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Microscopic hemorrhage is a common aspect of cancers, yet its potential role as an independent factor influencing both cancer progression and therapeutic response is largely ignored. Recognizing the essential function of macrophages in red blood cell disposal, we explored a pathway that connects intratumoral hemorrhage with the formation of cancer- promoting tumor-associated macrophages (TAMs). Using spatial transcriptomics, we found that NRF2-activated myeloid cells possessing characteristics of procancerous TAMs tend to cluster in perinecrotic hemorrhagic tumor regions. These cells resembled antiinflammatory erythrophagocytic macrophages. We identified heme, a red blood cell metabolite, as a pivotal microenvironmental factor steering macrophages toward protumorigenic activities. Single-cell RNA-Seq and functional assays of TAMs in 3D cell culture spheroids revealed how elevated intracellular heme signals via the transcription factor NRF2 to induce cancer-promoting TAMs. These TAMs stabilized epithelial- mesenchymal transition, enhancing cancer invasiveness and metastatic potential. Additionally, NRF2-activated macrophages exhibited resistance to reprogramming by IFN- [gamma] and anti-CD40 antibodies, reducing their tumoricidal capacity. Furthermore, MC38 colon adenocarcinoma-bearing mice with NRF2 constitutively activated in leukocytes were resistant to anti-CD40 immunotherapy. Overall, our findings emphasize hemorrhage-activated NRF2 in TAMs as a driver of cancer progression, suggesting that targeting this pathway could offer new strategies to enhance cancer immunity and overcome therapy resistance., Introduction Hemorrhage is omnipresent in solid cancers, occurring at macroscopic and microscopic levels due to invasive tumor growth, pathological vascularization, and therapy-induced or spontaneous necrosis. While traditionally perceived as a [...]

Itaconate has emerged as a critical immunoregulatory metabolite. Here, we examined the therapeutic potential of itaconate in atherosclerosis. We found that both itaconate and the enzyme that synthesizes it, aconitate decarboxylase 1 (Acod1, also known as immune-responsive gene 1 [IRG1]), are upregulated during atherogenesis in mice. Deletion of Acodl in myeloid cells exacerbated inflammation and atherosclerosis in vivo and resulted in an elevated frequency of a specific subset of M1-polarized proinflammatory macrophages in the atherosclerotic aorta. Importantly, Acod1 levels were inversely correlated with clinical occlusion in atherosclerotic human aorta specimens. Treating mice with the itaconate derivative 4- octyl itaconate attenuated inflammation and atherosclerosis induced by high cholesterol. Mechanistically, we found that the antioxidant transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), was required for itaconate to suppress macrophage activation induced by oxidized lipids in vitro and to decrease atherosclerotic lesion areas in vivo. Overall, our work shows that itaconate suppresses atherogenesis by inducing Nrf2-dependent inhibition of proinflammatory responses in macrophages. Activation of the itaconate pathway may represent an important approach to treat atherosclerosis., Introduction Itaconate has emerged as a compelling immunomodulatory metabolite produced in the tricarboxylic acid (TCA) cycle (1, 2). The enzyme cis-aconitate decarboxylase 1 (Acod1, also named Irg1) is responsible for [...]

Background: The organochlorine dichlorodiphenyltrichloroethane (DDT) is banned worldwide owing to its negative health effects. It is exceptionally used as an insecticide for malaria control. Exposure occurs in regions where DDT is applied, as well as in the Arctic, where its endocrine disrupting metabolite, p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) accumulates in marine mammals and fish. DDT and p,p'- DDE exposures are linked to birth defects, infertility, cancer, and neurodevelopmental delays. Of particular concern is the potential of DDT use to impact the health of generations to come via the heritable sperm epigenome. Objectives: The objective of this study was to assess the sperm epigenome in relation to p,p'-DDE serum levels between geographically diverse populations. Methods: In the Limpopo Province of South Africa, we recruited 247 VhaVenda South African men and selected 50 paired blood serum and semen samples, and 47 Greenlandic Inuit blood and semen paired samples were selected from a total of 193 samples from the biobank of the INUENDO cohort, an EU Fifth Framework Programme Research and Development project. Sample selection was based on obtaining a range of p,p'- DDE serum levels (mean = 870.734 [+ or -] 134.030 ng/mL). We assessed the sperm epigenome in relation to serump,p'-DDE levels using MethylC-Capture-sequencing (MCCseq) and chromatin immunoprecipitation followed by sequencing (ChIP-seq). We identified genomic regions with altered DNA methylation (DNAme) and differential enrichment of histone H3 lysine 4 trimethylation (H3K4me3) in sperm. Results: Differences in DNAme and H3K4me3 enrichment were identified at transposable elements and regulatory regions involved in fertility, disease, development, and neurofunction. A subset of regions with sperm DNAme and H3K4me3 that differed between exposure groups was predicted to persist in the preimplantation embryo and to be associated with embryonic gene expression. Discussion: These findings suggest that DDT and p,p'-DDE exposure impacts the sperm epigenome in a dose-response- like manner and may negatively impact the health of future generations through epigenetic mechanisms. Confounding factors, such as other environmental exposures, genetic diversity, and selection bias, cannot be ruled out. https://doi.org/10.1289/EHP12013, Introduction Dichlorodiphenyltrichloroethane (DDT) is a lipophilic organochlorine pollutant that is listed under the Stockholm Convention, with the objective to eliminate its use so as to protect human health and the [...]

Background: In 2015, the U.S. Consumer Product Safety Commission (CPSC) received and then, in 2017, granted a petition under the Federal Hazardous Substances Act to declare certain groups of consumer products as banned hazardous substances if they contain nonpolymeric, additive organohalogen flame retardants (OFRs). The petitioners asked the CPSC to regulate OFRs as a single chemical class with similar health effects. The CPSC later sponsored a National Academy of Sciences, Engineering, and Medicine (NASEM) report in 2019, which ultimately identified 161 OFRs and grouped them into 14 subclasses based on chemical structural similarity. In 2021, a follow-up discussion was held among a group of scientists from both inside and outside of the CPSC for current research on OFRs and to promote collaboration that could increase public awareness of CPSC work and support the class-based approach for the CPSC's required risk assessment of OFRs. OBJECTIVES: Given the extensive data collected to date, there is a need to synthesize what is known about OFR and how class-based regulations have previously managed this information. This commentary discusses both OFR exposure and OFR toxicity and fills some gaps for OFR exposure that were not within the scope of the NASEM report. The objective of this commentary is therefore to provide an overview of the OFR research presented at SOT 2021, explore opportunities and challenges associated with OFR risk assessment, and inform CPSC's work on an OFR class-based approach. DISCUSSION: A class-based approach for regulating OFRs can be successful. Expanding the use of read-across and the use of New Approach Methodologies (NAMs) in assessing and regulating existing chemicals was considered as a necessary part of the class- based process. Recommendations for OFR class-based risk assessment include the need to balance fire and chemical safety and to protect vulnerable populations, including children and pregnant women. The authors also suggest the CPSC should consider global, federal, and state OFR regulations. The lack of data or lack of concordance in toxicity data could present significant hurdles for some OFR subclasses. The potential for cumulative risks within or between subclasses, OFR mixtures, and metabolites common to more than one OFR all add extra complexity for class- based risk assessment. This commentary discusses scientific and regulatory challenges for a class-based approach suggested by NASEM. This commentary is offered as a resource for anyone performing class-based assessments and to provide potential collaboration opportunities for OFR stakeholders. https://doi.org/10.1289/EHP12725, Introduction Organohalogen Flame Retardants and the Petition Flame retardants (FRs) are chemicals added to materials to improve their resistance to ignition or reduce flame spread after ignition occurs, as defined [...]

Enabling the early detection and prevention of diabetic kidney damage has potential to substantially reduce the global burden of kidney failure. There is a critical need for identification of mechanistic biomarkers that can predict progression and serve as therapeutic targets. In this issue of the JCI, Sharma and colleagues used an integrated multiomics approach to identify the metabolite adenine as a noninvasive biomarker of progression in early diabetic kidney disease (DKD). The highest tertile of urine adenine/creatinine ratio (UAdCR) was associated with higher risk for end-stage kidney disease and mortality across independent cohorts, including participants with early DKD without macroalbuminuria. Spatial metabolomics, single-cell transcriptomics, and experimental studies localized adenine to regions of tubular pathology and implicated the mTOR pathway in adenine-mediated tissue fibrosis. Inhibition of endogenous adenine production was protective in a diabetic model. These findings exemplify the potential for multiomics to uncover mechanistic biomarkers and targeted therapies in DKD., Research gaps and opportunities in diabetic kidney disease Diabetic kidney disease (DKD), defined broadly as kidney damage due to diabetes, is the leading global cause of progressive chronic kidney disease [...]

Suppression of antitumor immunity is a prominent feature of the tumor microenvironment. In this issue of the JCI, Taves, Otsuka, and authors show that glucocorticoids (GCs), which are potent immunosuppressive hormones mainly produced by the adrenals, can be reconverted from their inactive form to active metabolites via the 11[beta]-hydroxysteroid dehydrogenase type 1 (11[beta]-HSD1) enzyme expressed by murine tumor cell lines. In the tumor microenvironment, GCs acted on CD[4.sup.+] regulatory T cells to enhance their immunosuppressive function and promote tumor growth. The findings suggest that targeting GC recycling as a strategy for modulating tumor immunosuppression has the potential to improve therapeutic efficacy of immune checkpoint blockade., Glucocorticoids mediate immunosuppression Immunosuppression is a prominent feature of cancer development, restraining antitumor effector T cell responses and limiting efficacy of therapeutic interventions. Immunosuppression can be mediated by multiple mechanisms, [...]

Background: Although much is known about cognitive dysfunction in attention-deficit/hyperactivity disorder (ADHD), few studies have examined the pathophysiology of disordered motor circuitry. We explored differences in neurometabolite levels and transcranial magnetic stimulation (TMS)-derived corticomotor representations among children with ADHD and typically developing children. Methods: We used magnetic resonance spectroscopy (MRS) protocols to measure excitatory (glutamate + glutamine [Glx]) and inhibitory ([gamma]-aminobutyric acid [GABA]) neurometabolite levels in the dominant primary motor cortex (M1) and the supplementary motor area (SMA) in children with ADHD and typically developing children. We used robotic neuronavigated TMS to measure corticospinal excitability and create corticomotor maps. Results: We collected data from 26 medication-free children with ADHD (aged 7-16 years) and 25 typically developing children (11-16 years). Children with ADHD had lower M1 Glx (p = 0.044, d = 0.6); their mean resting motor threshold was lower (p = 0.029, d = 0.8); their map area was smaller (p = 0.044, d = 0.7); and their hotspot density was higher (p = 0.008, d = 0.9). M1 GABA levels were associated with motor map area (p = 0.036). Limitations: Some TMS data were lost because the threshold of some children exceeded 100% of the machine output. The relatively large MRS voxel required to obtain sufficient signal- to-noise ratio and reliably measure GABA levels encompassed tissue beyond the M1, making this measure less anatomically specific. Conclusion: The neurochemistry and neurophysiology of key nodes in the motor network may be altered in children with ADHD, and the differences appear to be related to each other. These findings suggest potentially novel neuropharmacological and neuromodulatory targets for ADHD., Introduction Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by inattentiveness, impulsivity and motor hyperactivity. (1) It negatively affects individuals' performance at school and at home. (2) ADHD is [...]

Adaptation of the islet [beta] cell insulin-secretory response to changing insulin demand is critical for blood glucose homeostasis, yet the mechanisms underlying this adaptation are unknown. Here, we have shown that nutrient-stimulated histone acetylation plays a key role in adapting insulin secretion through regulation of genes involved in [beta] cell nutrient sensing and metabolism. Nutrient regulation of the epigenome occurred at sites occupied by the chromatin-modifying enzyme lysine-specific demethylase 1 (Lsd1) in islets. [beta] Cell-specific deletion of Lsd1 led to insulin hypersecretion, aberrant expression of nutrient-response genes, and histone hyperacetylation. Islets from mice adapted to chronically increased insulin demand exhibited shared epigenetic and transcriptional changes. Moreover, we found that genetic variants associated with type 2 diabetes were enriched at LSD1-bound sites in human islets, suggesting that interpretation of nutrient signals is genetically determined and clinically relevant. Overall, these studies revealed that adaptive insulin secretion involves Lsd1-mediated coupling of nutrient state to regulation of the islet epigenome., Introduction The ability to regulate nutrient metabolism in response to feeding and fasting is necessary for metabolic homeostasis. Nutrient utilization is acutely regulated by hormones and metabolites that change in [...]

Major depressive disorder, characterized by aberrant glutamatergic signaling in the prefrontal cortex (PFC), is a leading cause of disability worldwide. Depression is highly comorbid with metabolic disorders, but a mechanistic link is elusive. In this issue of the JCI, Fan and coauthors report that elevated posttranslational modification with the glucose metabolite N-acetylglucosamine (GlcNAc) by O-GlcNAc transferase (OGT) contributed to stress-induced establishment of depression-like behaviors in mice. This effect was specific to medial PFC (mPFC) astrocytes, with glutamate transporter-1 (GLT-1) identified as an OGT target. Specifically, O-GlcNAcylation of GLT-1 resulted in diminished glutamate clearance from excitatory synapses. Further, astrocytic OGT knockdown restored stress-induced deficits in glutamatergic signaling, promoting resilience. These findings provide a mechanistic link between metabolism and depression and have relevance for antidepressant targets., Major depressive disorder and metabolic deficits The proportion of the global population living with major depressive disorder (MDD) is estimated at 322 million people (4.4%), with an additional 260 million [...]

Major depressive disorder is a common and devastating psychiatric disease, and the prevalence and burden are substantially increasing worldwide. Multiple studies of depression patients have implicated glucose metabolic dysfunction in the pathophysiology of depression. However, the molecular mechanisms by which glucose and related metabolic pathways modulate depressive-like behaviors are largely uncharacterized. Uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) is a glucose metabolite with pivotal functions as a donor molecule for O-GlcNAcylation. O-GlcNAc transferase (OGT), a key enzyme in protein O-GlcNAcylation, catalyzes protein posttranslational modification by O-GlcNAc and acts as a stress sensor. Here, we show that Ogt mRNA was increased in depression patients and that astroglial OGT expression was specifically upregulated in the medial prefrontal cortex (mPFC) of susceptible mice after chronic social-defeat stress. The selective deletion of astrocytic OGT resulted in antidepressant-like effects, and moreover, astrocytic OGT in the mPFC bidirectionally regulated vulnerability to social stress. Furthermore, OGT modulated glutamatergic synaptic transmission through O-GlcNAcylation of glutamate transporter-1 (GLT-1) in astrocytes. OGT astrocyte-specific knockout preserved the neuronal morphology atrophy and [Ca.sup.2+] activity deficits caused by chronic stress and resulted in antidepressant effects. Our study reveals that astrocytic OGT in the mPFC regulates depressive-like behaviors through the O-GlcNAcylation of GLT-1 and could be a potential target for antidepressants., Introduction The lifetime prevalence (~17%), disability (as a leading cause), and socioeconomic burden associated with major depressive disorder (MDD) render it one of the most common and devastating psychiatric illnesses [...]

BACKGROUND. The kynurenine pathway (KP) has been identified as a potential mediator linking acute illness to cognitive dysfunction by generating neuroactive metabolites in response to inflammation. Delirium (acute confusion) is a common complication of acute illness and is associated with increased risk of dementia and mortality. However, the molecular mechanisms underlying delirium, particularly in relation to the KP, remain elusive. METHODS. We undertook a multicenter observational study with 586 hospitalized patients (248 with delirium) and investigated associations between delirium and KP metabolites measured in cerebrospinal fluid (CSF) and serum by targeted metabolomics. We also explored associations between KP metabolites and markers of neuronal damage and 1-year mortality. RESULTS. In delirium, we found concentrations of the neurotoxic metabolite quinolinic acid in CSF (CSF-QA) (OR 2.26 [1.78, 2.87], P < 0.001) to be increased and also found increases in several other KP metabolites in serum and CSF. In addition, CSF-QA was associated with the neuronal damage marker neurofilament light chain (NfL) (p 0.43, P < 0.001) and was a strong predictor of 1-year mortality (HR 4.35 [2.93, 6.45] for CSF-QA > 100 nmol/L, P < 0.001). The associations between CSF-QA and delirium, neuronal damage, and mortality remained highly significant following adjustment for confounders and multiple comparisons. CONCLUSION. Our data identified how systemic inflammation, neurotoxicity, and delirium are strongly linked via the KP and should inform future delirium prevention and treatment clinical trials that target enzymes of the KP. FUNDING. Norwegian Health Association and South-Eastern Norway Regional Health Authorities., Introduction The kynurenine pathway (KP) has been identified as a potential mediator linking acute illness to cognitive dysfunction by generating neuroactive metabolites in response to inflammation (1, 2). An imbalance [...]