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Endothelial cells (ECs) adapt their metabolism to enable the growth of new blood vessels, but little is known how ECs regulate metabolism to adopt a quiescent state. Here, we show that the metabolite S-2-hydroxyglutarate (S-2HG) plays a crucial role in the regulation of endothelial quiescence. We find that S-2HG is produced in ECs after activation of the transcription factor forkhead box O1 (FOXO1), where it limits cell cycle progression, metabolic activity and vascular expansion. FOXO1 stimulates S-2HG production by inhibiting the mitochondrial enzyme 2-oxoglutarate dehydrogenase. This inhibition relies on branched-chain amino acid catabolites such as 3-methyl-2-oxovalerate, which increase in ECs with activated FOXO1. Treatment of ECs with 3-methyl-2-oxovalerate elicits S-2HG production and suppresses proliferation, causing vascular rarefaction in mice. Our findings identify a metabolic programme that promotes the acquisition of a quiescent endothelial state and highlight the role of metabolites as signalling molecules in the endothelium.Andrade et al. show that FOXO1 regulates mitochondrial metabolism to stimulate the production of the metabolite S-2HG to promote acquisition of a quiescent endothelial state.

The identification of N 6 -methyldeoxyadenosine in the DNA of Xenopus laevis , mice and humans extends the presence of this mark to vertebrates, thus fostering the potential importance of this mark as a carrier of epigenetic information. Methylation of cytosine deoxynucleotides generates 5-methylcytosine (m 5 dC), a well-established epigenetic mark. However, in higher eukaryotes much less is known about modifications affecting other deoxynucleotides. Here, we report the detection of N 6 -methyldeoxyadenosine (m 6 dA) in vertebrate DNA, specifically in Xenopus laevis but also in other species including mouse and human. Our methylome analysis reveals that m 6 dA is widely distributed across the eukaryotic genome and is present in different cell types but is commonly depleted from gene exons. Thus, direct DNA modifications might be more widespread than previously thought.

A metabolomics study on the ischaemic heart identifies succinate as a metabolite that drives the production of reactive oxygen species and contributes to ischaemia-reperfusion injury; pharmacological inhibition of succinate accumulation ameliorates ischaemia-reperfusion injury in a mouse model of heart attack and a rat model of stroke. Succinate a heart breaker In this metabolomics study of the ischaemic heart, Michael Murphy and colleagues identify a metabolite that drives the production of reactive oxygen species and contributes to ischaemia reperfusion injury. They show that succinate is a conserved metabolic signature of ischaemia in several tissues. Succinate accumulates during ischaemia due to a reversal of the enzyme succinate dehydrogenase. Upon reperfusion the accumulated succinate is rapidly oxidized and drives reactive oxygen species production through reverse electron transport at mitochondrial complex I. Pharmacological blockade of succinate accumulation ameliorates ischaemia reperfusion injury in mouse models of heart attack and stroke. Ischaemia-reperfusion injury occurs when the blood supply to an organ is disrupted and then restored, and underlies many disorders, notably heart attack and stroke. While reperfusion of ischaemic tissue is essential for survival, it also initiates oxidative damage, cell death and aberrant immune responses through the generation of mitochondrial reactive oxygen species (ROS) 1 , 2 , 3 , 4 , 5 . Although mitochondrial ROS production in ischaemia reperfusion is established, it has generally been considered a nonspecific response to reperfusion 1 , 3 . Here we develop a comparative in vivo metabolomic analysis, and unexpectedly identify widely conserved metabolic pathways responsible for mitochondrial ROS production during ischaemia reperfusion. We show that selective accumulation of the citric acid cycle intermediate succinate is a universal metabolic signature of ischaemia in a range of tissues and is responsible for mitochondrial ROS production during reperfusion. Ischaemic succinate accumulation arises from reversal of succinate dehydrogenase, which in turn is driven by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle. After reperfusion, the accumulated succinate is rapidly re-oxidized by succinate dehydrogenase, driving extensive ROS generation by reverse electron transport at mitochondrial complex I. Decreasing ischaemic succinate accumulation by pharmacological inhibition is sufficient to ameliorate in vivo ischaemia-reperfusion injury in murine models of heart attack and stroke. Thus, we have identified a conserved metabolic response of tissues to ischaemia and reperfusion that unifies many hitherto unconnected aspects of ischaemia-reperfusion injury. Furthermore, these findings reveal a new pathway for metabolic control of ROS production in vivo , while demonstrating that inhibition of ischaemic succinate accumulation and its oxidation after subsequent reperfusion is a potential therapeutic target to decrease ischaemia-reperfusion injury in a range of pathologies.

WebTreatment of lipopolysaccharide-activated macrophages with the cell-permeable itaconate derivative 4-octyl itaconate activates the anti-inflammatory transcription factor Nrf2 by alkylating key cysteine residues on the KEAP1 protein. Anti-inflammatory effects of itaconate Macrophages are white blood cells that recognize and destroy invading bacterial pathogens, and later tone down inflammation to enable tissue repair. The endogenous metabolite itaconate inhibits a number of inflammatory cytokines during macrophage activation. Luke O'Neill and colleagues investigate the mechanism underlying this process. Treatment of lipopolysaccharide (LPS)-activated macrophages with the cell-permeable itaconate derivative 4-octyl itaconate activates the anti-oxidant and anti-inflammatory transcription factor Nrf2. This activation occurs via alkylation of key cysteine residues on the KEAP1 protein, which blocks KEAP1-dependent proteolysis of Nrf2. Pre-treating mouse models of LPS with the itaconate derivative activates Nrf2 and prolongs the survival of the animals after a lethal dose of LPS. The authors suggest that itaconate derivatives may prove useful in the treatment of inflammatory diseases. The endogenous metabolite itaconate has recently emerged as a regulator of macrophage function, but its precise mechanism of action remains poorly understood 1 , 2 , 3 . Here we show that itaconate is required for the activation of the anti-inflammatory transcription factor Nrf2 (also known as NFE2L2) by lipopolysaccharide in mouse and human macrophages. We find that itaconate directly modifies proteins via alkylation of cysteine residues. Itaconate alkylates cysteine residues 151, 257, 288, 273 and 297 on the protein KEAP1, enabling Nrf2 to increase the expression of downstream genes with anti-oxidant and anti-inflammatory capacities. The activation of Nrf2 is required for the anti-inflammatory action of itaconate. We describe the use of a new cell-permeable itaconate derivative, 4-octyl itaconate, which is protective against lipopolysaccharide-induced lethality in vivo and decreases cytokine production. We show that type I interferons boost the expression of Irg1 (also known as Acod1 ) and itaconate production. Furthermore, we find that itaconate production limits the type I interferon response, indicating a negative feedback loop that involves interferons and itaconate. Our findings demonstrate that itaconate is a crucial anti-inflammatory metabolite that acts via Nrf2 to limit inflammation and modulate type I interferons.

Emerging evidence suggests that cancer cell metabolism can be regulated by cancer-associated fibroblasts (CAFs), but the mechanisms are poorly defined. Here we show that CAFs regulate malignant cell metabolism through pathways under the control of FAK. In breast and pancreatic cancer patients we find that low FAK expression, specifically in the stromal compartment, predicts reduced overall survival. In mice, depletion of FAK in a subpopulation of CAFs regulates paracrine signals that increase malignant cell glycolysis and tumour growth. Proteomic and phosphoproteomic analysis in our mouse model identifies metabolic alterations which are reflected at the transcriptomic level in patients with low stromal FAK. Mechanistically we demonstrate that FAK-depletion in CAFs increases chemokine production, which via CCR1/CCR2 on cancer cells, activate protein kinase A, leading to enhanced malignant cell glycolysis. Our data uncover mechanisms whereby stromal fibroblasts regulate cancer cell metabolism independent of genetic mutations in cancer cells. Cancer associated fibroblasts (CAFs) have been suggested to regulate cancer cell metabolism, but the mechanisms are not completely elucidated. Here, the authors show that low FAK expression in stromal cells correlates with poor prognosis in breast and pancreatic cancer patients and that FAK-silencing in CAFs promotes tumourigenesis by the paracrine regulation of cancer cell metabolism.

Multi‐omics datasets can provide molecular insights beyond the sum of individual omics. Various tools have been recently developed to integrate such datasets, but there are limited strategies to systematically extract mechanistic hypotheses from them. Here, we present COSMOS (Causal Oriented Search of Multi‐Omics Space), a method that integrates phosphoproteomics, transcriptomics, and metabolomics datasets. COSMOS combines extensive prior knowledge of signaling, metabolic, and gene regulatory networks with computational methods to estimate activities of transcription factors and kinases as well as network‐level causal reasoning. COSMOS provides mechanistic hypotheses for experimental observations across multi‐omics datasets. We applied COSMOS to a dataset comprising transcriptomics, phosphoproteomics, and metabolomics data from healthy and cancerous tissue from eleven clear cell renal cell carcinoma (ccRCC) patients. COSMOS was able to capture relevant crosstalks within and between multiple omics layers, such as known ccRCC drug targets. We expect that our freely available method will be broadly useful to extract mechanistic insights from multi‐omics studies. SYNOPSIS A new approach integrates multi‐omics datasets with a prior knowledge network spanning signaling, metabolism and allosteric regulations. Application to a kidney cancer patient cohort captures relevant cross‐talks among deregulated processes. A causal multi‐omics network is built by integrating multiple ressources spanning signaling, metabolism and allosteric regulations. Transcriptomics, phosphoproteomics and metabolomics data are integrated in a set of coherent mechanistic hypotheses using CARNIVAL, a tool contextualizing causal networks. This set of coherent mechanistic hypotheses can be mined to identify disease mechanisms and therapeutic targets. A network built for a cohort of kidney cancer patients shows coherence with other studies and known therapeutic targets. Graphical Abstract A new approach integrates multi‐omics datasets with a prior knowledge network spanning signaling, metabolism and allosteric regulations. Application to a kidney cancer patient cohort captures relevant cross‐talks among deregulated processes.

The composition of seaweeds is complex, with vitamins, phenolic compounds, minerals, and polysaccharides being some of the factions comprising their structure. The main polysaccharide in brown seaweeds is fucoidan, and several biological activities have been associated with its structure. Chitosan is another marine biopolymer that is very popular in the biomedical field, owing to its suitable features for formulating drug delivery systems and, particularly, particulate systems. In this work, the ability of fucoidan to produce nanoparticles was evaluated, testing different amounts of a polymer and using chitosan as a counterion. Nanoparticles of 200–300 nm were obtained when fucoidan prevailed in the formulation, which also resulted in negatively charged nanoparticles. Adjusting the pH of the reaction media to 4 did not affect the physicochemical characteristics of the nanoparticles. The IC50 of fucoidan was determined, in both HCT−116 and A549 cells, to be around 160 µg/mL, whereas it raised to 675–100 µg/mL when nanoparticles (fucoidan/chitosan = 2/1, w/w) were tested. These marine materials (fucoidan and chitosan) provided features suitable to formulate polymeric nanoparticles to use in biomedical applications.

Purpose Extending the theory of planned behaviour (TPB), this paper aims to measure the relative importance of different barriers to sustainable fashion consumption (SFC). Design/methodology/approach Existing studies have mainly adopted a qualitative methodology for identifying barriers to uptake of SFC, this study uses six of the main identified barriers: environmental apparel knowledge, perceived value, price sensitivity, product attributes and variety, availability and scepticism into the TPB framework to test and reveal which barriers have the greater impact on the TPB cognitions and consequently on building intention towards SFC. To test this model a survey study among 669 consumers from Europe, Asian and North America was conducted, structural equation modelling is used to test the research hypotheses. Findings Findings confirm the role of TPB cognitions on predicting intention and show that the proposed barriers provide a satisfactory explanation of the TPB model. Furthermore, results show that product attributes and variety and environmental apparel knowledge have the greatest impact on the TPB cognitions and on building intention towards SFC. Differences were found between the impacts of the price for the three continents. Originality/value This research contributes to the emerging sustainable fashion literature by examining the impact of different barriers to SFC in an extended TPB framework. To the best of our knowledge price sensitivity, availability and scepticism have never been studied in the context of sustainable fashion. It also provides a multifactor group analysis which uncovers differences among consumers from different continents.

Glutamoptosis is the induction of apoptotic cell death as a consequence of the aberrant activation of glutaminolysis and mTORC1 signaling during nutritional imbalance in proliferating cells. The role of the bioenergetic sensor AMPK during glutamoptosis is not defined yet. Here, we show that AMPK reactivation blocks both the glutamine-dependent activation of mTORC1 and glutamoptosis in vitro and in vivo. We also show that glutamine is used for asparagine synthesis and the GABA shunt to produce ATP and to inhibit AMPK, independently of glutaminolysis. Overall, our results indicate that glutamine metabolism is connected with mTORC1 activation through two parallel pathways: an acute alpha-ketoglutarate-dependent pathway; and a secondary ATP/AMPK-dependent pathway. This dual metabolic connection between glutamine and mTORC1 must be considered for the future design of therapeutic strategies to prevent cell growth in diseases such as cancer. The metabolism of amino acids and the cellular energy sensor AMPK are both connected to mTORC1, but the pathway details have not been well defined. Here, the authors show that glutamine metabolism and mTORC1 have two regulatory connections with relevance to cancer therapeutics design.

PurposeBariatric surgery is an effective method for the treatment of severe obesity, however, binge eating disorder (BED) and negative body image can interfere with post-surgical evolution.ObjectiveTo describe the factors associated with BED in bariatric patients with a minimum of 2 years post-surgery.Materials and MethodsA cross-sectional observational study conducted with patients who underwent bariatric surgery through the Unified Health System (Sistema Único de Saúde [SUS]) and presenting a minimum of 2 years post-surgery. BED, depression symptoms, anxiety symptoms, quality of life and body image concerns were assessed by the Binge Eating Scale, Beck Depression Inventory, Beck Anxiety Inventory, Bariatric Analysis and Reporting Outcome System, and Body Shape Questionnaire, respectively. Socioeconomic and anthropometric data were also collected.ResultsBased on the ninety-two (92) patients evaluated, 83.7% were female, and had a mean age of 43.3 ± 9 years. Symptoms of depression (p = 0.002), anxiety (p = 0.000), body image concerns (p = 0.000), poor quality of life (p = 0.010), and obesity (p = 0.008) were associated with the presence of BED. All the anthropometric variables were higher in patients with BED, except excess weight loss. Regression analysis predicted BED through the presence of body image concern and anxiety symptoms.ConclusionAnxiety symptoms and body image concerns are associated with BED in patients who underwent bariatric surgery a minimum of 2 years.