2-oxoglutarate Research Articles

Potassium indole-3-butyric acid affects rice's adaptability to salt stress by regulating carbon metabolism, transcription factor genes expression, and biosynthesis of secondary metabolites.

Soil salinity pollution is increasing worldwide, seriously affecting plant growth and crop production. Existing reports on how potassium indole-3-butyric acid (IBAK) regulates rice salt stress adaptation by affecting rice carbon metabolism, transcription factor (TF) genes expression, and biosynthesis of secondary metabolites still have limitations. In this study, an IBAK solution at 40 mg L-1 was sprayed on rice leaves at the seedling stage. The results showed that the IBAK application could promote shoot and root growth, decrease sucrose and fructose content, increase starch content, and enhance acid invertase (AI) and neutral invertase (NI) activity under salt stress, indicating altered carbon allocation. Furthermore, the expression of TF genes belonging to the ethylene responsive factor (ERF), WRKY, and basic helix-loop-helix (bHLH) families was influenced by IBAK. Many key genes (OsSSIIc, OsSHM1, and OsPPDKB) and metabolites (2-oxoglutaric acid, fumaric acid, and succinic acid) were upregulated in the carbon metabolism pathway. In addition, this study highlighted the role of IBAK in regulating the biosynthesis of secondary metabolites pathway, potentially contributing to rice stress adaptability. The results of this study can provide new sustainable development solutions for agricultural production.

Anti-aging Metabolite-Based Polymeric Microparticles for Intracellular Drug Delivery and Bone Regeneration.

Alpha-ketoglutarate (AKG), a key component of the tricarboxylic acid (TCA) cycle, has attracted attention for its anti-aging properties. Our recent study indicates that locally delivered cell-permeable AKG significantly promotes osteogenic differentiation and mouse bone regeneration. However, the cytotoxicity and rapid hydrolysis of the metabolite limit its application. In this study, we synthesize novel AKG-based polymeric microparticles (PAKG MPs) for sustained release. In vitro data suggest that the chemical components, hydrophilicity, and size of the MPs can significantly affect their cytotoxicity and pro-osteogenic activity. Excitingly, these biodegradable PAKG MPs are highly phagocytosable for nonphagocytic pre-osteoblasts MC3T3-E1 and primary bone marrow mesenchymal stem cells (BMSCs), significantly promoting their osteoblastic differentiation. RNAseq data suggest that PAKG MPs strongly activate Wnt/β-catenin and PI3K-Akt pathways for osteogenic differentiation. Moreover, PAKG enables poly (L-lactic acid) and poly (lactic-co-glycolic acid) MPs (PLLA & PLGA MPs) for efficient phagocytosis. Our data indicate that PLGA-PAKG MPs-mediated intracellular drug delivery can significantly promote stronger osteoblastic differentiation compared to PLGA MPs-delivered phenamil. Notably, PAKG MPs significantly improve large bone regeneration in a mouse cranial bone defect model. Thus, the novel PAKG-based MPs show great promise to improve osteogenic differentiation, bone regeneration, and enable efficient intracellular drug delivery for broad regenerative medicine.

Causal relationship between genetically determined plasma metabolites and stroke: A two sample Mendelian randomization study

IntroductionThis study investigates the causal relationship between plasma metabolites and stroke. MethodThe primary analytical approach employed was the inverse variance weighted (IVW) method, complemented by the weighted median (WM) and MR Egger methods for Additionally, validation of the identified plasma metabolites was performed using the Steiger test and LD linkage disequilibrium score. Furthermore, the main results were confirmed through data from the UK Biobank. ResultThe IVW analysis revealed the most notable negative association found in X-17335 levels (OR [95 % CI]: 0.82 [0.72, 0.94]). On the other hand, the strongest positive effect was seen in the 5′-homophase (AMP) to phase ratio (OR [95 % CI]: 1.17 [1.03, 1.32]). Moving on to the validation dataset, the most significant positive effect was observed in the 13 HODE+9-HODE levels (OR [95 % CI]: 0.996 [0.993, 0.999]), whereas the most significant negative effect was seen in the Dihydroxide levels (OR [95 % CI]: 1.004 [1.00, 1.007]). Notably, Alpha ketoglutarate levels exhibited strong causal effects in both datasets (OR 0.908 [0.841, 0.981], p = 0.0144). Enrichment analysis highlighted the association of Alpha ketoglutarate levels with five plasma metabolites in metabolic pathways relevant to stroke, specifically Arginine biosynthesis, Butanoate metabolism, Citrate cycle (TCA cycle), Alanine, aspartate, and glutamate metabolism, and Lipid acid metabolism, all linked to oxoglutaric acid. ConclusionThe discovery dataset showed the most significant positive effect of the 5′-homophase (AMP) to phase ratio, while the validation dataset revealed the most significant positive effect of the 13 HODE+9-HODE levels. Additionally, alpha ketoglutarate may offer a potential protective effect on stroke by influencing five metabolic pathways that intersect with Oxoglutaric acid during the progression of the condition.

Fucoidan prevents diabetic cognitive dysfunction via promoting TET2-mediated active DNA demethylation in high-fat diet induced diabetic mice

Diabetic cognitive dysfunction (DCD) refers to cognitive impairment in individuals with diabetes, which is one of the most important comorbidities and complications. Preliminary evidence suggests that consuming sufficient dietary fiber could have benefits for both diabetes and cognitive function. However, the effect and underlying mechanism of dietary fiber on DCD remain unclear. We conducted a cross-sectional analysis using data from NHANES involving 2072 diabetics and indicated a significant positive dose-response relationship between the dietary fiber intake and cognitive performance in diabetics. Furthermore, we observed disrupted cognitive function and neuronal morphology in high-fat diet induced DCD mice, both of which were effectively restored by fucoidan supplementation through alleviating DNA epigenetic metabolic disorders. Moreover, fucoidan supplementation enhanced the levels of short-chain fatty acids (SCFAs) in the cecum of diabetic mice. These SCFAs enhanced TET2 protein stability by activating phosphorylated AMPK and improved TETs activity by reducing the ratio of (succinic acid + fumaric acid)/ α-ketoglutaric acid, subsequently enhancing TET2 function. The positive correlation between dietary fiber intake and cognitive function in diabetics was supported by human and animal studies alike. Importantly, fucoidan can prevent the occurrence of DCD by promoting TET2-mediated active DNA demethylation in the cerebral cortex of diabetic mice.

Solvent-Directed Bioactive Supramolecular Zinc(II)-Metallogels: Exploring Semiconducting Aptitudes of Fabricating p-n Junction and Schottky Devices.

α-Ketoglutaric acid-based supramolecular Zn(II) metallogels in N,N'-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) solvent (i.e., Zn-α-Glu-DMF and Zn-α-Glu-DMSO) were successfully achieved. Zinc(II) acetate salt and α-ketoglutaric acid directed a three-dimensional noncovalent supramolecular network individually entrapped with N,N'-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) solvent to accomplish their respective semisolid flexible metallogel frameworks. The gel features of these synthesized materials were verified by rheological experiments such as amplitude sweep and frequency sweep measurements. The discrete morphological arrangements were analyzed for these metallogel samples through field emission scanning electron microscopic (FESEM) analysis. Highly stacked interconnected blocks of Zn-α-Glu-DMF with hierarchical arrays are found due to the occurrence of diverse noncovalent supramolecular interactions present in the metallogel framework. A distinct spherical shaped microstructure with interconnected hierarchical assembly has been observed for the FESEM pattern of Zn-α-Glu-DMSO. FTIR spectroscopic measurement was carried out to detect some important stretching vibrations of xerogel samples of different metallogels as well as gel-constructing chemical ingredients. A substantial amount of peak shifting of xerogel samples for both metallogels is observed in FTIR analysis, indicating the presence of different noncovalent interactions. ESI-mass analysis portrays a possible metallogel-constructing strategy. The antibacterial potentialities of both metallogels were investigated. These materials exhibited good antimicrobial efficacy toward Gram-positive and Gram-negative bacterial strains (including Escherichia coli, Bacillus cereus, Staphylococcus aureus, Listeria monocytogenes, and Salmonella typhimurium). Both synthesized metallogels were successfully implemented to fabricate the photoresponsive semiconducting diode. These materials offer excellent photodiode parameters including an ideality factor and rectification ratio (ON/OFF ratio). Synthesized metallogels are used to successfully fabricate photodiodes with an Al/p-Si/metallogel/Au structure. The ideality factors (η) for Zn-α-Glu-DMF and Zn-α-Glu-DMSO are found as 1.3 and 2.3, respectively, in dark conditions. The rectification ratios for Zn-α-Glu-DMF and Zn-α-Glu-DMSO metallogels are also determined, and these are found as 40 and 10, respectively.

Branched-chain amino acid transaminase 1 confers EGFR-TKI resistance through epigenetic glycolytic activation

Third-generation EGFR tyrosine kinase inhibitors (TKIs), exemplified by osimertinib, have demonstrated promising clinical efficacy in the treatment of non-small cell lung cancer (NSCLC). Our previous work has identified ASK120067 as a novel third-generation EGFR TKI with remarkable antitumor effects that has undergone New Drug Application (NDA) submission in China. Despite substantial progress, acquired resistance to EGFR-TKIs remains a significant challenge, impeding the long-term effectiveness of therapeutic approaches. In this study, we conducted a comprehensive investigation utilizing high-throughput proteomics analysis on established TKI-resistant tumor models, and found a notable upregulation of branched-chain amino acid transaminase 1 (BCAT1) expression in both osimertinib- and ASK120067-resistant tumors compared with the parental TKI-sensitive NSCLC tumors. Genetic depletion or pharmacological inhibition of BCAT1 impaired the growth of resistant cells and partially re-sensitized tumor cells to EGFR TKIs. Mechanistically, upregulated BCAT1 in resistant cells reprogrammed branched-chain amino acid (BCAA) metabolism and promoted alpha ketoglutarate (α-KG)-dependent demethylation of lysine 27 on histone H3 (H3K27) and subsequent transcriptional derepression of glycolysis-related genes, thereby enhancing glycolysis and promoting tumor progression. Moreover, we identified WQQ-345 as a novel BCAT1 inhibitor exhibiting antitumor activity both in vitro and in vivo against TKI-resistant lung cancer with high BCAT1 expression. In summary, our study highlighted the crucial role of BCAT1 in mediating resistance to third-generation EGFR-TKIs through epigenetic activation of glycolysis in NSCLC, thereby supporting BCAT1 as a promising therapeutic target for the treatment of TKI-resistant NSCLC.

A thermal cross-linking approach to developing a reinforced elastic chitosan cryogel for hemostatic management of heavy bleeding

Uncontrolled hemorrhage stands as the primary cause of potentially preventable deaths following traumatic injuries in both civilian and military populations. Addressing this critical medical need requires the development of a hemostatic material with rapid hemostatic performance and biosafety. This work describes the engineering of a chitosan-based cryogel construct using thermo-assisted cross-linking with α-ketoglutaric acid after freeze-drying. The resulting cryogel exhibited a highly interconnected macro-porous structure with low thermal conductivity, exceptional mechanical properties, and great fluid absorption capacity. Notably, assessments using rabbit whole blood in vitro, as well as rat liver volume defect and femoral artery injury models simulating severe bleeding, showed the remarkable hemostatic performance of the chitosan cryogel. Among the cryogel variants with different chitosan molecular weights, the 150 kDa one demonstrated superior hemostatic efficacy, reducing blood loss and hemostasis time by approximately 73 % and 63 % in the hepatic model, and by around 60 % and 68 %, in the femoral artery model. Additionally, comprehensive in vitro and in vivo evaluations underscored the good biocompatibility of the chitosan cryogel. Taken together, these results strongly indicate that the designed chitosan cryogel configuration holds significant potential as a safe and rapid hemostatic material for managing severe hemorrhage.

Neonatal α-Ketoglutaric Acid Gavage May Potentially Alleviate Acute Heat Stress by Modulating Hepatic Heat Shock Protein 90 and Improving Blood Antioxidant Status of Broilers.

This study investigated the effect of neonatal α-ketoglutaric acid (AKG) gavage feeding on broilers. The first experiment was conducted to determine the effect of AKG on day-old broilers. A total of seventy-two-day-old Ross 308 broiler chicks were divided into four treatment groups: (i) Two groups of chicks with gavage feeding of 0.6 mL of distilled water (DDW) for four consecutive days (CON); (ii) chicks fed with 0.6 mL of 0.1% AKG dissolved in DDW on the day of hatch (AL) followed by 0.2%, 0.3%, and 0.4% for three consecutive days; and (iii) chicks fed with 0.6 mL of 0.2% AKG dissolved in DDW on the day of hatch (AH) followed by 0.4%, 0.6%, and 0.8% for three consecutive days. Twenty-four hours after the first gavage feeding, six birds per treatment were slaughtered to study the organ development. Chicks fed with AKG showed higher absolute (p = 0.015) and relative (p = 0.037) weights of the gizzard. The AH group had higher absolute (p = 0.012) and relative (p = 0.035) heart weights. The second experiment was carried out to determine the effect of AKG on 15-day-old broilers under acute heat stress (AHS) for 3.5 h at 33 ± 1 °C. Forty-eight birds (12 per treatment) were raised until 15 days of age, divided into four treatments with equal numbers (n = 12), and given one of the following four treatments: (i) CON group reared at standard temperature (25 ± 1 °C) (CON-NT); (ii) CON group subjected to AHS (33 ± 1 °C) for 3.5 h (CON-HT); (iii) AL group subjected to AHS (33 ± 1 °C) for 3.5 h (AL-HT); and (iv) AH group subjected to AHS (33 ± 1 °C) for 3.5 h (AH-HT). There was a significant reduction in the change in BW (ΔBW, p = 0.005), an increase in the final rectal temperature (RTf) (p = 0.001), and a decreased final body weight (BWf) for all the treatments under AHS. Further, AHS led to an increased expression of hepatic heat shock protein (HSP)70 (p = 0.009), nicotinamide adenine dinucleotide phosphate hydrogen oxidase (NOX)1 (p = 0.006), and NOX4 (p = 0.001), while nuclear factor erythroid 2-related factor (NRF2), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase 1 (GPX1) remained significantly unaffected. Hepatic expression of HSP90 decreased in the AL-HT treatment as compared to CON-HT (p = 0.008). Plasma antioxidant status measured by malondialdehyde (MDA) concentration and antioxidant balance (AB) improved linearly (p = 0.001) as the concentration of AKG increased. Neonatal gavage feeding of AKG could potentially alleviate heat stress in broilers by enhancing plasma antioxidant levels and modulating HSP90 expression in the liver.

Multi-Omics Revealed Resveratrol and β-Hydroxy-β-methyl Butyric Acid Alone or in Combination Improved the Jejunal Function in Tibetan Sheep.

Previous research studies confirmed that both resveratrol (RES) and β-hydroxy-β-methyl butyric acid (HMB) improved growth performance by altering intestinal microbiota. However, the mechanism underlying of RES and HMB on intestinal function remains unclear in ruminant. In this study, supplements of RES and HMB alone or in combination were evaluated as promoters of antioxidant capacity, immune response and barrier function, and modulators of the microbiota and metabolite profiles in the jejunum of Tibetan sheep. A total of 120 two-month-old Tibetan rams were randomly divided into four treatments (n = 30 per treatment), which were supplemented with a basal diet with 1.5 g RES/d (RES group), 1.25 g HMB/d (HMB group), 1.5 g RES/d plus 1.25 g HMB/d (RES-HMB group), and without additions (Control group). The results showed that RES and HMB improved the antioxidant capacity (CAT, GSH-Px, SOD, and T-AOC), immunity (IgA, IgG, and IgM), and digestive enzyme activity (α-amylase, lipase, and chymotrypsin) of the experimental lambs (p < 0.05). Additionally, jejunal morphology including villus width, villus height, and muscle layer thickness exhibited a significant difference when rams were fed diets supplemented with RES and HMB (p < 0.05). Furthermore, the determination of fermentation parameters showed that the butyrate concentration in the RES-HMB group was greater than those in the C and RES groups (p < 0.05). When compared to the C group, barrier-related gene expression (MUC-2, ZO-1, and IL-10) was significantly increased in the RES-HMB group (p < 0.05). Dietary RES and (or) HMB supplementation significantly increased the abundance of Methanobrevibacter, Actinobacteriota and Bacillus (p < 0.05). The abundance of differential bacteria was positively associated with butyrate concentration (p < 0.05). Metabolome analysis revealed that alpha ketoglutarate, succinic semialdehyde, and diacetyl as well as butanoate metabolism pathways connected to the improvements in butyrate concentration by RES and (or) HMB supplementation. Collectively, our results suggested that RES and (or) HMB supplementation improved butyrate concentration via regulating the microbial community (Methanobrevibacter, Actinobacteriota and Bacillus) and metabolism (alpha ketoglutarate, succinic semialdehyde, and diacetyl), thus contributing to jejunal morphology, antioxidant capacity, immune response, digestive enzyme activity, and barrier function.

Metabolic profiles in drought-tolerant wheat with enhanced abscisic acid sensitivity.

Global warming has led to the expansion of arid lands and more frequent droughts, which are the largest cause of global food production losses. In our previous study, we developed TaPYLox wheat overexpressing the plant hormone abscisic acid (ABA) receptor, which is important for the drought stress response in plants. TaPYLox showed resistance to drought stress and acquired water-saving traits that enable efficient grain production with less water use. In this study, we used TaPYLox to identify ABA-dependent and -independent metabolites in response to drought stress. We compared the variation of metabolites in wheat under well-watered, ABA treatment, and drought stress conditions using the ABA-sensitive TaPYLox line and control lines. The results showed that tagatose and L-serine were ABA-dependently regulated metabolites, because their stress-induced accumulation was increased by ABA treatment in TaPYLox. In contrast, L-valine, L-leucine, and DL-isoleucine, which are classified as branched chain amino acids, were not increased by ABA treatment in TaPYLox, suggesting that they are metabolites regulated in an ABA-independent manner. Interestingly, the accumulation of L-valine, L-leucine, and DL-isoleucine was suppressed in drought-tolerant TaPYLox under drought stress, suggesting that drought-tolerant wheat might be low in these amino acids. 3-dehydroshikimic acid and α-ketoglutaric acid were decreased by drought stress in an ABA-independent manner. In this study, we have succeeded in identifying metabolites that are regulated by drought stress in an ABA-dependent and -independent manner. The findings of this study should be useful for future breeding of drought-tolerant wheat.

Catabolic gene indices of hydrocarbon diminution in Ultisol treated with cropped Bacillus altitudinis-amendments

This study evaluated catabolic gene expression as an index of hydrocarbon breakdown in ultisol treated with Bacillus altitudinis-Cropped Biofertilizers derived from Biosolid and Brewer Spent Grain (BSG) using phenotypic and molecular methods. We observed significant reductions in Total Petroleum Hydrocarbons (TPH) concentrations with both amendments, albeit the biosolid based amendment was markedly more effective. Concurrently, there was a substantial increase in hydrocarbon-degrading bacteria. Notably, the bulk of Operational Taxonomic Units (OTUs) in biosolid (95.77 %) and BSG (93.00 %) amended Ultisol were Proteobacteria, Acidobacteria, Actinobacteria, and Planctomycetes, which are key players in hydrocarbon bioremediation. We observed the presence of eleven hydrocarbon-degrading genes through M5nr analysis. These genes encompass essential catalysts for aliphatic hydrocarbon degradation and hydrocarbon desulfurization. Notably, these enzymes/genes include Bacterial Flavin-bound Monooxygenase (AlmA), Alkane Monooxygenase (AlkM), Alpha Ketoglutarate Dependent Dioxygenase (alkB), Propane Monooxygenase (PrM), Cytochrome P450 (cP450), Methane Monooxygenase/Ammonia Monooxygenase (MMO/AMO) subunits A, B, and C, Alkane Sulfonate Monooxygenase (ssuD), Alkane Sulfonates Transport System Permease Protein (ssuC), Dibenzothiophene Monooxygenase (dszC), Dibenzothiophene-Sulfone Monooxygenase (dszA), and Dibenzothiophene-5,5-Dioxide Monooxygenase (dszB). These genes play pivotal roles in the degradation of aliphatic hydrocarbons and hydrocarbon desulfurization. Interestingly, unique gene expression patterns were observed for each amendment, with Actinomycetales and Bulkhoderiales orders expressing the majority of identified genes. These findings have revealed the amendment-specific microbial and genetic alterations and, the diversity and potential of the annotated genes induced by the Bacillus altitudinis-Cropped Biofertilizers (biosolid and BSG amendments) for effective remediation of hydrocarbon-contaminated soils.

Plasma metabolomics of immune-related adverse events for patients with lung cancer treated with PD-1/PD-L1 inhibitors

BackgroundMetabolomics has the characteristics of terminal effects and reflects the physiological state of biological diseases more directly. Several current biomarkers of multiple omics were revealed to be associated with immune-related...

Integrated multi-omics reveals the relationship between growth performance, rumen microbes and metabolic status of Hu sheep with different residual feed intakes

Residual feed intake (RFI) is a metric that provides a more accurate measure of feed efficiency. The lower the RFI, the higher the feed efficiency. The changes in the host microbiome and metabolome contribute to the greater feed efficiency of low RFI (LRFI) animals. The aim of this study was to explore the differences in rumen microorganisms, rumen metabolites and plasma metabolites of Hu sheep with differing RFI through the microbiome and metabolome. A total of 80 Hu sheep were used. The experiment consisted of a 15-d pretrial period and a 128-d experimental period. The RFI in the experimental period was calculated for all sheep, and the sheep were screened into high RFI (HRFI, n = 8) and LRFI (n = 8) groups. The HRFI and LRFI sheep did not differ in their initial and final body weights, average daily gain and body measurements, but the dry matter intake of LRFI sheep was significantly decreased (28.4%, P < 0.001). The sheep with LRFI had higher digestibility of crude protein (P = 0.010) and ether extract (P = 0.010) compared to HRFI group. The concentrations of acetate (P = 0.036), propionate (P = 0.010), valerate (P = 0.027) and total volatile fatty acids (P = 0.048) in rumen of LRFI group were higher compared to HRFI group. The results of 16S rDNA sequencing indicated that the sheep with LRFI had higher proportions of Prevotella genus in rumen liquid (P = 0.031). The rumen metabolome and plasma metabolome results showed that the citrate cycle, pyruvate metabolism and alanine, aspartate and glutamate metabolism processes were more active for sheep in LRFI group, which provided more energy substrate such as malic acid, oxoglutaric acid and citric acid. In conclusion, sheep with LRFI can utilize feed more efficiently, and the more active energy metabolism pathway and the production of energy substances may account for the higher feed efficiency.

Serum metabolic changes link metal mixture exposures to vascular endothelial inflammation in residents living surrounding rivers near abandoned lead–zinc mines

Metal exposure is associated with vascular endothelial inflammation, an early pathological phenotype of atherosclerotic cardiovascular events. However, the underlying mechanism linking exposure, metabolic changes, and outcomes remains unclear. We aimed to investigate the metabolic changes underlying the associations of chronic exposure to metal mixtures with vascular endothelial inflammation. We recruited 960 adults aged 20–75 years from residential areas surrounding rivers near abandoned lead–zinc mine and classified them into river area and non-river area exposure groups. Urine levels of 25 metals, Framingham risk score (FRS), and serum concentrations of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), as biomarkers of vascular endothelial inflammation, were assessed. A “meet-in-the-middle” approach was applied to identify causal intermediate metabolites and metabolic pathways linking metal exposure to vascular endothelial inflammation in representative metabolic samples from 64 participants. Compared to the non-river area exposure group, the river area exposure group had significantly greater urine concentrations of chromium, copper, cadmium, and lead; lower urine concentrations of selenium; elevated FRS; and increased concentrations of ICAM-1 and VCAM-1. In total, 38 differentially abundant metabolites were identified between the river area and non-river area exposure groups. Among them, 25 metabolites were significantly associated with FRS, 8 metabolites with ICAM-1 expression, and 10 metabolites with VCAM-1 expression. Furthermore, fructose, ornithine, alpha-ketoglutaric acid, urea, and cytidine monophosphate, are potential mediators of the relationship between metal exposure and vascular endothelial inflammation. Additionally, the metabolic changes underlying these effects included changes in arginine and proline metabolism, pyrimidine metabolism, starch and sucrose metabolism, galactose metabolism, arginine biosynthesis, and alanine, aspartate, and glutamate metabolism, suggesting the disturbance of amino acid metabolism, the tricarboxylic acid cycle, nucleotide metabolism, and glycolysis. Overall, our results reveal biomechanisms that may link chronic exposure to multiple metals with vascular endothelial inflammation and elevated cardiovascular risk.

Identification of Wheat Glutamate Synthetase Gene Family and Expression Analysis under Nitrogen Stress.

Nitrogen (N), as the main component of biological macromolecules, maintains the basic process of plant growth and development. GOGAT, as a key enzyme in the N assimilation process, catalyzes α-ketoglutaric acid and glutamine to form glutamate. In this study, six GOGAT genes in wheat (Triticum aestivum L.) were identified and classified into two subfamilies, Fd-GOGAT (TaGOGAT2s) and NADH-GOGAT (TaGOGAT3s), according to the type of electron donor. Subcellular localization prediction showed that TaGOGAT3-D was localized in mitochondria and that the other five TaGOGATs were localized in chloroplasts. Via the analysis of promoter elements, many binding sites related to growth and development, hormone regulation and plant stress resistance regulations were found on the TaGOGAT promoters. The tissue-specificity expression analysis showed that TaGOGAT2s were mainly expressed in wheat leaves and flag leaves, while TaGOGAT3s were highly expressed in roots and leaves. The expression level of TaGOGATs and the enzyme activity of TaGOGAT3s in the leaves and roots of wheat seedlings were influenced by the treatment of N deficiency. This study conducted a systematic analysis of wheat GOGAT genes, providing a theoretical basis not only for the functional analysis of TaGOGATs, but also for the study of wheat nitrogen use efficiency (NUE).

Differential metabolomic pathway analysis in Malaysian childhood acute lymphoblastic leukemia patients treated with high-dose methotrexate

BackgroundMethotrexate (MTX) is the mainstay of the consolidation and maintenance phase of chemotherapy protocol for childhood acute lymphoblastic leukemia (ALL). This study aimed to investigate the altered metabolism associated with high dose-MTX and determine the potential of the metabolic markers and differential pathways involved in MTX therapy. MethodsSerum samples were collected from 38 children with ALL at 2 time points: p-MTX; before induction chemotherapy was initiated, and post-MTX; after completion of the first high-dose MTX. The samples were analyzed using HPLC/MS-QTOF. Data acquisition was performed using Agilent MassHunterTMB.05.00 software for subsequent metabolomics analysis. Differential expressions of metabolites were analyzed using univariate Welch's t-test unequal variance. Compounds were identified using the METLIN Database. Pathways and network analyses were performed using Metaboanalyst 4.0. Potential biomarkers were analyzed using the Receiving Operator Characteristic curve. ResultsMetabolites with AUC between 0.7 and 0.9 include xanthine (0.889), oxoglutaric acid (0.770), and alpha-linolenic acid (ALA) (0.741). Alpha-linolenic acid abundance was detected in ALL patients with remission status, corresponding to a test sensitivity and specificity of 0.77 and 0.87, respectively. ALA has an antineoplastic effect that potentially inhibits the proliferation of leukemic cells by inhibiting caspase activation in the phosphatidylinositol 3-kinase (PI3K) pathway and Bcl-2 inhibition. ConclusionIn this study, ALA was found to be significantly higher in patients treated with high-dose MTX and associated with remission status than in pre-MTX treatment.

Associations between TCA cycle plasma metabolites and fatigue in black females with systemic lupus erythematosus: An untargeted metabolomics pilot study.

In this pilot study, we used untargeted metabolomics to identify biochemical mechanisms or biomarkers potentially underlying SLE-related fatigue. Metabolon conducted untargeted metabolomic plasma profiling using ultrahigh performance liquid chromatography/tandem mass spectrometry on plasma samples of 23 Black females with systemic lupus erythematosus (SLE) and 21 no SLE controls. Fatigue phenotypes of general fatigue, physical fatigue, mental fatigue, reduced activity, and reduced motivation were measured with the reliable and valid Multidimensional Fatigue Inventory (MFI). A total of 290 metabolites were significantly different between the SLE and no SLE groups, encompassing metabolites related to glycolysis, TCA cycle activity, heme catabolism, branched chain amino acids, fatty acid metabolism, and steroids. Within the SLE group, controlling for age and co-morbidities, TCA cycle metabolites of alpha-ketoglutarate (AKG) and succinate were statistically significantly associated (p < .05) with physical and general fatigue. While pervasive perturbations in the entire TCA cycle have been implicated as a potential mechanism for fatigue, our results suggest individual metabolites of AKG and succinate may be potential biomarkers or targets of intervention for fatigue symptom management in SLE. Additionally, perturbations in heme metabolism in the SLE group provide additional insights into mechanisms that promote systemic inflammation.

Adjustments in energy metabolism of brown adipose tissue in heat-acclimated Kunming mice

The thermogenic capacity of brown adipose tissue (BAT) in rodents decreases with prolonged heat exposure. However, the underlying mechanisms are not well understood. In this study, Kunming mice were acclimated at 23 ± 1 °C and 33 ± 1 °C for four weeks each to examine the body heat balance and BAT alterations. Results showed that heat-acclimated Kunming mice exhibited reduced body mass and elevated body temperature. Additionally, they displayed lower resting metabolic rates, diminished non-shivering thermogenesis, and reduced BAT thermogenic function. Metabolically, there was a significant reduction in several key metabolites involved in energy metabolism in BAT, including thiamine pyrophosphate, citric acid, cis-Aconitate, isocitric acid, oxoglutaric acid, succinate, fumarate, L-Malic acid, oxaloacetate, flavin mononucleotide, nicotinamide adenine dinucleotide, and adenosine 5′-triphosphate. These findings suggest that BAT adapts to heat acclimation by regulating pathways related to pyruvate oxidation, tricarboxylic acid cycle, and oxidative phosphorylation, which may help maintain thermal homeostasis in Kunming mice.

Abnormally Low Alanine Aminotransferase Ameliorated by a Living Donor Liver Transplantation: A Case Report

Alanine aminotransferase (ALT) is an enzyme that catalyzes the transfer of amino groups from alanine to ketoglutaric acid. ALT is an established marker of liver diseases. Occasionally, ALT levels may be abnormally low due to various factors, making accurate assessment difficult. To date, no studies have documented ALT alterations following Living donor liver transplantation (LDLT) in patients with low ALT levels. Here, we present a case of abnormally low ALT levels that were ameliorated by LDLT. A 27-year-old woman underwent LDLT for refractory cholangitis with biliary atresia. The patient's preoperative ALT level was 1 IU/L. Following graft reperfusion, ALT levels increased (peak value, 456 IU/L), primarily attributed to the donor liver. After LDLT, ALT levels consistently surpassed the lower limit. The differential diagnosis of abnormally low ALT levels suggested a genetic mutation as the most probable underlying cause. Even after LDLT, ALT levels in organs other than the transplanted liver would remain abnormally low. Therefore, to prevent underestimating liver damage, the standard ALT range for such cases should be set lower than the typical range.

The tricarboxylic acid cycle is inhibited under acute stress from carbonate alkalinity in the gills of Eriocheir sinensis

Owing to population growth and environmental pollution, freshwater aquaculture has been rapidly shrinking in recent years. Aquaculture in saline-alkaline waters is a crucial strategy to meet the increasing demand for aquatic products. The Chinese mitten crab is an important economic food in China, but the molecular mechanism by which it tolerates carbonate alkalinity (CA) in water remains unclear. Here, we found that enzyme activities of the tricarboxylic acid (TCA) cycle in the gills, such as citrate synthase, isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and malate dehydrogenase, were markedly reduced under CA stress induced by 40 mM NaHCO3. Secondly, the TCA cycle in the gills is inhibited under acute CA stress, according to proteomic and metabolomic analyses. The expressions of six enzymes, namely aconitate hydratase, isocitrate dehydrogenase, 2-oxoglutarate dehydrogenase, dihydrolipoyl dehydrogenase, succinate-CoA ligase, and malate dehydrogenase, were downregulated, resulting in the accumulation of phosphoenolpyruvic acid, citric acid, cis-aconitate, and α-ketoglutaric acid. Finally, we testified that if the TCA cycle is disturbed by malonate, the survival rate increases in CA water. To our knowledge, this is the first study to show that the TCA cycle in the gills is inhibited under CA stress. Overall, the results provide new insights into the molecular mechanism of tolerance to saline-alkaline water in crabs, which helped us expand the area for freshwater aquaculture and comprehensively understand the physiological characteristics of crab migration.