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[Display omitted] Population-based studies have highlighted the link between chronic urticaria (CU) and metabolic syndrome, and metabolic alterations have been revealed in CU. However, to our knowledge, a comprehensive metabolomics study on a large cohort of patients with CU has not been reported. We sought to explore the underlying metabolic subtypes and novel metabolite biomarkers for CU diagnosis and therapy. Plasma samples from 80 patients with CU and 82 healthy controls were collected for metabolomics quantification and bioinformatics analysis. Another independent cohort consisting of 144 patients with CU was studied to validate the findings. Bone marrow–derived mast cells and mice with IgE-induced passive cutaneous anaphylaxis were used for in vitro and in vivo experiments, respectively. We observed clear metabolome differences between CU patients and healthy controls. Meanwhile, differential metabolites N6-acetyl- l -lysine, l -aspartate, maleic acid, and pyruvic acid were used to construct random forest classifiers and achieved area under receiver operating characteristic curve values greater than 0.85, suggesting their potential as diagnostic biomarkers of CU. More importantly, by exploring the underlying metabolic subtypes of CU, we found that the low abundance of pyruvic acid and maleic acid was significantly related to the activity of CU, poor efficacy of second-generation H 1 antihistamines, and short relapse-free time. The results were validated in the independent cohort. Moreover, supplementation with pyruvate or maleate could significantly attenuate IgE-mediated mast cell activation in vitro and in vivo. Plasma pyruvic acid and maleic acid may be effective biomarkers for predicting disease activity, therapeutic efficacy, and prognosis for patients with CU. [ABSTRACT FROM AUTHOR]

If a mechanism of more efficient glycolysis depending on pyruvate is present in stallion spermatozoa, detrimental effects of higher glucose concentrations that are common in current commercial extenders could be counteracted. To test this hypothesis, spermatozoa were incubated in a 67 mM Glucose modified Tyrode's media in the presence of 1- or 10-mM pyruvate and in the Tyrode's basal media which contains 5 mM glucose. Spermatozoa incubated for 3 h at 37 °C in 67 mM Tyrode's media with 10 mM pyruvate showed increased motility in comparison with aliquots incubated in Tyrode's 5 mM glucose and Tyrode's 67 mM glucose (57.1 ± 3.5 and 58.1 ± 1.9 to 73.0 ± 1.1 %; P < 0.01). Spermatozoa incubated in Tyrode's with 67 mM glucose 10 mM pyruvate maintained the viability along the incubation (64.03 ± 15.4 vs 61.3 ± 10.2), while spermatozoa incubated in 67 mM Glucose-Tyrode's showed a decrease in viability (38.01 ± 11.2, P < 0.01). 40 mM oxamate, an inhibitor of the lactate dehydrogenase LDH, reduced sperm viability (P < 0.05, from 76 ± 5 in 67 mM Glucose/10 mM pyruvate to 68.0 ± 4.3 %, P < 0.05). Apoptotic markers increased in the presence of oxamate. (P < 0.01). UHPLC/MS/MS showed that 10 mM pyruvate increased pyruvate, lactate, ATP and NAD+ while phosphoenolpyruvate decreased. The mechanisms that explain the improvement of in presence of 10 mM pyruvate involve the conversion of lactate to pyruvate and increased NAD+ enhancing the efficiency of the glycolysis. • 10 mM pyruvate in a 67 mM Glucose-Tyrode's media maintains sperm functionality in comparison with a 67 mM glucose- Tyrode's. • Motility, linear motility, velocities membrane integrity, mitochondrial membrane potential and glutathione content were higher in the 10 mM pyruvate, 67 mM glucose media. • LACTATE and NAD+ content were higher in the spermatozoa incubated in the 10 mM pyruvate in a 67 mM Glucose-Tyrode's media. • The mechanism explaining the improvements may involve conversion of pyruvate to lactate and regeneration of NAD+. • The stallion spermatozoa may produce significant amounts of lactate under high Oxygen (Warburg effect). [ABSTRACT FROM AUTHOR]

This article proposes an evolutionary trajectory for the development of biological energy producing systems. Six main stages of energy producing system evolution are described, from early evolutionary pyrite-pulled mechanism through the Last Universal Common Ancestor (LUCA) to contemporary systems. We define the Last Pure Chemical Entity (LPCE) as the last completely non-enzymatic entity. LPCE could have had some life-like properties, but lacked genetic information carriers, thus showed greater instability and environmental dependence than LUCA. A double bubble model is proposed for compartmentalization and cellularization as a prerequisite to both highly efficient protein synthesis and transmembrane ion-gradient. The article finds that although LUCA predominantly functioned anaerobically, it was a non-exclusive anaerobe, and sulfur dominated metabolism preceded phosphate dominated one. • Fe-S motifs are essential through the evolution of bioenergetics. • Imidazole is important factor in deprotonation at the origin of metabolic pathways. • Last Pure Chemical Entity fully operating without enzymes had to exist. • Last Universal Common Ancestor must have been a facultative aerobe. • In the course of evolution of bioenergetics the efficacy increased. [ABSTRACT FROM AUTHOR]

Pyruvate is an important energy substance during early embryonic development of mammals. However, the underlying mechanisms of pyruvate during early embryonic development in pigs and its role in zygotic genome activation (ZGA) are not fully understood. Here, based on a previous RNA-seq dataset of porcine early embryos, we found that pyruvate metabolism-related genes started to be expressed at the 4-cell stage and that pyruvate metabolism-related genes were correlated with porcine ZGA marker genes. To determine the function of pyruvate in porcine embryos, in vitro fertilization (IVF) embryos were cultured in PZM-3 medium (control group); modified PZM-3 medium that only contains pyruvate and lactate plus salts (+P group); or modified PZM-3 medium lacking pyruvate (-P group). The 4-cell arrest rate at 72 h was significantly increased in the -P group compared to the +P group (P < 0.05). In addition, we observed that the reactive oxygen species (ROS) level was significantly increased and that the adenosine triphosphate (ATP) level was significantly (P < 0.05) decreased in the -P group compared to the +P group. Moreover, the expression of ZGA marker genes and SIRT1 protein in embryos was significantly decreased in the -P group compared to the +P group (P < 0.05). Furthermore, the acetylation level of H3K9 was significantly decreased (P < 0.05) and the methylation level of H3K9 was significantly increased (P < 0.05) in the -P group compared to the +P group. In summary, our findings demonstrate that pyruvate affects early embryonic development in pigs by promoting ZGA and reducing oxidative stress levels. • Genes related to pyruvate metabolism were correlated with porcine zygotic genome activation marker genes. • Pyruvate can reduce 4-cell arrest and oxidative stress levels in porcine embryos. • Pyruvate can promote ZGA by affecting H3K9 modification levels in porcine embryos. [ABSTRACT FROM AUTHOR]

ParaHydrogen Induced Polarization-Side Arm Hydrogenation (PHIP-SAH) is an inexpensive tool to obtain hyperpolarized pyruvate (and other metabolites) that can be applied to in vivo diagnostics, for the investigation of metabolic processes. This method is based on hydrogenation, using hydrogen enriched in the para-isomer, of unsaturated substrates, catalyzed, usually, by a homogeneous rhodium(I) complex. In this work, the effect of the solvent on the hydrogenation efficiency and the hyperpolarization level were investigated. Coordinating solvents, such as acetone and methanol, can increase significantly either the efficiency or the hyperpolarization level, but they are not compatible with the intended metabolic applications. The phase extraction of the hyperpolarized product (sodium pyruvate) in an aqueous solution was obtained carrying out the hydrogenation reaction in chloroform and toluene. The traces of the organic solvents in the water phase were removed, by means of filtration through a lipophilic resin, thus improving the biocompatibility of the aqueous solution of the hyperpolarized product. [Display omitted] • Hydrogenation in acetone or methanol can be quite efficient or give high polarization. • Chloroform and toluene were used to extract pyruvate in an aqueous solvent. • Traces of solvents are removed from the aqueous solution using a lipophilic resin. [ABSTRACT FROM AUTHOR]

Accurate and objective estimation of the postmortem interval (PMI) is crucial in forensic practice. This study aimed to infer PMI through equations based on the relationship between PMI and metabolomics biomarkers.Rats were subjected to models representing various temperatures and causes of death, with blood collected at different intervals. Untargeted gas chromatography mass spectrometry metabolomics detection methods were developed, and candidate biomarkers were chosen as co-differentially expressed metabolites in four models. A targeted method was then developed for quantitatively determining candidate biomarkers. Animal tests and human cadaver samples with clearly documented causes of death and time were used to verify the reliability of the regression equation.Results: Unique differential metabolites for CO poisoning deaths included 2,3-butanediol, hypoxanthine, and dehydrated hexanol, while those for mechanical asphyxia deaths comprised propylamine, 1,3-propylene glycol, phosphoric acid, and sorbitol. Pyruvate, glycerol and isoleucine were identified as candidate biomarkers. Human case results demonstrated the method's potential (error rate < 20 %). The findings of this study may offer reference points for estimating PMI and causes of death in forensic practice. • The probable bio-markers of CO poisoning are 2,3-butanediol, hypoxanthine, and dehydrated hexanol. • Pyruvate, glycerol and isoleucine were identified as PMI candidate biomarkers. • Human case results demonstrated the method's potential (error rate < 20 %). [ABSTRACT FROM AUTHOR]

A vexing problem in mitochondrial medicine is our limited capacity to evaluate the extent of brain disease in vivo. This limitation has hindered our understanding of the mechanisms that underlie the imaging phenotype in the brain of patients with mitochondrial diseases and our capacity to identify new biomarkers and therapeutic targets. Using comprehensive imaging, we analyzed the metabolic network that drives the brain structural and metabolic features of a mouse model of pyruvate dehydrogenase deficiency (PDHD). As the disease progressed in this animal, in vivo brain glucose uptake and glycolysis increased. Propionate served as a major anaplerotic substrate, predominantly metabolized by glial cells. A combination of propionate and a ketogenic diet extended lifespan, improved neuropathology, and ameliorated motor deficits in these animals. Together, intermediary metabolism is quite distinct in the PDHD brain—it plays a key role in the imaging phenotype, and it may uncover new treatments for this condition. [Display omitted] • Glucose uptake and metabolism are increased in the PDHD brain in vivo • Two entry points of carbon sustain Krebs cycle activity in the PDHD brain • Propionate is a major anaplerotic substrate in the PDHD brain • Propionate in conjunction with a ketogenic diet improves neurological outcomes in PDHD In this study, Marin-Valencia et al. show that elevated glucose uptake and glycolysis in the PDH-deficient (PDHD) brain in vivo are indicators of disease progression. Propionate is a key anaplerotic substrate in this condition, and its supplementation with a ketogenic diet prolongs lifespan and improves neurological outcomes in PDHD mice. [ABSTRACT FROM AUTHOR]

The cell wall of endophytic strain Rathayibacter oskolensis VKM Ac-2121T (family Microbacteriaceae, class Actinomycetes) was found to contain neutral and acidic glycopolymers. The neutral polymer is a block-type rhamnomannan partially should be substitutied by xylose residues, [→2)-α-[β-D-Xylp-(1 → 3)]-D-Man p -(1 → 3)-α-D-Rhap-(1→] ∼30 [→2)-α-D-Man p -(1 → 3)-α-D-Rha p -(1→] ∼45. The acidic polymer has branched chain, bearing lactate and pyruvate residues, →4)-α-D-[ S -Lac-(2–3)-α-L-Rha p -(1 → 3)]-D-Man p -(1 → 3)-α-D-[4,6- R -Pyr]-D-Gal p- (1 → 3)-β-D-Glc p -(1 →. The structures of both glycopolymers were not described in the Gram-positive bacteria to date. The glycopolymers were studied by chemical and NMR spectroscopic methods. The results of this study provide new data on diversity of bacterial glycopolymers and may prove useful in the taxonomy of the genus Rathayibacter and for understanding the molecular mechanisms of interaction between plants and plant endophytes. [Display omitted] • New structures of neutral and acidic polysaccharides are presented. • Neutral polymer is a block-type rhamnomannan partially substituted by Xyl p residues. • The acidic polymer is branched lactate- and pyruvate-containing polysaccharide. [ABSTRACT FROM AUTHOR]

Energy is essential for early embryogenesis, and fertilized eggs can successfully develop to blastocyst in in vitro culture medium with an appropriate energy supply. Conversely, embryonic development is negatively affected by a suboptimal energy supply. We previously observed that a low level of pyruvate greatly arrests mouse embryos at the 2-cell stage. However, how methylation modifications are affected at this specific stage remains unknown. In this study, we found that mouse embryos could timely develop to the 4-cell stage in K+simplex optimized medium (KSOM) with control level of pyruvate, but embryos were significantly arrested at the 2-cell stage when pyruvate was reduced to 0.2-fold of the control level. Moreover, the fluorescence intensities of 5 mC, H3K4me2, H3K9me2 and H3K27me2 in the 2-cell stage embryos of the 0.2-fold pyruvate group were notedly lower than those of the control group, but N6-methyladenosine (m6A) fluorescence intensity was higher, suggesting that global genomic DNA, histone and m6A methylation modifications are disrupted with low levels of pyruvate. Consistently, the mRNA levels of genes related to DNA methylation, histone methylation and m6A modifications were also disturbed in the 2-cell stage embryos cultured with low levels of pyruvate. In summary, our findings demonstrate that insufficient pyruvate in culture medium results in mouse embryonic developmental arrest, at least in part due to defects in methylation modifications. • The low-level pyruvate in culture medium strongly arrests mouse embryos at the 2-cell stage. • The low-level pyruvate disturbs methylation modifications in embryos at the 2-cell stage. • The low-level pyruvate mediated-embryonic development arrest causes at least in part the defective methylation modifications. [ABSTRACT FROM AUTHOR]

The mechanism of pyruvate-underproduction of aneuploid sake yeast was investigated in this study. In our previous report, we revealed that an increase in chromosome XI decreases pyruvate productivity of sake yeast. In this report, we found that increased copy number of CCP1 , which is located on chromosome XI and encodes cytochrome- c peroxidase, decreased the pyruvate productivity of sake yeasts. Introducing an extra copy of CCP1 activated respiratory metabolism governed by Hap4 and increased reactive oxygen species. Therefore, it was concluded that increased copy number of CCP1 on chromosome XI activated respiratory metabolism and decreased pyruvate levels in an aneuploid sake yeast. This is the first report that describes a mechanism underlying the improvement of brewery yeast by chromosomal aneuploidy. [ABSTRACT FROM AUTHOR]

Incapacitated regulatory T cells (Tregs) contribute to immune-mediated diseases. Inflammatory Tregs are evident during human inflammatory bowel disease; however, mechanisms driving the development of these cells and their function are not well understood. Therefore, we investigated the role of cellular metabolism in Tregs relevant to gut homeostasis. Using human Tregs, we performed mitochondrial ultrastructural studies via electron microscopy and confocal imaging, biochemical and protein analyses using proximity ligation assay, immunoblotting, mass cytometry and fluorescence-activated cell sorting, metabolomics, gene expression analysis, and real-time metabolic profiling utilizing the Seahorse XF analyzer. We used a Crohn's disease single-cell RNA sequencing dataset to infer the therapeutic relevance of targeting metabolic pathways in inflammatory Tregs. We examined the superior functionality of genetically modified Tregs in CD4+ T-cell–induced murine colitis models. Mitochondria–endoplasmic reticulum appositions, known to mediate pyruvate entry into mitochondria via voltage-dependent anion channel 1 (VDAC1), are abundant in Tregs. VDAC1 inhibition perturbed pyruvate metabolism, eliciting sensitization to other inflammatory signals reversible by membrane-permeable methyl pyruvate supplementation. Notably, interleukin (IL) 21 diminished mitochondria–endoplasmic reticulum appositions, resulting in enhanced enzymatic function of glycogen synthase kinase 3 β, a putative negative regulator of VDAC1, and a hypermetabolic state that amplified Treg inflammatory response. Methyl pyruvate and glycogen synthase kinase 3 β pharmacologic inhibitor (LY2090314) reversed IL21-induced metabolic rewiring and inflammatory state. Moreover, IL21-induced metabolic genes in Tregs in vitro were enriched in human Crohn's disease intestinal Tregs. Adoptively transferred Il21r –/– Tregs efficiently rescued murine colitis in contrast to wild-type Tregs. IL21 triggers metabolic dysfunction associated with Treg inflammatory response. Inhibiting IL21-induced metabolism in Tregs may mitigate CD4+ T-cell–driven chronic intestinal inflammation. [Display omitted] Interleukin 21 induces metabolic alterations and acquisition of an inflammatory-like phenotype by perturbing mitochondria–endoplasmic reticulum crosstalk, thereby diminishing the capacity of Tregs in suppressing inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

Using 13C 6 glucose labeling coupled to gas chromatography-mass spectrometry and 2D 1H-13C heteronuclear single quantum coherence NMR spectroscopy, we have obtained a comparative high-resolution map of glucose fate underpinning β cell function. In both mouse and human islets, the contribution of glucose to the tricarboxylic acid (TCA) cycle is similar. Pyruvate fueling of the TCA cycle is primarily mediated by the activity of pyruvate dehydrogenase, with lower flux through pyruvate carboxylase. While the conversion of pyruvate to lactate by lactate dehydrogenase (LDH) can be detected in islets of both species, lactate accumulation is 6-fold higher in human islets. Human islets express LDH, with low-moderate LDHA expression and β cell-specific LDHB expression. LDHB inhibition amplifies LDHA-dependent lactate generation in mouse and human β cells and increases basal insulin release. Lastly, cis -instrument Mendelian randomization shows that low LDHB expression levels correlate with elevated fasting insulin in humans. Thus, LDHB limits lactate generation in β cells to maintain appropriate insulin release. [Display omitted] • Human and rodent islets generate lactate following glucose stimulation • β cells specifically express LDHB, which acts to limit lactate generation • LDHB inhibition leads to inappropriate insulin release at low glucose • LHDB cis -EQTLs associate with fasting glucose in humans Cuozzo et al. show that glucose-stimulated rodent and human islets generate lactate. Transcriptomic, imaging, and Mendelian randomization analyses reveal that LDHB restrains β cell lactate production and contributes to basal/fasting insulin release. LDHB expression and thus regulated lactate generation might reflect a key mechanism underlying β cell metabolism and function. [ABSTRACT FROM AUTHOR]

Energy homeostasis and accomplishment of maternal-to-zygotic transition (MZT), which involves the timed processes of maternal mRNA clearance and zygotic genome activation (ZGA), are essential for mammalian embryogenesis. However, how energy substrates regulate maternal mRNA clearance and the underlying mechanisms have not yet been fully elucidated. Here, we found that mouse embryos were arrested at the 2-cell stage when the pyruvate level was reduced to one-fifth of the control level. Moreover, we observed that the mitochondrial contents and ROS levels were reduced. Interestingly, some maternal mRNA, including transcripts involved in the maternal factor-mediated mRNA decay (M-decay) pathway, was vastly degraded from 1-cell to 2-/4-cell embryos when cultured with control pyruvate levels, but the clearance of these transcripts was hindered when the pyruvate level was reduced. In contrast, some transcripts involved in the zygotic factor-mediated mRNA decay (Z-decay) pathway were vastly downregulated by the reduction in pyruvate. This effect was possibly due to a reduction in global transcription, as the embryos cultured with low-level pyruvate had lower transcription activity than embryos cultured with control pyruvate level. In summary, our findings demonstrate that low-level pyruvate inhibits maternal mRNA clearance, possibly by disrupting the M- and Z-decay pathways, extending our current understanding of the energy requirements of embryogenesis. • This study explored the effects of energy substrate pyruvate on maternal mRNA clearance and the underlying causes. • Our findings demonstrated that developmental arrest is more likely to occur at low levels of pyruvate but not high levels. • We observed that pyruvate deficiency hinders maternal mRNA clearance, possibly by disrupting the M- and Z-decay pathways. [ABSTRACT FROM AUTHOR]

A pyruvated exopolysaccharide designated as LPE-1 was isolated and purified from the fermentation broth of Lactobacillus plantarum AR307 and characterized for its chemical structure. The results indicated that LPE-1 contained galactopyranose (Gal p) and glucopyranose (Glc p) at a molar ratio of 2: 1. The weight-averaged molecular weight (M w) of LPE-1 was 605 kDa, with a polydispersity index (PDI) of 1.57, intrinsic viscosity ([ ƞ ]) of 3.28 dL/g, Mark-Houwink-Sakurada exponent α of 0.65 and gyration of radius (R g) of 36.10 nm. The results of GC–MS and NMR revealed that pyruvate (Pyr) was found to form cyclic ketals at O -4 and O -6 position of terminal galactopyranose (T-Gal p). The backbone of LPE-1 was identified to be consisted of 1,4-β-D-Glc p (23.19%), 1,4-α-D-Glc p (11.38%) and 1,4,6-β-D-Gal p (12.05%), branched by 1,6-β-D-Gal p (38.88%) at O -6 position of 1,4,6-β-D-Gal p residue and terminated by T-β-D-Gal p (5.60%) or T-β-D-(4,6-Pyr)-Gal p (8.90%). A possible structural unit was proposed for LPE-1 as follows: [Display omitted] where Gal p * is either T-β-D-(4,6-Pyr)-Gal p or T-β-D-Gal p. The presence of pyruvate group in LPE-1 would play an important role in improving the viscosity and plasticity of dairy products. • A novel exopolysaccharide LPE-1 was isolated from Lactobacillus plantarum AR307. • LPE-1 was a galactoglucan with 1,4 and 1,6 glycosidic bonds. • The pyruvate substituent was found linked to O -4 and O -6 position of T-Gal p. [ABSTRACT FROM AUTHOR]

• Exogenous sodium pyruvate displays anti-melanogenic properties. • Intracellular pyruvate suppresses dendrite elongation by inhibiting Rac1 pathway. • Pyruvate treatment alleviates UV-induced hyperpigmentation in reconstructed human skin equivalent. Melanin is synthesized in melanocytes and transferred to keratinocytes through dendrites. Endogenous pyruvate is a key metabolite for ATP production in glycolysis, and the tricarboxylic acid (TCA) cycle and exogenous pyruvate provide protection against oxidative stress and acidosis in the intercellular space. The function of pyruvate in the regulation of dendrite outgrowth remains to be elucidated. We examined the effect of pyruvate on dendritic elongation and skin pigmentation Murine B16F10 melanoma cells and human primary melanocytes were used for in vitro analysis. Melanin quantitation and histochemical staining were performed in a 3D pigmented human skin model. We demonstrated the participation of monocarboxylate transporters (MCTs) responsible for the membrane transport of pyruvate in B16F10 melanoma cells. The accumulation of pyruvate occurred in a pH-dependent manner, which was highly sensitive to a specific MCT inhibitor (α-cyano-4-hydroxycinnamic acid). α-MSH-induced morphological changes, including dendrite elongation and growth-cone-like structure, were diminished in B16F10 cells upon treatment with pyruvate. In addition, the number of dendrite branches was reduced in normal human epidermal melanocytes. As the Rho-subfamily of monomeric GTP-binding proteins modulates dendrite formation, we subsequently examined the suppression of Rac1 activation by pyruvate, but not RhoA and Cdc42. Furthermore, pyruvate showed anti-melanogenic effects against UV-induced pigmentation in reconstructed pigmented epidermis, established by co-seeding autologous melanocytes and keratinocytes, which act similar to in vivo skin tissue. These results suggest that pyruvate treatment may be an alternative or additive therapeutic strategy to prevent hyperpigmentation. [ABSTRACT FROM AUTHOR]

POxNPs/PGE = Pyruvate oxidase nanoparticles; PGE = Pencil graphite electrode • Prepared and characterized pyruvate oxidase nanoparticles (POxNPs). • Immobilized POxNPs onto pencil graphite electrode to construct improved amperometric pyruvate biosensor. • Biosensor displayed limit of detection as 0.58 μM within a linear working range, 0.001–6000 μM. • Biosensor measured elevated level of pyruvate in sera of heart patients. • Working electrode showed storage stability of 210 days, while being stored dry at 4 °C. This present study was aimed to fabricate a sensitive and improved amperometric biosensor by the nanoparticles of pyruvate oxidase, which were prepared and immobilized covalently onto pencil graphite electrode. The biosensor showed ideal working within 5 s under defined conditions of pH 6.0 and incubation temperature of 30 °C at an applied voltage of -0.1 V. Under standard assay conditions, a linear response was obtained between pyruvate concentration ranging from 0.001 to 6000 μM and current (μA). A lower detection limit (0.58 μM) and an excellent correlation coefficient (R2 = 0.999) with standard spectrophotometric assay was obtained for the present biosensor. Within and between batches of coefficients of variation were calculated and found to be 3.61 % and 3.33 %, respectively. The biosensor was put to continual use for over 210 days. The biosensor was employed for the measurement of pyruvate level in sera of normal healthy individuals and persons suffering from heart disease. [ABSTRACT FROM AUTHOR]

Triple negative breast cancer (TNBC) is an aggressive malignancy for which chemotherapy remains the standard treatment. However, between 3 and 5 years after chemotherapy, about half patients will relapse and it is essential to identify vulnerabilities of cancer cells surviving neoadujuvant therapy. In this study, we established persistent TNBC cell models after treating MDA-MB-231 and SUM159-PT TNBC cell lines with epirubicin and cyclophosphamide, and then with paclitaxel, for a total of 18 weeks. The resulting chemo-persistent cell lines were more proliferative, both in vitro and in xenografted mice. Interestingly, MDA-MB-231 persistent cells became less sensitive to chemotherapeutic drugs, whereas SUM159-PT persistent cells kept similar sensitivity compared to control cells. The reduced sensitivity to chemotherapy in MDA-MB-231 persistent cells was found to be associated with an increased oxidative phosphorylation (OXPHOS) and modified levels of tricarboxylic acid cycle (TCA) intermediates. Integration of data from proteomics and metabolomics demonstrated TCA cycle among the most upregulated pathways in MDA-MB-231 persistent cells. The absence of glucose and pyruvate impeded OXPHOS in persistent cells, while the absence of glutamine did not. In contrast, OXPHOS was not modified in control cells independently of TCA substrates, indicating that MDA-MB-231 persistent cells evolved towards a more pyruvate dependent profile. Finally, the inhibition of pyruvate entry into mitochondria with UK-5099 reduced OXPHOS and re-sensitized persistent cells to therapeutic agents. Together, these findings suggest that targeting mitochondrial pyruvate metabolism may help to overcome mitochondrial adaptation of chemo-persistent TNBC. [ABSTRACT FROM AUTHOR]

Post-stroke depression (PSD) is a common and serious complication following stroke. Both stroke and depression have independently been associated with pathologically elevated glutamate levels in the brain's extra-cerebral fluid (ECF). Here we evaluate an alternative therapeutic approach to PSD with pyruvate. Rats were randomly assigned into one of 3 groups: Middle Cerebral Artery Occlusion (MCAO) plus pyruvate treatment, MCAO plus placebo treatment, and sham operated rats. Post-MCAO depressive and anxiety-like behavior was assessed, along with neurological status, brain infarct zone, brain edema, blood brain barrier (BBB) breakdown, cerebrospinal fluid and blood glutamate levels. Anxiety-like behavior and levels of blood alanine and α-ketoglutarate were measured in naïve rats treated with pyruvate, as a control. Post-stroke neurological deficit with concurrent elevation in glutamate levels were demonstrated, with peak glutamate levels 24 h after MCAO. Treatment with pyruvate led to reduced glutamate levels 24 h after MCAO and improved neurologic recovery. Pyruvate treatment reduced lesion volume, brain edema and the extent of BBB permeability 24 h post-MCAO. Naïve rats treated with pyruvate showed increased levels of α-ketoglutarate. Rats demonstrated post-stroke depressive behavior that was improved by the administration of pyruvate. There was less anxiety-like behavior in post-stroke rats treated with placebo in comparison to the post-stroke rats treated with pyruvate or sham operated rats. Glutamate scavenging with pyruvate appears to be an effective as a method in providing neuroprotection following stroke and as a therapeutic option for the treatment of PSD by reducing the consequent elevations in CNS glutamate levels. • Post-stroke neurological deficit with concurrent elevation in glutamate levels were demonstrated, with peak glutamate levels 24 h after MCAO. • Treatment with pyruvate led to reduced glutamate levels 24 h after MCAO and improved neurologic recovery. • Rats demonstrated post-stroke depressive behavior that was improved by the administration of pyruvate. • There was less anxiety-like behavior in post-stroke rats treated with placebo in comparison to the post-stroke rats treated with pyruvate or sham operated rats. • Our main conclusion was that glutamate scavenging with pyruvate appears to be an effective as a method in providing neuroprotection following stroke and as a therapeutic option for the treatment of PSD by reducing the consequent elevations in CNS glutamate levels. [ABSTRACT FROM AUTHOR]

Abstract Tricarboxylic acid cycle (TCA cycle) is the most effective energy metabolism pathway in higher plants and animals. However, there is no information about its response in plants under environmental stress, especially under polycyclic aromatic hydrocarbons (PAHs) pollution. Here, this study is the first to discuss the intermediate and related enzyme changes in TCA cycle in plants. We applied high performance liquid chromatography (HPLC) and isobaric tags for relative and absolute quantitation (iTRAQ) proteomics to analyze the intermediate concentration and related protein response in wheat leaf cells, respectively. The concentrations of citrate and malate (0.37 and 0.57 mg kg−1) in the treatment with 1.0 mg L−1 phenanthrene were higher than those in the control, and the concentrations of the other five intermediates (i.e., α-ketoglutarate, fumarate, oxaloacetate, pyruvate and succinate) in the treatment were lower than those in the control. Three detected proteins (pyruvate dehydrogenase, dihydrolipoyllysine-residue succinyltransferase and fumarate hydratase) involved in TCA cycle were up-regulated when phenanthrene was accumulated in wheat leaf cells. Meanwhile, real-time PCR results of seven key TCA cycle enzymes genes further confirmed the aforementioned enzyme results. The gene expressions of ketoglutarate dehydrogenase, fumarase and pyruvate dehydrogenase were promoted when phenanthrene was accumulated, while the other four genes were suppressed. In general, pyruvate decrease is the key reason for TCA cycle inactivation under exposure to phenanthrene. Meanwhile, malate concentration increases significantly (P < 0.05), and all the three conversion enzymes turn active. Our results offer helpful information for understanding TCA cycle energy metabolism response to PAH exposure. Graphical abstract Unlabelled Image Highlights • Pyruvate decrease is the key reason for TCA cycle inactivation upon exposure to PAHs. • The genes of α-ketoglutarate dehydrogenase and fumarase are promoted. • Malate and citrate concentrations increase significantly. • Oxaloacetate and succinate concentrations decrease when phenanthrene accumulates. [ABSTRACT FROM AUTHOR]

Abstract Pyruvate (carboxylate anion of pyruvic acid) is an organic molecule, with a backbone of 3‑carbon atoms. Pyruvate is known to undergo several fates depending upon the organism under consideration. It is one of the only molecules involved in both synthesis and breakdown pathways, thereby making it a very busy molecule. Aberrant levels of this metabolite are known to cause several disorders like diabetes, cirrhosis, cardiovascular diseases and severe brain abnormalities. This is an attractive candidate for bodybuilders as a supplement, and also holds an important position in the food and beverage industry. Recent research also showed pyruvate as a screening molecule for cancer. Thereby, detection of this metabolite is an important aspect from the clinical and diagnostic point of view. Conventional methods available for the detection of pyruvate had several disadvantages such as tedious, time-consuming, non-specific, expensive instrumental setup, the requirement of trained personnel's, especially for chromatographic techniques. Biosensing techniques overcome these pitfalls, as these are easy, highly sensitive and fast. Pyruvate biosensors deciphered till date work optimally within 6–180 s, between pH ranging from 5.7 to 7.0 and temperature 30–35 °C and pyruvate concentration ranging from 4 to 16,000 μM. Numerous biosensors have been elucidated to detect pyruvate levels in biological fluids like serum of diseased patients, calf serum and in food products like yogurt, onion and garlic. This review illustrates the various analytical parameters for pyruvate determination with a special focus on pyruvate biosensors. Also, the future scope for improvement and enhancement of pyruvate biosensors are discussed. Highlights • Pyruvate, an alpha-keto acid is a screening molecule for cancer diagnosis. • Elevated levels of pyruvate are correlated with cardiovascular diseases, brain abnormalities and diabetes mellitus. • Analysis of pyruvate helps in quality assurance of pungent food products like onion, garlic. • Present review illustrates principles, merits and demerits of conventional methods with special emphasis on biosensors. • The future research could be focused on miniaturization of pyruvate biosensors. [ABSTRACT FROM AUTHOR]

Highlights • We comprehensively review the importance of NADP-ME under different stress conditions. • We focus in particular on the responses of NADP-ME to stress at the levels of activity and gene expression. • We discuss the importance of NADPH in apoplastic oxidative burst, ascorbate-glutathione pathway and flavonoid synthesis. • CRISPR technology would be a potential approach for analyzing redundancy between NADP-ME isoforms or between NADP-ME and other dehydrogenases. • Our review also places emphasis on the reversibility of the NADP-ME reaction. Abstract Under natural conditions, plants constantly encounter various fluctuating environmental stresses, which potentially restrict plant growth, plant development and even limit crop productivity. In addition to carbon fixation activity in C4 photosynthesis, NADP-dependent malic enzyme (NADP-ME) has been suggested to play important roles in diverse stress responses in plants. NADP-ME is one of the essential enzymes metabolizing malate, which is important for stabilizing cytoplasmic pH, controlling stomatal aperture, increasing resistance to aluminum excess and pathogen. Pyruvate, another product of NADP-ME reaction, participates in the synthesis of defense compounds such as flavonoids and lignin, which are involved in stresses tolerance such as mechanical wounding and pathogen invasion. Moreover, NADP-ME provides essential reductive coenzyme NADPH in the biosynthesis of flavonoids and lignin. On the other hand, NADPH is crucial for reactive active species (ROS) metabolizing systems such as the ascorbate-glutathione pathway and NADPH-dependent thioredoxin reductase, and is also required by apoplastic oxidative burst in most plant-pathogen interactions. This mini-review is largely focus on the characteristics of gene expression and activity of NADP-ME, as well as its interaction with ROS signaling under a variety of biotic and abiotic stress responses, which will provide a theoretical foundation for breeding of stress resistant crops. [ABSTRACT FROM AUTHOR]

Highlights • Among ESKAPE bacteria, 3-bromopyruvate selectively inhibits Staphylococcus aureus. • 3-bromopyruvate kills both metabolically active and inactive cells. • 3-bromopyruvate has potent biofilm-disrupting activity. ABSTRACT Increased antibacterial resistance jeopardizes current therapeutic strategies to control infections, soliciting the development of novel antibacterial drugs with new mechanisms of action. This study reports the discovery of potent and selective antistaphylococcal activity of 3-bromopyruvate (3BP), an antimetabolite in preclinical development as an anticancer drug. 3BP showed bactericidal activity against Staphylococcus aureus , with active concentrations comparable with those reported to be effective against cancer cells. In contrast, no relevant activity was observed against other ESKAPE bacteria (Enterococcus faecium, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.). The antistaphylococcal activity of 3BP was confirmed using a panel of human and veterinary strains, including multi-drug-resistant isolates. 3BP showed highest antibacterial activity under conditions that increase its stability (acidic pH) or promote S. aureus fermentative metabolism (anaerobiosis), although 3BP was also able to kill metabolically inactive cells. 3BP showed synergism with gentamicin, and also disrupted preformed S. aureus biofilms at concentrations only slightly higher than those inhibiting planktonic cells. This study unravels novel antibacterial and antibiofilm activities for the anticancer drug 3BP, paving the way for further preclinical studies. [ABSTRACT FROM AUTHOR]

Highlights • E. coli was engineered to produce pyruvate from glucose under anoxic conditions. • Efficient substrate-to-product conversion was resulted from the respiro-fermentative process. • Reoxidation of NADH was ensured via anaerobic respiration with external electron acceptor. • Artificial futile cycle was implemented to enforced anaerobic ATP hydrolysis. • Yield of 1.73 mol/mol, amounting to 87% of theoretical maximum, was achieved. Abstract An Escherichia coli K-12 MG1655-derived strain was engineered for respiro-fermentative production of pyruvate from glucose under anoxic conditions, which is preferred for industrial-scale microbial synthesis of valuable chemicals. The pathways of anaerobic pyruvate dissimilation were blocked in the strain by the deletion of the ackA , pta , poxB , ldhA , adhE , and pflB genes. The phosphoenolpyruvate-dependent phosphotransferase system of glucose transport and phosphorylation was substituted by an alternative ATP-dependent system resulting from the overexpression of galP and glk upon deletion of ptsG. The channelling of pyruvate towards the oxidative branch of the TCA cycle under respiratory conditions was prevented in the strain due to the deletion of aceEF genes, encoding components of pyruvate dehydrogenase, while the operation of the entire reductive branch of the TCA cycle was interrupted by knocking out frdAB and sdhAB. Reoxidation of glycolytic NADH was ensured via anaerobic respiration with nitrate serving as an external electron acceptor. To enforce anaerobic ATP hydrolysis, an ATP-consuming futile cycle of pyruvate-oxaloacetate-malate-pyruvate was established in the strain by expressing the Bacillus subtilis pycA gene, encoding pyruvate carboxylase. In the presence of sufficient amounts of an external electron acceptor and CO 2 source, the engineered strain was able to efficiently utilise glucose and convert it to pyruvate anaerobically with a yield of 1.73 mol/mol, amounting to 87% of the theoretical maximum. The implemented strategy offers the potential for the development of highly efficient processes of bio-based pyruvate production. [ABSTRACT FROM AUTHOR]

For many years lactate was seen as a metabolite from glucose metabolism. However, since the last century researchers have shown that this molecule has an important role on liver, muscle, and brain metabolism. Lactate traffics along whole body mediating many biological processes depending on specific situations. For example, glucose is the main substrate used during exercise but lactate released by striated skeletal muscle is used by own muscle as secondary fuel. On the other hand, neuronal firing in the brain is almost totally lactate-dependent. In addition, lactate has an important role on BDNF-mediated neuroplasticity. As this molecule has a pleiotropic role in the body, it was called as "lactormone" in 2009. Here we show basic concepts on peripheral and central metabolism and discuss neurobiological pathways of lactate, including an alternative hypothesis on lactate released during exercise. [ABSTRACT FROM AUTHOR]

Abstract This review analyzes electrochemical biosensors for the determination of lactate (lactic acid) and pyruvate (pyruvic acid) concentrations in liquid samples, especially in the blood serum. The biosensor systems for the simultaneous determination of both substances and commercial variants of the biosensors are presented, and the biosensors for medical diagnostics are highlighted. The information concerning the necessity of separate and simultaneous determination of lactate and pyruvate, as well as lactate to pyruvate ratio, is given; the traditional methods for the determination of these substances are briefly described. Lactate dehydrogenase and lactate oxidase are shown to be most commonly used in the biosensors for lactate detection. Pyruvate oxidase and living cells are used in the biosensors for pyruvate detection. Different methods of the enzymes immobilization are presented, as well as strategies for enhancement of the biosensor sensitivity. An additional requirement for practical applications is the biosensor resistance to electroactive interferents, inhibitors, biofouling, and electrode passivation; thus, the variants of solving these problems in the biosensors for lactate and pyruvate detection are analyzed. Highlights • Necessity of the detection of lactate, pyruvate and their ratio in blood is shown. • Electrochemical biosensors for the lactate and pyruvate determination are compared. • The biosensors contain lactate dehydrogenase, lactate oxidase, or pyruvate oxidase. • Biosensor systems (arrays) and commercial variants of the biosensors are presented. • The importance of further development of such biosensors is discussed. [ABSTRACT FROM AUTHOR]

• LC-MS/MS dual method for simultaneous quantitation of ketone bodies, keto-acids, lactate and pyruvate for clinical diagnostics. • The methods includes stable isotopically enriched tracer quantitation for clinical in vivo metabolite fluxes research. • Blood sampling procedures, and freezer analyte stability is an issue, and utmost care should be taken for especially acetoacetate. An important area within clinical research is in vivo metabolism of ketone bodies (β-hydroxybutyrate and acetoacetate) and in connection metabolites that may affect their production and/or cellular transport such as the keto-acids from the branched-chain amino acids, lactate and pyruvate. To determine in vivo metabolite turnover, availability of accurate and sensitive methods for analyzing the plasma concentrations of these metabolites and their stable isotopically labeled enrichments is mandatory. Therefore, the present study describes a high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous analysis of ketone bodies, α-keto acids, lactate, pyruvate, and their tracer enrichments in humans using 2 different derivatization techniques with 4-bromo-N-methylbenzylamine and O-benzylhydroxylamine as derivatization reagents, and 1-ethyl-3-dimethylaminopropyl carbodiimide as coupling compound followed by a single LC-MS/MS run. The method was validated for matrix effects, linearity, accuracy, precision, recovery, stability, and enrichment (ratio) analysis of a stable isotopically labelled analytes (tracers) continuously infused in humans divided by the unlabeled endogenous analyte (tracee) that makes it possible to quantify the analyte in vivo synthesis and degradation rates. The applied parallel derivatization procedure yielded good sensitivity for all analytes of interest and their tracers. Despite the double derivatization method, mixing the ethyl acetate portions at the final stage made it possible to simultaneously analyze all compounds in a single LC-MS/MS run. Moreover, the liquid chromatography method was optimized to robustly quantify the keto acids derived from leucine (α-keto-isocaproic acid) and isoleucine (α-keto-β-methylvaleric acid), the compounds with similar chemical structure and identical molecular weights. The presented method is designed and validated for human plasma. However, care should be taken in blood sampling and processing procedures as well as quick freezing and storage at −80 °C due to the instability of especially acetoacetate. [ABSTRACT FROM AUTHOR]

• Tumour metabolism can be imaged using hyperpolarised (HP) 13C-MRI. • HP [1-13C]pyruvate and its conversion to [1-13C]lactate can be imaged dynamically. • Response to neoadjuvant chemotherapy changes tumour metabolism. Tumour metabolism can be imaged with a novel imaging technique termed hyperpolarised carbon-13 (13C)-MRI using probes, i.e., endogenously found molecules that are labeled with 13C. Hyperpolarisation of the 13C label increases the sensitivity to a level that allows dynamic imaging of the distribution and metabolism of the probes. Dynamic imaging of [1-13C]pyruvate metabolism is of particular biological interest in cancer because of the Warburg effect resulting in the intratumoural accumulation of [1-13C]pyruvate and conversion to [1-13C]lactate. Numerous preclinical studies in breast cancer and other tumours have shown that hyperpolarised 13C-pyruvate has potential for metabolic phenotyping and response assessment at earlier timepoints than the current clinical imaging techniques allow. The clinical feasibility of hyperpolarised 13C-MRI after the injection of pyruvate in patients with breast cancer has now been demonstrated, with increased 13C-label exchange between pyruvate and lactate present in higher grade tumours with associated increased expression of the monocarboxylate transporter 1 (MCT1), the transmembrane transporter mediating intracellular pyruvate uptake, and lactate dehydrogenase (LDH) as the enzyme catalysing the conversion of pyruvate to lactate. Furthermore, a study in patients with breast cancer undergoing neoadjuvant chemotherapy suggested that early changes in 13C-label exchange can distinguish between patients who reach pathologic complete response (pCR) and those who do not. This review summarises the current literature on preclinical and clinical research on hyperpolarised 13C-MRI with [1-13C]-pyruvate in breast cancer imaging. [ABSTRACT FROM AUTHOR]

Abstract Introduction Coenzyme Q10 (CoQ10), as a supplement with a special role in mitochondrial electron transport chain, could be used as a successful migraine preventative therapy. The purpose of this study was to investigate the effect of CoQ10 supplementation on lactate, pyruvate, Matrix metalloproteinase 9 (MMP-9) and nitric oxide (NO) levels in addition to migraine attacks in women with migraine. Methods This randomized, double-blind, placebo-controlled clinical trial was performed among 46 patients diagnosed with migraine. Subjects were randomly assigned to placebo group (n = 23) and/or intervention group (n = 23), supplemented with 400 mg/day of CoQ10. The duration of the intervention was 12 weeks. Blood samples were collected at baseline and at the end of the intervention, in order to measure serum levels of CoQ10, lactate, pyruvate, MMP-9 and NO. Results Treatment with CoQ10 significantly reduced serum concentrations of lactate, pyruvate, MMP-9 and NO while CoQ10 concentrations increased after 12 weeks ( p < 0.05). There was a significant reduction in lactate/pyruvate ratio in intervention group. None of these changes had been observed in placebo treated group ( p > 0.05). The results of this study showed that CoQ10 supplementation significantly decreased frequency, severity and duration of migraine attacks compared with placebo receiving group ( p < 0.05). Conclusion In the current trial, 12 weeks of oral CoQ10 supplementation demonstrated positive effects on control of migraine attacks, mitochondrial function, serum levels of NO and MMP-9 as an involvement factors in the pathophysiology of migraines. [ABSTRACT FROM AUTHOR]

Objective After blunt thoracic trauma (TxT) and hemorrhagic shock with resuscitation (H/R) intense local inflammatory response and cell loss frequently impair the pulmonary function. Ethyl pyruvate (EP) has been reported to improve the pathophysiologic derangements in models of acute inflammation. Here, we studied the effects of EP on inflammation and lung damage after TxT + H/R. Methods Twenty four female Lewis rats (180–240 g) were randomly divided into 3 groups: two groups underwent TxT followed by hemorrhagic shock (35 ± 3 mmHg) for 60 min and resuscitation with either Ringers-Lactat (RL) alone or RL supplemented with EP (EP, 50 mg/kg). Sham operated animals underwent surgical procedures. Two hours later bronchoalveolar lavage fluid (BAL), lung tissue and blood were collected for analyses. Results EP significantly improved pO 2 levels compared to RL after TxT + H/R. TxT + H/R induced elevated levels of lactate dehydrogenase, total protein concentration in BAL and lung damage as evidenced by lung histology; these effects were significantly reduced by EP. Local inflammatory markers, lung TNF-alpha protein levels and infiltration with polymorphonuclear leukocytes (PMNL) significantly decreased in EP vs. RL group after TxT + H/R. Indicators of apoptosis as reduced BCL-2 and increased FAS gene expression after TxT + H/R were significantly increased or decreased, respectively, by EP after TxT + H/R. EP reduced TxT + H/R-induced p65 phosphorylation, which was concomitant with reduced HMGB1 levels in lung sections. Conclusions Taken together, TxT + H/R induced strong inflammatory response and apoptotic changes as well as lung injury which were markedly diminished by EP. Our results suggest that this might be mediated via NF-κB and/or HMGB1 dependent mechanism. [ABSTRACT FROM AUTHOR]

Background High methylglyoxal content disrupts cell physiology, but mammals have scavengers to prevent glycolytic and mitochondrial dysfunctions. In yeast, methylglyoxal accumulation triggers methylglyoxal-oxidizing alcohol dehydrogenase (Adh1) activity. While methylglyoxal reductases and glyoxalases have been well studied in prokaryotes and eukaryotes, experimental evidence for methylglyoxal dehydrogenase (Mgd) and other catalytic activities of this enzyme affecting glycolysis and the tricarboxylic acid cycle is lacking. Methods A glycine-rich cytoplasmic Mgd protein, designated as Mgd1/Grp2, was isolated from glutathione-depleted Candida albicans . The effects of Mgd1/Grp2 activities on metabolic pathophysiology were investigated using knockout and overexpression mutants. We measured glutathione-(in)dependent metabolite contents and metabolic effects, including viability, oxygen consumption, ADH1 transcripts, and glutathione reductase and α-ketoglutarate dehydrogenase activities in the mutants. Based on the findings, methylglyoxal-oxidizing proteins were monitored to determine effects of MGD1 / GRP2 disruption on methylglyoxal-scavenging traits during glutathione deprivation. Results Methylglyoxal-oxidizing NAD(H)-linked Mgd1/Grp2 was found solely in glutathione auxotrophs, and it catalyzed the reduction of both methylglyoxal and pyruvate. MGD1 / GRP2 disruptants showed growth defects, cell-cycle arrest, and methylglyoxal and pyruvate accumulation with mitochondrial impairment, regardless of ADH1 compensation. Other methylglyoxal-oxidizing enzymes were identified as key glycolytic enzymes with enhanced activity and transcription in MGD1 / GRP2 disruptants, irrespective of glutathione content. Conclusions Failure of methylglyoxal and pyruvate dissimilation by Mgd1/Grp2 deficiency leads to poor glutathione-dependent redox regulation despite compensation by Adh1. General significance This is the first report that multifunctional Mgd activities contribute to scavenging methylglyoxal and pyruvate to maintain metabolic homeostasis and the redox pool via glycolytic enzymes and Adh1 expression. [ABSTRACT FROM AUTHOR]

Potential adverse effects of human exposure to carbon black (CB) have been reported, but limited knowledge regarding CB-regulated metabolism is currently available. To evaluate how physical parameters of CB influence metabolism, we investigated CB and diesel exhaust particles (DEPs) and attempted to relate various physical parameters, including the hydrodynamic diameter, zeta potential, and particle number concentrations, to lung energy metabolism in female BALB/c mice. A body weight increase was arrested by 3 months of exposure to CB of smaller-size fractions, which was negatively correlated with pyruvate in plasma. There were no significant differences in cytotoxic lactate dehydrogenase (LDH) or total protein in bronchoalveolar lavage fluid (BALF) after 3 months of CB exposure. However, we observed alterations in acetyl CoA and the NADP/NADPH ratio in lung tissues with CB exposure. Additionally, the NADP/NADPH ratio was associated with the zeta potential of CB. Mild peribronchiovascular and interstitial inflammation and multinucleated giant cells (macrophages) with a transparent and rhomboid appearance and containing foreign bodies were observed in lung sections. We suggest that physical characteristics of CB, such as the zeta potential, may disrupt metabolism after pulmonary exposure. These results, therefore, provide the first evidence of a link between pulmonary exposure to CB and metabolism. [ABSTRACT FROM AUTHOR]

Objective We used transcriptomic profiling and immunohistochemistry (IHC) to search for a functional imaging strategy to resolve common problems with morphological imaging of cystic neoplasms and benign cystic lesions of the pancreas. Methods Resected pancreatic cancer (n = 21) and normal pancreas were laser-capture micro-dissected, and transcripts were quantified by RNAseq. Functional imaging targets were validated at the protein level by IHC on a pancreatic adenocarcinoma tissue microarray and a newly created tissue microarray of resected intraductal papillary mucinous neoplasms (IPMNs) and IPMN-associated adenocarcinomas. Results Genes encoding proteins responsible for cellular import of pyruvate, export of lactate, and conversion of pyruvate to lactate were highly upregulated in pancreatic adenocarcinoma compared to normal pancreas. Strong expression of MCT4 and LDHA was observed by IHC in >90% of adenocarcinoma specimens. In IPMNs, the pyruvate-to-lactate signature was significantly elevated in high grade dysplasia (HGD) and IPMN-associated adenocarcinoma. Additionally, cores containing HGD and/or adenocarcinoma exhibited a higher number of peri-lesional stromal cells and a significant increase in peri-lesional stromal cell staining of LDHA and MCT4. Interestingly, the pyruvate-to-lactate signature was significantly upregulated in cores containing only low grade dysplasia (LGD) from patients with histologically confirmed IPMN-associated adenocarcinoma versus LGD cores from patients with non-invasive IPMNs. Conclusion Our results suggest prospective studies with hyperpolarized [1– 13 C]-pyruvate magnetic resonance spectroscopic imaging are warranted. If these IHC results translate to functional imaging findings, a positive pyruvate-to-lactate imaging signature might be a risk factor for invasion that would warrant resection of IPMNs in the absence of other worrisome features. [ABSTRACT FROM AUTHOR]

The aim of this study was to metabolically construct Saccharomyces cerevisiae for achievement of direct methanol utilization and value added product (mainly pyruvate) production. After successful integration of methanol oxidation pathway originated from Pichia pastoris into the chromosome of S. cerevisiae , the recombinant showed 1.04 g/L consumption of methanol and 3.13% increase of cell growth (OD 600 ) when using methanol as the sole carbon source. Moreover, 0.26 g/L of pyruvate was detected in the fermentation broth. The supplementation of 1 g/L yeast extract could further improve cell growth with increase of 11.70% and methanol consumption to 2.35 g/L. This represents the first genetically modified non-methylotrophic eukaryotic microbe for direct methanol utilization and would be of great value concerning the development of biotechnological processes. [ABSTRACT FROM AUTHOR]

Pyruvate participates in diverse metabolic pathways in the body and is normally present in human blood at 40–120 μM, with concentrations outside this range associated with various diseases. Therefore, accurate and stable blood pyruvate level tests are necessary for effective disease detection. However, traditional analytical techniques require complicated instrumentation and are time consuming and expensive, prompting researchers to develop improved methods based on biosensors and bioassays. Here, we designed a highly stable bioelectrochemical pyruvate sensor affixed to a glassy carbon electrode (GCE). To maximize biosensor stability, 0.1 U of lactate dehydrogenase was affixed to the GCE using a sol-gel process, resulting in generation of Gel/LDH/GCE. Next, 2.0 mg/mL AuNPs-rGO was added to enhance current signal strength, resulting in generation of the bioelectrochemical sensor Gel/AuNPs-rGO/LDH/GCE. AuNPs-rGO synthesized in advance was verified as correct using transmission electron microscopy and UV–Vis, Fourier-transform infrared and X-ray photoelectron spectroscopy. Pyruvate detection conducted via differential pulse voltammetry in phosphate buffer (pH 7.4, 100 mM) at 37 °C for 1–4500 μM pyruvate provided detection sensitivity as high as 254.54 μA/mM/cm2. The reproducibility, regenerability and storage stability were analyzed with the relative standard deviation of 5 bioeletrochemical sensors detection was 4.60% and biosensor accuracy after 9 cycles was 92%, with accuracy remaining at 86% after 7 days. In the presence of D-glucose, citric acid, dopamine, uric acid and ascorbic acid, the Gel/AuNPs-rGO/LDH/GCE sensor exhibited excellent stability, high anti-interference ability and better performance than conventional spectroscopic methods for detection of pyruvate in artificial serum. [Display omitted] • LDH was immobilized in a film made from sol-gel. • The signal was enhanced by AuNPs-rGO which was added in the sol-gel film. • The sensor performance excellent stability and sensitivity in pyruvate detection. • The sensor shows better accuracy of pyruvate detection in artificial serum compared with spectroscopy. [ABSTRACT FROM AUTHOR]

The structures of two cell wall glycopolymers were studied in the plant pathogenic bacterium Clavibacter tesselarius VKM Ac-1406T (family Microbacteriaceae, order Micrococcales, class Actinomycetes). The predominant polymer was a novel (1 → 6)-linked β- d -galactofuranan with a highly branched repeating unit, α-L-Rha p -(1 → 3)-α-D-Gal p -(1 → 2)-[α-L-Rha p -(1 → 3)]-α-D-Fuc p -(1 →, at O-2 on every second galactofuranose residue. The second polymer present in small amounts was acidic with the repeating unit, →3)-α-D-Gal p -(1 → 3)-α-D-[4,6- S -Pyr]-Man p -(1 → 3)-α-D-Man p- [2OAc] 0.2 -(1→, and was reported in all Clavibacter species investigated to date. The presented results expand our knowledges of structural diversity of phosphate-free cell wall glycopolymers and provide evidence in support of their taxonomic specificity for bacterial species and genera. [Display omitted] • A cell wall galactomannan and a novel (1. → 6)-linked galactofuranan are identified. • The galactofuranan has a side branched tetrasaccharide at O-2 on every second Gal f. • The branched tetrasaccharide consists of Fuc p , Gal p , Rha p in the ratio 1:1:2. • The galactomannan has Gal p , [4,6Pyr]-Man p , and partly acetylated Man p in the ratio 1:1:1. [ABSTRACT FROM AUTHOR]

Branched-chain amino acid (BCAA) metabolism is linked to glucose homeostasis, but the underlying signaling mechanisms are unclear. We find that gluconeogenesis is reduced in mice deficient of Ppm1k , a positive regulator of BCAA catabolism, which protects against obesity-induced glucose intolerance. Accumulation of branched-chain keto acids (BCKAs) inhibits glucose production in hepatocytes. BCKAs suppress liver mitochondrial pyruvate carrier (MPC) activity and pyruvate-supported respiration. Pyruvate-supported gluconeogenesis is selectively suppressed in Ppm1k -deficient mice and can be restored with pharmacological activation of BCKA catabolism by BT2. Finally, hepatocytes lack branched-chain aminotransferase that alleviates BCKA accumulation via reversible conversion between BCAAs and BCKAs. This renders liver MPC most susceptible to circulating BCKA levels hence a sensor of BCAA catabolism. [Display omitted] • Gluconeogenesis is impaired in mice with decreased BCAA catabolism due to Ppm1k deficiency • BCKAs selectively inhibit pyruvate-supported glucose production in hepatocytes • BCKAs inhibit mitochondrial pyruvate carrier (MPC) in hepatocytes • BCATm in non-hepatocytes protects against BCKA accumulation, alleviates the inhibition of MPC Nishi et al. report that mice with impaired BCAA catabolism due to Ppm1k deficiency show reduced gluconeogenesis. Mechanistically, accumulated BCKAs inhibit liver MPC activity, resulting in reduced glucose production from pyruvate. Furthermore, BCATm in non-hepatic mitochondria mitigates the inhibition of MPC by converting BCKAs into BCAAs. [ABSTRACT FROM AUTHOR]

Upon antigen-specific T cell receptor (TCR) engagement, human CD4+ T cells proliferate and differentiate, a process associated with rapid transcriptional changes and metabolic reprogramming. Here, we show that the generation of extramitochondrial pyruvate is an important step for acetyl-CoA production and subsequent H3K27ac-mediated remodeling of histone acetylation. Histone modification, transcriptomic, and carbon tracing analyses of pyruvate dehydrogenase (PDH)-deficient T cells show PDH-dependent acetyl-CoA generation as a rate-limiting step during T activation. Furthermore, T cell activation results in the nuclear translocation of PDH and its association with both the p300 acetyltransferase and histone H3K27ac. These data support the tight integration of metabolic and histone-modifying enzymes, allowing metabolic reprogramming to fuel CD4+ T cell activation. Targeting this pathway may provide a therapeutic approach to specifically regulate antigen-driven T cell activation. [Display omitted] • PDH is required for histone acetylation and transcription after T cell activation • MPC1 and ACLY are not required for T cell activation and transcriptional reprogramming • T cell activation leads to PDH nuclear translocation close to chromatin-remodeling complexes After T cell activation, histone acetylation and transcriptional reprogramming require glycolysis and the pyruvate dehydrogenase (PDH)-dependent production of extramitochondrial acetyl-CoA. Mocholi et al. show that PDH translocates to the nucleus close to chromatin-remodeling complexes, highlighting how metabolic and histone-modifying enzymes cooperate in regulating T cell activation. [ABSTRACT FROM AUTHOR]

Even-chain acylcarnitine (AC) metabolites, most of which are generated as byproducts of incomplete fatty acid oxidation (FAO), are viewed as biomarkers of mitochondrial lipid stress attributable to one or more metabolic bottlenecks in the β-oxidation pathway. The origins and functional implications of FAO bottlenecks remain poorly understood. Here, we combined a sophisticated mitochondrial phenotyping platform with state-of-the-art molecular profiling tools and multiple two-state mouse models of respiratory function to uncover a mechanism that connects AC accumulation to lipid intolerance, metabolic inflexibility, and respiratory inefficiency in skeletal muscle mitochondria. These studies also identified a short-chain carbon circuit at the C4 node of FAO wherein reverse flux of glucose-derived acetyl CoA through medium-chain ketothiolase enhances lipid tolerance and redox stability in heart mitochondria by regenerating free CoA and NAD+. The findings help to explain why diminished FAO capacity, AC accumulation, and metabolic inflexibility are tightly linked to poor health outcomes. [Display omitted] • The pathway of long-chain fatty acid oxidation is prone to metabolic bottlenecks • Bottlenecks in fat oxidation can lead to CoA trapping and respiratory inefficiency • Reverse flux of pyruvate-derived acetyl CoA through MKT regenerates free CoA • High levels of MKT in heart and red muscles promote mitochondrial lipid tolerance Researchers identify a short-chain carbon circuit that enables reverse flux of pyruvate-derived acetyl CoA through medium-chain ketothiolase (MKT) to regenerate critical co-factors necessary for β-oxidation of long-chain fatty acids, thereby promoting mitochondrial lipid tolerance. Insufficient MKT flux leads to lipid-induced energy instability and metabolic inflexibility. [ABSTRACT FROM AUTHOR]

Objectives Ethyl pyruvate (EP) is the ethyl ester of pyruvate and has antioxidative and anti-inflammatory effects. This study aimed to evaluate the therapeutic effect of EP in inflammatory arthritis and to identify the underlying mechanisms. Methods Mice with collagen-induced arthritis (CIA) were treated with the vehicle control or EP at 20 mg/kg, and clinical and histological analyses were performed on the animals. The differentiation of murine CD4 + T cells into T helper 17 (Th17) cells in the presence of EP was investigated in vitro . The effects of EP on osteoclastogenesis were determined by staining for tartrate-resistant acid phosphatase, and measuring the mRNA levels of osteoclastogenesis-related genes. The expression of high-mobility group box 1 (HMGB1) was evaluated after EP therapy using immunohistochemical staining and Western blotting. Results EP significantly improved the clinical and histological features of arthritis in CIA mice. EP suppressed the differentiation of CD4 + T cells into Th17 cells, and inhibited the expression of RORγt. The generation of osteoclasts and osteoclastogenic markers from murine and human monocytes was significantly reduced in the presence of EP. The expression of HMGB1 in the synovium was significantly lower in CIA mice treated with EP, compared to control CIA mice. During osteoclastogenesis, HMGB1 release from monocytes was inhibited in the presence of EP. Conclusions EP attenuated synovial inflammation and bone destruction in the experimental arthritis model through suppression of IL-17 and HMGB-1. The data suggests that EP could be a novel therapeutic agent for the treatment of inflammatory arthritis, such as rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Due to the decrease of intracellular NADH availability, gluconate metabolism is more conducive to pyruvate production than glucose. Transcriptome analysis revealed that the Entner–Doudoroff (ED) pathway was activated by gluconate in Escherichia coli YP211 (MG1655 Δ ldhA Δ pflB Δ pta-ackA Δ poxB Δ ppc Δ frdBC ). To construct a new pyruvate producing strain with glucose metabolism via ED pathway, the genes ppsA , ptsG , pgi and gnd were deleted sequentially to reduce the demand for PEP and block the Embden–Meyerhor–Parnas pathway and Pentose-Phosphate pathway. After nearly 1000 generations of growth-based selection, the evolved strain YP404 was isolated and the ED pathway was proved to be activated as the primary glycolytic pathway. Comparing with YP211, the pyruvate concentration and yield increased by 59% and 10.1%, respectively. In fed-batch fermentation, the pyruvate concentration reached 83.5 g l −1 with a volumetric productivity of 2.3 g l −1 h −1 . This was the first time to produce pyruvate via ED pathway, and prove that this was a more effective way. [ABSTRACT FROM AUTHOR]

D-erythroascorbate peroxidase ( EAPX1 ) deficiency causes glutathione deprivation, leading to the accumulation of methylglyoxal and reactive oxygen species (ROS), and especially, induction of cytochrome c peroxidase (Ccp1) in Candida albicans . Nevertheless, reciprocal effects between changes in Ccp1 activity and the antioxidative D-erythroascorbic acid- and glutathione-dependent redox status, which reflects methylglyoxal biosynthesis altering pathophysiology are unclear in eukaryotes. To elucidate the effect of CCP1 expression on EAPX1 and glutathione reductase (Glr1) activity-mediated D-erythroascorbic acid biosynthesis and redox homeostasis, the CCP1 gene was disrupted and overexpressed. First, we demonstrated both glutathione-independent and-dependent metabolite contents and their corresponding gene transcripts and enzyme activities (i.e., Ccp1, catalase-peroxidase [KatG], superoxide dismutase [Sod], Eapx1, and Glr1) in CCP1 mutants. Second, methylglyoxal-oxidizing alcohol dehydrogenase (Adh1) and methylglyoxal-reducing oxidoreductase activity on glycolytic methylglyoxal and pyruvate production and NAD(P)H content were determined in these mutants. Contrary to our expectation, CCP1 disruption (42.19 ± 3.22 nmol O 2 h −1 mg wet cell −1 ) failed to affect cell respiration compared to the wild-type strain (41.62 ± 7.11 nmol O 2 h −1 mg wet cell −1 ) under cyanide treatment, and in contrast to hydrogen peroxide (H 2 O 2 ) treatment (21.74 ± 1.03 nmol O 2 h −1 mg wet cell −1 ). Additionally, Ccp1 predominantly detoxified H 2 O 2 rather than negligible scavenging activities towards methylglyoxal and other oxidants. CCP1 deficiency stimulated Sod and Adh1 activity but downregulated Glr1, Eapx1, catalase, and peroxidase activity while enhancing KatG , EAPX1 , and GLR1 transcription by decreasing glutathione and D-erythroascorbic acid and increasing pyruvate. Noticeably, the ROS-accumulating CCP1- deficient mutant maintained steady-state levels of methylglyoxal, which was revealed to be regulated by methylglyoxal-oxidizing and −reducing activity with drastic changes in NAD(P)H. We confirmed and clarified our results by showing that CCP1/EAPX1 double disruptants underwent severe growth defects due to the D-erythroascorbic acid and glutathione depletion because of pyruvate overaccumulation. These observations were made in both budding and hyphal-growing CCP1 mutants. The revealed metabolic network involving Ccp1 and other redox regulators affected ROS and methylglyoxal through D-erythroascorbic acid and glutathione-dependent metabolites, thereby influencing dimorphism. This is the first report of the Ccp1-mediated D-erythroascorbic acid and glutathione biosynthesis accompanying methylglyoxal scavengers for full fungal virulence. [ABSTRACT FROM AUTHOR]

The cell walls of two strains of the genus Promicromonospora (phylum Actinobacteria) were found to include non-phosphorylated anionic glycopolymers with pyruvic acid acetals of R -configuration. The cell wall of the type strain P. citrea 665 T contains two glycopolymers of the sort, including the Kdn-teichulosonic acid with the repeating unit →6)-α- d -Gl≿ p /→6)-α- d -Gl≿ p 3SO 3 − -(1 → 4)-α-[7,9Pyr]-Kdn-(2→, and the galactan with the repeating unit →3)-α-[4,6Pyr]- d -Gal p- 2OAc-(1 → . The cell wall of Promicromonospora sp.VKM Ac-1028 contains the teichuronic acid with the repeating unit →6)-α- d -Gl≿ p -(1 → 4)-β-[2,3Pyr]- d -Glc p A-(1 → . The detected glycopolymer structures are reported for the first time. Presented results expand the notion on the diversity of the organic world and on the role of the structures and composition of cell wall polymers in bacterial taxonomy. The glycopolymer structures were established by using a combination of chemical methods, NMR- and IR-spectroscopy, and ESI MS. [ABSTRACT FROM AUTHOR]

Chitin is the second most abundant organic compound on the planet and thus has been regarded as an alternative resource to petroleum feedstocks. One of the key challenges in the biological conversion of biomass-derived polysaccharides, such as cellulose and chitin, is to close the gap between optimum temperatures for enzymatic saccharification and microbial fermentation and to implement them in a single bioreactor. To address this issue, in the present study, we aimed to perform an in vitro , one-pot bioconversion of chitin to pyruvate, which is a precursor of a wide range of useful metabolites. Twelve thermophilic enzymes, including that for NAD + regeneration, were heterologously produced in Escherichia coli and semi-purified by heat treatment of the crude extract of recombinant cells. When the experimentally decided concentrations of enzymes were incubated with 0.5 mg mL −1 colloidal chitin (equivalent to 2.5 mM N -acetylglucosamine unit) and an adequate set of cofactors at 70°C, 0.62 mM pyruvate was produced in 5 h. Despite the use of a cofactor-balanced pathway, determination of the pool sizes of cofactors showed a rapid decrease in ATP concentration, most probably due to the thermally stable ATP-degrading enzyme(s) derived from the host cell. Integration of an additional enzyme set of thermophilic adenylate kinase and polyphosphate kinase led to the deceleration of ATP degradation, and the final product titer was improved to 2.1 mM. [ABSTRACT FROM AUTHOR]

Escherichia coli cells were inactivated by high hydrostatic pressure (HHP) at 400–600 MPa and their recovery under various conditions was evaluated by colony counting and flow cytometer (FCM) analyses. The lag time in colony formation and an improved recovery of cells under less oxidative conditions (pyruvate addition to the medium and incubation in anaerobic conditions) were observed for HHP treated cells, which indicated that a significant portion of cells were injured and recovered during incubation after HHP treatment. The lag time for colony formation varied, which suggested a wave of resuscitation and recovered cells may multiply before other injured cells complete resuscitation. The recovery process was monitored by FCM: The FCM profile of cells stained using propidium iodide and SYTO9 indicated that while the majority of cells died just after HHP treatment, the staining pattern of possibly injured cells displayed a specific spectrum that gradually became consistent with that of the dead cell population and a living cell population simultaneously appeared. Pyruvate addition to the medium not only enhanced viability of HHP treated cells, but also reduced the lethal effect of HHP. These observations suggested that the degree of damage by HHP may differ cell-by-cell, and oxidative stress may continue after HHP treatment. Pyruvate addition to the recovery medium enhanced viability of E. coli cells inactivated by HHP treatment in tomato juice as well. [ABSTRACT FROM AUTHOR]

Onion pyruvate concentration is used as a predictor of flavor intensity and nutraceutical value. The protocol of Schwimmer and Weston (SW) (1961) is the most widespread methodology for estimating onion pyruvate. Anthon and Barret (AB) (2003) proposed modifications to this procedure. Here, we compared these spectrophotometry-based procedures for pyruvate analysis using a diverse collection of onion cultivars. The SW method always led to over-estimation of pyruvate levels in colored, but not in white onions, by up to 65%. Identification of light-absorbance interfering compounds was performed by spectrophotometry and HPLC analysis. Interference by quercetin and anthocyanins, jointly, accounted for more than 90% of the over-estimation of pyruvate. Pyruvate determinations according to AB significantly reduced absorbance interference from compounds other than pyruvate. This study provides evidence about the mechanistic basis underlying differences between the SW and AB methods for indirect assessment of onion flavor and nutraceutical value. [ABSTRACT FROM AUTHOR]

A growing interest has emerged in the field of studying the cross-talk between cancer cell cycle and metabolism. In this review, we aimed to present how metabolism and cell cycle are correlated and how cancer cells get energy to drive cell cycle. Cell proliferation and cell death largely depend on the metabolic activity of the cell. Cell cycle proteins, e.g. cyclin D, cyclin dependent kinase (CDK), some pro-apoptotic and anti-apoptotic proteins, and P53 have been shown to be regulated by metabolic crosstalk. Dysregulation of this cross-talk between metabolism and cell cycle leads to degenerative disorder(s) and cancer. It is not fully understood the actual reason of aberration between metabolism and cell cycle, but it is a hallmark of cancer research. Herein, we discussed the role of some regulatory molecules relative of cell cycle and metabolism and highlight how they control the function of each other. We also pointed out, current therapeutic opportunities and some additional crucial therapeutic targets on these fields that could be a breakthrough in cancer research. [ABSTRACT FROM AUTHOR]

Modulation of host metabolic machinery by Mycobacterium tuberculosis is a well established phenomenon. In our earlier study ( Mehrotra et al., 2014 ), we observed a marked increase in acetyl-CoA levels in cells bearing virulent M. tuberculosis infections compared to host cells harbouring avirulent infections. The difference was observed inspite of similar levels of total host cellular pyruvate in both infection types. The present study aimed in capturing the cause for such a phenomenon that defines the pathogenicity of M. tuberculosis . Through mathematical model, we dissected the relative importance of virulence mediated effect on Pyruvate dehydrogenase (PDH) activity, rate of acetyl-CoA consumption and mitochondrial pyruvate transporter (MPC) activity in causing the observed outcomes. Simulation results exhibit MPC to be the key regulatory junction perturbed by virulent strains of M. tuberculosis leading to alteration of mitochondrial metabolic flux and regulation of acetyl-CoA formation. As an experimental validation, drug mediated inhibition of MPC activity was sufficient to reduce virulent bacillary loads, pointing towards a possible mechanistic target for drug discovery. [ABSTRACT FROM AUTHOR]

The goal of this project was to develop and apply techniques for T 2 mapping and 3D high resolution (1.5 mm isotropic; 0.003 cm 3 ) 13 C imaging of hyperpolarized (HP) probes [1- 13 C]lactate, [1- 13 C]pyruvate, [2- 13 C]pyruvate, and [ 13 C, 15 N 2 ]urea in vivo. A specialized 2D bSSFP sequence was implemented on a clinical 3T scanner and used to obtain the first high resolution T 2 maps of these different hyperpolarized compounds in both rats and tumor-bearing mice. These maps were first used to optimize timings for highest SNR for single time-point 3D bSSFP acquisitions with a 1.5 mm isotropic spatial resolution of normal rats. This 3D acquisition approach was extended to serial dynamic imaging with 2-fold compressed sensing acceleration without changing spatial resolution. The T 2 mapping experiments yielded measurements of T 2 values of > 1 s for all compounds within rat kidneys/vasculature and TRAMP tumors, except for [2- 13 C]pyruvate which was ~ 730 ms and ~ 320 ms, respectively. The high resolution 3D imaging enabled visualization the biodistribution of [1- 13 C]lactate, [1- 13 C]pyruvate, and [2- 13 C]pyruvate within different kidney compartments as well as in the vasculature. While the mouse anatomy is smaller, the resolution was also sufficient to image the distribution of all compounds within kidney, vasculature, and tumor. The development of the specialized 3D sequence with compressed sensing provided improved structural and functional assessments at a high (0.003 cm 3 ) spatial and 2 s temporal resolution in vivo utilizing HP 13 C substrates by exploiting their long T 2 values. This 1.5 mm isotropic resolution is comparable to 1 H imaging and application of this approach could be extended to future studies of uptake, metabolism, and perfusion in cancer and other disease models and may ultimately be of value for clinical imaging. [ABSTRACT FROM AUTHOR]

Until recently, molecular imaging using magnetic resonance (MR) has been limited by the modality's low sensitivity, especially with non-proton nuclei. The advent of hyperpolarized (HP) MR overcomes this limitation by substantially enhancing the signal of certain biologically important probes through a process known as external nuclear polarization, enabling real-time assessment of tissue function and metabolism. The metabolic information obtained by HP MR imaging holds significant promise in the clinic, where it could play a critical role in disease diagnosis and therapeutic monitoring. This review will provide a comprehensive overview of the developments made in the field of hyperpolarized MR, including advancements in polarization techniques and delivery, probe development, pulse sequence optimization, characterization of healthy and diseased tissues, and the steps made towards clinical translation. [ABSTRACT FROM AUTHOR]