Systems biology has primarily focused on studying genomics, transcriptomics, and proteomics and their dynamic interactions. These, however, represent only the potential for a biological outcome since the ultimate phenotype at the level of the eventually produced metabolites is not taken into consideration. The emerging field of metabolomics provides complementary guidance toward an integrated approach to this problem: It allows global profiling of the metabolites of a cell, tissue, or host and presents information on the actual end points of a response. A wide range of data collection methods are currently used and allow the extraction of global or tissue-specific metabolic profiles. The great amount and complexity of data that are collected require multivariate analysis techniques, but the increasing amount of work in this field has made easy-to-use analysis programs readily available. Metabolomics has already shown great potential in drug toxicity studies, disease modeling, and diagnostics and may be integrated with genomic and proteomic data in the future to provide in-depth understanding of systems, pathways, and their functionally dynamic interactions. In this review we discuss the current state of the art of metabolomics, its applications, and future potential.

IntroductionTwo recent, independent, studies conducted novel metabolomics analyses relevant to human sepsis progression; one was a human model of endotoxin (lipopolysaccharide (LPS)) challenge (experimental endotoxemia) and the other was community acquired pneumonia and sepsis outcome diagnostic study (CAPSOD). The purpose of the present study was to assess the concordance of metabolic responses to LPS and community-acquired sepsis.MethodsWe tested the hypothesis that the patterns of metabolic response elicited by endotoxin would agree with those in clinical sepsis. Alterations in the plasma metabolome of the subjects challenged with LPS were compared with those of sepsis patients who had been stratified into two groups: sepsis patients with confirmed infection and non-infected patients who exhibited systemic inflammatory response syndrome (SIRS) criteria. Common metabolites between endotoxemia and both these groups were individually identified, together with their direction of change and functional classifications.ResultsResponse to endotoxemia at the metabolome level elicited characteristics that agree well with those observed in sepsis patients despite the high degree of variability in the response of these patients. Moreover, some distinct features of SIRS have been identified. Upon stratification of sepsis patients based on 28-day survival, the direction of change in 21 of 23 metabolites was the same in endotoxemia and sepsis survival groups.ConclusionsThe observed concordance in plasma metabolomes of LPS-treated subjects and sepsis survivors strengthens the relevance of endotoxemia to clinical research as a physiological model of community-acquired sepsis, and gives valuable insights into the metabolic changes that constitute a homeostatic response. Furthermore, recapitulation of metabolic differences between sepsis non-survivors and survivors in LPS-treated subjects can enable further research on the development and assessment of rational clinical therapies to prevent sepsis mortality. Compared with earlier studies which focused exclusively on comparing transcriptional dynamics, the distinct metabolomic responses to systemic inflammation with or without confirmed infection, suggest that the metabolome is much better at differentiating these pathophysiologies. Finally, the metabolic changes in the recovering patients shift towards the LPS-induced response pattern strengthening the notion that the metabolic, as well as transcriptional responses, characteristic to the endotoxemia model represent necessary and “healthy” responses to infectious stimuli.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-0783-2) contains supplementary material, which is available to authorized users.

A randomized, double-blind, placebo-controlled, 52-week study (NCT03068468) evaluated gosuranemab, an anti-tau monoclonal antibody, for progressive supranuclear palsy (PSP). In total, 486 participants dosed were assigned to gosuranemab (n=321) or placebo (n=165).Efficacy was not demonstrated on adjusted mean change of PSP Rating Scale score at week 52 between gosuranemab and placebo (10.4 versus 10.6; P=0.85; primary endpoint) or secondary endpoints, resulting in discontinuation of the open-label long-term extension.Unbound N-terminal tau in cerebrospinal fluid decreased by 98% with gosuranemab and increased by 11% with placebo (P<0.0001). Incidences of AEs and deaths were similar between groups. This well-powered study suggests N-terminal tau neutralization does not translate to clinical efficacy.

Endotoxemia induced by the administration of low-dose lipopolysaccharide (LPS) to healthy human volunteers is a well-established experimental protocol and has served as a reproducible platform for investigating the responses to systemic inflammation. Since metabolic composition of a tissue or body fluid is uniquely altered by stimuli and provide information about the dominant regulatory mechanisms at various cellular processes, understanding the global metabolic response to systemic inflammation constitutes a major part in this investigation complementing the studies undertaken so far in both clinical and systems biology fields. This article communicates the first proof-of-principle metabonomic analysis which comprised of global biochemical profiles in human plasma samples from healthy subjects given intravenous endotoxin at 2 ng/kg. Concentrations of a total of 366 plasma biochemicals were determined in archived blood samples collected from 15 endotoxin treated subjects at 5 time points within 24 hour post-treatment and compared with control samples collected from 4 saline treated subjects. Principal component analysis within this dataset determined the 6th hour as a critical time point separating development and recovery phases of the LPS induced metabolic changes. Consensus clustering of the differential metabolites identified two distinct subsets of metabolites which displayed common coherent profiles with opposing directionality. The first group of metabolites, which were mostly associated with pathways related to lipid metabolism, was up-regulated within the first 6 hr and down-regulated by the 24th hr following LPS administration. The second group of metabolites, in contrast, was first down-regulated until the 6th hr, then up-regulated. Metabolites in this group were predominantly amino acids or their derivatives. In sum, non-targeted biochemical profiling and unsupervised multivariate analyses highlighted the prominent roles of lipid and protein metabolism in regulating the response to systemic inflammation while also revealing their dynamics in opposite directions.

Coronary arterial disease, one of the leading causes of adult mortality, is triggered by atherosclerosis. A disease with complex etiology, atherosclerosis results from the progressive long-term combination of atherogenesis, the accumulation of modified lipoproteins within blood vessel walls, along with vascular and systemic inflammatory processes. The management of atherosclerosis is challenged by the localized flare-up of several multipronged signaling interactions between activated monocytes, atherogenic macrophages and inflamed or dysfunctional endothelial cells. A new generation of approaches is now emerging founded on multifocal, targeted therapies that seek to reverse or ameliorate the athero-inflammatory cascade within the vascular intima. This article reviews the various classes and primary examples of bioactive configurations of nanoscale assemblies. Of specific interest are polymer-based or polymer-lipid micellar assemblies designed as multimodal receptor-targeted blockers or drug carriers whose activity can be tuned by variations in polymer hydrophobicity, charge, and architecture. Also reviewed are emerging reports on multifunctional nanoassemblies and nanoparticles for improved circulation and enhanced targeting to athero-inflammatory lesions and atherosclerotic plaques.