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We report identification of 5 patients with infections caused by NDM-5-producing Escherichia coli harboring PBP3 mutations that showed reduced susceptibility to aztreonam-avibactam and cefiderocol. Durlobactam, a novel diazabicyclooctane β-lactamase inhibitor, demonstrated minimum inhibitory concentrations ranging from 0.5 to 2 µg/mL supporting future investigations into a potential role in clinical management. [ABSTRACT FROM AUTHOR]

Gut microbiota plays a vital role in host metabolism; however, the influence of gut microbes on polyamine metabolism is unknown. Here, we found germ-free models possess elevated polyamine levels in the colon. Mechanistically, intestinal Lactobacillus murinus-derived small RNAs in extracellular vesicles down-regulate host polyamine metabolism by targeting the expression of enzymes in polyamine metabolism. In addition, Lactobacillus murinus delays recovery of dextran sodium sulfate-induced colitis by reducing polyamine levels in mice. Notably, a decline in the abundance of small RNAs was observed in the colon of mice with colorectal cancer (CRC) and human CRC specimens, accompanied by elevated polyamine levels. Collectively, our study identifies a specific underlying mechanism used by intestinal microbiota to modulate host polyamine metabolism, which provides potential intervention for the treatment of polyamine-associated diseases. [ABSTRACT FROM AUTHOR]

This study was designed to screen 6 lysosomal storage diseases (LSDs) in neonates using tandem mass spectrometry (MS/MS), and establish cutoff values for these LSDs with 3000 dried blood spots (DBS) samples. Cutoff values for α-L-iduronidase (IDUA), α-galactosidase (GLA), acid beta glucosidase (ABG), β-galactocerebrosidase (GALC), acid sphingomyelinase (ASM), and acid alpha glucosidase (GAA) were as follows: GLA, > 2.06 μmol/L·h; ABG, > 1.78 μmol/L·h; ASM, > 0.99 μmol/L·h; IDUA, > 1.33 μmol/L·h; GALC, > 0.84 μmol/L·h; and GAA, > 2.06 μmol/L·h. There were 30 positives in initial MS/MS screening test, and 15 samples were still positive with repeat testing. Their parents/guardians were recontacted and DBS samples were collected again for test. Only 1 child showed abnormal GAA enzyme activity after recontacting process, and was diagnosed with Pompe disease after genetic screening. Eventually, cutoff values of 6 specific enzyme activities were established and MS/MS is effective for early LSDs screening. [ABSTRACT FROM AUTHOR]

Taraxacum kok-saghyz Rodin (TKS) is a recognized alternative source of natural rubber comparable to the rubber tree. The geranylgeranyl pyrophosphate synthase (GGPS) catalyzed the synthesis of geranylgeranyl pyrophosphate (GGPP), which is an important enzyme in the secondary metabolism pathway. In this study, we present the first analysis of the GGPS gene family in TKS, where a total of seven TkGGPS family members were identified. Their core motifs, conserved structural domains, gene structures, and cis-acting elements were described. In addition, two phylogenetic trees were constructed based on the Neighbor-Joining and Maximum-Likelihood methods, and the TkGGPSs were highly conserved and exhibited good collinearity with the other species. Transcriptome data showed that seven TkGGPS gene members were expressed in all the 12 tissues measured, and TkGGPS1, TkGGPS3, and TkGGPS6 were highly expressed in latex, suggesting that they may be associated with natural rubber synthesis. Meanwhile, quantitative real-time PCR (qRT-PCR) showed that the expression levels of the TkGGPS genes were regulated by the ethylene and methyl jasmonate (MeJA) pathways. Subcellular localization results indicated that all the TkGGPS proteins were also located in chloroplasts involved in photosynthesis in plants. This study will provide valuable insights into the selection of candidate genes for molecular breeding and natural rubber biosynthesis in TKS. [ABSTRACT FROM AUTHOR]

Rice is an important food crop worldwide but is usually susceptible to saline stress. When grown on soil with excessive salt, rice plants experience osmotic, ionic, and oxidative stresses that adversely affect growth performance. γ-Aminobutyric acid (GABA) is a nonproteinogenic amino acid that plays an important role in the metabolic activities of organisms. Glutamate decarboxylase (GAD) is the rate-limiting enzyme in GABA metabolism. Here, we genetically modified rice GAD by overexpression or CRISPR-mediated genome editing. These lines, named gad3-ox1 and gad3-ox2 or gad1/3-ko, were used to explore the effects of endogenous GABA accumulation on salt tolerance in rice. Both the gad3-ox1 and gad3-ox2 lines exhibited significant accumulation of the GABA content, whereas the gad1/3-ko line presented a reduced GABA content in vivo. Notably, the two overexpression lines were markedly resistant to salt stress compared with the wild-type and knockout lines. Furthermore, our results demonstrated that endogenous GABA accumulation in the gad3-ox1 and gad3-ox2 lines increased the contents of antioxidant substances and osmotic regulators, decreased the content of membrane lipid peroxidation products and the Na+ content, and resulted in strong tolerance to salt stress. Together, these data provide a theoretical basis for cultivating rice varieties with strong salt tolerance. [ABSTRACT FROM AUTHOR]

This study investigates the impact of various molecular weights (MWs) of fulvic acid (FA) on maize growth, grain yield, and nutrient uptake under different nitrogen levels (NLs). A 2 × 3 balanced design was employed, with high (0.2 g N/kg) and low (0.05 g N/kg) NLs, and three FA MW ranges (W1 = 3 000 D, 3 000 < W2 = 10 000 D, W3 > 10 000 D) were applied at 25 mg/kg in soil. Significant interactions between NLs and FA MWs were observed in chlorophyll a/b ratio, nitrate reductase and glutamate dehydrogenase activities, nitrogen content, and nitrogen uptake efficiency. Overall, under different NLs, FA application reduced chlorophyll a/b ratio, increased nitrogen metabolism enzyme activities, promoted maize growth, and thereby improved grain yield and nitrogen fertiliser uptake efficiency. Additionally, the promotion effect of low MW FA on these indicators outweighed that of high MW FA, yet the latter exhibited a more pronounced effect on increasing grain nitrogen concentration. Structural equation model analysis revealed direct effects of chlorophyll content, nitrogen accumulation, nitrogen uptake efficiency, NLs and FA MWs on maize grain yield, with FA MWs negatively impacting yield. [ABSTRACT FROM AUTHOR]

AbstractHead and neck squamous cell carcinoma ranks seventh globally in malignancy prevalence, with persistent high mortality rates despite treatment advancements. Glucose, pivotal in cancer metabolism via the Warburg effect, enters cells via glucose transporters, notably GLUT proteins. Glycolysis, aerobic oxidation, and the pentose phosphate pathway in glucose metabolism significantly impact HNSCC progression. HNSCC exhibits elevated expression of glucose metabolism enzymes and GLUT proteins, correlating with prognosis. Heterogeneity in HNSCC yields varied metabolic profiles, influenced by factors like HPV status and disease stage. This review highlights glucose metabolism’s role and potential as therapeutic targets and cancer imaging tracers in HNSCC. [ABSTRACT FROM AUTHOR]

Background: Invertases (INVs) are key enzymes in sugar metabolism, cleaving sucrose into glucose and fructose and playing an important role in plant development and the stress response, however, the INV gene family in passion fruit has not been systematically reported. Results: In this study, a total of 16 PeINV genes were identified from the passion fruit genome and named according to their subcellular location and chromosome position. These include six cell wall invertase (CWINV) genes, two vacuolar invertase (VINV) genes, and eight neutral/alkaline invertase (N/AINV) genes. The gene structures, phylogenetic tree, and cis-acting elements of PeINV gene family were predicted using bioinformatics methods. Results showed that the upstream promoter region of the PeINV genes contained various response elements; particularly, PeVINV2, PeN/AINV3, PeN/AINV5, PeN/AINV6, PeN/AINV7, and PeN/AINV8 had more response elements. Additionally, the expression profiles of PeINV genes under different abiotic stresses (drought, salt, cold temperature, and high temperature) indicated that PeCWINV5, PeCWINV6, PeVINV1, PeVINV2, PeN/AINV2, PeN/AINV3, PeN/AINV6, and PeN/AINV7 responded significantly to these abiotic stresses, which was consistent with cis-acting element prediction results. Sucrose, glucose, and fructose are main soluble components in passion fruit pulp. The contents of total soluble sugar, hexoses, and sweetness index increased significantly at early stages during fruit ripening. Transcriptome data showed that with an increase in fruit development and maturity, the expression levels of PeCWINV2, PeCWINV5, and PeN/AINV3 exhibited an up-regulated trend, especially for PeCWINV5 which showed highest abundance, this correlated with the accumulation of soluble sugar and sweetness index. Transient overexpression results demonstrated that the contents of fructose, glucose and sucrose increased in the pulp of PeCWINV5 overexpressing fruit. It is speculated that this cell wall invertase gene, PeCWINV5, may play an important role in sucrose unloading and hexose accumulation. Conclusion: In this study, we systematically identified INV genes in passion fruit for the first time and further investigated their physicochemical properties, evolution, and expression patterns. Furthermore, we screened out a key candidate gene involved in hexose accumulation. This study lays a foundation for further study on INV genes and will be beneficial on the genetic improvement of passion fruit breeding. [ABSTRACT FROM AUTHOR]

[Objectives] The purpose of this paper was to investigate the changes in sugar content and metabolism-related enzyme activities and gene expression of longan fruits during postharvest storage at room temperature (RT) and low temperature (LT), and to provide a reference basis for postharvest storage and preservation of longan fruits. [Methods] Taking‘Chuliang'longan as the test material, 4 ℃ and 25 ℃ treatments were set to investigate the changes of total soluble solids (TSS), sucrose, glucose and fructose contents, and the change rules of related sugar metabolism enzyme activities and related gene expressions. [Results] Sugar content of longan fruit varied differentially at different storage temperatures. Sucrose content decreased, glucose and fructose content increased during RT storage, while LT storage maintained high sucrose content, glucose and fructose content decreased rapidly. Compared with RT storage, sucrose phosphate synthase (SPS) activity increased, neutral invertase (NI), acid invertase (AI), sucrose synthase (SS), fructokinase (FRK) and hexokinase (HXK) activities were inhibited and the expression of DlNI, DlAI, DlSPS, DlFRK, DlHXK genes was inhibited at LT storage. Correlation analysis showed that the relationship about sucrose content, sugar metabolism-related enzyme activities and gene expression were altered in longan fruits at LT storage. In addition, principal component analysis also indicated that LT storage delayed the onset of sucrose metabolism in longan fruit and maintained better fruit quality. [Conclusions] By regulating the expression of genes related to sugar metabolism in longan fruits, low temperature storage affected the activity of related enzymes and then changed the sugar components, so that longan fruits maintained high sucrose content and delayed the quality deterioration of longan fruits. [ABSTRACT FROM AUTHOR]

Definition: In recent decades, phosphoinositides (or PIs) have emerged as essential signaling molecules. Despite their low cellular abundance, PIs are found to be involved in various cellular processes, including cell migration, vesicular trafficking, cell cycle regulation, metabolism, cytoskeletal remodeling, autophagy, aging, apoptosis, and cell signaling. Recent studies have shown that aberrant activity of either lipid kinases or phosphatases leads to various medical implications like cancer, diabetes, and microbial infections, suggesting an essential role for these lipid molecules and enzymes in their metabolism. This entry focused on one of the critical enzymes involved in phosphoinositide metabolism: phosphatidyl inositol 4-kinase (PI4-Kinase). [ABSTRACT FROM AUTHOR]

Elemental sulfur (S80)‐oxidising Sulfolobales (Archaea) dominate high‐temperature acidic hot springs (>80°C, pH <4). However, genomic analyses of S80‐oxidising members of the Sulfolobales reveal a patchy distribution of genes encoding sulfur oxygenase reductase (SOR), an S80 disproportionating enzyme attributed to S80 oxidation. Here, we report the S80‐dependent growth of two Sulfolobales strains previously isolated from acidic hot springs in Yellowstone National Park, one of which associated with bulk S80 during growth and one that did not. The genomes of each strain encoded different sulfur metabolism enzymes, with only one encoding SOR. Dialysis membrane experiments showed that direct contact is not required for S80 oxidation in the SOR‐encoding strain. This is attributed to the generation of hydrogen sulfide (H2S) from S80 disproportionation that can diffuse out of the cell to solubilise bulk S80 to form soluble polysulfides (Sx2−) and/or S80 nanoparticles that readily diffuse across dialysis membranes. The Sulfolobales strain lacking SOR required direct contact to oxidise S80, which could be overcome by the addition of H2S. High concentrations of S80 inhibited the growth of both strains. These results implicate alternative strategies to acquire and metabolise sulfur in Sulfolobales and have implications for their distribution and ecology in their hot spring habitats. [ABSTRACT FROM AUTHOR]

This review article is focused on the progress made in the synthesis of 5′-α-P-modified nucleoside triphosphates (α-phosphate mimetics). A variety of α-P-modified nucleoside triphosphates (NTPαXYs, Y = O, S; X = S, Se, BH3, alkyl, amine, N-alkyl, imido, or others) have been developed. There is a unique class of nucleoside triphosphate analogs with different properties. The main chemical approaches to the synthesis of NTPαXYs are analyzed and systematized here. Using the data presented here on the diversity of NTPαXYs and their synthesis protocols, it is possible to select an appropriate method for obtaining a desired α-phosphate mimetic. Triphosphates' substrate properties toward nucleic acid metabolism enzymes are highlighted too. We reviewed some of the most prominent applications of NTPαXYs including the use of modified dNTPs in studies on mechanisms of action of polymerases or in systematic evolution of ligands by exponential enrichment (SELEX). The presence of heteroatoms such as sulfur, selenium, or boron in α-phosphate makes modified triphosphates nuclease resistant. The most distinctive feature of NTPαXYs is that they can be recognized by polymerases. As a result, S-, Se-, or BH3-modified phosphate residues can be incorporated into DNA or RNA. This property has made NTPαXYs a multifunctional tool in molecular biology. This review will be of interest to synthetic chemists, biochemists, biotechnologists, or biologists engaged in basic or applied research. [ABSTRACT FROM AUTHOR]

Simple Summary: This review provides a comprehensive and detailed explanation of the various functions of the ubiquitin-conjugating enzyme E2 O (UBE2O). It examines UBE2O's role in a wide range of biological processes under both physiological and pathological conditions. The review also explores UBE2O's involvement in several human cancers, with a particular focus on its role in leukemias and solid cancers. Furthermore, this review delves into the dual role of UBE2O, not only as a potential therapeutic target but also as a crucial factor in the regulation of the development and progressoin of several human malignancies. In summary, this review underscores UBE2O importance in cancer biology and its potential for future therapeutic applications. Protein degradation is a biological phenomenon essential for cellular homeostasis and survival. Selective protein degradation is performed by the ubiquitination system which selectively targets proteins that need to be eliminated and leads them to proteasome degradation. In this narrative review, we focus on the ubiquitin-conjugating enzyme E2 O (UBE2O) and highlight the role of UBE2O in many biological and physiological processes. We further discuss UBE2O's implications in various human diseases, particularly in leukemias and solid cancers. Ultimately, our review aims to highlight the potential role of UBE2O as a therapeutic target and offers new perspectives for developing targeted treatments for human cancers. [ABSTRACT FROM AUTHOR]

Centromeric localization of evolutionarily conserved CENP-A (Cse4 in Saccharomyces cerevisiae) is essential for chromosomal stability. Mislocalization of overexpressed CENP-A to noncentromeric regions contributes to chromosomal instability in yeasts, flies, and humans. Overexpression and mislocalization of CENP-A observed in many cancers are associated with poor prognosis. Previous studies have shown that F-box proteins, Cdc4 and Met30 of the Skp, Cullin, F-box ubiquitin ligase cooperatively regulate proteolysis of Cse4 to prevent Cse4 mislocalization and chromosomal instability under normal physiological conditions. Mck1 -mediated phosphorylation of Skp, Cullin, F-box- Cdc4 substrates such as Cdc6 and Rcn1 enhances the interaction of the substrates with Cdc4. Here, we report that Mck1 interacts with Cse4 , and Mck1 -mediated proteolysis of Cse4 prevents Cse4 mislocalization for chromosomal stability. Our results showed that mck1 Δ strain overexpressing CSE4 (GAL- CSE4) exhibits lethality, defects in ubiquitin-mediated proteolysis of Cse4 , mislocalization of Cse4 , and reduced Cse4 – Cdc4 interaction. Strain expressing GAL- cse4 -3A with mutations in three potential Mck1 phosphorylation consensus sites (S10, S16, and T166) also exhibits growth defects, increased stability with mislocalization of Cse4 -3A, chromosomal instability, and reduced interaction with Cdc4. Constitutive expression of histone H3 (Δ16H3) suppresses the chromosomal instability phenotype of GAL- cse4 -3A strain, suggesting that the chromosomal instability phenotype is linked to Cse4 -3A mislocalization. We conclude that Mck1 and its three potential phosphorylation sites on Cse4 promote Cse4 – Cdc4 interaction and this contributes to ubiquitin-mediated proteolysis of Cse4 preventing its mislocalization and chromosomal instability. These studies advance our understanding of pathways that regulate cellular levels of CENP-A to prevent mislocalization of CENP-A in human cancers. [ABSTRACT FROM AUTHOR]

In early stages of drug development, the absence of authentic metabolite standards often results in semi-quantitative measurements of metabolite formation in reaction phenotyping studies using mass spectrometry (MS), leading to inaccuracies in the determination of enzyme kinetic parameters, such as the Michaelis constant (K m). Moreover, it is impossible to ascertain the maximum rate of enzyme-catalyzed reactions (k cat or V max). The use of radiolabeled parent compounds can circumvent this problem. However, radiometric detection exhibits significantly lower sensitivity compared to MS. To address these challenges, we have developed a stepwise approach that leverages biosynthesized radiolabeled and non-radiolabeled metabolites as standards, enabling accurate determination of K m , k cat or V max without the need for authentic metabolite standards. This approach, using the carbon-14 [14C] labeled metabolite to calibrate the unlabeled metabolite (14C calibration method), combines radiometric with LC-MS/MS detection to generate both [14C]-labeled and unlabeled metabolite standard curves to ensure that the sample concentrations measured are accurately quantitated. Two case studies were presented to demonstrate the utility of this method. We first compared the accuracy of the 14C calibration method to the use of authentic standards for quantitating imipramine metabolites. Next, we biosynthesized and quantitated the metabolites of BI 894416 using 14C calibration method and evaluated the enzyme kinetics of metabolite formation. The K m values of the metabolite formation demonstrated substantially improved accuracy compared to MS semi-quantitation. Moreover, the 14C calibration method offers a streamlined approach to prepare multiple metabolite standards from a single biosynthesis, reducing the time required for structure elucidation and metabolite synthesis. [ABSTRACT FROM AUTHOR]

Activating Ca2+-sensitive enzymes of oxidative metabolism while preventing calcium overload that leads to mitochondrial and cellular injury requires dynamic control of mitochondrial Ca2+ uptake. This is ensured by the mitochondrial calcium uptake (MICU)1/2 proteins that gate the pore of the mitochondrial calcium uniporter (mtCU). MICU1 is relatively sparse in the heart, and recent studies claimed the mammalian heart lacks MICU1 gating of mtCU. However, genetic models have not been tested. We find that MICU1 is present in a complex with MCU in nonfailing human hearts. Furthermore, using murine genetic models and pharmacology, we show that MICU1 and MICU2 control cardiac mitochondrial Ca2+ influx, and that MICU1 deletion alters cardiomyocyte mitochondrial calcium signaling and energy metabolism. MICU1 loss causes substantial compensatory changes in the mtCU composition and abundance, increased turnover of essential MCU regulator (EMRE) early on and, later, of MCU, that limit mitochondrial Ca2+ uptake and allow cell survival. Thus, both the primary consequences of MICU1 loss and the ensuing robust compensation highlight MICU1's relevance in the beating heart. [ABSTRACT FROM AUTHOR]

Background: Endometrial cancer (EC) is a prevalent gynecological malignancy globally, with a rising incidence trend. While classic androgens have been implicated with EC risk, the role of their 11-oxygenated metabolites is poorly understood. Here, we studied 11-oxyandrogen formation from steroid precursors in EC for the first time. Methods: We performed in vitro studies on a panel of four EC cell lines of varying differentiation degree and molecular subtype and a control cell line of normal endometrium to assess 11-oxyandrogen formation from steroid precursors. We also characterized the transcriptomic effects of dihydrotestosterone (DHT) and 11-keto-DHT on Ishikawa and RL95-2. Key molecular players in 11-oxyandrogen metabolism and action were explored in endometrial tumors using public transcriptomic datasets. Results: We discovered that within endometrial tumors, the formation of 11-oxyandrogens does not occur from classic androgen precursors. However, we observed distinct regulatory mechanisms at a pre-receptor level in normal endometrium compared to cancerous tissue, and between low- and highgrade tumors. Specifically, in vitro models of low-grade EC formed higher levels of bioactive 11-keto-testosterone from 11-oxyandrogen precursors compared to models of noncancerous endometrium and high-grade, TP53-mutated EC. Moreover, the potent androgen, DHT and its 11-keto homologue induced mild transcriptomic effects on androgen receptor (AR)-expressing EC model, Ishikawa. Finally, using public transcriptomic datasets, we found HSD11B2 and SRD5A2, coding for key enzymes in steroid metabolism, to be associated with better disease-specific survival, whereas higher intra-tumoral AR expression correlated with lower recurrence in TP53-wt tumors. Conclusions: The intra-tumoral metabolism of 11-oxyandrogen precursors is characteristic for low-grade EC of non-TP53-alt molecular subtypes. Our findings support further exploration of circulating 11-oxyandrogens as prognostic biomarkers in EC. [ABSTRACT FROM AUTHOR]

Camellia drupifera, a significant woody oil crop in southern China, produces oil from its fruit seeds. Understanding sugar metabolism enzyme regulation is crucial for sugar accumulation and oil synthesis in fruit organs. This study examines the dynamic changes in sugar metabolism across four developmental stages of C. drupifera fruits, from rapid fruit enlargement to oil conversion. We analyzed sugar content, enzyme activity, and transcriptomic data to identify key periods and mechanisms involved in sugar metabolism. Our findings indicate that photosynthetic products are rapidly transported from leaves to fruit organs after synthesis, with transport efficiency decreasing significantly after 48 hours. September was identified as a critical period for oil conversion, during which the highest sucrose levels and SuSy-II enzyme activity were detected in the kernels. A positive correlation was found between high expression of ten genes related to sugar metabolism enzymes and sugar transport proteins and sucrose content. Notably, the expression levels of c158337.graph_c0 (SPS), c166323.graph_c0 (SuSy), c159295.graph_c0 (SUC2-like), and c156402.graph_c0 (SUC2-like) significantly increased during the oil conversion phase.These findings provide a crucial theoretical foundation for elucidating the molecular mechanisms of sugar metabolism in C. drupifera fruits, offering insights that could enhance its economic yield. [ABSTRACT FROM AUTHOR]

AbstractCytochrome P40 (CYP) enzymes dominate the metabolism of numerous endogenous and xenobiotic substances. While it is commonly believed that CYP-catalysed reactions result in the detoxication of foreign substances, these reactions can also yield reactive intermediates that can bind to cellular macromolecules to cause cytotoxicity or irreversibly inactivate CYPs that create them.Mechanism-based inactivation (MBI) produces either irreversible or quasi-irreversible inactivation and is commonly caused by CYP metabolic bioactivation to an electrophilic reactive intermediate. Many drugs that have been known to cause MBI in CYPs have been discovered as perpetrators in drug-drug interactions throughout the last 20–30 years.This review will highlight the key findings from the recent literature about the mechanisms of CYP enzyme inhibition, with a focus on the broad mechanistic elements of MBI for widely used drugs linked to the phenomenon. There will also be a brief discussion of the clinical or pharmacokinetic consequences of CYP inactivation with regard to drug interaction and toxicity risk.Gaining knowledge about the selective inactivation of CYPs by common therapeutic drugs helps with the assessment of factors that affect the systemic clearance of co-administered drugs and improves comprehension of anticipated interactions with other drugs or xenobiotics.Cytochrome P40 (CYP) enzymes dominate the metabolism of numerous endogenous and xenobiotic substances. While it is commonly believed that CYP-catalysed reactions result in the detoxication of foreign substances, these reactions can also yield reactive intermediates that can bind to cellular macromolecules to cause cytotoxicity or irreversibly inactivate CYPs that create them.Mechanism-based inactivation (MBI) produces either irreversible or quasi-irreversible inactivation and is commonly caused by CYP metabolic bioactivation to an electrophilic reactive intermediate. Many drugs that have been known to cause MBI in CYPs have been discovered as perpetrators in drug-drug interactions throughout the last 20–30 years.This review will highlight the key findings from the recent literature about the mechanisms of CYP enzyme inhibition, with a focus on the broad mechanistic elements of MBI for widely used drugs linked to the phenomenon. There will also be a brief discussion of the clinical or pharmacokinetic consequences of CYP inactivation with regard to drug interaction and toxicity risk.Gaining knowledge about the selective inactivation of CYPs by common therapeutic drugs helps with the assessment of factors that affect the systemic clearance of co-administered drugs and improves comprehension of anticipated interactions with other drugs or xenobiotics. [ABSTRACT FROM AUTHOR]

Rubisco (D-ribulose 1,5-bisphosphate carboxylase/oxygenase) is the most abundant enzyme in the world, constituting up to half of the soluble protein content in plant leaves. Such is its ubiquity that its chemical fingerprint can be detected in the geological record spanning billions of years. Rubisco catalyses the conversion of inorganic CO 2 into organic sugars, which underpin almost all of the biosphere, including our entire food chain. Due to its central role in the global carbon cycle, rubisco has been the subject of intense research for over 50 years. Rubisco is often considered inefficient due to its slow rate of carboxylation compared with other central metabolism enzymes, and its promiscuous oxygenase activity, which competes with the productive carboxylation reaction. It is hoped that engineering improved CO 2 fixation will have significant advantages in agriculture and climate change mitigation. However, rubisco has proven difficult to engineer, with decades of efforts yielding limited results. Recent research has focused on reconstructing the evolutionary trajectory of rubisco to help elucidate its cryptic origins. Such evolutionary studies have led to a better understanding of both the origins of more complex rubisco forms and the broader relationship between rubisco's structure and function. Taylor-Kearney et al. discuss the evolution and origins of the enzyme rubisco. [ABSTRACT FROM AUTHOR]

The PI3K/AKT/GSK-3β signaling pathway plays a pivotal role in numerous physiological and pathological processes, including cell proliferation, apoptosis, differentiation, and metabolic regulation. Aberrant activation of the PI3K/AKT pathway is intricately linked to development of tumor. GSK-3β, belonging to the serine/threonine protein kinase family, is crucial in the pathogenesis of liver cancer. As a key rate-limiting enzyme in the glucose metabolism pathway, GSK-3β significantly impacts the growth, proliferation, metastasis, and apoptosis of liver cancer cells. It is also implicated in chemotherapy resistance. Elevated expression of GSK-3β diminishes the sensitivity of liver cancer cells to chemotherapeutic agents, thereby playing a substantial role in the development of drug resistance. Consequently, targeting of GSK-3β, particularly within the PI3K/AKT signaling pathway, is regarded as a promising therapeutic strategy for liver cancer. The precise identification and subsequent modulation of this pathway represent a substantial potential for innovative clinical interventions in the management of liver cancer. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is associated with dysregulated choline metabolism, but the underlying mechanisms remain unclear. This study investigated the expression of key enzymes in this pathway in R6/2 HD mice and human HD postmortem brain tissues. We further explored the therapeutic potential of modulating choline metabolism for HD. Both R6/2 mice and HD patients exhibited reduced expression of glycerophosphocholine phosphodiesterase 1 (GPCPD1), a key enzyme in choline metabolism, in the striatum and cortex. The striatum of R6/2 mice also showed decreased choline and phosphorylcholine, and increased glycerophosphocholine, suggesting disruption in choline metabolism due to GPCPD1 deficiency. Treatment with citicoline significantly improved motor performance, upregulated anti‐apoptotic Bcl2 expression, and reduced oxidative stress marker malondialdehyde in both brain regions. Metabolomic analysis revealed partial restoration of disrupted metabolic patterns in the striatum and cortex following citicoline treatment. These findings strongly suggest the role of GPCPD1 deficiency in choline metabolism dysregulation in HD. The therapeutic potential of citicoline in R6/2 mice highlights the choline metabolic pathway as a promising target for future HD therapies. [ABSTRACT FROM AUTHOR]

This study was conducted to investigate whether methionyl-tRNA synthetase (MetRS) is a mediator of methionine (Met)-induced crop milk protein synthesis via the janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) signalling pathway in breeding pigeons. In Experiment 1, a total of 216 pairs of breeding pigeons were divided into three groups (control, Met-deficient, and Met-rescue groups). In Experiments 2 and 3, forty pairs of breeding pigeons from each experiment were allocated into four groups. The second experiment included a control group and three MetRS inhibitor (REP8839) groups. The third experiment included a Met-deficient group, Met-sufficient group, REP8839 + Met-deficient group and REP8839 + Met-sufficient group. Experiment 1 showed that Met supplementation increased crop development, crop milk protein synthesis, the protein expression of MetRS and JAK2/STAT5 signalling pathway, and improved squab growth. Experiment 2 showed that crop development, crop milk protein synthesis and the protein expression of MetRS and the JAK2/STAT5 signalling pathway were decreased, and squab growth was inhibited by the injection of 1·0 mg/kg body weight REP8839, which was the selected dose for the third experiment. Experiment 3 showed that Met supplementation increased crop development, crop milk protein synthesis and the expression of MetRS and JAK2/STAT5 signalling pathway and rescued squab growth after the injection of REP8839. Moreover, the co-immunoprecipitation results showed that there was an interaction between MetRS and JAK2. Taken together, these findings indicate that MetRS mediates Met-induced crop milk protein synthesis via the JAK2/STAT5 signalling pathway, resulting in improved squab growth in breeding pigeons. [ABSTRACT FROM AUTHOR]

Sphingolipids (SLs) constitute a discrete subdomain of metabolism, and they display both structural and signaling functions. Accumulating evidence also points to intimate connections between intermediary metabolism and SL metabolism. Given that many SLs exhibit bioactive properties (i.e. transduce signals), these raise the possibility that an important function of SLs is to relay information on metabolic changes into specific cell responses. This could occur at various levels. Some metabolites are incorporated into SLs, whereas others may initiate regulatory or signaling events that, in turn, modulate SL metabolism. In this review, we elaborate on the former as it represents a poorly appreciated aspect of SL metabolism, and we develop the hypothesis that the SL network is highly sensitive to several specific metabolic changes, focusing on amino acids (serine and alanine), various fatty acids, choline (and ethanolamine), and glucose. [ABSTRACT FROM AUTHOR]

Wheat grain starch content displays large variations within different pearling fractions, which affecting the processing quality of corresponding flour, while the underlying mechanism on starch gradient formation is unclear. Here, we show that wheat caryopses acquire sugar through the transfer of cells (TCs), inner endosperm (IE), outer endosperm (OE), and finally aleurone (AL) via micro positron emission tomography-computed tomography (PET-CT). To obtain integrated information on spatial transcript distributions, developing caryopses are laser microdissected into AL, OE, IE, and TC. Most genes encoding carbohydrate transporters are upregulated or specifically expressed, and sugar metabolites are more highly enriched in the TC group than in the AL group, in line with the PET-CT results. Genes encoding enzymes in sucrose metabolism, such as sucrose synthase, beta-fructofuranosidase, glucose-1-phosphate adenylyltransferase show significantly lower expression in AL than in OE and IE, indicating that substrate supply is crucial for the formation of starch gradients. Furthermore, the low expressions of gene encoding starch synthase contribute to low starch content in AL. Our results imply that transcriptional regulation represents an important means of impacting starch distribution in wheat grains and suggests breeding targets for enhancing specially pearled wheat with higher quality. This study classifies tissue-specific variations in metabolites and transcripts involved in starch biosynthesis and illustrates the factors affecting the spatial distribution of starch in wheat grain. [ABSTRACT FROM AUTHOR]

This study investigated sex-specific differences in high-energy phosphate, glycolytic, and mitochondrial enzyme activities and also metabolite transporter protein levels in the skeletal muscles of adult (5 months old), middle-aged (12 months old), and advanced-aged (24 months old) mice. While gastrocnemius glycogen content increased with age regardless of sex, gastrocnemius triglyceride levels increased only in advanced-aged female mice. Aging decreased creatine kinase and adenylate kinase activities in the plantaris muscle of both sexes and in the soleus muscle of male mice but not in female mice. Irrespective of sex, phosphofructokinase and lactate dehydrogenase (LDH) activities decreased in the plantaris and soleus muscles. Additionally, hexokinase activity in the plantaris muscle and LDH activity in the soleus muscle decreased to a greater extent in aged male mice compared with those in aged female mice. Mitochondrial enzyme activities increased in the plantaris muscle of aged female mice but did not change in male mice. The protein content of the glucose transporter 4 in the aged plantaris muscle and fatty acid translocase/cluster of differentiation 36 increased in the aged plantaris and soleus muscles of both sexes, with a significantly higher content in female mice. These findings suggest that females possess a better ability to maintain metabolic enzyme activity and higher levels of metabolite transport proteins in skeletal muscle during aging, despite alterations in lipid metabolism. Our data provide a basis for studying muscle metabolism in the context of age-dependent metabolic perturbations and diseases that affect females and males differently. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer is a difficult-to-cure disease with high worldwide incidence and mortality. Among the many changes observed in cancer cells and patient samples is altered glycosylation, a commonly observed modification of biomolecules such as proteins. These glycan structures can dictate protein function, and dysregulation of glycosylation can contribute to tumor migration and metastasis. Thus, manipulation of glycosylation states may be a novel approach to cancer treatment. One target of the well-known tumor suppressor p53 is FUCA1, encoding alpha-L-fucosidase, which plays a role in glycosylation, although the exact mechanism linking FUCA1 to cancer is unclear. Investigation into these glycosylation processes and the mechanisms linking the p53-FUCA1 axis to cancer development may provide new insights into this disease and suggest new drug targets for cancer therapies. Cancer is a difficult-to-cure disease with high worldwide incidence and mortality, in large part due to drug resistance and disease relapse. Glycosylation, which is a common modification of cellular biomolecules, was discovered decades ago and has been of interest in cancer research due to its ability to influence cellular function and to promote carcinogenesis. A variety of glycosylation types and structures regulate the function of biomolecules and are potential targets for investigating and treating cancer. The link between glycosylation and carcinogenesis has been more recently revealed by the role of p53 in energy metabolism, including the p53 target gene alpha-L-fucosidase 1 (FUCA1), which plays an essential role in fucosylation. In this review, we summarize roles of glycan structures and glycosylation-related enzymes to cancer development. The interplay between glycosylation and tumor microenvironmental factors is also discussed, together with involvement of glycosylation in well-characterized cancer-promoting mechanisms, such as the epidermal growth factor receptor (EGFR), phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) and p53-mediated pathways. Glycan structures also modulate cell–matrix interactions, cell–cell adhesion as well as cell migration and settlement, dysfunction of which can contribute to cancer. Thus, further investigation of the mechanistic relationships among glycosylation, related enzymes and cancer progression may provide insights into potential novel cancer treatments. [ABSTRACT FROM AUTHOR]

Simple Summary: This study employed microbial culturing to isolate four strains of bacteria with protease activity from the gut of an omnivorous insect. The four bacteria were precisely identified using whole-genome relatedness indices, based on conventional bacterial species identification methods. Furthermore, their whole-genome functional information was analyzed and compared, establishing a technical foundation for the development and utilization of protease-producing microorganisms from the insect gut. The insect gut harbors a diverse array of functional microorganisms that warrant further exploration and utilization. However, there is currently a paucity of research reports on the discovery of protease-producing microorganisms with industrial application value in the gut. Here, we employed microbial culturing to screen and identify the protease-producing microorganisms in the gut extract of Gryllotalpa orientalis. Based on morphological, physiological, and biochemical characterization, 16S rRNA sequencing, as well as ANI and dDDH values of whole genome, the protease-producing strains isolated from the insect gut were identified as Priestia aryahattai DBM-1 and DX-4, P. megaterium DX-3, and Serratia surfactantfaciens DBM-5. According to whole-genome analysis, strain DBM-5, which exhibited the highest enzyme activity, possesses abundant membrane transport genes and carbohydrate metabolism enzymes. In contrast, strains DX-3 and DX-4 not only have the ability to hydrolyze proteins but also demonstrate the capability to hydrolyze plant materials. Furthermore, strains that are closely related tend to have similar metabolic product gene clusters in their genomes. The screening and identification of protease resources are essential for the subsequent development and utilization of gut functional microorganisms and genetic resources in insects. [ABSTRACT FROM AUTHOR]

Cholestasis, a chronic liver condition, disrupts bile acid homeostasis and complicates drug disposition, posing significant challenges in medicating cholestatic patients. Drug metabolism enzymes and transporters (DMETs) are pivotal in drug clearance. Research indicates that cholestasis leads to alterations in both hepatic and extrahepatic DMETs, with changes in expression and function documented in rodents and humans. This review synthesizes the modifications in key drug disposition components within cholestasis, focusing on cytochrome P450 (CYP450), drug transporters, and their substrates. Additionally, we briefly discuss certain drugs that have demonstrated efficacy in restoring DMET expression in cholestatic conditions. Ultimately, these insights necessitate a reevaluation of drug selection and dosing guidelines for patients with cholestasis. [ABSTRACT FROM AUTHOR]

Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. It bears a significant global health burden with limited treatment options, thus calling for the development of new and effective drugs. Certain trypanosomal metabolic enzymes have been suggested to be druggable and valid for subsequent inhibition. In this study, the crystal structure of glycerol kinase from T. cruzi, a key enzyme in glycerol metabolism in this parasite, is presented. Structural analysis allowed a detailed description of the glycerol binding pocket, while comparative assessment pinpointed a potential regulatory site which may serve as a target for selective inhibition. These findings advance the understanding of glycerol metabolism in eukaryotes and provide a solid basis for the future treatment of Chagas disease. [ABSTRACT FROM AUTHOR]

Cytochrome P450 3A4 (CYP3A4) is a crucial enzyme in the metabolism of xenobiotics, particularly in drug metabolism interactions (DDIs), making it a significant factor in clinical drug use. However, current assay techniques are both laborious and costly, making it difficult to construct a high-throughput monitoring method that can be used in conjunction with the clinic. This poses certain safety hazards for drug combination. Therefore, it is crucial to develop a synchronized monitoring method for the inhibition and induction of CYP3A4. In this study, we utilized 3D culture technology to develop a HepaRG cells spheroid model. The CYP450 and transporter expression, the albumin secretion, and urea synthesis capacity characteristics were analyzed. The NEN probe was utilized as a tracer molecule for CYP3A4. The fluorescence intensity of metabolites was characterized by laser confocal technique to determine the inhibition and expression of CYP3A4 in the HepaRG cell spheroid model by the antibiotics for sepsis. The results indicate that the HepaRG sphere model successfully possessed the physiological phenotype of the liver, which could be used for drug interaction monitoring. Through positive drug testing, NEN probe was able to achieve bidirectional characterization of CYP3A4 induction and inhibition. The monitoring method described in this paper was successfully applied to drug interaction monitoring of commonly used antibiotics in sepsis patients, which is a convenient and rapid monitoring method. The proposed method offers a new strategy for monitoring CYP3A4-mediated drug-drug interactions with a high-throughput assay, which will help to improve the safety of clinical drug combination. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is a gaseous signaling molecule in plants. Paclobutrazol is a widely used plant growth retardant in agriculture and gibberellic acid (GA) biosynthesis inhibitor in research. Both of them involving in various biological processes. However, the crosstalk of paclobutrazol and NO was unclear. In this study, we explored the effect of paclobutrazol treatment on seed germination of Arabidopsis Col-0 and nia1nia2. The results showed that endogenous NO deficiency alleviated the inhibition effect of paclobutrazol on seed germination in nia1nia2. On the transcriptome level, NO and paclobutrazol commonly regulated the expression level of genes involving in oxidation–reduction process, phytohormone response, photosynthesis, light stimulus response, and abiotic stress response, etc. In the GA response pathways, NO deficiency reversed or offset the effect of paclobutrazol on the transcription of most of genes encoding GA metabolism enzymes and two DELLA proteins, RGA and RGL2. The global S-nitrosylated protein level was regulated not only by NO, but also paclobutrazol. Paclobutrazol enhanced the S-nitrosylated protein level in both of Col-0 and nia1nia2 seeds, but the level was constantly higher in Col-0 seeds. Our results suggest that NO may regulate the inhibition effect of paclobutrazol on seed germination in Arabidopsis, via S-nitrosylation of target proteins. [ABSTRACT FROM AUTHOR]

Drought stress significantly affects the growth, development, and yield of cotton, triggering the response of multiple genes. Among them, ascorbate peroxidase (APX) is one of the important antioxidant enzymes in the metabolism of reactive oxygen species in plants, and APX enhances the ability of plants to resist oxidation, thus increasing plant stress tolerance. Therefore, enhancing the activity of APX in cells is crucial to improving plant stress resistance. Previous studies have isolated differentially expressed proteins under drought stress (GhAPX7) in drought-resistant (KK1543) and drought-sensitive (XLZ26) plants. Thus, this study analyzed the expression patterns of GhAPX7 in different cotton tissues to verify the drought resistance function of GhAPX7 and explore its regulatory pathways. GhAPX7 had the highest expression in cotton leaves, which significantly increased under drought stress, suggesting that GhAPX7 is essential for improving antioxidant capacity and enzyme activities in cotton. GhAPX7 silencing indirectly affects pronounced leaf yellowing and wilting in drought-resistant and drought-sensitive plants under drought stress. Malondialdehyde (MDA) content was significantly increased and chlorophyll and proline content and APX enzyme activity were generally decreased in silenced plants compared to the control. This result indicates that GhAPX7 may improve drought resistance by influencing the contents of MDA, chlorophyll, proline, and APX enzyme activity through increased expression levels. Transcriptome analysis revealed that the drought-related differentially expressed genes between the control and treated groups enriched plant hormone signal transduction, MAPK signaling, and plant–pathogen interaction pathways. Therefore, the decreased expression of GhAPX7 significantly affects the expression levels of genes in these three pathways, reducing drought resistance in plants. This study provides insights into the molecular mechanisms of GhAPX7 and its role in drought resistance and lays a foundation for further research on the molecular mechanisms of response to drought stress in cotton. [ABSTRACT FROM AUTHOR]

The recent re-emergence and the increasing popularity of nitazenes, a group of new synthetic opioids (NSO) that belong to the benzimidazole chemical class, has raised public health concerns. As a class of potential opioid analgesic agents whose development was discontinued in the 1960s due to their high potential for abuse, very little is known about their metabolism and physiologic disposition. In the current study, three nitazenes-butonitazene, isotonitazene and protonitaze were incubated in human liver microsomes (HLM), human S9 (HS9) fractions and recombinant cytochrome P450 enzymes. All three nitazenes were rapidly metabolized in both HLM and HS9 with over 95% depletion within 60 min. In HLM, butonitazene, isotonitazene and protonitazene had in vitro intrinsic clearance (CLint) (µL/min/mg protein) values of 309, 221 and 216 respectively compared to 150 of verapamil, the positive control. In HS9, CLint values were 217, 139, and 150 for butonitazene, isotonitazene and protonitazene respectively compared to only 35 for testosterone, the control probe substrate. Putative metabolite identified from this study include products of hydroxylation, desethylation, dealkylation, desethylation followed by dealkylation, and desethylation followed by hydroxylation. The metabolic phenotyping showed CYP2D6, CYP2B6 and CYP2C8 and the major hepatic enzymes responsible for the metabolism of nitazenes. Within 30 min of incubation, CYP2D6 depleted butonitazene (99%), isotonitazene (72%) and butonitazene (100%) significantly. The rapid metabolism of nitazenes may be an important factor in accurate and timely detections and quantitation of the unchanged drugs in human matrices following intoxication or in forensic analysis. The involvement of multiple polymorphic CYPs in their metabolism may play important roles in the susceptibility to intoxication and/or addiction, depending on the activity of the metabolites. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Metabolism characterization and toxicity of N-hydap, a marine candidate drug for lung cancer therapy by LC-MS method" published in the journal Natural Products & Bioprospecting. The correction addresses mistakes in the original article, specifically related to the bioavailability and distribution of N-hydap. The corrected information states that N-hydap has a favorable bioavailability of 24.0% and exhibits a higher distribution in the lungs, making it effective against small cell lung cancer. The correction also includes updates to the graphical abstract and a table presenting pharmacokinetic parameters. The corrected article concludes that N-hydap, with its improved bioavailability, is a promising candidate for anti-small cell lung cancer therapy. [Extracted from the article]

The cereal cyst nematode (Heterodera latipons) is becoming an economically important species in global cereal production as it is being identified in many new cereal cultivated areas and causes significant losses. Consequently, understanding its biology becomes crucial for researchers in identifying its vulnerabilities and implementing effective control measures. In the current study, different morphological and biochemical changes of H. latipons cysts containing eggs with infective juveniles from a barley field in Jordan were studied during the summer of 2021, at two sample dates. The first, at the harvest of the cereal crop (June 2021), when the infective second-stage juveniles (J2s) were initiating diapause, and the second, before planting the sequent cereal crop (late October 2021), when the J2s were ending diapause. The studied population was characterized morphologically and molecularly, showing 98.4% molecular similarity to both JOD from Jordan and Syrian "300" isolates of H. latipons. The obtained results and observations revealed that there were dramatic changes in all the investigated features of the cysts and eggs they contained. Morphological changes such as cyst color, sub-crystalline layer, and thickness of the rigid eggshell wall were observed. A slight change in the emergence time of J2s from cysts was observed without any difference in the number of emerged J2s. The results of biochemical changes showed that the total contents of carbohydrates, glycogen, trehalose, glycerol, and protein were higher in cysts collected in October when compared to those cysts collected in June. The SDS-PAGE pattern indicated the presence of a protein with the size of ca. 100 kDa in both sampling dates, whereas another protein (ca. 20 kDa) was present only in the cysts of October. Furthermore, the expression of trehalase (tre) gene was detected only in H. latipons collected in October. The outcomes of this study provide new helpful information that elucidates diapause in H. latipons and may be used for the implementation of new management strategies of cyst nematodes. [ABSTRACT FROM AUTHOR]

D-1,2,4-butanetriol (BT) is a widely used fine chemical that can be manufactured by engineered Escherichia coli expressing heterologous pathways and using xylose as a substrate. The current study developed a glucose-xylose dual metabolic channel system in an engineered E. coli and Combinatorially optimized it using multiple strategies to promote BT production. The carbon catabolite repression effects were alleviated by deleting the gene ptsG that encodes the major glucose transporter IICBGlc and mutating the gene crp that encodes the catabolite repressor protein, thereby allowing C-fluxes of both glucose and xylose into their respective metabolic channels separately and simultaneously, which increased BT production by 33% compared with that of the original MJ133K-1 strain. Then, the branch metabolic pathways of intermediates in the BT channel were investigated, the transaminase HisC, the ketoreductases DlD, OLD, and IlvC, and the aldolase MhpE and YfaU were identified as the enzymes for the branched metabolism of 2-keto-3-deoxy-xylonate, deletion of the gene hisC increased BT titer by 21.7%. Furthermore, the relationship between BT synthesis and the intracellular NADPH level was examined, and deletion of the gene pntAB that encodes a transhydrogenase resulted in an 18.1% increase in BT production. The combination of the above approaches to optimize the metabolic network increased BT production by 47.5%, resulting in 2.67 g/L BT in 24 deep-well plates. This study provides insights into the BT biosynthesis pathway and demonstrates effective strategies to increase BT production, which will promote the industrialization of the biosynthesis of BT. • A glucose-xylose dual metabolic channel system was developed for BT biosynthesis • BT synthesis was promoted by utilizing glucose and xylose in their respective channels • The intermediate 2-keto-3-deoxy-xylonate was metabolized via multiple branch routes • Intracellular NADPH levels affect BT biosynthesis • Combinatorial optimization was an effective strategy for BT biosynthesis [ABSTRACT FROM AUTHOR]

Despite extensive research on the metabolism of polychlorinated biphenyls (PCBs), knowledge gaps persist regarding their isoform-specific biotransformation pathways. This study aimed to elucidate the role of different cytochrome P450 enzymes in PCB metabolism, focusing on WHO-congeners 2,4,4′-trichlorobiphenyl (PCB28), 2,2′,5,5′-tetrachlorobiphenyl (PCB52), and 2,2′,4,5,5′-pentachlorobiphenyl (PCB101). Utilizing engineered HEK293 cell lines, we investigated the in vitro metabolism of these PCBs by CYP1A2, CYP2C8, CYP2C9, CYP3A4, CYP2A6, and CYP2E1, revealing robust production of hydroxylated metabolites. Our results show that CYP2A6 plays a major role in the metabolism of these congeners responsible for predominant formation of para-position hydroxylated metabolites, with concentrations reaching up to 1.61 µg/L (5,89 nM) for PCB28, 316.98 µg/L (1,03 µM) for PCB52, and 151.1 µg/L (441 nM) for PCB101 from a 20 µM parent PCB concentration. Moreover, concentration-dependent cytotoxic and cytostatic effects induced by reactive intermediates of the PCB hydroxylation pathway were observed in HEK293CYP2A6 cells, for all three congeners tested. CYP2A6 was specifically capable of activating PCBs 28 and 101 to genotoxic metabolites which produced genetic defects which were propagated to subsequent generations, potentially contributing to carcinogenesis. In a clinical study examining CYP2A6 enzyme activity in formerly exposed individuals with elevated internal PCB levels, a participant with increased enzyme activity showed a direct association between the phenotypic activity of CYP2A6 and the metabolism of PCB28, confirming the role of CYP2A6 in the in vivo metabolism of PCB28 also in humans. These results altogether reinforce the concept that CYP2A6 plays a pivotal role in PCB congener metabolism and suggest its significance in human health, particularly in the metabolism of lower chlorinated, volatile PCB congeners. [ABSTRACT FROM AUTHOR]

Plant-beneficial Pseudomonas bacteria hold the potential to be used as inoculants in agriculture to promote plant growth and health through various mechanisms. The discovery of new strains tailored to specific agricultural needs remains an open area of research. In this study, we report the isolation and characterization of four novel Pseudomonas species associated with the wheat rhizosphere. Comparative genomic analysis with all available Pseudomonas type strains revealed species-level differences, substantiated by both digital DNADNA hybridization and average nucleotide identity, underscoring their status as novel species. This was further validated by the phenotypic differences observed when compared to their closest relatives. Three of the novel species belong to the P. fluorescens species complex, with two representing a novel lineage in the Pseudomonas phylogeny. Functional genome annotation revealed the presence of specific features contributing to rhizosphere colonization, including flagella and components for biofilm formation. The novel species have the genetic potential to solubilize nutrients by acidifying the environment, releasing alkaline phosphatases and their metabolism of nitrogen species, indicating potential as biofertilizers. Additionally, the novel species possess traits that may facilitate direct promotion of plant growth through the modulation of the plant hormone balance, including the ACC deaminase enzyme and auxin metabolism. The presence of biosynthetic clusters for toxins such as hydrogen cyanide and nonribosomal peptides suggests their ability to compete with other microorganisms, including plant pathogens. Direct inoculation of wheat roots significantly enhanced plant growth, with two strains doubling shoot biomass. Three of the strains effectively antagonized fungal phytopathogens (Thielaviopsis basicola, Fusarium oxysporum, and Botrytis cinerea), demonstrating their potential as biocontrol agents. Based on the observed genetic and phenotypic differences from closely related species, we propose the following names for the four novel species: Pseudomonas grandcourensis sp. nov., type strain DGS24T (= DSM 117501T = CECT 31011T), Pseudomonas purpurea sp. nov., type strain DGS26T (= DSM 117502T = CECT 31012T), Pseudomonas helvetica sp. nov., type strain DGS28T (= DSM 117503T = CECT 31013T) and Pseudomonas aestiva sp. nov., type strain DGS32T (= DSM 117504T = CECT 31014T). [ABSTRACT FROM AUTHOR]

Simple Summary: This paper reviews the role of ENO2, a protein involved in sugar metabolism, in advanced prostate cancer. Analysing five studies, we found that ENO2 levels tend to be higher in aggressive forms of prostate cancer, particularly those that have spread or become resistant to hormone therapy. This increased presence might be linked to how prostate cancer cells change their energy production as the disease progresses, shifting to rely more on sugar breakdown in advanced stages. The study also suggests that ENO2 can be influenced by the tumour's environment, such as low hormone levels or the presence of bone cells, which is relevant, as prostate cancer often spreads to bones. While not proving a direct causal relationship, the research indicates that ENO2 could be an important marker for aggressive disease and potentially a target for future treatments, warranting further investigation into its role in prostate cancer progression, especially in bone metastasis. Prostate cancer (PCa) is the second leading cause of male cancer deaths in the UK and the fifth worldwide. The presence of distant PCa metastasis can reduce the 5-year survival rate from 100% to approximately 30%. Enolase 2 (ENO2), a crucial glycolytic enzyme in cancer metabolism, is associated with the metastasis of multiple cancers and is also used as a marker for neuroendocrine tumours. However, its role in PCa metastasis remains unclear. In this study, we systematically reviewed the current literature to determine the association between ENO2 and metastatic PCa. Medline, Web of Science, and PubMed were searched for eligible studies. The search yielded five studies assessing ENO2 expression in PCa patients or cell lines. The three human studies suggested that ENO2 expression is correlated with late-stage, aggressive PCa, including castrate-resistant PCa (CRPC), metastatic CRPC, and neuroendocrine PCa (NEPC). This was further supported by two in vitro studies indicating that ENO2 expression can be regulated by the tumour microenvironment, such as androgen deprived conditions and the presence of bone-forming osteoblasts. Therefore, ENO2 may functionally contribute to PCa metastasis, possibly due to the unique metabolic features of PCa, which are glycolysis dependent only at the advanced metastatic stage. [ABSTRACT FROM AUTHOR]

The incidence of perturbed gastrointestinal integrity, as well as resulting systemic immune responses and gastrointestinal symptoms, otherwise known as exercised-induced gastrointestinal syndrome (EIGS), is common among individuals who partake in prolonged exercise. EIGS may cause the translocation of pathogenic material, including whole bacteria and bacterial endotoxins, from the lumen into circulation, which may progress into clinical consequences such as sepsis, and potentially subsequent fatality. However, further investigation is warranted to assess the possibility of food allergen and/or digestive enzyme luminal to circulatory translocation in response to exercise, and the clinical consequences. Findings from this narrative literature review demonstrate evidence that whole bacteria and bacterial endotoxins translocation from the gastrointestinal lumen to systemic circulation occurs in response to exercise stress, with a greater propensity of translocation occurring with accompanying heat exposure. It has also been demonstrated that food allergens can translocate from the lumen to systemic circulation in response to exercise stress and initiate anaphylaxis. To date, no research investigating the effect of exercise on the translocation of digestive enzymes from the lumen into systemic circulation exists. It is evident that EIGS and consequential pathogenic translocation presents life-threatening clinical implications, warranting the development and implementation of effective management strategies in at-risk populations. [ABSTRACT FROM AUTHOR]

Sesame is an important oilseed crop that provides invaluable nutrients in food products. Due to the fact that it is neglected, little is known on how sprouting days affect its nutritional quality. This study aimed to determine the effect of sprouting durations on the nutritional composition of two sesame varieties grown in Ghana. The experimental design was a 2x5 factorial design in Completely Randomized Design with three replications. Factor one was sesame varieties at two levels (Grey and Brown) and factor two was sprouting durations at five levels (0, 2, 4, 6, 8 day). The study revealed that highest carbohydrate (30.64%), protein (35.77%) and moisture (87.79%) contents were produced by the grey variety which was sprouted for 8 durations. Moreover, the best crude fibre (25.88%) content was produced by the brown variety which was not sprouted, whiles highest fat content was produced by the grey variety which was sprouted for 2 durations. Highest calcium (2.37mg/kg), phosphorus (1.49mg/kg) and potassium (1.39mg/kg) content was produced by the grey variety which was sprouted for 8 durations whiles highest magnesium content (0.79mg/kg) was produced by the brown variety which was sprouted for 2 durations. Sprouting durations and the varieties did not significantly influence sodium content of sprouted seeds. Highest nutrients from sesame seeds can be obtained by sprouting the grey variety for 8 days. [ABSTRACT FROM AUTHOR]

Maltose metabolism is a critical process during plant growth, which provides energy during development and reproduction. To investigate maltose metabolism in C4 plants, we identified and analyzed the expression of the heteroglycan glucosidase 1 (HGL1) enzyme from Cenchrus americanus (L.) Morrone. The sequenced cDNA of CaHGL1 (3469 bp) encoded for a deduced protein of 1047 aa. Transmembrane topology revealed that CaHGL1 is a membrane-bound protein that comprises a signal peptide and a transmembrane helix. The promoter of CaHGL1 contains cis-elements related to the responses to light, abiotic stress and phytohormones. Real-time PCR revealed high expression in inflorescence and roots during the vegetative stage. Moreover, phytohormone treatments caused an activation of CaHGL1 expression in the seedling root and shoot by ABA, cytokinin, and BL, and an inhibition by JA in the seedling root and shoot. However, treatment with GA and IAA caused an activation in the CaHGL1 expression only in the shoot. Stress treatment induced the expression of CaHGL1 under drought, cold, and salt stress. The results of the current study give insight into the activity of the HGL1 enzyme in maltose metabolism under abiotic stress, which can aid in understanding the different metabolic pathways in Cenchrus americanus under stress. [ABSTRACT FROM AUTHOR]

The study examined the effects of jasmonic acid (100 nmol, JA) priming and foliar application of spermidine (1 mM, Spd), both individually and combined, on mitigating cadmium (100 μM, Cd) stress- induced oxidative damage in wheat. Cadmium stress reduced plant height and dry mass, but JA priming and/or Spd treatment increased resistance. Cd stress significantly decreased carotenoids, total chlorophylls, glutamate 1-semialdehyde (GSA), and δ-aminolevulinic acid (ALA), but JA and Spd treatments counteracted these reductions. Photosynthetic parameters improved under JA and Spd treatments, with combined treatment showing greater alleviation. Cd exposure increased lipid peroxidation, hydrogen peroxide, electrolyte leakage, and superoxide, but these oxidative stress indicators were significantly reduced after JA and Spd treatment. Antioxidant enzyme activity was upregulated by JA priming and Spd application, both under unstressed and Cd-stressed conditions. JA and/or Spd treatments also increased ascorbic acid, lowered glutathione concentration, and upregulated glyoxylase activity, reducing methylglyoxal accumulation. Additionally, secondary compounds (phenols and flavonoids) and osmolytes (proline and glycine betaine) levels improved. Proline oxidase activity decreased, indicating controlled proline buildup, while γ-glutamyl kinase activity increased. JA and/or Spd treatments significantly reduced Cd accumulation in seedlings. The study concluded that JA and Spd treatments enhance the plant's defensive mechanisms against oxidative stress by boosting antioxidant enzymes and secondary metabolism. [ABSTRACT FROM AUTHOR]

To investigate the role of the HvnAnt2 gene in the formation of different qingke barley grain colours, HvnAnt2 was isolated from the leaves of the White 91-97-3 (white), Blue qingke (blue), Kunlun 17 (black), and Purple qingke (purple). The HvnAnt2 gene encodes a hydrophilic unstable protein consisting of 561 amino acids, without a transmembrane structure and without a signal peptide, with one bHLH-MYC_N and one HLH domain at amino acids 22-204 and 387-436, respectively. The HvnAnt2 of qingke barley was most closely related to Hordeum vulgare and most distantly related to Triticum monococcum; it was mainly related to light responsiveness and methyl jasmonate responsiveness. The Ant2 gene was highly expressed in Kunlun 17 and Purple qingke barley grains during the later stage of development. The protein interaction prediction showed that flavonoid 3'-monooxygenase, anthocyanin biosynthesis gene regulators, and key enzymes in folate metabolism interacted with the Ant2 protein. This study provides a reference for further analysis of the Ant2 gene in the anthocyanin synthesis pathways of qingke barley with different grain colours. [ABSTRACT FROM AUTHOR]

The accurate segregation of homologous chromosomes during the Meiosis I reductional division in most sexually reproducing eukaryotes requires crossing over between homologs. In baker's yeast approximately 80% of meiotic crossovers result from Mlh1 – Mlh3 and Exo1 acting to resolve double-Holliday junction intermediates in a biased manner. Little is known about how Mlh1 – Mlh3 is recruited to recombination intermediates to perform its role in crossover resolution. We performed a gene dosage screen in baker's yeast to identify novel genetic interactors with Mlh1 – Mlh3. Specifically, we looked for genes whose lowered dosage reduced meiotic crossing over using sensitized mlh3 alleles that disrupt the stability of the Mlh1 – Mlh3 complex and confer defects in mismatch repair but do not disrupt meiotic crossing over. To our surprise we identified genetic interactions between MLH3 and DMC1 , the recombinase responsible for recombination between homologous chromosomes during meiosis. We then showed that Mlh3 physically interacts with Dmc1 in vitro and in vivo. Partial complementation of Mlh3 crossover functions was observed when MLH3 was expressed under the control of the CLB1 promoter (NDT80 regulon), suggesting that Mlh3 function can be provided late in meiotic prophase at some functional cost. A model for how Dmc1 could facilitate Mlh1 – Mlh3 's role in crossover resolution is presented. [ABSTRACT FROM AUTHOR]

Genomes of oleaginous yeast strains Rhodotorula glutinis CON-5 and Rhodotorula kratochvilovae POR-3, isolated from areas in the northern Peruvian Andes using SPAdes, were sequenced and assembled applying Illumina and de novo. Genomes of 20,515,696 and 20,738,185 bp, respectively, were determined. From the structural and functional annotations, the Basidiomycota phylum showed a similarity of 76.8% and 86.5% with 6,976 and 8,124 pairs of proteins in both yeasts respectively, with homologues in the UniProt data bank. Using OrthoVenn, a relationship between both yeasts was obtained from 450 orthologous groups. Likewise, the above-mentioned yeasts and R. toruloides (oleaginous Basidiomycota) showed 1,574 orthologous groups, indicating a good relationship. Construction of phylogenetic trees of genes encoding metabolic enzymes was also carried out, based on the ITS sequences which showed that CON-5 and POR-3 have a greater relationship with R graminis. Their phylogenetic relationship was ascertained and determined that the enzymes involved in the metabolism of CON-5 and POR-3 are related to each other. It was also found that the protein sequences of the Basidiomycota phylum differ from Ascomycota. The study showed functional evidence regarding the lipid accumulation phenotype, an important aspect in the context of obtaining lipids or oleochemicals. [ABSTRACT FROM AUTHOR]

Simple Summary: The present research investigates the counterintuitive effects of sublethal chemotherapy doses in non-small-cell lung cancer (NSCLC), focusing on their role in enhancing cancer cell malignancy and the role of Aldo-keto reductase family 1 member B10 (AKR1B10) in this process. This study is designed to understand how sublethal doses of chemotherapy drugs like taxol and doxorubicin lead to increased cancer cell migration, invasion, metastasis, and the consequent upregulation of AKR1B10. Our findings uncover the fact that AKR1B10 plays a crucial role in NSCLC progression and chemoresistance, with its increased expression being linked to enhanced malignancy. The results are significant for the research community as they provide insight into the currently paradoxical molecular mechanisms of chemotherapy-induced resistance in lung cancer. This could lead to the potential development of more effective treatment strategies that consider the impact of chemotherapy dosing on cancer cell behavior, potentially improving patient outcomes by preventing the unintentional enhancement of cancer aggressiveness. Chemotherapy remains a cornerstone in lung cancer treatment, yet emerging evidence suggests that sublethal low doses may inadvertently enhance the malignancy. This study investigates the paradoxical effects of sublethal low-dose chemotherapy on non-small-cell lung cancer (NSCLC) cells, emphasizing the role of Aldo-keto reductase family 1 member B10 (AKR1B10). We found that sublethal doses of chemotherapy unexpectedly increased cancer cell migration approximately 2-fold and invasion approximately threefold, potentially promoting metastasis. Our analysis revealed a significant upregulation of AKR1B10 in response to taxol and doxorubicin treatment, correlating with poor survival rates in lung cancer patients. Furthermore, silencing AKR1B10 resulted in a 1–2-fold reduction in cell proliferation and a 2–3-fold reduction in colony formation and migration while increasing chemotherapy sensitivity. In contrast, the overexpression of AKR1B10 stimulated growth rate by approximately 2-fold via ERK pathway activation, underscoring its potential as a target for therapeutic intervention. The reversal of these effects upon the application of an ERK-specific inhibitor further validates the significance of the ERK pathway in AKR1B10-mediated chemoresistance. In conclusion, our findings significantly contribute to the understanding of chemotherapy-induced adaptations in lung cancer cells. The elevated AKR1B10 expression following sublethal chemotherapy presents a novel molecular mechanism contributing to the development of chemoresistance. It highlights the need for strategic approaches in chemotherapy administration to circumvent the inadvertent enhancement of cancer aggressiveness. This study positions AKR1B10 as a potential therapeutic target, offering a new avenue to improve lung cancer treatment outcomes by mitigating the adverse effects of sublethal chemotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: The breakdown of glucose in the glycolytic pathway provides energy and essential building blocks to support cell division and growth in important body processes such as embryo development but also can promote disease pathologies including tumor formation. A family of enzymes called the PFKFBs are important regulators of this pathway, and the PFKFB3 family member plays a key role. Examining the functions of PFKFB3 in live animals is critical for fully understanding its role in glycolysis, and we have developed a new mouse model that can knock out PFKFB3 to evaluate these functions. In our studies, we have found that these mice have decreased PFKFB3 levels and activity and that knocking out PFKFB3 markedly impairs the growth of tumors that closely mimic human cancer. Our data establish a new and effective model for examining the regulation of glucose metabolism by PFKFB3 and highlight its importance in tumor growth. Rapidly proliferative processes in mammalian tissues including tumorigenesis and embryogenesis rely on the glycolytic pathway for energy and biosynthetic precursors. The enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) plays an important regulatory role in glycolysis by activating the key rate-limiting glycolytic enzyme, 6-phosphofructo-1-kinase (PFK-1). We have previously determined that decreased PFKFB3 expression reduced glycolysis and growth in transformed cells in vitro and suppressed xenograft growth in vivo. In earlier studies, we created a constitutive knockout mouse to interrogate the function of PFKFB3 in vivo but failed to generate homozygous offspring due to the requirement for PFKFB3 for embryogenesis. We have now developed a novel transgenic mouse model that exhibits inducible homozygous pan-tissue Pfkfb3 gene deletion (Pfkfb3fl/fl). We have induced Pfkfb3 genomic deletion in these mice and found that it effectively decreased PFKFB3 expression and activity. To evaluate the functional consequences of Pfkfb3 deletion in vivo, we crossed Cre-bearing Pfkfb3fl/fl mice with oncogene-driven tumor models and found that Pfkfb3 deletion markedly decreased their glucose uptake and growth. In summary, our studies reveal a critical regulatory function for PFKFB3 in glycolysis and tumorigenesis in vivo and characterize an effective and powerful model for further investigation of its role in multiple biological processes. [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB) is the most common and deadliest extracranial solid tumor in children. Targeting tumor-associated macrophages (TAMs) is a strategy for attenuating tumor-promoting states. The crosstalk between cancer cells and TAMs plays a pivotal role in mediating tumor progression in NB. The overexpression of Hexokinase-3 (HK3), a pivotal enzyme in glucose metabolism, has been associated with poor prognosis in NB patients. Furthermore, it correlates with the infiltration of M2-like macrophages within NB tumors, indicating its significant involvement in tumor progression. Therefore, HK3 not only directly regulates the malignant biological behaviors of tumor cells, such as proliferation, migration, and invasion, but also recruits and polarizes M2-like macrophages through the PI3K/AKT-CXCL14 axis in neuroblastoma. The secretion of lactate and histone lactylation alterations within tumor cells accompanies this interaction. Additionally, elevated expression of HK3 in M2-TAMs was found at the same time. Modulating HK3 within M2-TAMs alters the biological behavior of tumor cells, as demonstrated by our in vitro studies. This study highlights the pivotal role of HK3 in the progression of NB malignancy and its intricate regulatory network with M2-TAMs. It establishes HK3 as a promising dual-functional biomarker and therapeutic target in combating neuroblastoma. [ABSTRACT FROM AUTHOR]