Advanced Proteomics Approaches Hold Potential for the Risk Assessment of Metabolism-Disrupting Chemicals as Omics-Based NAM: A Case Study Using the Phthalate Substitute DINCH.

The concept of metabolic disruption through exposure to chemicals has expanded our understanding of how environmental pollution can contribute to metabolic dysregulation and, ultimately, diseases like obesity. New strategies for assessing the risks posed by chemicals are needed, and omics technologies, including proteomics, have proven to be powerful tools for investigating the molecular mechanisms of these metabolism-disrupting chemicals (MDCs). A potential MDC is the plasticizer DINCH─an alternative to legacy phthalates like DEHP, whose primary metabolite MINCH has been linked to the induction of adipogenesis and lipid accumulation.

Serum proteomics of adults with acute liver failure provides mechanistic insights and attractive prognostic biomarkers.

Background & Aims: Acute liver failure (ALF) is defined as rapid onset coagulopathy and encephalopathy in patients without a prior history of liver disease. We performed untargeted and targeted serum proteomics to delineate processes occurring in adult patients with ALF and to identify potential biomarkers.

Methods: Sera of 319 adult patients with ALF (∼50% acetaminophen [APAP]-related cases) were randomly selected from admission samples of the multicenter USA Acute Liver Failure Study Group consortium and subdivided into discovery/validation cohorts.

FGF21 and its underlying adipose tissue-liver axis inform cardiometabolic burden and improvement in obesity after metabolic surgery.

Background: This research investigates the determinants of circulating FGF21 levels in a cohort reflecting metabolic disease progression, examining the associations of circulating FGF21 with morphology and function of adipose tissue (AT), and with metabolic adjustments following metabolic surgery.

Methods: We measured serum FGF21 in 678 individuals cross-sectionally and in 189 undergoing metabolic surgery longitudinally. Relationships between FGF21 levels, AT histology, transcriptomes and proteomes, cardiometabolic risk factors, and post-surgery metabolic adjustments were assessed using univariate and multivariate analyses, causal mediation analysis, and network integration of AT transcriptomes and proteomes.

Proteomic analysis of extracellular vesicles derived from canine mammary tumour cell lines identifies protein signatures specific for disease state.

Background: Canine mammary tumours (CMT) are among the most common types of tumours in female dogs. Diagnosis currently requires invasive tissue biopsies and histological analysis. Tumour cells shed extracellular vesicles (EVs) containing RNAs and proteins with potential for liquid biopsy diagnostics.

Dysregulated cytokine and oxidative response in hyper-glycolytic monocytes in obesity.

Introduction: Obesity is associated with a plethora of health complications, including increased susceptibility to infections or decreased vaccine efficacy, partly due to dysregulated immune responses. Monocytes play a crucial role in innate immunity, yet their functional alterations in obesity remain poorly understood.

Methods: Here, we employed proteomic and metabolomic analyses to investigate monocyte characteristics in individuals with overweight, obesity, impaired glucose tolerance (IGT), and type 2 diabetes (T2D), compared to lean donors.

Unveiling the dynamics of acetylation and phosphorylation in SGBS and 3T3-L1 adipogenesis.

Obesity, characterized by enlarged and dysfunctional adipose tissue, is among today's most pressing global public health challenges with continuously increasing prevalence. Despite the importance of post-translational protein modifications (PTMs) in cellular signaling, knowledge of their impact on adipogenesis remains limited. Here, we studied the temporal dynamics of transcriptome, proteome, central carbon metabolites, and the acetyl- and phosphoproteome during adipogenesis using LC-MS/MS combined with PTM enrichment strategies on human (SGBS) and mouse (3T3-L1) adipocyte models.

Triclosan and its alternatives, especially chlorhexidine, modulate macrophage immune response with distinct modes of action.

Since European regulators restricted the use of bacteriocidic triclosan (TCS), alternatives for TCS are emerging. Recently, TCS has been shown to reprogram immune metabolism, trigger the NLRP3 inflammasome, and subsequently the release of IL-1β in human macrophages, but data on substitutes is scarce. Hence, we aimed to examine the effects of TCS compared to its alternatives at the molecular level in human macrophages.

Oxidation is an underappreciated post-translational modification in the regulation of immune responses associated with changes in phosphorylation.

Although macrophages are known to be affected by their redox status, oxidation is not yet a well-recognized post-translational modification (PTM) in regulating macrophages and immune cells in general. While it has been described that the redox status of single cysteines in specific proteins is relevant for macrophage functions, global oxidation information is scarce. Hence, we globally assessed the impact of oxidation on macrophage activation using untargeted proteomics and PTM-omics.

A comparative proteomics analysis of four contact allergens in THP-1 cells shows distinct alterations in key metabolic pathways.

Allergic contact dermatitis (ACD) is the predominant form of immunotoxicity in humans. The sensitizing potential of chemicals can be assessed in vitro. However, a better mechanistic understanding could improve the current OECD-validated test battery.

Biomarkers of hepatocellular synthesis in patients with decompensated cirrhosis.

Background And Aim: Since hepatocytes produce majority of serum proteins, patients with cirrhosis display substantial alterations in the serum proteome. The aim of the current study was to characterize these changes and to study the prognostic utility of hepatocellular proteins available in routine clinical testing.

Methods: Sera from 29 healthy controls and 43 patients with cirrhosis were subjected to untargeted proteomic analysis.

Cold-adapted amphipod species upon heat stress: Proteomic responses and their correlation with transcriptomic responses.

The cellular heat shock response (HSR) comprises transcriptomic and proteomic reactions to thermal stress. It was here addressed, how the proteomic, together with the transcriptomic HSR, relate to the thermal sensitivities of three cold-adapted but differently thermo-sensitive freshwater amphipod species. The proteomes of thermosensitive Eulimnogammarus verrucosus and thermotolerant Eulimnogammarus cyaneus, both endemic to Lake Baikal, and of thermotolerant Holarctic Gammarus lacustris were investigated upon 24 h exposure to the species-specific 10 % lethal temperatures (LT10).

Human chorionic gonadotropin promotes murine Treg cells and restricts pregnancy-harmful proinflammatory Th17 responses.

An equilibrium between proinflammatory and anti-inflammatory immune responses is essential for maternal tolerance of the fetus throughout gestation. To study the participation of fetal tissue-derived factors in this delicate immune balance, we analyzed the effects of human chorionic gonadotropin (hCG) on murine Treg cells and Th17 cells , and on pregnancy outcomes, fetal and placental growth, blood flow velocities and remodeling of the uterine vascular bed . Compared with untreated CD4CD25 T cells, hCG increased the frequency of Treg cells upon activation of the LH/CG receptor.

Di-(2-ethylhexyl) phthalate substitutes accelerate human adipogenesis through PPARγ activation and cause oxidative stress and impaired metabolic homeostasis in mature adipocytes.

The obesity pandemic is presumed to be accelerated by endocrine disruptors such as phthalate-plasticizers, which interfere with adipose tissue function. With the restriction of the plasticizer di-(2-ethylhexyl)-phthalate (DEHP), the search for safe substitutes gained importance. Focusing on the master regulator of adipogenesis and adipose tissue functionality, the peroxisome proliferator-activated receptor gamma (PPARγ), we evaluated 20 alternative plasticizers as well as their metabolites for binding to and activation of PPARγ and assessed effects on adipocyte lipid accumulation.

An environmental ecocorona influences the formation and evolution of the biological corona on the surface of single-walled carbon nanotubes.

Nanomaterials (NMs) taken up from the environment carry a complex ecocorona consisting of dissolved organic matter. An ecocorona is assumed to influence the interactions between NMs and endogenous biomolecules and consequently affects the formation of a biological corona (biocorona) and the biological fate of the NMs. This study shows that biomolecules in fish plasma attach immediately (within <5 min) to the surface of SWCNTs and the evolution of the biocorona is a size dependent phenomenon.

Danger signal extracellular calcium initiates differentiation of monocytes into SPP1/osteopontin-producing macrophages.

The danger signal extracellular calcium is pathophysiologically increased in the synovial fluid of patients with rheumatoid arthritis (RA). Calcium activates the NLRP3-inflammasome via the calcium-sensing receptor in monocytes/macrophages primed by lipopolysaccharide, and this effect is mediated by the uptake of calciprotein particles (CPPs) formed out of calcium, phosphate, and fetuin-A. Aim of the study was to unravel the influence of calcium on monocytes when the priming signal is not present.

Proteomic Characterization of the Cellular Effects of AhR Activation by Microbial Tryptophan Catabolites in Endotoxin-Activated Human Macrophages.

Sensing microbial tryptophan catabolites by the aryl hydrocarbon receptor (AhR) plays a pivotal role in host-microbiome homeostasis by modulating the host immune response. Nevertheless, the involved cellular processes triggered by the metabolites are mainly unknown. Here, we analyzed proteomic changes in macrophages after treatment with the tryptophan metabolites indole-3-acetic acid (I3AA) or indole-3-aldehyde (IAld), as well as the prototypic exogenous AhR-ligand benzo(a)pyrene (BaP) in the absence and presence of lipopolysaccharide (LPS) to identify affected cellular processes and pathways.

Multiomics reveal unique signatures of human epiploic adipose tissue related to systemic insulin resistance.

Objective: Human white adipose tissue (AT) is a metabolically active organ with distinct depot-specific functions. Despite their locations close to the gastrointestinal tract, mesenteric AT and epiploic AT (epiAT) have only scarcely been investigated. Here, we aim to characterise these ATs in-depth and estimate their contribution to alterations in whole-body metabolism.

The Emerging Plasticizer Alternative DINCH and Its Metabolite MINCH Induce Oxidative Stress and Enhance Inflammatory Responses in Human THP-1 Macrophages.

The use of the plasticizer bis(2-ethylhexyl)phthalate (DEHP) and other plasticizers in the manufacture of plastic products has been restricted due to adverse health outcomes such as obesity, metabolic syndrome, and asthma, for which inflammation has been described to be a driving factor. The emerging alternative plasticizer 1,2-cyclohexanedioic acid diisononyl ester (DINCH) still lacks information regarding its potential effects on the immune system. Here, we investigated the effects of DINCH and its naturally occurring metabolite monoisononylcyclohexane-1,2-dicarboxylic acid ester (MINCH) on the innate immune response.

Nanomaterials induce different levels of oxidative stress, depending on the used model system: Comparison of in vitro and in vivo effects.

The immense diversity and constant development of nanomaterials (NMs) increase the need for a facilitated risk assessment, which requires knowledge of the modes of action (MoAs) of NMs. This necessitates a comprehensive data basis, which can be obtained using omics. Furthermore, the establishment of suitable in vitro test systems is essential to follow the 3R concept and to cope with the high number of NMs.

Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation.

Bisphenol A (BPA), which is used in a variety of consumer-related plastic products, was reported to cause adverse effects, including disruption of adipocyte differentiation, interference with obesity mechanisms, and impairment of insulin- and glucose homeostasis. Substitute compounds are increasingly emerging but are not sufficiently investigated.We aimed to investigate the mode of action of BPA and four of its substitutes during the differentiation of human preadipocytes to adipocytes and their molecular interaction with peroxisome proliferator-activated receptor γ (PPARγ), a pivotal regulator of adipogenesis.

A Multi-Omics Analysis of Mucosal-Associated-Invariant T Cells Reveals Key Drivers of Distinct Modes of Activation.

The function of mucosal-associated invariant T (MAIT) cells highly depends on the mode of activation, either by recognition of bacterial metabolites their T cell receptor (TCR) or in a TCR-independent manner cytokines. The underlying molecular mechanisms are not entirely understood. To define the activation of MAIT cells on the molecular level, we applied a multi-omics approach with untargeted transcriptomics, proteomics and metabolomics.

Non-Genomic AhR-Signaling Modulates the Immune Response in Endotoxin-Activated Macrophages After Activation by the Environmental Stressor BaP.

Emerging studies revealed that the Aryl hydrocarbon receptor (AhR), a receptor sensing environmental contaminants, is executing an immunomodulatory function. However, it is an open question to which extent this is achieved by its role as a transcription factor or non-genomic signaling. We utilized a multi-post-translational modification-omics approach to examine non-genomic AhR-signaling after activation with endogenous (FICZ) or exogenous (BaP) ligand in endotoxin-activated (LPS) monocyte-derived macrophages.

The gut bacterium produces secondary bile acids and influences liver physiology in gnotobiotic mice.

is a newly described mouse gut bacterium which metabolizes cholic acid (CA) to deoxycholic acid (DCA) via 7α-dehydroxylation. Although bile acids influence metabolic and inflammatory responses, few models exist for studying their metabolism and impact on the host. Mice were colonized from birth with the simplified community Oligo-MM with or without .

Systematic Review of Multi-Omics Approaches to Investigate Toxicological Effects in Macrophages.

Insights into the modes of action (MoAs) of xenobiotics are of utmost importance for the definition of adverse outcome pathways (AOPs), which are essential for a mechanism-based risk assessment. A well-established strategy to reveal MoAs of xenobiotics is the use of omics. However, often an even more comprehensive approach is needed, which can be achieved using multi-omics.

Comparison of quantitation methods in proteomics to define relevant toxicological information on AhR activation of HepG2 cells by BaP.

The application of quantitative proteomics provides a new and promising tool for standardized toxicological research. However, choosing a suitable quantitative method still puzzles many researchers because the optimal method needs to be determined. In this study, we investigated the advantages and limitations of two of the most commonly used global quantitative proteomics methods, namely label-free quantitation (LFQ) and tandem mass tags (TMT).