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Hyperpolarized13 C magnetic resonance spectroscopy can provide unique insights into metabolic activity in vivo. Despite the advantages of this technology, certain metabolic pathways such as the tricarboxylic acid (TCA) cycle are more challenging to examine due to the limitations associated with currently available hyperpolarized13 C probes. In this report, we systematically employ computational analyses, synthetic techniques, and in vitro studies to facilitate the design of new chemical probes for the TCA cycle. This platform allows for the rapid identification of probe scaffolds that are amenable to hyperpolarized13 C experimentation. Using these results, we have developed two13 C-labeled chemical probes, [1,4-13 C2 ]-dipropyl succinate and [1,4-13 C2 ]-diallyl succinate, which are employed in hyperpolarized13 C metabolic studies. [ABSTRACT FROM AUTHOR]

Scenedesmus sp. is a species of the Scenedesmus genus within the phylum Chlorophyta, commonly found as a planktonic algal species in freshwater and known for its rapid growth rate. This study employs room-temperature, atmospheric-pressure plasma mutagenesis for the breeding of Scenedesmus sp., utilizing transcriptomic analysis to investigate the biosynthesis mechanism of triglycerides. Further analysis of differentially expressed genes in transcriptome by measuring the macroscopic biological indicators of mutant and original algal strains. The findings of the study suggest that the mutant strain's photosynthesis has been enhanced, leading to improved light energy utilization and CO2 fixation, thereby providing more carbon storage and energy for biomass and lipid production. The intensification of glycolysis and the TCA (tricarboxylic acid) cycle results in a greater shift in carbon flux towards lipid accumulation. An elevated expression level of related enzymes in starch and protein degradation pathways may enhance acetyl CoA accumulation, facilitating a larger substrate supply for fatty acid production and thereby increasing lipid yield. [ABSTRACT FROM AUTHOR]

Background: Targeting the tumor microenvironment represents an emerging therapeutic strategy for cancer. Macrophages are an essential part of the tumor microenvironment. Macrophage polarization is modulated by mitochondrial metabolism, including oxidative phosphorylation (OXPHOS), the tricarboxylic acid (TCA) cycle, and reactive oxygen species content. Isocitrate dehydrogenase 2 (IDH2), an enzyme involved in the TCA cycle, reportedly promotes cancer progression. However, the mechanisms through which IDH2 influences macrophage polarization and modulates tumor growth remain unknown. Methods: In this study, IDH2-deficient knockout (KO) mice and primary cultured bone marrow-derived macrophages (BMDMs) were used. Both in vivo subcutaneous tumor experiments and in vitro co-culture experiments were performed, and samples were collected for analysis. Western blotting, RNA quantitative analysis, immunohistochemistry, and flow cytometry were employed to confirm changes in mitochondrial function and the resulting polarization of macrophages exposed to the tumor microenvironment. To analyze the effect on tumor cells, subcutaneous tumor size was measured, and growth and metastasis markers were identified. Results: IDH2-deficient macrophages co-cultured with cancer cells were found to possess increased mitochondrial dysfunction and fission than wild-type BMDM. Additionally, the levels of M2-associated markers decreased, whereas M1-associated factor levels increased in IDH2-deficient macrophages. IDH2-deficient macrophages were predominantly M1. Tumor sizes in the IDH2-deficient mouse group were significantly smaller than in the wild-type mouse group. IDH2 deficiency in macrophages was associated with inhibited tumor growth and epithelial–mesenchymal transition. Conclusions: Our findings suggest that IDH2 deficiency inhibits M2 macrophage polarization and suppresses tumorigenesis. This study underlines the potential contribution of IDH2 expression in macrophages and tumor microenvironment remodeling, which could be useful in clinical cancer research. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the most common form of dementia. Although drugs focusing on reducing amyloid β slow progression, they fail to improve cognitive function. Deficits in glucose metabolism are reflected in FDG-PET and parallel the neurodegeneration and synaptic marker loss closely preceding cognitive decline, but the role of metabolic deficits as a cause or consequence of neurodegeneration is unclear. Pyruvate dehydrogenase (PDH) is lost in AD and an important enzyme connecting glycolysis and the tricarboxylic acid (TCA) cycle by converting pyruvate into acetyl-CoA. It is negatively regulated by pyruvate dehydrogenase kinase (PDHK) through phosphorylation. Methods: In the present study, we assessed the in vitro/ in vivo pharmacological profile of the novel PDHK inhibitor that we discovered, Compound A. We also assessed the effects of Compound A on AD-related phenotypes including neuron loss and cognitive impairment using 5xFAD model mice. Results: Compound A inhibited human PDHK1, 2 and 3 but had no inhibitory activity on PDHK4. In primary neurons, Compound A enhanced pyruvate and lactate utilization, but did not change glucose levels. In contrast, in primary astrocytes, Compound A enhanced pyruvate and glucose utilization and enhanced lactate production. In an efficacy study using 5xFAD mice, Compound A ameliorated the cognitive dysfunction in the novel object recognition test and Morris water maze. Moreover, Compound A prevented neuron loss in the hippocampus and cerebral cortex of 5xFAD without affecting amyloid β deposits. Conclusions: These results suggest ameliorating metabolic deficits by activating PDH by Compound A can limit neurodegeneration and is a promising therapeutic strategy for treating AD. [ABSTRACT FROM AUTHOR]

Aims: Drug resistance in ovarian cancer (OC) cells often leads to recurrence, metastasis, and high mortality rates among OC patients. Hydroxytyrosol (HT) has been reported to inhibit the proliferation of ovarian and other types of cancer cells. Here we synthesized a novel cyclohexane-hydroxytyrosol derivative (Chx-HT) for enhanced anticaner efficacy. We examined the growth-suppressing effect of Chx-HT on OC cells in vitro and in a xenograft mouse model and investigated the underlying mechanism. Results: We demonstrated that Chx-HT inhibits proliferation, promotes apoptosis, and remodels glucose and lipid metabolism by reducing fatty acid β-oxidation while increasing glycolysis, de novo fatty acid synthesis (FAS), and lipid droplet (LD) accumulation, impairs mitochondrial respiration, and induces oxidative stress both in vitro and in vivo. In addition, Chx-HT blocks autophagic flux by obstructing the maturation of lysosomal cathepsins in the late stage, but also activates autophagy through the p-AMPK/p-mTOR/p-ULK1 pathway in response to energy deficit. Innovation and Conclusion: Reactive oxidative species (ROS) play a critical role in mediating the effects of Chx-HT on proliferation, apoptosis, autophagy, tricarboxylic acid (TCA) cycle, fatty acid β-oxidation, and mitochondrial respiration, and the autophagic activation underlies the effects of Chx-HT on glycolysis, de novo FAS, and LD accumulation in OC cells. Cotreating OC cells with Chx-HT and autophagic inhibitor or glycolytic inhibitor results in an additive inhibition of proliferation. Our study indicates that Chx-HT stands for a promising OC therapeutic by ROS and autophagy blockade-mediated metabolic remodeling. [ABSTRACT FROM AUTHOR]

Blue mold caused by Penicillium expansum infection results in severe postharvest deterioration of apples. Salicylic acid (SA) is an effective elicitor of fruit resistance. However, the metabolic mechanism of P. expansum infection of apples and the SA-mediated metabolic responses are still unknown. In this study, the metabolite changes during P. expansum infection of apples and SA-mediated disease resistance were explored by performing ultra-performance liquid chromatography and quadrupole-time-of-flight mass spectrometry. A total of 472 different metabolites were identified between the five groups of sample comparisons, and the correlated metabolic pathways were revealed by bioinformatics analysis. The upregulation of the tricarboxylic acid (TCA) cycle, galactose metabolism, and starch and sucrose metabolism reflected energy conversion for P. expansum invasion and fruit disease resistance. Changes in glyoxylate and dicarboxylate metabolism and carbapenem biosynthesis reflected the biosynthesis of virulence factors and secondary metabolites for fungal infection. Metabolic pathways related to apple natural disease resistance mainly included the upregulation of secondary metabolite biosynthesis and sphingolipid metabolism. SA promoted the TCA cycle, reactive oxygen metabolism, and secondary metabolite biosynthesis of apples for disease resistance. This study revealed the metabolic pathways of P. expansum infection of apples and SA-mediated disease resistance, which helps to improve the understanding of the pathogenic mechanism and disease control. [ABSTRACT FROM AUTHOR]

Background: Although WD repeat domain 45 (WDR45) mutations have been linked to β -propeller protein-associated neurodegeneration (BPAN), the precise molecular and cellular mechanisms behind this disease remain elusive. This study aims to shed light on the impacts of WDR45-deficiency on neurodegeneration, specifically axonal degeneration, within the midbrain dopaminergic (DAergic) system. We hope to better understand the disease process by examining pathological and molecular alterations, especially within the DAergic system. Methods: To investigate the impacts of WDR45 dysfunction on mouse behaviors and DAergic neurons, we developed a mouse model in which WDR45 was conditionally knocked out in the midbrain DAergic neurons (WDR45cKO). Through a longitudinal study, we assessed alterations in the mouse behaviors using open field, rotarod, Y-maze, and 3-chamber social approach tests. We utilized a combination of immunofluorescence staining and transmission electron microscopy to examine the pathological changes in DAergic neuron soma and axons. Additionally, we performed proteomic and lipidomic analyses of the striatum from young and aged mice to identify the molecules and processes potentially involved in the striatal pathology during aging. Further more, primary midbrain neuronal culture was employed to explore the molecular mechanisms leading to axonal degeneration. Results: Our study of WDR45cKO mice revealed a range of deficits, including impaired motor function, emotional instability, and memory loss, coinciding with the profound reduction of midbrain DAergic neurons. The neuronal loss, we observed massive axonal enlargements in the dorsal and ventral striatum. These enlargements were characterized by the accumulation of extensively fragmented tubular endoplasmic reticulum (ER), a hallmark of axonal degeneration. Proteomic analysis of the striatum showed that the differentially expressed proteins were enriched in metabolic processes. The carbohydrate metabolic and protein catabolic processes appeared earlier, and amino acid, lipid, and tricarboxylic acid metabolisms were increased during aging. Of note, we observed a tremendous increase in the expression of lysophosphatidylcholine acyltransferase 1 (Lpcat1) that regulates phospholipid metabolism, specifically in the conversion of lysophosphatidylcholine (LPC) to phosphatidylcholine (PC) in the presence of acyl-CoA. The lipidomic results consistently suggested that differential lipids were concentrated on PC and LPC. Axonal degeneration was effectively ameliorated by interfering Lpcat1 expression in primary cultured WDR45-deficient DAergic neurons, proving that Lpcat1 and its regulated lipid metabolism, especially PC and LPC metabolism, participate in controlling the axonal degeneration induced by WDR45 deficits. Conclusions: In this study, we uncovered the molecular mechanisms underlying the contribution of WDR45 deficiency to axonal degeneration, which involves complex relationships between phospholipid metabolism, autophagy, and tubular ER. These findings greatly advance our understanding of the fundamental molecular mechanisms driving axonal degeneration and may provide a foundation for developing novel mechanistically based therapeutic interventions for BPAN and other neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

In the realm of renewable energy technologies, the development of efficient and durable electrocatalysts is paramount, especially for applications like electrochemical water splitting. This research focuses on synthesizing a novel bimetallic metal‐organic framework (BMMOF11) using earth‐abundant elements, cobalt (Co) and cadmium (Cd). BMMOF11 showcases a distinctive structure with distorted octahedral chains of CoO and CdO, linked by benzene tricarboxylic acid (BTC). Our study primarily investigates the electrocatalytic efficiency of BMMOF11, particularly in water oxidation reactions. For practical analysis, BMMOF11 was anchored onto nickel foam, forming BMMOF11/NF, to evaluate its electrocatalytic properties. Electrochemical testing revealed that BMMOF11/NF begins water oxidation at an onset potential of 1.62 V versus RHE, demonstrating high activity with a lower overpotential of 0.4 V to achieve a current density of 10 mA/cm2. Moreover, BMMOF11/NF maintained stable water splitting performance, sustaining a current density of approximately 70 mA/cm2 under a voltage of 1.9 V relative to RHE. These findings indicate that BMMOF11/NF is a promising candidate for large‐scale electrochemical water splitting, offering a blend of high activity and stability. [ABSTRACT FROM AUTHOR]

Protein post-translational modifications (PTMs) are crucial for cancer cells to adapt to hypoxia; however, the functional significance of lysine crotonylation (Kcr) in hypoxia remains unclear. Herein we report a quantitative proteomics analysis of global crotonylome under normoxia and hypoxia, and demonstrate 128 Kcr site alterations across 101 proteins in MDA-MB231 cells. Specifically, we observe a significant decrease in K131cr, K156cr and K220cr of phosphoglycerate kinase 1 (PGK1) upon hypoxia. Enoyl-CoA hydratase 1 (ECHS1) is upregulated and interacts with PGK1, leading to the downregulation of PGK1 Kcr under hypoxia. Abolishment of PGK1 Kcr promotes glycolysis and suppresses mitochondrial pyruvate metabolism by activating pyruvate dehydrogenase kinase 1 (PDHK1). A low PGK1 K131cr level is correlated with malignancy and poor prognosis of breast cancer. Our findings show that PGK1 Kcr is a signal in coordinating glycolysis and the tricarboxylic acid (TCA) cycle and may serve as a diagnostic indicator for breast cancer. The functional relevance of lysine crotonylation in cancer remains to be further explored. Here, the authors show that hypoxia-induced downregulation of PGK1 lysine crotonylation promotes glycolysis and suppresses mitochondrial pyruvate metabolism, contributing to breast cancer progression. [ABSTRACT FROM AUTHOR]

Citrate synthase catalyzes the first and the rate-limiting reaction of the tricarboxylic acid (TCA) cycle, producing citrate from the condensation of oxaloacetate and acetyl-coenzyme A. The parasitic protozoan Toxoplasma gondii has full TCA cycle activity, but its physiological roles remain poorly understood. In this study, we identified three proteins with predicted citrate synthase (CS) activities two of which were localized in the mitochondrion, including the 2-methylcitrate synthase (PrpC) that was thought to be involved in the 2-methylcitrate cycle, an alternative pathway for propionyl-CoA detoxification. Further analyses of the two mitochondrial enzymes showed that both had citrate synthase activity, but the catalytic efficiency of CS1 was much higher than that of PrpC. Consistently, the deletion of CS1 resulted in a significantly reduced flux of glucose-derived carbons into TCA cycle intermediates, leading to decreased parasite growth. In contrast, disruption of PrpC had little effect. On the other hand, simultaneous disruption of both CS1 and PrpC resulted in more severe metabolic changes and growth defects than a single deletion of either gene, suggesting that PrpC does contribute to citrate production under physiological conditions. Interestingly, deleting Δcs1 and Dprpc individually or in combination only mildly or negligibly affected the virulence of parasites in mice, suggesting that both enzymes are dispensable in vivo. The dispensability of CS1 and PrpC suggests that either the TCA cycle is not essential for the asexual reproduction of tachyzoites or there are other routes of citrate supply in the parasite mitochondrion. [ABSTRACT FROM AUTHOR]

The Pichia kluyveri, a proliferation commonly found in Sichuan pickles (SCPs), can accelerate the growth and reproduction of spoilage bacteria, causing off-odor development and decay. Although D-limonene, a common natural preservative, effectively restricts P. kluyveri, its inhibitory mechanism remains unclear. This study aimed to elucidate this molecular mechanism by investigating the impact on basic P. kluyveri metabolism. The findings revealed that D-limonene inhibited P. kluyveri growth and disrupted the transcription of the genes responsible for encoding the enzymes involved in cell wall and membrane synthesis, oxidative phosphorylation, glycolysis, and the tricarboxylic acid (TCA) cycle pathway. The results indicated that these events disrupted crucial metabolism such as cell wall and membrane integrity, adenosine triphosphate (ATP) synthesis, and reactive oxygen species (ROS) balance. These insights provided a comprehensive understanding of the inhibitory effect of D-limonene on the growth and reproduction of P. kluyveri while highlighting its potential application in the SCP industry. [ABSTRACT FROM AUTHOR]

Simple Summary: This review outlines the use of metabolomics to detect biomarkers for bovine mastitis, offering insights into disease prediction and early diagnosis. It details the use of various biological samples for metabolomic analysis, including milk, blood, urine, rumen fluid, feces, and mammary tissue. Bovine mastitis is an inflammatory disease of the mammary glands, and its pathogenesis and diagnosis are complicated. Through qualitative and quantitative analysis of small-molecule metabolites, the metabolomics technique plays an important role in finding biomarkers and studying the metabolic mechanism of bovine mastitis. Therefore, this paper reviews the predictive and diagnostic biomarkers of bovine mastitis that have been identified using metabolomics techniques and that are present in samples such as milk, blood, urine, rumen fluid, feces, and mammary tissue. In addition, the metabolic pathways of mastitis-related biomarkers in milk and blood were analyzed; it was found that the tricarboxylic acid (TCA) cycle was the most significant (FDR = 0.0015767) pathway in milk fluid, and glyoxylate and dicarboxylate metabolism was the most significant (FDR = 0.0081994) pathway in blood. The purpose of this review is to provide useful information for the prediction and early diagnosis of bovine mastitis. [ABSTRACT FROM AUTHOR]

Aminoglycoside antibiotics target ribosomes and are effective against a wide range of bacteria. Here, we demonstrated that knockout strains related to energy metabolism in Escherichia coli showed increased tolerance to aminoglycosides during the mid-exponential growth phase. Contrary to expectations, these mutations did not reduce the proton motive force or aminoglycoside uptake, as there were no significant changes in metabolic indicators or intracellular gentamicin levels between wild-type and mutant strains. Our comprehensive proteomics analysis unveiled a noteworthy upregulation of proteins linked to the tricarboxylic acid (TCA) cycle in the mutant strains during the mid-exponential growth phase, suggesting that these strains compensate for the perturbation in their energy metabolism by increasing TCA cycle activity to maintain their membrane potential and ATP levels. Furthermore, our pathway enrichment analysis shed light on local network clusters displaying downregulation across all mutant strains, which were associated with both large and small ribosomal binding proteins, ribosome biogenesis, translation factor activity, and the biosynthesis of ribonucleoside monophosphates. These findings offer a plausible explanation for the observed tolerance of aminoglycosides in the mutant strains. Altogether, this research provides valuable insights into the mechanisms of aminoglycoside tolerance, paving the way for novel strategies to combat such cells. [ABSTRACT FROM AUTHOR]

Fluorite, as a vital calcium-containing mineral, usually coexists with calcite. When using the traditional collector sodium oleate (NaOL), froth flotation could not separate fluorite and calcite well on account of their similar surface properties. Meanwhile, a large amount of sodium silicate (SS) needs to be added to depress calcite, resulting in difficulties in tailings settlement and wastewater treatment. Therefore, a nontoxic and inexpensive surfactant saponified tricarboxylic acid (TA) was developed as a new collector. The flotation test results showed that TA had a higher selectivity for fluorite than NaOL, leading to the selective separation of both minerals. Zeta potential measurements indicated that TA was negatively charged and was strongly adsorbed on fluorite due to electrostatic interactions at pH 9.0. FTIR, XPS, DFT, and crystal chemistry calculations revealed TA had a stronger chemical interaction with fluorite due to its higher surface Ca activity and density, forming a TA-Ca complex through the bidentate coordination. In contrast, the interaction of TA with calcite could be ignored. In addition, the results of the surface tension and dynamic foam stability tests revealed that TA possessed the excellent foam performance. Therefore, these properties give TA excessive potential for industrial application and environmental protection in fluorite flotation. Density and activity of Ca atoms on fluorite are higher than those on calcite. TA could selectively separate fluorite from calcite without any depressants. TA had a stronger chemical interaction with fluorite to form the Ca – TA complex. TA possesses excellent foam properties and suitable hydrophobicity. [ABSTRACT FROM AUTHOR]

Itaconic acid is an excellent polymeric precursor with a wide range of industrial applications. The efficient production of itaconate from various renewable substrates was demonstrated by engineered Escherichia coli. However, limitation in the itaconic acid precursor supply was revealed by finding out the key intermediate of the tricarboxylic acid in the itaconic acid pathway. Efforts of enhancing the cis-aconitate flux and preserving the isocitrate pool to increase itaconic acid productivity are required. In this study, we introduce a synthetic protein scaffold system between CadA and AcnA to physically combine the two enzymes. Through the introduction of a synthetic protein scaffold, 2.1 g L−1 of itaconic acid was produced at pH 7 and 37 °C. By fermentation, 20.1 g L−1 for 48 h of itaconic acid was produced with a yield of 0.34 g g−1 glycerol. These results suggest that carbon flux was successfully increased itaconic acid productivity. [ABSTRACT FROM AUTHOR]

Pathogenic bacteria's metabolic adaptation for survival and proliferation within hosts is a crucial aspect of bacterial pathogenesis. Here, we demonstrate that citrate, the first intermediate of the tricarboxylic acid (TCA) cycle, plays a key role as a regulator of gene expression in Staphylococcus aureus. We show that citrate activates the transcriptional regulator CcpE and thus modulates the expression of numerous genes involved in key cellular pathways such as central carbon metabolism, iron uptake and the synthesis and export of virulence factors. Citrate can also suppress the transcriptional regulatory activity of ferric uptake regulator. Moreover, we determined that accumulated intracellular citrate, partly through the activation of CcpE, decreases the pathogenic potential of S. aureus in animal infection models. Therefore, citrate plays a pivotal role in coordinating carbon metabolism, iron homeostasis, and bacterial pathogenicity at the transcriptional level in S. aureus, going beyond its established role as a TCA cycle intermediate. Author summary: Citrate is the first intermediate of the TCA cycle, and its classic role is as a participant in metabolic reactions. In this study, we explored the non-metabolic role of citrate in Staphylococcus aureus. The results suggested that citrate can influence central carbon metabolism, iron homeostasis and the expression of virulence factors by modulating the regulatory activity of the catabolite control protein E (CcpE) and ferric uptake regulator (Fur). For instance, we revealed a new axis, named citrate-CcpE-pycA, was responsible for controlling the endogenous biosynthesis of aspartate, which likely resulted in changes in metabolic adaptation in the host and influenced the pathogenesis of this important human pathogen. Thus, citrate serves as a key signaling molecule for the modulation of gene expression in S. aureus. [ABSTRACT FROM AUTHOR]

Having multiple rounds of translation of the same mRNA creates dynamic complexities along with opportunities for regulation related to ribosome pausing and stalling at specific sequences. Yet, mechanisms controlling these critical processes and the principles guiding their evolution remain poorly understood. Through genetic, genomic, physiological, and biochemical approaches, we demonstrate that regulating ribosome pausing at specific amino acid sequences can produce ~2-fold changes in protein expression levels which strongly influence cell growth and therefore evolutionary fitness. We demonstrate, both in vivo and in vitro, that the ABC-F protein EttA directly controls the translation of mRNAs coding for a subset of enzymes in the tricarboxylic acid (TCA) cycle and its glyoxylate shunt, which modulates growth in some chemical environments. EttA also modulates expression of specific proteins involved in metabolically related physiological and stress-response pathways. These regulatory activities are mediated by EttA rescuing ribosomes paused at specific patterns of negatively charged residues within the first 30 amino acids of nascent proteins. We thus establish a unique global regulatory paradigm based on sequence-specific modulation of translational pausing. The physiological function of the ABC-F translation factor has remained elusive. Here, the authors show that one of them, EttA, regulates the translation of mRNAs encoding early acidic residues, and that impacts the physiology of central metabolism. [ABSTRACT FROM AUTHOR]

Antimicrobial and UV-blocking textiles (protective textiles) are quite required especially for outdoor workers and in hot weather countries. Herein, for the first time, under the effect of infrared radiation, the preparation of multi-finished viscose fabrics via the incorporation of metal organic framework-based on Cesium (Ce-MOF) is investigated. Ce-MOF using different ligands including 1,4-benzendicarboxylic acid (BDC), 1,2,4-benzene tricarboxylic acid (BDC-COOH) and 2-amino-1,4-dicarboxyic acid (BDC-NH2) were incorporated within viscose and cationic viscose (Q-viscose) fabrics in one-pot process. MOF uptake was significantly improved from 88.6 – 96.8 mg/g to 122.5 – 152.2 mg/g after the cationization process. Due to incorporation of Ce-MOF, viscose fabrics acquired creamy to yellowish color and became more thermally stable. Tensile strength was lowered by 8.9 – 17.4% for viscose and 17.1 – 20.3% for Q-viscose, after modification with Ce-MOFs. The estimated UV-protection factor (UPF) for Q-viscose fabrics was significantly increased to be 50.1– 88.1 after incorporation of Ce-BDC-COOH & Ce-BDC-NH2, achieving maximum UV protection. By comparing between Ce-BDC and Ce-BDC-COOH, the fabrics treated with Ce-BDC-NH2 showed the highest microbial protection against bacteria and fungus. After immobilization of Ce-MOF, the estimated inhibition zones were 11–14 mm & 15–18 mm against E. coli and 13–15 mm & 17–19 mm against C. albicans, for viscose and Q-viscose, respectively. [ABSTRACT FROM AUTHOR]

Monascus pigments (MPs) and monacolin K (MK) are important secondary metabolites produced by Monascus spp. This study aimed to investigate the effect of soybean protein isolate (SPI) on the biosynthesis of MPs and MK based on the analysis of physiological indicators, transcriptomes, and metabolomes. The results indicated that the growth, yellow MPs, and MK production of Monascus pilosus MS-1 were significantly enhanced by SPI, which were 8.20, 8.01, and 1.91 times higher than that of the control, respectively. The utilization of a nitrogen source, protease activity, the production and utilization of soluble protein, polypeptides, and free amino acids were also promoted by SPI. The transcriptomic analysis revealed that the genes mokA, mokB, mokC, mokD, mokE, mokI, and mokH which are involved in MK biosynthesis were significantly up-regulated by SPI. Moreover, the glycolysis/gluconeogenesis, pyruvate metabolism, fatty acid degradation, tricarboxylic acid (TCA) cycle, and amino acid metabolism were effectively up-regulated by SPI. The metabolomic analysis indicated that metabolisms of amino acid, lipid, pyruvate, TCA cycle, glycolysis/gluconeogenesis, starch and sucrose, and pentose phosphate pathway were significantly disturbed by SPI. Thus, MPs and MK production promoted by SPI were mainly attributed to the increased biomass, up-regulated gene expression level, and more precursors and energies. [ABSTRACT FROM AUTHOR]

Simple Summary: In cancer cells, gross changes in gene expression help to enhance the uptake of glucose—the blood sugar—for the increased formation of building blocks for the cancer cells' unlimited growth. An issue related to the rewired cancer cell metabolism is that even under sufficient oxygen supply, cancer cells metabolize a large fraction of the glucose to lactic acid (or "lactate"). In non-cancerous cells, lactate would be formed only during oxygen deprivation in order to re-oxidize the cytosolic electron carrier NADH, which forms during the glycolytic glucose breakdown. This phenomenon of lactate secretion from cancer cells under aerobic conditions was named the "Warburg Effect", but the actual reasons for that are often regarded as not yet understood. However, when we acknowledge that the reprogramming of the different metabolic pathways of cancer cells is not neatly fine-tuned, it becomes plausible that lactate formation just serves to dispose of cytosolic electrons that exceed the capacity of the mitochondrial electron transport chain to accept cytosolic electrons. Interestingly, the kinetic properties of the enzymes that metabolize the glycolysis end product pyruvate are sufficient to explain the priorities for metabolite flux at the pyruvate junction in cancer cells: 1. mitochondrial oxidative phosphorylation for efficient ATP production, 2. cytosolic electrons that exceed oxidative phosphorylation capacity need to be disposed of and secreted as lactate, and 3. biosynthesis reactions for cancer cell growth. In other words, a number of cytosolic electrons just take the "emergency exit" from the cell by lactate secretion to maintain the cytosolic redox balance. Cancer cells metabolize a large fraction of glucose to lactate, even under a sufficient oxygen supply. This phenomenon—the "Warburg Effect"—is often regarded as not yet understood. Cancer cells change gene expression to increase the uptake and utilization of glucose for biosynthesis pathways and glycolysis, but they do not adequately up-regulate the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS). Thereby, an increased glycolytic flux causes an increased production of cytosolic NADH. However, since the corresponding gene expression changes are not neatly fine-tuned in the cancer cells, cytosolic NAD+ must often be regenerated by loading excess electrons onto pyruvate and secreting the resulting lactate, even under sufficient oxygen supply. Interestingly, the Michaelis constants (KM values) of the enzymes at the pyruvate junction are sufficient to explain the priorities for pyruvate utilization in cancer cells: 1. mitochondrial OXPHOS for efficient ATP production, 2. electrons that exceed OXPHOS capacity need to be disposed of and secreted as lactate, and 3. biosynthesis reactions for cancer cell growth. In other words, a number of cytosolic electrons need to take the "emergency exit" from the cell by lactate secretion to maintain the cytosolic redox balance. [ABSTRACT FROM AUTHOR]

Copper–zinc benzene tricarboxylic acid bimetallic organic framework (Cu–Zn–BTC MOF) was synthesized by solvothermal process and characterized using various characterization techniques, i.e., SEM, XRD, EDX, TGA and FTIR spectroscopy. The synthesized Cu–Zn–BTC MOF was used as an effective adsorbent for methylene blue (MB) removal from water. Different experimental parameters, i.e., solution pH, adsorbent dosage, agitation time, initial dye concentration and temperature were optimized. Various kinetics and isotherms models were applied to analyze adsorption data. Pseudo-second order and Langmuir model fitted the kinetics and isotherms data well, with correlation coefficient (R2) values ≈ 0.99. The maximum monolayer adsorption capacity calculated for Cu–Zn–BTC was 339.5 mg/g at 298 K. The thermodynamic parameters, i.e., ΔG, ΔS and ΔH°, confirmed the spontaneity and exothermic nature of adsorption. The used Cu–Zn–BTC adsorbent was regenerated using ethanol and reused for up to five consecutive cycles. Results revealed that Cu–Zn–BTC is effective for MB decontamination and can be efficiently used for purification of wastewater. [ABSTRACT FROM AUTHOR]

The interplay between viral pathogens and host metabolism plays a pivotal role in determining the outcome of viral infections. Upon viral detection, the metabolic landscape of the host cell undergoes significant changes, shifting from oxidative respiration via the tricarboxylic acid (TCA) cycle to increased aerobic glycolysis. This metabolic shift is accompanied by elevated nutrient accessibility, which is vital for cell function, development, and proliferation. Furthermore, depositing metabolites derived from fatty acids, TCA intermediates, and amino acid catabolism accelerates the immunometabolic transition, facilitating pro‐inflammatory and antimicrobial responses. Immunometabolites refer to small molecules involved in cellular metabolism regulating the immune response. These molecules include nutrients, such as glucose and amino acids, along with metabolic intermediates and signaling molecules adenosine, lactate, itaconate, succinate, kynurenine, and prostaglandins. Emerging evidence suggests that immunometabolites released by immune cells establish a complex interaction network within local niches, orchestrating and fine‐tuning immune responses during viral diseases. However, our current understanding of the immense capacity of metabolites to convey essential cell signals from one cell to another or within cellular compartments remains incomplete. Unraveling these complexities would be crucial for harnessing the potential of immunometabolites in therapeutic interventions. In this review, we discuss specific immunometabolites and their mechanisms of action in viral infections, emphasizing recent findings and future directions in this rapidly evolving field. [ABSTRACT FROM AUTHOR]

[Display omitted] The CO preferential oxidation reaction (CO-PROX) is an effective strategy to remove residual poisonous CO in proton exchange membrane fuel cells, in which oxygen vacancies play a critical role in CO adsorption and activation. Herein, a series of CuO/CeO 2 catalysts derived from Ce-MOFs precursors were synthesized using different organic ligands via the hydrothermal method and the CO-PROX performance was investigated. The CuO/CeO 2 -135 catalyst derived from homophthalic tricarboxylic acid (1,3,5-H 3 BTC) exhibited superior catalytic performance with 100 % CO conversion at a relatively low temperature (T 100% = 100 °C), with a wide reaction temperature range and excellent stability. The superior catalytic properties were attributed to the structural improvements provided by the 1,3,5-H 3 BTC precursors and the promotional effects of oxygen vacancies. Additionally, in-situ Raman spectroscopy was performed to verify the dynamic roles of oxygen vacancies for CO adsorption and activation, while in-situ DRIFTS analysis revealed key intermediates in the CO-PROX reaction, shedding light on the mechanistic aspects of the catalytic process. This work not only demonstrates insights into the effective CuO/CeO 2 catalysts for CO preferential oxidation, but also provides a feasible way to synthesize MOF-derived catalysts. [ABSTRACT FROM AUTHOR]

Mortierella alpina is popular for lipid production, but the low carbon conversion rate and lipid yield are major obstacles for its economic performance. Here, external addition of organic acids involved in tricarboxylic acid cycle was used to tune carbon flux and improve lipid production. Citrate was determined to be the best organic acid that can be used for enhancing lipid production. By the addition of citrate, the lipid titer and content were approximately 1.24 and 1.34 times higher, respectively. Meanwhile, citrate supplement also promoted the accumulation of succinate, an important value-added platform chemical. Owing to the improved lipid and succinate production through adding citrate, the carbon conversion rate of M. alpina reached up to 52.17%, much higher than that of the control group (14.11%). The addition of citrate could redistribute carbon flux by regulating the expression level of genes related to tricarboxylic acid cycle metabolism. More carbon fluxes flow to lipid and succinate synthesis, which greatly improved the carbon conversion efficiency of M. alpina. This study provides an effective and straightforward strategy with potential economic benefits to improve carbon conversion efficiency in M. alpina. [ABSTRACT FROM AUTHOR]

Lung cancer (LC) is a serious threat to mankind. The survival of LC patients is still poor despite the enormous efforts that have been made to develop novel treatments. A copper-dependent cell death termed cuproptosis is distinct from known programmed cell death (PCD). Cuproptosis is induced by the disruption of the binding of copper to lipoylated tricarboxylic acid (TCA) cycle proteins of mitochondrial respiratory chains. Potential approaches for treating LC are inducing cell cuproptosis and targeting cell copper death mechanisms. Thus, in this review, we summarize the systemic and cellular metabolic processes of copper. We highlight the possible therapeutic options of employing copper ionophores and chelators for inducing cuproptosis. Moreover, we summarize the prognostic models based on cuproptosis-related genes (CRGs) to identify promising biomarkers for tumor diagnosis and therapy. This review aims to provide a comprehensive summary of CRGs-based prognostic models and promising therapeutic options for cuproptosis induction in LC. [ABSTRACT FROM AUTHOR]

Oncometabolites refer to pro-oncogenic metabolites that are aberrantly accumulated due to distorted metabolic pathways in cancer cells, and play a crucial role in promoting cancer malignancy. In recent years, the concept of oncometabolites has been broadened beyond their original definition. Emerging evidence has suggested that oncometabolites also exert crucial functions in non-cancer cells within the tumor microenvironment, and can even be produced by these cells. In this review, we summarize the expanded understanding of oncometabolites by presenting an overview of their functions and mechanisms in oncogenesis and cancer progression from the viewpoint of the tumor microenvironment, with a special attention to metabolite-mediated cell-cell crosstalk in promoting cancer progression. With this review, we hope to gain a better understanding of roles and the regulation of the rewired metabolism in cancer and inspire novel therapeutic avenues for treating oncometabolite-driven cancers. [ABSTRACT FROM AUTHOR]

Emerging evidence published over the past decade has highlighted the role of DNA methylation in skeletal muscle function and health, including as an epigenetic transducer of the adaptive response to exercise. In this review, we aim to synthesize the latest findings in this field to highlight: (1) the shifting understanding of the genomic localization of altered DNA methylation in response to acute and chronic aerobic and resistance exercise in skeletal muscle (e.g., promoter, gene bodies, enhancers, intergenic regions, un-annotated regions, and genome-wide methylation); (2) how these global/regional methylation changes relate to transcriptional activity following exercise; and (3) the factors (e.g., individual demographic or genetic features, dietary, training history, exercise parameters, local epigenetic characteristics, circulating hormones) demonstrated to alter both the pattern of DNA methylation after exercise, and the relationship between DNA methylation and gene expression. Finally, we discuss the changes in non-CpG methylation and 5-hydroxymethylation after exercise, as well as the importance of emerging single-cell analyses to future studies—areas of increasing focus in the field of epigenetics. We anticipate that this review will help generate a framework for clinicians and researchers to begin developing and testing exercise interventions designed to generate targeted changes in DNA methylation as part of a personalized exercise regimen. [ABSTRACT FROM AUTHOR]

Phytopathogenic Fusarium graminearum poses significant threats to crop health and soil quality. Although our laboratory-cultivated Pseudomonas sp. P13 exhibited potential biocontrol capacities, its effectiveness against F. graminearum and underlying antifungal mechanisms are still unclear. In light of this, our study investigated a significant inhibitory effect of P13 on F. graminearum T1, both in vitro and in a soil environment. Conducting genomic, metabolomic, and transcriptomic analyses of P13, we sought to identify evidence supporting its antagonistic effects on T1. The results revealed the potential of P13, a novel Pseudomonas species, to produce active antifungal components, including phenazine-1-carboxylate (PCA), hydrogen cyanide (HCN), and siderophores [pyoverdine (Pvd) and histicorrugatin (Hcs)], as well as the dynamic adaptive changes in the metabolic pathways of P13 related to these active ingredients. During the logarithmic growth stage, T1-exposed P13 strategically upregulated PCA and HCN biosynthesis, along with transient inhibition of the tricarboxylic acid (TCA) cycle. However, with growth stabilization, upregulation of PCA and HCN synthesis ceased, whereas the TCA cycle was enhanced, increasing siderophores secretion (Pvd and Hcs), suggesting that this mechanism might have caused continuous inhibition of T1. These findings improved our comprehension of the biocontrol mechanisms of P13 and provided the foundation for potential application of Pseudomonas strains in the biocontrol of phytopathogenic F. graminearum. [ABSTRACT FROM AUTHOR]

For centuries, Gram‐negative pathogens have infected the human population and been responsible for numerous diseases in animals and plants. Despite advancements in therapeutics, Gram‐negative pathogens continue to evolve, with some having developed multi‐drug resistant phenotypes. For the successful control of infections caused by these bacteria, we need to widen our understanding of the mechanisms of host–pathogen interactions. Gram‐negative pathogens utilise an array of effector proteins to hijack the host system to survive within the host environment. These proteins are secreted into the host system via various secretion systems, including the integral Type III secretion system (T3SS). The T3SS spans two bacterial membranes and one host membrane to deliver effector proteins (virulence factors) into the host cell. This multifaceted process has multiple layers of regulation and various checkpoints. In this review, we highlight the multiple strategies adopted by these pathogens to regulate or maintain virulence via the T3SS, encompassing the regulation of small molecules to sense and communicate with the host system, as well as master regulators, gatekeepers, chaperones, and other effectors that recognise successful host contact. Further, we discuss the regulatory links between the T3SS and other systems, like flagella and metabolic pathways including the tricarboxylic acid (TCA) cycle, anaerobic metabolism, and stringent cell response. [ABSTRACT FROM AUTHOR]

BACKGROUND: Although sodium-glucose cotransporter-2 inhibitors have been shown to improve cardiovascular outcomes in general, little is presently known about any sex-specific changes that may result from this therapy. We sought to investigate and quantify potential sex-specific changes seen with the sodium-glucose cotransporter-2 inhibitor canagliflozin (CAN) in a swine model of chronic myocardial ischemia. STUDY DESIGN: Eighteen Yorkshire swine underwent left thoracotomy with placement of an ameroid constrictor. Two weeks postop, swine were assigned to receive either control (F = 5 and M = 5) or CAN 300 mg daily (F = 4 and M = 4). After 5 weeks of therapy, swine underwent myocardial functional measurements, and myocardial tissue was sent for proteomic analysis. RESULTS: Functional measurements showed increased cardiac output, stroke volume, ejection fraction, and ischemic myocardial flow at rest in male swine treated with CAN compared with control male swine (all p < 0.05). The female swine treated with CAN had no change in cardiac function as compared with control female swine. Proteomic analysis demonstrated 6 upregulated and 97 downregulated proteins in the CAN female group compared with the control female group. Pathway analysis showed decreases in proteins in the tricarboxylic acidic cycle. The CAN male group had 639 upregulated and 172 downregulated proteins compared with control male group. Pathway analysis showed increases in pathways related to cellular metabolism and decreases in pathways relevant to the development of cardiomyopathy and to oxidative phosphorylation. CONCLUSIONS: Male swine treated with CAN had significant improvements in cardiac function that were not observed in female swine treated with CAN. Moreover, CAN treatment in male swine was associated with significantly more changes in protein expression than in female swine treated with CAN. The increased proteomic changes seen in the CAN male group likely contributed to the more robust changes in cardiac function seen in male swine treated with CAN. [ABSTRACT FROM AUTHOR]

The Lycoris radiata (L' Herit.) Herb. is a perennial bulbous plant characterized by its high ornamental and medicinal value, exhibiting a unique growth rhythm where the flower and leaf do not coexist and a period of summer dormancy. However, its metabolic response to various developmental stages remains unclear. To address this gap, we conducted a non-targeted metabolomic analysis spanning six developmental stages of L. radiata. The results showed that most differentially accumulated metabolites (DAMs) demonstrated enrichment predominantly in carbohydrate and amino acid metabolism pathways, with the former being more active during vegetative growth and the latter during reproductive stages. The proportion of DAMs categorized under "quaternary ammonium salts", "tricarboxylic acids and derivatives", "fatty acids and conjugates", and "pyrimidine nucleotide sugars" was notably higher in comparisons between the flowering and dormancy stages than in other comparative groups. Furthermore, DAMs involved in the KEGG pathways of C5-branched dibasic acid metabolism and lysine biosynthesis were uniquely identified during the transition from Dormancy to Flowering. The proportion of DAMs associated with "linoleic acids and derivatives" and "pyridines and pyridine derivatives" was notably higher in the leafing out versus flowering comparison than in other comparative groups. Furthermore, the glycolysis/gluconeogenesis pathway was uniquely enriched by DAMs during this phase. This study provided an in-depth view of metabolite changes in L. radiata over its annual growth cycle, enriching our understanding of the regulatory mechanisms governing its development, dormancy, and flowering. [ABSTRACT FROM AUTHOR]

Novel electrode and electrolyte materials are crucial for enhancing supercapacitor efficiency. Metal–organic frameworks (MOFs) have gained attention owing to their high porosity and surface area. However, their low capacity limits their usage. To tackle this, a highly effective mechanochemical annealing strategy is implemented to improve their efficiency. Three different forms of metal oxides NiCo2O4 are derived from bimetallic MOFs by incorporating Ni2+ and Co2+ with linkers 1,3,5‐benzene tricarboxylic acid (MO‐1), 2,6‐naphthalene dicarboxylic acid (MO‐2), and 1,2,4,5‐benzene tetracarboxylic acid (MO‐3). The synthesized metal oxides have different morphologies due to different linkers and displayed remarkable electrochemical performance, attributed to favorable charge transport paths and enhanced electrochemical double‐layer capacitance with an enlarged specific surface area. These metal oxides exhibit specific capacitance values of 913.3, 43.4, and 210 F g−1 at operating voltages of 0.55, 0.55, and 0.6 V for MO‐1, MO‐2, and MO‐3, respectively. Notably, MO‐1 shows extended discharging time and demonstrates the characteristic behavior of battery‐type supercapacitors, making it versatile. The fabricated hybrid supercapacitor (bimetal hybrid supercapacitor) shows pseudocapacitive behavior, reaching up to 1.5 V with a specific capacitance of 65.6 F g−1, energy density of 73.83 W h kg−1, and power density of 1181.2 W kg−1. [ABSTRACT FROM AUTHOR]

Hydroxyectoine is an important compatible solute that holds potential for development into a high-value chemical with broad applications. However, the traditional high-salt fermentation for hydroxyectoine production presents challenges in treating the high-salt wastewater. Here, we report the rational engineering of Halomonas salifodinae to improve the bioproduction of hydroxyectoine under lower-salt conditions. The comparative transcriptomic analysis suggested that the increased expression of ectD gene encoding ectoine hydroxylase (EctD) and the decreased expressions of genes responsible for tricarboxylic acid (TCA) cycle contributed to the increased hydroxyectoine production in H. salifodinae IM328 grown under high-salt conditions. By blocking the degradation pathway of ectoine and hydroxyectoine, enhancing the expression of ectD, and increasing the supply of 2-oxoglutarate, the engineered H. salifodinae strain HS328-YNP15 (ΔdoeA::PUP119-ectD p-gdh) produced 8.3-fold higher hydroxyectoine production than the wild-type strain and finally achieved a hydroxyectoine titer of 4.9 g/L in fed-batch fermentation without any detailed process optimization. This study shows the potential to integrate hydroxyectoine production into open unsterile fermentation process that operates under low-salinity and high-alkalinity conditions, paving the way for next-generation industrial biotechnology. Key points: • Hydroxyectoine production in H. salifodinae correlates with the salinity of medium • Transcriptomic analysis reveals the limiting factors for hydroxyectoine production • The engineered strain produced 8.3-fold more hydroxyectoine than the wild type [ABSTRACT FROM AUTHOR]

Background: Microbial engineering aims to enhance the ability of bacteria to produce valuable products, including vitamin B6 for various applications. Numerous microorganisms naturally produce vitamin B6, yet the metabolic pathways involved are rigorously controlled. This regulation by the accumulation of vitamin B6 poses a challenge in constructing an efficient cell factory. Results: In this study, we conducted transcriptome and metabolome analyses to investigate the effects of the accumulation of pyridoxine, which is the major commercial form of vitamin B6, on cellular processes in Escherichia coli. Our omics analysis revealed associations between pyridoxine and amino acids, as well as the tricarboxylic acid (TCA) cycle. Based on these findings, we identified potential targets for fermentation optimization, including succinate, amino acids, and the carbon-to-nitrogen (C/N) ratio. Through targeted modifications, we achieved pyridoxine titers of approximately 514 mg/L in shake flasks and 1.95 g/L in fed-batch fermentation. Conclusion: Our results provide insights into pyridoxine biosynthesis within the cellular metabolic network for the first time. Our comprehensive analysis revealed that the fermentation process resulted in a remarkable final yield of 1.95 g/L pyridoxine, the highest reported yield to date. This work lays a foundation for the green industrial production of vitamin B6 in the future. [ABSTRACT FROM AUTHOR]

The expanding geriatric population, whose predisposition toward disabling morbidities and age-related diseases (ARD) is well-documented, has become a paramount social issue, exerting an onerous burden on both the healthcare industry and wider society. ARD manifest as the progressive deterioration of bodily tissues and organs, eventually resulting in the failure of these vital components. At present, no efficacious measures exist to hinder the onset of ARD. Copper, an essential trace element, is involved in a wide range of physiological processes across different cell types. In recent research, a novel variant of copper-dependent cell death, termed cuproptosis, has been identified. This mode of cellular demise stands apart from previously recognized types of cell death. Cuproptosis occurs when copper binds with acyl-CoA synthetase in the tricarboxylic acid (TCA) cycle, resulting in protein aggregation and protein toxicity stress, ultimately leading to cell death. In this paper, we provide a concise overview of the current understanding concerning the metabolism of copper, copper-related diseases, the hallmarks of copper toxicity, and the mechanisms that regulate copper toxicity. Additionally, we discuss the implications of cuproptosis mutations in the development of ARD, as well as the potential for targeting cuproptosis as a treatment for ARD. [ABSTRACT FROM AUTHOR]

Summary: Over the past decade, there has been a surge in discoveries of how metabolic pathways regulate immune cell function in health and disease, establishing the field of immunometabolism. Specifically, pathways such as glycolysis, the tricarboxylic acid (TCA) cycle, and those involving lipid metabolism have been implicated in regulating immune cell function. Viral infections cause immunometabolic changes which lead to antiviral immunity, but little is known about how metabolic changes regulate interferon responses. Interferons are critical cytokines in host defense, rapidly induced upon pathogen recognition, but are also involved in autoimmune diseases. This review summarizes how metabolic change impacts interferon production. We describe how glycolysis, lipid metabolism (specifically involving eicosanoids and cholesterol), and the TCA cycle‐linked intermediates itaconate and fumarate impact type I interferons. Targeting these metabolic changes presents new therapeutic possibilities to modulate type I interferons during host defense or autoimmune disorders. [ABSTRACT FROM AUTHOR]

Ferroptosis and apoptosis are key cell‐death pathways implicated in several human diseases including cancer. Ferroptosis is driven by iron‐dependent lipid peroxidation and currently has no characteristic biomarkers or gene signatures. Here a continuous phenotypic gradient between ferroptosis and apoptosis coupled to transcriptomic and metabolomic landscapes is established. The gradual ferroptosis‐to‐apoptosis transcriptomic landscape is used to generate a unique, unbiased transcriptomic predictor, the Gradient Gene Set (GGS), which classified ferroptosis and apoptosis with high accuracy. Further GGS optimization using multiple ferroptotic and apoptotic datasets revealed highly specific ferroptosis biomarkers, which are robustly validated in vitro and in vivo. A subset of the GGS is associated with poor prognosis in breast cancer patients and PDXs and contains different ferroptosis repressors. Depletion of one representative, PDGFA‐assaociated protein 1(PDAP1), is found to suppress basal‐like breast tumor growth in a mouse model. Omics and mechanistic studies revealed that ferroptosis is associated with enhanced lysosomal function, glutaminolysis, and the tricarboxylic acid (TCA) cycle, while its transition into apoptosis is attributed to enhanced endoplasmic reticulum(ER)‐stress and phosphatidylethanolamine (PE)‐to‐phosphatidylcholine (PC) metabolic shift. Collectively, this study highlights molecular mechanisms underlying ferroptosis execution, identified a highly predictive ferroptosis gene signature with prognostic value, ferroptosis versus apoptosis biomarkers, and ferroptosis repressors for breast cancer therapy. [ABSTRACT FROM AUTHOR]

This study explores the impact of a novel phytogenic product containing citric acid, carvacrol, and cinnamaldehyde on buffel grass (Cenchrus ciliaris) seedling emergence. A dilution series of the phytogenic solution revealed a concentration range that promoted seedling emergence, with an optimal concentration of 0.5%. Transcriptomic analysis using RNA-seq was performed to investigate gene expression changes in seedlings under the influence of the phytogenic product. The results revealed that the phytogenic treatment significantly altered the gene expression, with a prevalent boost in transcriptional activity compared to the control. Functional analysis indicated the positive alteration of key metabolic pathways, including the tricarboxylic acid (TCA) cycle, glycolysis, and pentose phosphate pathways. Moreover, pathways related to amino acids, nucleotide biosynthesis, heme biosynthesis, and formyltetrahydrofolate biosynthesis showed substantial modulation. The study provides valuable insights into the molecular mechanisms underlying the phytogenic product's effects on grass seedling establishment and highlights its ability to promote energy metabolism and essential biosynthetic pathways for plant growth. [ABSTRACT FROM AUTHOR]

The tricarboxylic acid (TCA) cycle metabolite fumarate nonenzymatically reacts with the amino acid cysteine to form S-(2-succino) cysteine (2SC), referred to as protein succination. The immunometabolite itaconate accumulates during lipopolysaccharide (LPS) stimulation of macrophages and microglia. Itaconate nonenzymatically reacts with cysteine residues to generate 2,3-dicarboxypropylcysteine (2,3-DCP), referred to as protein dicarboxypropylation. Since fumarate and itaconate levels dynamically change in activated immune cells, the levels of both 2SC and 2,3-DCP reflect the abundance of these metabolites and their capacity to modify protein thiols. We generated ethyl esters of 2SC and 2,3-DCP from protein hydrolysates and used stable isotope dilution mass spectrometry to determine the abundance of these in LPS-stimulated Highly Aggressively Proliferating Immortalized (HAPI) microglia. To quantify the stoichiometry of the succination and dicarboxypropylation, reduced cysteines were alkylated with iodoacetic acid to form S-carboxymethylcysteine (CMC), which was then esterified. Itaconate-derived 2,3-DCP, but not fumarate-derived 2SC, increased in LPS-treated HAPI microglia. Stoichiometric measurements demonstrated that 2,3-DCP increased from 1.57% to 9.07% of total cysteines upon LPS stimulation. This methodology to simultaneously distinguish and quantify both 2SC and 2,3-DCP will have broad applications in the physiology of metabolic diseases. In addition, we find that available anti-2SC antibodies also detect the structurally similar 2,3-DCP, therefore "succinate moiety" may better describe the antigen recognized. [ABSTRACT FROM AUTHOR]

Gut microbes supporting body growth are known but the mechanisms are less well documented. Using the microbial tryptophan metabolite indole, known to regulate prokaryotic cell division and metabolic stress conditions, we mono-colonized germ-free (GF) mice with indole-producing wild-type Escherichia coli (E. coli) or tryptophanase-encoding tnaA knockout mutant indole-non-producing E. coli. Indole mutant E. coli mice showed multiorgan growth retardation and lower levels of glycogen, cholesterol, triglycerides, and glucose, resulting in an energy deficiency despite increased food intake. Detailed analysis revealed a malfunctioning intestine, enlarged cecum, and reduced numbers of enterochromaffin cells, correlating with a metabolic phenotype consisting of impaired gut motility, diminished digestion, and lower energy harvest. Furthermore, indole mutant mice displayed reduction in serum levels of tricarboxylic acid (TCA) cycle intermediates and lipids. In stark contrast, a massive increase in serum melatonin was observed—frequently associated with accelerated oxidative stress and mitochondrial dysfunction. This observational report discloses functional roles of microbe-derived indoles regulating multiple organ functions and extends our previous report of indole-linked regulation of adult neurogenesis. Since indoles decline by age, these results imply a correlation with age-linked organ decline and levels of indoles. Interestingly, increased levels of indole-3-acetic acid, a known indole metabolite, have been shown to correlate with younger biological age, further supporting a link between biological age and levels of microbe-derived indole metabolites. The results presented in this resource paper will be useful for the future design of food intervention studies to reduce accelerated age-linked organ decline. [ABSTRACT FROM AUTHOR]

Understanding how plants grow is critical for agriculture and fundamental for illuminating principles of multicellular development. Here, we apply desorption electrospray ionization mass spectrometry imaging (DESI-MSI) to the chemical mapping of the developing maize root. This technique reveals a range of small molecule distribution patterns across the gradient of stem cell differentiation in the root. To understand the developmental logic of these patterns, we examine tricarboxylic acid (TCA) cycle metabolites. In both Arabidopsis and maize, we find evidence that elements of the TCA cycle are enriched in developmentally opposing regions. We find that these metabolites, particularly succinate, aconitate, citrate, and α-ketoglutarate, control root development in diverse and distinct ways. Critically, the developmental effects of certain TCA metabolites on stem cell behavior do not correlate with changes in ATP production. These results present insights into development and suggest practical means for controlling plant growth.

Cancer cells have adapted to rapid tumor growth and evade immune attack by reprogramming their metabolic pathways. Glutamine is an important nitrogen resource for synthesizing amino acids and nucleotides and an important carbon source in the tricarboxylic acid (TCA) cycle and lipid biosynthesis pathway. In this review, we summarize the significant role of glutamine metabolism in tumor development and highlight the vulnerabilities of targeting glutamine metabolism for effective therapy. In particular, we review the reported drugs targeting glutaminase and glutamine uptake for efficient cancer treatment. Moreover, we discuss the current clinical test about targeting glutamine metabolism and the prospective direction of drug development. [ABSTRACT FROM AUTHOR]

Aging is a time-dependent progressive physiological process, which results in impaired immune system function. Age-related changes in immune function increase the susceptibility to many diseases such as infections, autoimmune diseases, and cancer. Different metabolic pathways including glycolysis, tricarboxylic acid cycle, amino acid metabolism, pentose phosphate pathway, fatty acid oxidation and fatty acid synthesis regulate the development, differentiation, and response of adaptive and innate immune cells. During aging all these pathways change in the immune cells. In addition to the changes in metabolic pathways, the function and structure of mitochondria also have changed in the immune cells. Thereby, we will review changes in the metabolism of different innate immune cells during the aging process. [ABSTRACT FROM AUTHOR]

Integrative and conjugative elements (ICEs) are self-transmissible mobile elements that transfer functional genetic units across broad phylogenetic distances. Accessory genes shuttled by ICEs can make significant contributions to bacterial fitness. Most ICEs characterized to date encode readily observable phenotypes contributing to symbiosis, pathogenicity, and antimicrobial resistance, yet the majority of ICEs carry genes of unknown function. Recent observations of rapid acquisition of ICEs in a pandemic lineage of Pseudomonas syringae pv. actinidae led to investigation of the structural and functional diversity of these elements. Fifty-three unique ICE types were identified across the P. syringae species complex. Together they form a distinct family of ICEs (PsICEs) that share a distant relationship to ICEs found in Pseudomonas aeruginosa. PsICEs are defined by conserved backbone genes punctuated by an array of accessory cargo genes, are highly recombinogenic, and display distinct evolutionary histories compared to their bacterial hosts. The most common cargo is a recently disseminated 16-kb mobile genetic element designated Tn6212. Deletion of Tn6212 did not alter pathogen growth in planta, but mutants displayed fitness defects when grown on tricarboxylic acid (TCA) cycle intermediates. RNA-seq analysis of a set of nested deletion mutants showed that a Tn6212-encoded LysR regulator has global effects on chromosomal gene expression. We show that Tn6212 responds to preferred carbon sources and manipulates bacterial metabolism to maximize growth. [ABSTRACT FROM AUTHOR]

Chlorpyrifos (CPF) poisoning is a public health problem for which there is not currently any effective prophylaxis. In this study, we investigated the protective effect of grape seed extract (GSE) against CPF-induced hepatotoxicity. Rats were daily treated either with CPF (2 mg/kg) or CPF and GSE (20 mg/kg) for 1 week, sacrificed, and their livers dissected for biochemical, molecular, and histopathological analyses. CPF generated liver dysfunction by altering carbohydrate, lipid, amino acid, ammonia and urea metabolism, and provoked mitochondrial impairment through disturbing tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), and mitochondrial viability. CPF also induced cholinergic excitotoxicity along with oxidative stress and histopathological alterations. Interestingly, treatment with GSE prevented all the detrimental effects of CPF through the regulation of cytochrome P450 (CYP450) gene expression. Molecular docking analysis indicated that GSE-containing polyphenols acted as epigenetic modulators through inhibiting DNA (cytosine-5)-methyltransferase 1 (DNMT1), thus favoring the CYP2C6 detoxification pathway. Thereby, GSE might be a promising strategy in the protection of the liver against CPF toxicity. [ABSTRACT FROM AUTHOR]

[1′‐13C]Citric acid (1) was efficiently prepared from dimethyl 1,3‐acetonedicarboxylate in two steps as a probe for a breath test. The synthetic method was selected because of the yield and reproducibility. Compound 1 was orally administrated to rats, and the time course of the increase of 13CO2/12CO2 ratios (Δ13CO2) in their breath was successfully followed, indicating the metabolism of 1. Thus, the 13C‐breath test using 1 is a promising method to evaluate tricarboxylic acid (TCA) cycle flux. [ABSTRACT FROM AUTHOR]

The hypothalamus is a key integrating center that is involved in the initiation of the corticosteroid stress response, and in regulating nutrient homeostasis. Although cortisol, the principal glucocorticoid in humans and teleosts, plays a central role in feeding regulation, the mechanisms are far from clear. We tested the hypothesis that the metabolic changes to cortisol exposure signal an energy excess in the hypothalamus, leading to feeding suppression during stress in fish. Rainbow trout (Oncorhynchus mykiss) were administered a slow-release cortisol implant for 3 days, and the metabolite profiles in the plasma, hypothalamus, and the rest of the brain were assessed. Also, U-13C-glucose was injected into the hypothalamus by intracerebroventricular (ICV) route, and the metabolic fate of this energy substrate was followed in the brain regions by metabolomics. Chronic cortisol treatment reduced feed intake, and this corresponded with a downregulation of the orexigenic gene agrp, and an upregulation of the anorexigenic gene cart in the hypothalamus. The U-13C-glucose-mediated metabolite profiling indicated an enhancement of glycolytic flux and tricarboxylic acid intermediates in the rest of the brain compared with the hypothalamus. There was no effect of cortisol treatment on the phosphorylation status of AMPK or mechanistic target of rapamycin in the brain, whereas several endogenous metabolites, including leucine, citrate, and lactate were enriched in the hypothalamus, suggesting a tissue-specific metabolic shift in response to cortisol stimulation. Altogether, our results suggest that the hypothalamus-specific enrichment of leucine and the metabolic fate of this amino acid, including the generation of lipid intermediates, contribute to cortisol-mediated feeding suppression in fish. [ABSTRACT FROM AUTHOR]

Objective: Tumor cells can acquire a large amount of energy and structural components by reprogramming energy metabolism; moreover, metabolic profiles slightly differ according to cancer type. This study compared and assessed the metabolic profile of head and neck squamous cell carcinoma (HNSCC) and normal tissues, which were collected from patients without cancer. Subjects and Methods: Overall, 23 patients with HNSCC and 6 patients without cancer were included in the analysis. Metabolomic profiles were analyzed using capillary electrophoresis‐mass spectrometry. Gene expression was evaluated using real‐time reverse transcription‐polymerase chain reaction. Results: Glycolysis, the pentose phosphate pathway, tricarboxylic acid cycle, and glutamine metabolism were upregulated in HNSCC tissues based on gene expression analysis. HNSCC could then have enhanced energy production and structural component. The levels of lactate, succinate, glutathione, 2‐hydroxyglutarate, and S‐adenosylmethionine, considered as oncometabolites, increased and these had accumulated in HNSCC tissues. Conclusions: The level of metabolites and the expression of enzymes differ between HNSCC and normal tissues. Reprogramming metabolism in HNSCC provides an energy source as well as structural components, creating a system that offers rapid proliferation, progression, and is less likely to be eliminated. [ABSTRACT FROM AUTHOR]

Isocitrate dehydrogenase is an enzyme converting isocitrate to α-ketoglutarate in the canonical tricarboxylic acid (TCA) cycle. There are three different types of isocitrate dehydrogenase documented in eukaryotes. Our study points out the complex evolutionary history of isocitrate dehydrogenases across kinetoplastids, where the common ancestor of Trypanosomatidae and Bodonidae was equipped with two isoforms of the isocitrate dehydrogenase enzyme: the NADP+-dependent isocitrate dehydrogenase 1 with possibly dual localization in the cytosol and mitochondrion and NADP+-dependent mitochondrial isocitrate dehydrogenase 2. In the extant trypanosomatids, isocitrate dehydrogenase 1 is present only in a few species suggesting that it was lost upon separation of Trypanosoma spp. and replaced by the mainly NADP+-dependent cytosolic isocitrate dehydrogenase 3 of bacterial origin in all the derived lineages. In this study, we experimentally demonstrate that the omnipresent isocitrate dehydrogenase 2 has a dual localization in both mitochondrion and cytosol in at least four species that possess only this isoform. The apparent lack of the NAD+-dependent isocitrate dehydrogenase activity in trypanosomatid mitochondrion provides further support to the existence of the noncanonical TCA cycle across trypanosomatids and the bidirectional activity of isocitrate dehydrogenase 3 when operating with NADP+ cofactor instead of NAD+. This observation can be extended to all 17 species analyzed in this study, except for Leishmania mexicana , which showed only low isocitrate dehydrogenase activity in the cytosol. The variability in isocitrate oxidation capacity among species may reflect the distinct metabolic strategies and needs for reduced cofactors in particular environments. [ABSTRACT FROM AUTHOR]

Objectives: Colitis is a global disease usually accompanied by intestinal epithelial damage and intestinal inflammation, and an increasing number of studies have found natural products to be highly effective in treating colitis. Anemoside B4 (AB4), an abundant saponin isolated from Pulsatilla chinensis (Bunge), which was found to have strong anti-inflammatory activity. However, the exact molecular mechanisms and direct targets of AB4 in the treatment of colitis remain to be discovered. Methods: The anti-inflammatory activities of AB4 were verified in LPS-induced cell models and 2, 4, 6-trinitrobenzene sulfonic (TNBS) or dextran sulfate sodium (DSS)-induced colitis mice and rat models. The molecular target of AB4 was identified by affinity chromatography analysis using chemical probes derived from AB4. Experiments including proteomics, molecular docking, biotin pull-down, surface plasmon resonance (SPR), and cellular thermal shift assay (CETSA) were used to confirm the binding of AB4 to its molecular target. Overexpression of pyruvate carboxylase (PC) and PC agonist were used to study the effects of PC on the anti-inflammatory and metabolic regulation of AB4 in vitro and in vivo. Results: AB4 not only significantly inhibited LPS-induced NF-κB activation and increased ROS levels in THP-1 cells, but also suppressed TNBS/DSS-induced colonic inflammation in mice and rats. The molecular target of AB4 was identified as PC, a key enzyme related to fatty acid, amino acid and tricarboxylic acid (TCA) cycle. We next demonstrated that AB4 specifically bound to the His879 site of PC and altered the protein's spatial conformation, thereby affecting the enzymatic activity of PC. LPS activated NF-κB pathway and increased PC activity, which caused metabolic reprogramming, while AB4 reversed this phenomenon by inhibiting the PC activity. In vivo studies showed that diisopropylamine dichloroacetate (DADA), a PC agonist, eliminated the therapeutic effects of AB4 by changing the metabolic rearrangement of intestinal tissues in colitis mice. Conclusion: We identified PC as a direct cellular target of AB4 in the modulation of inflammation, especially colitis. Moreover, PC/pyruvate metabolism/NF-κB is crucial for LPS-driven inflammation and oxidative stress. These findings shed more light on the possibilities of PC as a potential new target for treating colitis. [ABSTRACT FROM AUTHOR]