitic acid (PA) triggers pro-inflammatory pathways in the brain. The use of synthetic neurosteroids such as tibolone has demonstrated neuro-protective mechanisms. However, broad studies, with a systemic point of view on the neurodegenerative role of PA and the neuro-protective mechanisms of tibolone are lacking. In this study, we performed the integration of multi-omic data (transcriptome and proteome) into a human astrocyte genomic scale metabolic model to study the astrocytic response during palmitate treatment. We evaluated metabolic fluxes in three scenarios (healthy, induced inflammation by PA, and tibolone treatment under PA inflammation). We also applied a control theory approach to identify those reactions that exert more control in the astrocytic system. Our results suggest that PA generates a modulation of central and secondary metabolism, showing a switch in energy source use through inhibition of folate cycle and fatty acid ß-oxidation and upregulation of ketone bodies formation. We found 25 metabolic switches under PA-mediated cellular regulation, 9 of which were critical only in the inflammatory scenario but not in the protective tibolone one. Within these reactions, inhibitory, total, and directional coupling profiles were key findings, playing a fundamental role in the (de)regulation in metabolic pathways that may increase neurotoxicity and represent potential treatment targets. Finally, the overall framework of our approach facilitates the understanding of complex metabolic regulation, and it can be used for in silico exploration of the mechanisms of astrocytic cell regulation, directing a more complex future experimental work in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Metabolism is the set of biochemical reactions of an organism that enables it to assimilate nutrients from its environment and to generate building blocks for growth and proliferation. It forms a complex network that is intertwined with the many molecular and cellular processes that take place within cells. Systems biology aims to capture the complexity of cells, organisms, or communities by reconstructing models based on information gathered by high-throughput analyses (omics data) and prior knowledge. One type of model is a genome-scale metabolic model (GEM) that allows studying the distributions of metabolic fluxes, i.e., the "mass-flow" through the network of biochemical reactions. GEMs are nowadays widely applied and have been reconstructed for various microbial pathogens, either in a free-living state or in interaction with their hosts, with the aim to gain insight into mechanisms of pathogenicity. In this review, we first introduce the principles of systems biology and GEMs. We then describe how metabolic modeling can contribute to unraveling microbial pathogenesis and host–pathogen interactions, with a specific focus on oomycete plant pathogens and in particular Phytophthora infestans. Subsequently, we review achievements obtained so far and identify and discuss potential pitfalls of current models. Finally, we propose a workflow for reconstructing high-quality GEMs and elaborate on the resources needed to advance a system biology approach aimed at untangling the intimate interactions between plants and pathogens. [ABSTRACT FROM AUTHOR]

The growing importance of astrocytes in the field of neuroscience has led to a greater number of computational models devoted to the study of astrocytic functions and their metabolic interactions with neurons. The modeling of these interactions demands a combined understanding of brain physiology and the development of computational frameworks based on genomic-scale reconstructions, system biology, and dynamic models. These computational approaches have helped to highlight the neuroprotective mechanisms triggered by astrocytes and other glial cells, both under normal conditions and during neurodegenerative processes. In the present review, we evaluate some of the most relevant models of astrocyte metabolism, including genome-scale reconstructions and astrocyte-neuron interactions developed in the last few years. Additionally, we discuss novel strategies from the multi-omics perspective and computational models of other glial cell types that will increase our knowledge in brain metabolism and its association with neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Genome-scale metabolic models (GEMs) have become a popular tool for systems biology, and they have been used in many fields such as industrial biotechnology and systems medicine. Since more and more studies are being conducted using GEMs, they have recently received considerable attention. In this review, we introduce the basic concept of GEMs and provide an overview of their applications in biotechnology, systems medicine, and some other fields. In addition, we describe the general principle of the applications and analyses built on GEMs. The purpose of this review is to introduce the application of GEMs in biological analysis and to promote its wider use by biologists. [ABSTRACT FROM AUTHOR]