Acyl-CoA formation initiates cellular fatty acid metabolism. Acyl-CoAs are generated by the ligation of a fatty acid to Coenzyme A mediated by a large family of acyl-CoA synthetases (ACS). ...Conversely, acyl-CoAs can be hydrolyzed by a family of acyl-CoA thioesterases (ACOT). Here, we have determined the transcriptional regulation of all ACS and ACOT enzymes across tissues and in response to metabolic perturbations. We find patterns of coordinated regulation within and between these gene families as well as distinct regulation occurring in a tissue- and physiologically-dependent manner. Due to observed changes in long-chain ACOT mRNA and protein abundance in liver and adipose tissue, we determined the consequence of increasing cytosolic long-chain thioesterase activity on fatty acid metabolism in these tissues by generating transgenic mice overexpressing a hyperactive mutant of Acot7 in the liver or adipose tissue. Doubling cytosolic acyl-CoA thioesterase activity failed to protect mice from diet-induced obesity, fatty liver or insulin resistance, however, overexpression of Acot7 in adipocytes rendered mice cold intolerant. Together, these data suggest distinct modes of regulation of the ACS and ACOT enzymes and that these enzymes act in a coordinated fashion to control fatty acid metabolism in a tissue-dependent manner.
Upon antigen recognition and co-stimulation, T lymphocytes upregulate the metabolic machinery necessary to proliferate and sustain effector function. This metabolic reprogramming in T cells regulates ...T cell activation and differentiation but is not just a consequence of antigen recognition. Although such metabolic reprogramming promotes the differentiation and function of T effector cells, the differentiation of regulatory T cells employs different metabolic reprogramming. Therefore, we hypothesized that inhibition of glycolysis and glutamine metabolism might prevent graft rejection by inhibiting effector generation and function and promoting regulatory T cell generation. We devised an anti-rejection regimen involving the glycolytic inhibitor 2-deoxyglucose (2-DG), the anti-type II diabetes drug metformin, and the inhibitor of glutamine metabolism 6-diazo-5-oxo-L-norleucine (DON). Using this triple-drug regimen, we were able to prevent or delay graft rejection in fully mismatched skin and heart allograft transplantation models.
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•Metabolic reprogramming is crucial for effector T cell differentiation and function•Blocking glycolysis and glutamine metabolism can prevent allograft rejection•Targeting effector cell metabolism preserves mechanisms of immunoregulation•Targeting metabolism represents a paradigm-shifting approach to transplantation
Lee et al. demonstrate that simultaneously blocking glycolysis and glutamine pathways can effectively inhibit allo-specific T cell responses while preserving mechanisms of immune regulation. Such a regimen represents a paradigm-shifting approach toward inhibiting acute rejection and promoting allograft survival.
Pregnancy may be the most nutritionally sensitive stage in the life cycle, and improved metabolic health during gestation and early postnatal life can reduce the risk of chronic disease in adulthood. ...Successful pregnancy requires coordinated metabolic, hormonal, and immunological communication. In this review, maternal–fetal metabolic communication is defined as the bidirectional communication of nutritional status and metabolic demand by various modes including circulating metabolites, endocrine molecules, and other secreted factors. Emphasis is placed on metabolites as a means of maternal–fetal communication by synthesizing findings from studies in humans, non-human primates, domestic animals, rabbits, and rodents. In this review, fetal, placental, and maternal metabolic adaptations are discussed in turn. (1) Fetal macronutrient needs are summarized in terms of the physiological adaptations in place to ensure their proper allocation. (2) Placental metabolite transport and maternal physiological adaptations during gestation, including changes in energy budget, are also discussed. (3) Maternal nutrient limitation and metabolic disorders of pregnancy serve as case studies of the dynamic nature of maternal–fetal metabolic communication. The review concludes with a summary of recent research efforts to identify metabolites, endocrine molecules, and other secreted factors that mediate this communication, with particular emphasis on serum/plasma metabolomics in humans, non-human primates, and rodents. A better understanding of maternal–fetal metabolic communication in health and disease may reveal novel biomarkers and therapeutic targets for metabolic disorders of pregnancy.
Iturins and closely related lipopeptides constitute a family of antifungal compounds known as iturinic lipopeptides that are produced by species in the
group. The compounds that comprise the family ...are: iturin, bacillomycin D, bacillomycin F, bacillomycin L, mycosubtilin, and mojavensin. These lipopeptides are prominent in many
strains that have been commercialized as biological control agents against fungal plant pathogens and as plant growth promoters. The compounds are cyclic heptapeptides with a variable length alkyl sidechain, which confers surface activity properties resulting in an affinity for fungal membranes. Above a certain concentration, enough molecules enter the fungal cell membrane to create a pore in the cell wall, which leads to loss of cell contents and cell death. This study identified 330 iturinic lipopeptide clusters in publicly available genomes from the
species group. The clusters were subsequently assigned into distinguishable types on the basis of their unique amino acid sequences and then verified by HPLC MS/MS analysis. The results show some lipopeptides are only produced by one species, whereas certain others can produce up to three. In addition, four species previously not known to produce iturinic lipopeptides were identified. The distribution of these compounds among the
group species suggests that they play an important role in their speciation and evolution.
A critical component of innate immune response to infection and tissue damage is the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome, and this pathway and its activation ...products have been implicated in the pathophysiology of a variety of diseases. NLRP3 inflammasome activation leads to the cleavage of pro-IL-1β and pro-IL-18, as well as the subsequent release of biologically active IL-1β, IL-18, and other soluble mediators of inflammation. In this study, we further define the pharmacology of the previously reported NLRP3 inflammasome-selective, IL-1β processing inhibitor CP-456,773 (also known as MCC950), and we demonstrate its efficacy in two in vivo models of inflammation. Specifically, we show that in human and mouse innate immune cells CP-456,773 is an inhibitor of the cellular release of IL-1β, IL-1α, and IL-18, that CP-456,773 prevents inflammasome activation induced by disease-relevant soluble and crystalline NLRP3 stimuli, and that CP-456,773 inhibits R848- and imiquimod-induced IL-1β release. In mice, CP-456,773 demonstrates potent inhibition of the release of proinflammatory cytokines following acute i.p. challenge with LPS plus ATP in a manner that is proportional to the free/unbound concentrations of the drug, thereby establishing an in vivo pharmacokinetic/pharmacodynamic model for CP-456,773. Furthermore, CP-456,773 reduces ear swelling in an imiquimod cream-induced mouse model of skin inflammation, and it reduces airway inflammation in mice following acute challenge with house dust mite extract. These data implicate the NLRP3 inflammasome in the pathogenesis of dermal and airway inflammation, and they highlight the utility of CP-456,773 for interrogating the contribution of the NLRP3 inflammasome and its outputs in preclinical models of inflammation and disease.
MicroRNAs (miRNAs) are a specialized class of small silencing RNAs that regulate gene expression. They have a limited phylogenetic distribution among eukaryotes, suggestive of at least two ...independent origins from an ancestral small RNA-producing pathway. A set of 21 abundantly expressed miRNAs are clearly conserved among the angiosperms; many of these function to regulate transcription factors involved in developmental control. Recent experiments have uncovered a much larger set of weakly expressed, less conserved miRNAs in plants, and this group has provided insights into the origins of miRNAs and their targets. These data have provided a coherent set of hypotheses explaining the birth, selection and death of miRNAs in land plants.
The mental health impact of the pandemic after the initial lockdowns has not been well studied in the USA. Thus, the purpose of this study was to conduct a comprehensive and systematic national ...assessment of the prevalence of depression and anxiety in the adult US population.
A multi-item, valid and reliable questionnaire was deployed online via mTurk and social media sites to recruit adult US participants in the general population across the USA. A total of 1978 individuals participated in the study, where the majority were: females (51%), whites (74%), non-Hispanic (81%), married (56%), employed full time (68%) and with a bachelor's degree or higher (78%).
The prevalence of depression (39%), anxiety (42%) and psychological distress (39%) were computed from the PHQ-4 scale. In multiple regression analyses, depression, anxiety and psychological distress burden (assessed by PHQ-4 scale) was predicted significantly based on race, ethnicity, age, having children at home, employment as a healthcare worker, annual household income and area of residence. Males were more likely to have depression, and females were more likely to have anxiety symptoms.
Given the high prevalence of depression and anxiety, interdisciplinary and multisectoral approaches are recommended in the USA along with population-based interventions on mental health improvement.
A data-centric medicinal chemistry approach led to the invention of a potent and selective IDO1 inhibitor 4f, INCB24360 (epacadostat). The molecular structure of INCB24360 contains several previously ...unknown or underutilized functional groups in drug substances, including a hydroxyamidine, furazan, bromide, and sulfamide. These moieties taken together in a single structure afford a compound that falls outside of “drug-like” space. Nevertheless, the in vitro ADME data is consistent with the good cell permeability and oral bioavailability observed in all species (rat, dog, monkey) tested. The extensive intramolecular hydrogen bonding observed in the small molecule crystal structure of 4f is believed to significantly contribute to the observed permeability and PK. Epacadostat in combination with anti-PD1 mAb pembrolizumab is currently being studied in a phase 3 clinical trial in patients with unresectable or metastatic melanoma.
While the brain's high energy demands are largely met by glucose, brain is also equipped with the ability to oxidize fatty acids for energy and metabolism. The brain expresses the carnitine ...palmitoyltransferases (CPTs) that mediate carnitine‐dependent entry of long‐chain acyl‐CoAs into the mitochondrial matrix for β‐oxidation – CPT1a and CPT2 located on the outer and inner mitochondrial membranes, respectively. Their developmental profile, regional distribution and activity as well as cell type expression remain unknown. We determined that brain CPT1a RNA and total protein expression were unchanged throughout post‐natal development (PND0, PND7, PND14, PND21 and PND50); however, CPT2 RNA peaked at PND 21 and remained unchanged through PND50 in all regions studied (cortex, hippocampus, midbrain, and cerebellum). Both long‐chain acyl CoA dehydrogenase and medium acyl‐CoA dehydrogenase showed a similar developmental profile to CPT2. Acylcarnitines, generated as a result of CPT1a activity, significantly increased with age and peaked at PND21 in all brain regions, concurrent with the increased expression of enzymes involved in mitochondrial β‐oxidation. The CPT system is highly enriched in vivo in hippocampus and cerebellum, relative to cortex and midbrain, and is exclusively present in astrocytes and neural progenitor cells, while absent in neurons, microglia, and oligodendrocytes. Using radiolabeled oleate, we demonstrate regional differences in brain fatty acid oxidation that may be blocked by the irreversible CPT1a inhibitor etomoxir. This study contributes to the field of knowledge in brain cell‐specific metabolic pathways, which are important for understanding normal brain development and aging, as well as pathophysiology of neurological diseases.
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The high metabolic demands of mammalian brain are largely met by glucose, but brain can also oxidize fatty acids. Here we describe the expression profiles of the enzymes required for mitochondrial β‐oxidation of fatty acids across early postnatal development in rat brain. We observed increased expression of the β‐oxidation enzymatic machinery through postnatal day 21, and these enzymes are enriched in astrocytes and neural progenitor cells. This work contributes to a better understanding of cell‐type‐specific brain metabolism during normal development.
Read the Editorial Comment for this article on page 347.
•Soybeans obtained from many 2013-2016 production locations around the United States.•Analysis of total isoflavone and total saponin quantification performed by HPLC.•Preprocessing algorithms were ...applied to NIRS spectra to minimize variation.•Multiple Linear Regression based models predict isoflavone content.•Predictions had high regression coefficients, low standard errors of calibration.
Over 3200 discrete soybean samples were obtained from production locations around the United States during the years 2012–2016. Ground samples were scanned on near infrared spectrometers (NIRS) and analyzed by HPLC for total isoflavone and total saponin composition, as well as total carbohydrate composition. Multiple Linear Regression (MLR) analysis of preprocessed spectral data was used to develop optimized models to predict isoflavone content. The selection of a suitable calibration model was based on a high regression coefficient (R2), and lower standard error of calibration (SEC) values. Robust validated predictions were obtained for isoflavones, however less than robust calibrations were obtained for the total saponins. The correlations were not as robust for predicting the carbohydrate composition. NIRS is a suitable, rapid, nondestructive method to determine isoflavone composition in ground soybeans. Useful isoflavone composition predictions for large numbers of soybean samples can be obtained from quickly obtained NIRS scans.
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