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[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]

Metabolomic research involves the comprehensive analysis of metabolites in biological samples and has many applications. Gas chromatography-mass spectrometry (GC-MS) is an established and widely used approach for metabolic profiling. However, sample preparation and metabolite derivatization are time-consuming, and derivatization options are limited. We propose gas–solid phase derivatization (GSPD) as a novel sampling and derivatization method that uses a silica monolith substrate and gaseous derivatization reagents for metabolomics using GC-MS. We developed a method to measure the organic acids and sugar phosphates responsible for glycolysis and the tricarboxylic acid (TCA) cycle. GSPD simplifies the sample preparation and can be applied to derivatization reactions that are difficult to perform in solution owing to solvent limitations. The developed method was applied to human plasma and tomato pulp and was shown to have a higher detection performance than the conventional method. This study provides a strategy to simplify sample preparation and expand derivatization options for GC-MS-based metabolomics. [Display omitted] • Gas–solid phase derivatization (GSPD) as a novel gas-phase derivatization for GC-MS-based metabolomics was proposed. • GSPD methods for organic acids and sugar phosphates were developed. • The GSPD was applied to human plasma and tomato pulp. • The GSPD was shown to have a higher detection performance than the conventional method. [ABSTRACT FROM AUTHOR]

In this work, we evaluate the bonding characteristics and interfacial electron transfer dynamics of three heteroleptic ruthenium photosensitizers featuring different terpyridine (tpy) acceptor end configurations through quantum-chemical calculations. These photosensitizers feature tpy ligands with a mono/tricarboxylic acid or a phenyl-carboxylic acid anchor and a trans-disposed –NCS and N-heterocyclic carbene ligand in a C^N donor set. Adiabatic transitions reveal significant overlap between higher-excited and ground-state orbitals and correlate with the experimentally observed anti-Kasha fluorescence. In all complexes, two carboxylate-O atoms of the central anchor effectively bind with TiO2 by bridging two titanium sites. However, appending an additional anchor on each peripheral pyridine of tpy renders binding through only one anchor's –C＝O atom to TiO2. Contrary to the complex bearing three anchors, those featuring monocarboxylate-functionalized tpy exhibit faster electron injection within 100 fs. In all, this study provides insights into the photosensitization attributes of the ruthenium complexes for dye-sensitized solar cells. [ABSTRACT FROM AUTHOR]

Introduction: Alfalfa (Medicago sativa L.) is a globally important legume crop with high nutritional and ecological value. Drought poses a serious threat to alfalfa acreage and yields. Spermine (Spm) has been shown to protect plants from drought damage. The aim of this study was to clarify the mechanism of exogenous Spm to improve drought resistance of alfalfa. Methods: In this study, we root applied 0.1, 0.5, and 1mM Spm to Gannong No. 3 (G3) alfalfa under drought stress, and then determined their physiological and metabolic changes. Results: The results showed that exogenous Spm increased chlorophyll content, chlorophyll fluorescence parameters and gas exchange parameters, enhanced antioxidant enzymes activity, improved ascorbic acid-glutathione (AsA-GSH) cycle, increased osmoregulatory substances content, reduced hydrogen peroxide and superoxide anion levels, and inhibited malondialdehyde accumulation in alfalfa under drought stress, thereby increasing plant height and leaf relative water content and enhancing drought tolerance of alfalfa. The redundancy analysis of the above physiological indicators showed that the addition of the optimal Spm to improve drought tolerance of alfalfa under drought stress was mainly achieved by increasing catalase activity and improving the ASA-GSH cycle. In addition, metabolomics analysis revealed that exogenous Spm increased the content of oxobutanedioic acid, citric acid, fumaric acid and malic acid to enhance the tricarboxylic acid cycle. Meanwhile, exogenous Spm increased endogenous Spm and proline (Pro) content to resist drought stress by enhancing Spm and Pro metabolism. Moreover, exogenous Spm increased the accumulation of the signaling substance abscisic acid. Discussion: In conclusion, exogenous Spm enhanced drought resistance of alfalfa leaves under drought stress. [ABSTRACT FROM AUTHOR]

During focal ischemia, neurons can use lactate as an alternative source of energy through its oxidation into pyruvate by the lactate dehydrogenase (LDH). After cardiac arrest, the neurological consequences of this phenomenon are unknown. Experimental study. Experimental laboratory. Male New-Zealand rabbits. Animals were surgically instrumented and randomly divided into five groups receiving short infusion duration of either lactate or pyruvate or a pre-cardiac arrest infusion of oxamate (an inhibitor of the lactate dehydrogenase) or injection of fluorocitrate (an inhibitor of astrocytic tricarboxylic acid), or Saline (lactate, pyruvate, Oxa, FC and Control groups, respectively). After randomization, animals were submitted to 10 min of ventricular fibrillation and subsequent resuscitation. All animals were then either followed during 4 h, for the evaluation of the cerebral net uptake and concentrations of metabolites by microdialysis (n = 6 in each experimental group, n = 12 in control group), or during 48 h for the evaluation of their neurological outcome (n = 7 in each groups and n = 14 in control group). Cardiac arrest was associated with a dramatic increase in cerebral net uptake of lactate during 120 min after resuscitation, which was increased by lactate or pyruvate administration. This was associated with an increase in the mean neurological dysfunction score (66.7 ± 4.7, 79.0 ± 4.5 vs 57.7 ± 1.5 in Lactate, Pyruvate and Control group respectively) at 48 h after cardiac arrest. Oxamate and FC administration were associated with a lower lactate cerebral uptake after cardiac arrest and with an improvement of the neurological recovery (28.85 ± 9.4, 23.86 ± 6.2 vs 57.7 ± 1.5 in Oxa, FC and Control group respectively). After cardiac arrest, immediate isotonic lactate or pyruvate administration is deleterious. Pre-cardiac arrest LDH inhibition was potently neuroprotective in this setting. [ABSTRACT FROM AUTHOR]

Small molecules selectively inducing peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α acetylation and inhibiting glucagon-dependent gluconeogenesis causing anti-diabetic effects have been identified. However, how these small molecules selectively suppress the conversion of gluconeogenic metabolites into glucose without interfering with lipogenesis is unknown. Here, we show that a small molecule SR18292 inhibits hepatic glucose production by increasing lactate and glucose oxidation. SR18292 increases phosphoenolpyruvate carboxykinase 1 (PCK1) acetylation, which reverses its gluconeogenic reaction and favors oxaloacetate (OAA) synthesis from phosphoenolpyruvate. PCK1 reverse catalytic reaction induced by SR18292 supplies OAA to tricarboxylic acid (TCA) cycle and is required for increasing glucose and lactate oxidation and suppressing gluconeogenesis. Acetylation mimetic mutant PCK1 K91Q favors anaplerotic reaction and mimics the metabolic effects of SR18292 in hepatocytes. Liver-specific expression of PCK1 K91Q mutant ameliorates hyperglycemia in obese mice. Thus, SR18292 blocks gluconeogenesis by enhancing gluconeogenic substrate oxidation through PCK1 lysine acetylation, supporting the anti-diabetic effects of these small molecules. [Display omitted] • SR18292 increases oxidation of glucose and gluconeogenic substrates • SR18292-mediated gluconeogenic inhibition does not induce de novo lipogenesis • Small molecule SR18292 enhances PCK1 acetylation, leading to OAA synthesis from PEP • Acetyl-mimetic mutation at K91 of PCK1 recapitulates the effects of SR18292 Although suppression of liver glucose production reduces hyperglycemia in diabetes, this inhibition can promote de novo lipogenesis from gluconeogenic substrates, exacerbating hepatic steatosis and compromising clinical interventions. Mutlu et al. elucidate how the small molecule SR18292 represses hepatic gluconeogenesis without perturbation of lipogenesis. [ABSTRACT FROM AUTHOR]

Lysine β‐hydroxybutyrylation (Kbhb) is a post‐translational modification that has recently been found to regulate protein functions. However, whether and how protein Kbhb modification participates in Alzheimer's disease (AD) remains unknown. Herein, we carried out 4D label‐free β‐hydroxybutylation quantitative proteomics using brain samples of 8‐month‐old and 2‐month‐old APP/PS1 AD model mice and wild‐type (WT) controls. We identified a series of tricarboxylic acid (TCA) cycle‐associated enzymes including citrate synthase (CS) and succinate‐CoA ligase subunit alpha (SUCLG1), whose Kbhb modifications were decreased in APP/PS1 mice at pathological stages. Sodium β‐hydroxybutyrate (Na‐β‐OHB) treatment markedly increased Kbhb modifications of CS and SUCLG1 and their enzymatic activities, leading to elevated ATP production. We further found that Kbhb modifications at lysine 393 site in CS and at lysine 81 site in SUCLG1 were crucial for their enzymatic activities. Finally, we found that β‐OHB levels were decreased in the brain of APP/PS1 mice at pathological stages. While ketogenic diet not only significantly increased β‐OHB levels, Kbhb modifications and enzymatic activities of CS and SUCLG1, and ATP production, but also dramatically attenuated β‐amyloid plaque pathologies and microgliosis in APP/PS1 mice. Together, our findings indicate the importance of protein Kbhb modification for maintaining normal TCA cycle and ATP production and provide a novel molecular mechanism underlying the beneficial effects of ketogenic diet on energy metabolism and AD intervention. [ABSTRACT FROM AUTHOR]

Severe and chronic infections, including pneumonia, sepsis, and tuberculosis (TB), induce long-lasting epigenetic changes that are associated with an increase in all-cause postinfectious morbidity and mortality. Oncology studies identified metabolic drivers of the epigenetic landscape, with the tricarboxylic acid (TCA) cycle acting as a central hub. It is unknown if the TCA cycle also regulates epigenetics, specifically DNA methylation, after infection-induced immune tolerance. The following studies demonstrate that lipopolysaccharide and Mycobacterium tuberculosis induce changes in DNA methylation that are mediated by the TCA cycle. Infection-induced DNA hypermethylation is mitigated by inhibitors of cellular metabolism (rapamycin, everolimus, metformin) and the TCA cycle (isocitrate dehydrogenase inhibitors). Conversely, exogenous supplementation with TCA metabolites (succinate and itaconate) induces DNA hypermethylation and immune tolerance. Finally, TB patients who received everolimus have less DNA hypermethylation demonstrating proof of concept that metabolic manipulation can mitigate epigenetic scars. [ABSTRACT FROM AUTHOR]

Deficiencies in the electron transport chain (ETC) lead to mitochondrial diseases. While mutations are distributed across the organism, cell and tissue sensitivity to ETC disruption varies, and the molecular mechanisms underlying this variability remain poorly understood. Here we show that, upon ETC inhibition, a non-canonical tricarboxylic acid (TCA) cycle upregulates to maintain malate levels and concomitant production of NADPH. Our findings indicate that the adverse effects observed upon CI inhibition primarily stem from reduced NADPH levels, rather than ATP depletion. Furthermore, we find that Pyruvate carboxylase (PC) and ME1, the key mediators orchestrating this metabolic reprogramming, are selectively expressed in astrocytes compared to neurons and underlie their differential sensitivity to ETC inhibition. Augmenting ME1 levels in the brain alleviates neuroinflammation and corrects motor function and coordination in a preclinical mouse model of CI deficiency. These studies may explain why different brain cells vary in their sensitivity to ETC inhibition, which could impact mitochondrial disease management. Mitochondrial diseases caused by ETC deficiencies affect cells differently. Here, the authors show that ETC inhibition activates a non-canonical TCA cycle to maintain NADPH levels, which explains the differential sensitivity observed between astrocytes and neurons. [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]

The neuronal tricarboxylic acid and glutamate/glutamine (Glu/Gln) cycles play important roles in brain function. These processes can be measured in vivo using dynamic 1H–[13C] MRS during administration of 13C‐labeled glucose. Proton‐observed carbon‐edited (POCE) MRS enhances the signal‐to‐noise ratio (SNR) compared with direct 13C‐MRS. Ultra‐high field further boosts the SNR and increases spectral dispersion; however, even at 7 T, Glu and Gln 1H‐resonances may overlap. Further gain can be obtained with selective POCE (selPOCE). Our aim was to create a setup for indirect dynamic 1H–[13C] MRS in the human brain at 7 T. A home‐built non‐shielded transmit–receive 13C‐birdcage head coil with eight transmit–receive 1H‐dipole antennas was used together with a 32‐channel 1H‐receive array. Electromagnetic simulations were carried out to ensure that acquisitions remained within local and global head SAR limits. POCE‐MRS was performed using slice‐selective excitation with semi‐localization by adiabatic selective refocusing (sLASER) and stimulated echo acquisition mode (STEAM) localization, and selPOCE‐MRS using STEAM. Sequences were tested in a phantom containing non‐enriched Glu and Gln, and in three healthy volunteers during uniformly labeled 13C‐glucose infusions. In one subject the voxel position was alternated between bi‐frontal and bi‐occipital placement within one session. [4‐13C]Glu‐H4 and [4‐13C]Gln‐H4 signals could be separately detected using both STEAM‐POCE and STEAM‐selPOCE in the phantom. In vivo, [4,5‐13C]Glx could be detected using both sLASER‐POCE and STEAM‐POCE, with similar sensitivities, but [4,5‐13C]Glu and [4,5‐13C]Gln signals could not be completely resolved. STEAM‐POCE was alternately performed bi‐frontal and bi‐occipital within a single session without repositioning of the subject, yielding similar results. With STEAM‐selPOCE, [4,5‐13C]Glu and [4,5‐13C]Gln could be clearly separated. We have shown that with our setup indirect dynamic 1H–[13C] MRS at 7 T is feasible in different locations in the brain within one session, and by using STEAM‐selPOCE it is possible to separate Glu from Gln in vivo while obtaining high quality spectra. [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]

Metal–organic frameworks (MOFs) have emerged as promising materials for triboelectric nanogenerators (TENGs), but the effects of ligand choice on triboelectric charge remain underexplored. Hence, this paper demonstrates the effect of single, binary, and ternary ligands on TENG performance of cobalt/cerium‐based (Co─Ce) bimetallic MOFs utilizing 2‐methylimidazole (2Melm), terephthalic acid (BDC), and benzene tricarboxylic acid (BTC) as ligands. The detailed structural characterization revealed that varying ligand chemistries led to distinct MOF features affecting TENG performance. Single ligand bimetallic MOFs (designated as CoCe‐2MeIm, CoCe‐BDC, CoCe‐BTC) has lower performance than binary ligand (designated as CoCe‐2MeIm‐BDC, CoCe‐2MeIm‐BTC, CoCe‐BDC‐BTC) and ternary ligand MOFs (designated as CoCe‐2MeIm‐BDC‐BTC). Among all, the binary ligand MOF, CoCe‐2MeIm‐BTC, shows the best results (598 V, 26.7 µA) due to the combined effect of imidazole ring and (─COO─) groups. This is attributed to lone pairs on nitrogen atoms and a delocalized π‐electron system in imidazole system in this material. CoCe‐BTC has the lowest results (31 V, 3.2 µA) due to the bulkier nature of the electron‐withdrawing (─COO─) groups and their impact on the π‐electron system of the benzene ring. This study showcases the potential of ligand chemistry manipulation to control triboelectric charge and thereby enhance MOF‐based TENG performance. [ABSTRACT FROM AUTHOR]

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]

Cuproptosis represents the copper-dependent novel cell death pattern. However, the effects of cuproptosis-related sorafenib-resistant genes on prognosis, treatment response, and sorafenib resistance in hepatocellular carcinoma (HCC) patients are still unclear. The present work aims to develop a cuproptosis-related signature for predicting HCC prognosis. Cuproptosis-related sorafenib-resistant differentially expressed genes (CRSRDEGs) were identified by correlation analysis between cuproptosis genes and sorafenib-resistant genes using electronic databases TCGA and GEO. Besides, the cuproptosis-related sorafenib-resistant risk score model (CRSRRSM) was established through LASSO and univariate Cox regression analyses. Later, this model was adopted for analyzing HCC patient prognosis. Certain potential drugs and treatment sensitivity were also analyzed in HCC patients receiving sorafenib or transarterial chemoembolization (TACE) treatment. The CRSRRSM achieved excellent efficiency in predicting the prognosis and sorafenib or TACE treatment response of HCC patients. As revealed by somatic mutational analyses, CRSRRSM was associated with tumor mutational burden (TMB), especially for TP53, CSMD3, and OBSCN mutations. According to functional enrichment analysis, CRSRRSM was closely correlated with tumor-related pathways, cuproptosis-related tricarboxylic acid (TCA) cycle, and drug resistance. Notably, potential drugs such as sepantronium bromide, AZD8055, and RO-3306, the promising alternatives for treating HCC patients with sorafenib resistance, were also proposed based on CRSRRSM. Furthermore, single-cell transcriptomic analysis revealed that high-risk malignant cells demonstrated an increased capacity of proliferation and immune evasion. A model, designated CRSRRSM, was constructed that can effectively predict the prognosis, sorafenib treatment response, and potential drugs for sorafenib resistance in HCC patients. This model provides potential implications for clinical management of HCC patients with sorafenib resistance. [ABSTRACT FROM AUTHOR]

Background: In humans with pheochromocytomas (PCCs), targeted metabolomics is used to determine the catecholamine phenotype or to uncover underlying pathogenic variants in tricarboxylic acid (TCA) cycle genes such as succinate dehydrogenase subunits (SDHx). Hypothesis/Objectives: To analyze catecholamine contents and TCA cycle metabolites of PCCs and normal adrenals (NAs). Animals: Ten healthy dogs, 21 dogs with PCC. Methods: Prospective observational study. Dogs diagnosed with PCC based on histopathological and immunohistochemical confirmation were included. Tissue catecholamine contents and TCA metabolites in PCCs and NAs were measured by liquid chromatography with mass spectrometry or electrochemical detection. Results: Compared to NAs, PCCs had significantly higher tissue proportion of norepinephrine (88% [median: range, 38%‐98%] vs 14% [11%‐26%]; P <.001), and significantly lower tissue proportion of epinephrine (12% [1%‐62%] vs 86% [74%‐89%]; P <.001). Pheochromocytomas exhibited significantly lower fumarate (0.4‐fold; P <.001), and malate (0.5‐fold; P =.008) contents than NAs. Citrate was significantly higher in PCCs than in NAs (1.6‐fold; P =.015). One dog in the PCC group had an aberrant succinate : fumarate ratio that was 25‐fold higher than in the other PCCs, suggesting an SDHx mutation. Conclusions and Clinical Importance: This study reveals a distinct catecholamine content and TCA cycle metabolite profile in PCCs. Metabolite profiling might be used to uncover underlying pathogenic variants in TCA cycle genes in dogs. [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]

The regulation of complex energy metabolism is intricately linked to cellular energy demands. Caloric restriction (CR) plays a pivotal role in modulating the expression of genes associated with key metabolic pathways, including glycolysis, the tricarboxylic acid (TCA) cycle, and the glyoxylate cycle. In this study, the chronological lifespan (CLS) of 35 viable single‐gene deletion mutants under both non‐restricted and CR conditions, focusing on genes related to these metabolic pathways is evaluated. CR is found to increase CLS predominantly in mutants associated with the glycolysis and TCA cycle. However, this beneficial effect of CR is not observed in mutants of the glyoxylate cycle, particularly those lacking genes for critical enzymes like isocitrate lyase 1 (icl1Δ) and malate synthase 1 (mls1Δ). This analysis revealed an increase in isocitrate lyase activity, a key enzyme of the glyoxylate cycle, under CR, unlike the activity of isocitrate dehydrogenase, which remains unchanged and is specific to the TCA cycle. Interestingly, rapamycin, a compound known for extending lifespan, does not increase the activity of the glyoxylate cycle enzyme. This suggests that CR affects lifespan through a distinct metabolic mechanism. [ABSTRACT FROM AUTHOR]

Succinate dehydrogenase (also known as complex II) plays a dual role in respiration by catalyzing the oxidation of succinate to fumarate in the tricarboxylic acid (TCA) cycle and transferring electrons from succinate to ubiquinone in the mitochondrial electron transport chain (ETC). Owing to the privileged position of SDH/CII, its dysfunction leads to TCA cycle arrest and altered respiration. This review aims to elucidate the widely documented profound metabolic effects of SDH/CII deficiency, along with the newly unveiled survival mechanisms in SDH/CII-deficient cells. Such an understanding reveals exploitable vulnerabilities for strategic targeting, which is crucial for the development of novel and more precise therapies for primary mitochondrial diseases, as well as for familial and sporadic cancers associated with SDH/CII mutations. [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]

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]