Changes In Metabolic Activity Research Articles

Alveolar and Bone Marrow-derived Macrophages Differ in Metabolism and Glutamine Utilization.

Changes in metabolic activity are key regulators of macrophage activity. Pro-inflammatory macrophages upregulate glycolysis, which promotes an inflammatory phenotype, whereas pro-repair macrophages rely upon oxidative metabolism and glutaminolysis to support their activity. Work to understand how metabolism regulates macrophage phenotype has been done primarily in macrophage cell lines and bone marrow-derived macrophages (BMDM). Our study sought to understand changes in metabolic activity of murine tissue-resident alveolar macrophages (AM) in response to LPS stimulation and to contrast them to BMDM. These studies also determined the contribution of glutamine metabolism using the glutamine inhibitor, DON. We found that compared to BMDM, AM have higher rates of oxygen consumption and contain a higher concentration of intracellular metabolites involved in fatty acid oxidation. In response to LPS, BMDM but not AM increased rates of glycolysis. Inhibition of glutamine metabolism using DON altered the metabolic activity of AM but not BMDM. Within AM, glutamine inhibition led to increases in intracellular metabolites involved in glycolysis, the TCA cycle, fatty acid oxidation, and amino acid metabolism. Glutamine inhibition also altered the metabolic response to LPS within AM but not BMDM. Our data reveal striking differences in the metabolic activity of AM and BMDM.

ProcCluster® and procaine hydrochloride inhibit the growth of Aspergillus species and exert antimicrobial properties during coinfection with influenza A viruses and A. fumigatus in vitro.

Influenza-associated pulmonary aspergillosis is associated with high mortality rates and limited treatment options. The current standard practice involves treating each pathogen separately. However, the use of antifungal drugs can lead to serious side effects, and the presence of triazole-resistant Aspergillus strains can complicate antifungal therapy. In addition, drug-resistant influenza viruses are becoming an increasing concern in clinics. A drug that affects fungal and viral propagation could overcome these disadvantages. Thus, we conducted a study to examine the antifungal and antiviral properties of ProcCluster® and procaine hydrochloride (HCl), which are prodrugs derived from the local anesthetic procaine. Conidia of different A. fumigatus strains, A. flavus and A. terreus were treated with the test substances in a human cell-free system and antifungal properties were analyzed either by fluorescence microscopy or absorption measurements. Changes in metabolic activity and intracellular Ca2+ distribution during treatment of A. fumigatus with ProcCluster® were observed using fluorescence microscopy. In addition, antifungal and antiviral properties of ProcCluster® and procaine HCl were investigated during in vitro coinfection of lung epithelial cells with A. fumigatus and influenza A viruses (IAV). Analysis was performed by fluorescence microscopy, standard plaque assay and Western blot assay. Both substances inhibited the growth of the fungus, even when applied after germination or in the presence of purified IAV particles. ProcCluster® remained effective against triazole-resistant A. fumigatus strains. However, the addition of CaCl2 reversed the antifungal effect, indicating that ProcCluster® inhibited fungal growth by disrupting fungal Ca2+ homeostasis. Furthermore, in vitro studies showed that ProcCluster® and procaine HCl reduced the pathogen load of IAV and A. fumigatus during coinfection. Finally, the combination of ProcCluster® with the antiviral drug favipiravir exhibited increased antipathogenic activity, particularly against IAV replication. This research highlights ProcCluster® and procaine HCl as substances with anti-infective properties against various pathogens.

18 F-FDG PET Metabolic Parameters for the Prediction of Histological Response to Induction Chemotherapy in Osteosarcoma and Ewing Sarcoma : A Systematic Review and Network Meta-analysis.

This study aimed to evaluate the ability of 18 F-FDG PET/CT metabolic parameters to predict the histological response to neoadjuvant chemotherapy in patients with osteosarcoma and Ewing sarcoma. This systematic review and network meta-analysis adhered to the PRISMA-NMA and Cochrane guidelines. Electronic databases were searched from January 2008 to January 2024; this search was supplemented by snowballing methods. The risk of bias was evaluated with QUADAS-2, and evidence certainty was assessed using the GRADE approach. The prognostic value of 18 F-FDG PET/CT parameters, including pretreatment and posttreatment SUVs (SUV1, SUV2 and the SUV2/SUV1 ratio), metabolic tumor volume (MTV1, MTV2, ΔMTV), and total lesion glycolysis (TLG1, TLG2, ΔTLG), was examined. The meta-analysis of 18 studies (714 patients) identified the ΔTLG, ΔMTV, and SUV ratio as superior predictors of histological response. The changes in metabolic activity, as indicated by these parameters, provided a robust indication of treatment effectiveness. Baseline parameters showed limited predictive value compared with posttreatment assessments. The study's robustness was confirmed through meta-regression, which revealed that the predictive value of the SUV2 and SUV ratio was consistent across various cutoff thresholds. 18 F-FDG PET/CT metabolic parameters, particularly those measuring changes posttherapy, are effective in predicting the histological response in patients with osteosarcoma and Ewing sarcoma. These findings underscore the potential of 18 F-FDG PET/CT in guiding early treatment decisions, thereby enhancing personalized therapeutic approaches.

Ionic release from bioactive SiO2-CaOCME/poly(tetrahydrofuran)/poly(caprolactone) hybrids drives human-bone marrow stromal cell osteogenic differentiation

This study demonstrates that dissolution products of inorganic/organic SiO2-CaOCME/PTHF/PCL-diCOOH hybrid (70S30CCME-CL) drive human bone marrow stromal cells (h-BMSCs) down an osteogenic pathway with the production of mineralised matrix. We investigated osteogenesis through combined analyses of mRNA dynamics for key markers and targeted staining of mineralised matrix. We demonstrate that h-BMSCs undergo accelerated differentiation in vitro in response to the 70S30CCME-CL ionic milieu, as compared to incubation with osteogenic media. Extracts from 70S30CCME-CL promote osteogenesis by inducing changes in cellular metabolic activity, promoting changes in cell morphology consistent with the osteogenic lineage, and by enhancing mineralisation of hydroxyapatite in the extracellular matrix. Additionally, our results show that 70S30CCME-CL hybrids prove sustained functional resilience by maintaining osteostimulatory effects despite cumulated dissolution cycles. In co-differentiation medium, 70S30CCME-CL ionic release can modulate signalling pathways associated with non-osteogenic functions, further supporting their potential for bone regeneration applications. Overall, our study provides compelling experimental evidence that the 70S30CCME-CL hybrid is a promising biomaterial for bone tissue regeneration applications.

Characterization of acute effects of football competition on hamstring muscles by muscle functional MRI techniques.

Muscle functional MRI identifies changes in metabolic activity in each muscle and provides a quantitative index of muscle activation and damage. No previous studies have analyzed the hamstrings activation over a football match. This study aimed at detecting different patterns of hamstring muscles activation after a football game, and to examine inter- and intramuscular differences (proximal-middle-distal) in hamstring muscles activation using transverse relaxation time (T2)-weighted magnetic resonance images. Eleven healthy football players were recruited for this study. T2 relaxation time mapping-MRI was performed before (2 hours) and immediately after a match (on average 13 min). The T2 values of each hamstring muscle at the distal, middle, and proximal portions were measured. The primary outcome measure was the increase in T2 relaxation time value after a match. Linear mixed models were used to detect differences pre and postmatch. MRI examination showed that there was no obvious abnormality in the shape and the conventional T2 weighted signal of the hamstring muscles after a match. On the other hand, muscle functional MRI T2 analysis revealed that T2 relaxation time significantly increased at distal and middle portions of the semitendinosus muscle (p = 0.0003 in both cases). By employing T2 relaxation time mapping, we have identified alterations within the hamstring muscles being the semitendinosus as the most engaged muscle, particularly within its middle and distal thirds. This investigation underscores the utility of T2 relaxation time mapping in evaluating muscle activation patterns during football matches, facilitating the detection of anomalous activation patterns that may warrant injury reduction interventions.

Energetic Costs of Stress in Developing Fishes: Quantifying Allostasis and Allostatic Load.

Stress exerts negative effects on fish health through stimulation of the hypothalamic-pituitary-interrenal axis and autonomic nervous system, resulting in heightened neural and neuroendocrine responses. Energetic investment and physiological adaptation are then required to re-establish homeostatic stability or reach a new allostatic state. The cost of the energetic investment is referred to as allostatic load (AL). While determining the sources of stress and assessing their consequences have resulted in estimates of AL, most of this work has been conducted in adult mammals and humans; no ALs exist for developing fish. From a series of experiments on a model species, zebrafish (Danio rerio), whose yolk-sac larvae were exposed to two chronic stressors (high-temperature and hypoxia), ALs were quantified based on biomarkers of ontogenetic changes in growth, morphometrics, and metabolic activities. Results showed that for zebrafish yolk-sac larvae, chronic stress imposed high AL and, thus, high total allostatic energetic costs, (Rt (AL)), because of prolonged energy demand in the face of limited resources (e.g., yolk). Under severe chronic stress, energetic costs were sufficiently large that energy-limited developing fish may not be able to fully compensate, resulting in maladaptive responses from allostatic overload, leading either to death or to novel allostatic states, possibly more resilient to environmental change.

Estimating Enzyme Expression and Metabolic Pathway Activity in Borreliella-Infected and Uninfected Mice.

Evaluating changes in metabolic pathway activity is essential for studying disease mechanisms and developing new treatments, with significant benefits extending to human health. Here, we propose EMPathways2, a maximum likelihood pipeline that is based on the expectation-maximization algorithm, which is capable of evaluating enzyme expression and metabolic pathway activity level. We first estimate enzyme expression from RNA-seq data that is used for simultaneous estimation of pathway activity levels using enzyme participation levels in each pathway. We implement the novel pipeline to RNA-seq data from several groups of mice, which provides a deeper look at the biochemical changes occurring as a result of bacterial infection, disease, and immune response. Our results show that estimated enzyme expression, pathway activity levels, and enzyme participation levels in each pathway are robust and stable across all samples. Estimated activity levels of a significant number of metabolic pathways strongly correlate with the infected and uninfected status of the respective rodent types.

Acclimated green microalgae consortium to treat sewage in an alternative urban WWTP in a coastal area of Central Italy

This study exposed a microalgal consortium formed by Auxenochlorella protothecoides, Tetradesmus obliquus, and Chlamydomonas reinhardtii to six mixed wastewater media containing different proportions of primary (P) or secondary (S) effluents diluted in centrate (C). Algae could grow at centrate concentrations up to 50 %, showing no significant differences between effluents. After acclimation, microalgae cultivated in 50%P-50%C and 50%S-50%C grew at a rate similar to that of control cultures (0.59–0.66 d−1). These results suggest that the consortium acclimated to both sewage streams by modulating the proportion of the species and their metabolism. Acclimation also altered the photosynthetic activity of wastewater-grown samples compared to the control, probably due to partial photoinhibition, changes in consortium composition, and changes in metabolic activity. No major differences were observed between the two streams with respect to biochemical composition, biomass yield, or bioremediation capacity of the cultivated algae but algae grown in the secondary effluent showed qualitatively higher exopolysaccharides (EPS) production than algae grown in primary. Regarding wastewater remediation, microalgae grown in both WW media showed proficient nutrient removal efficiencies (close to 100 %); however, the final pH value (close to 11) would be controversial if the system were upscaled as it is over the legal limit and would cause phosphorus precipitation, so that CO2 addition would be required. The theoretical scale-up of the microalgae system could achieve water treatment costs of 0.109 €·m−3, which was significantly lower than the costs of typical activated sludge systems.

Supplementation of a High-Fat Diet with Pentadecylresorcinol Increases the Representation of Akkermansia muciniphila in the Mouse Small and Large Intestines and May Protect against Complications Caused by Imbalanced Nutrition.

Imbalanced nutrition, such as a high-fat/high-carbohydrate diet, is associated with negative effects on human health. The composition and metabolic activity of the human gut microbiota are closely related to the type of diet and have been shown to change significantly in response to changes in food content and food supplement administration. Alkylresorcinols (ARs) are lipophilic molecules that have been found to improve lipid metabolism and glycemic control and decrease systemic inflammation. Furthermore, alkylresorcinol intake is associated with changes in intestinal microbiota metabolic activity. However, the exact mechanism through which alkylresorcinols modulate microbiota activity and host metabolism has not been determined. In this study, alterations in the small intestinal microbiota (SIM) and the large intestinal microbiota (LIM) were investigated in mice fed a high-fat diet with or without pentadecylresorcinol (C15) supplementation. High-throughput sequencing was applied for jejunal and colonic microbiota analysis. The results revealed that C15 supplementation in combination with a high-fat diet could decrease blood glucose levels. High-throughput sequencing analysis indicated that C15 intake significantly increased (p < 0.0001) the abundance of the probiotic bacteria Akkermansia muciniphila and Bifidobacterium pseudolongum in both the small and large intestines and increased the alpha diversity of LIM (p < 0.05), but not SIM. The preliminary results suggested that one of the mechanisms of the protective effects of alkylresorcinol on a high-fat diet is the modulation of the content of SIM and LIM and metabolic activity to increase the probiotic bacteria that alleviate unhealthy metabolic changes in the host.

Overcoming the effects of fluid shear stress in ovarian cancer cell lines: Doxorubicin alone or photodynamic priming to target platinum resistance

AbstractResistance to platinum‐based chemotherapies remains a significant challenge in advanced‐stage high‐grade serous ovarian carcinoma, and patients with malignant ascites face the poorest outcomes. It is, therefore, important to understand the effects of ascites, including the associated fluid shear stress (FSS), on phenotypic changes and therapy response, specifically FSS‐induced chemotherapy resistance and the underlying mechanisms in ovarian cancer. This study investigated the effects of FSS on response to cisplatin, a platinum‐based chemotherapy, and doxorubicin, an anthracycline, both of which are commonly used to manage advanced‐stage ovarian cancer. Consistent with prior research, OVCAR‐3 and Caov‐3 cells cultivated under FSS demonstrated significant resistance to cisplatin. Examination of the role of mitochondria revealed an increase in mitochondrial DNA copy number and intracellular ATP content in cultures grown under FSS, suggesting that changes in mitochondria number and metabolic activity may contribute to platinum resistance. Interestingly, no resistance to doxorubicin was observed under FSS, the first such observation of a lack of resistance under these conditions. Finally, this study demonstrated the potential of photodynamic priming using benzoporphyrin derivative, a clinically approved photosensitizer that localizes in part to mitochondria and endoplasmic reticula, to enhance the efficacy of cisplatin, but not doxorubicin, thereby overcoming FSS‐induced platinum resistance.

Effects of natural flood management woody dams on benthic macroinvertebrates and benthic metabolism in upland streams: Importance of wood‐induced geomorphic changes

AbstractNatural Flood Management (NFM) aims to reduce flood hazard by working with nature and is gaining prominence worldwide. One particular NFM technique involves the use of channel‐spanning woody dams that maintain a clearance height above baseflow. These dams function by increasing channel roughness during high flows and by forcing excessive water onto the floodplain. Whether these dams provide additional benefits to nature remains unclear. While there are many existing studies on natural in‐stream wood structures, very few have documented the impact of NFM woody dams in particular. This study adopted a multidisciplinary approach and a Before–After Control–Impact (BACI) research design to assess whether NFM woody dams installed in a small upland catchment had driven changes in benthic macroinvertebrate assemblages and benthic metabolic activities through the geomorphic changes that they had created. Statistical results indicate that macroinvertebrate density, richness, and diversity did not show any difference between stream reaches with and without NFM woody dams. The metrics were generally not related to grain‐size parameters and volumes of sediments eroded or deposited. However, individual genera such as Baetis and Rhithrogena became more dominant in the control reach towards the end of the study period, likely due to the higher flow velocities and coarser sediments there resulting from the lack of flow resistance in the absence of NFM woody dams. Rates of benthic respiration (but not rates of photosynthesis) were consistently significantly higher in woody dam reaches than in control reaches, likely due to the presence of patches of finer sediments in the former.

Phenotypic and proteomic differences in biofilm formation of two Lactiplantibacillus plantarum strains in static and dynamic flow environments

Lactiplantibacillus plantarum is a Gram-positive non-motile bacterium capable of producing biofilms that contribute to the colonization of surfaces in a range of different environments. In this study, we compared two strains, WCFS1 and CIP104448, in their ability to produce biofilms in static and dynamic (flow) environments using an in-house designed flow setup. This flow setup enables us to impose a non-uniform flow velocity profile across the well. Biofilm formation occurred at the bottom of the well for both strains, under static and flow conditions, where in the latter condition, CIP104448 also showed increased biofilm formation at the walls of the well in line with the higher hydrophobicity of the cells and the increased initial attachment efficacy compared to WCFS1. Fluorescence and scanning electron microscopy showed open 3D structured biofilms formed under flow conditions, containing live cells and ∼30 % damaged/dead cells for CIP104448, whereas the WCFS1 biofilm showed live cells closely packed together. Comparative proteome analysis revealed minimal changes between planktonic and static biofilm cells of the respective strains suggesting that biofilm formation within 24 h is merely a passive process. Notably, observed proteome changes in WCFS1 and CIP104448 flow biofilm cells indicated similar and unique responses including changes in metabolic activity, redox/electron transfer and cell division proteins for both strains, and myo-inositol production for WCFS1 and oxidative stress response and DNA damage repair for CIP104448 uniquely. Exposure to DNase and protease treatments as well as lethal concentrations of peracetic acid showed highest resistance of flow biofilms. For the latter, CIP104448 flow biofilm even maintained its high disinfectant resistance after dispersal from the bottom and from the walls of the well. Combining all results highlights that L. plantarum biofilm structure and matrix, and physiological state and stress resistance of cells is strain dependent and strongly affected under flow conditions. It is concluded that consideration of effects of flow on biofilm formation is essential to better understand biofilm formation in different settings, including food processing environments.

Molecular mechanisms of cytochrome P450-mediated detoxification of tetraniliprole, spinetoram, and emamectin benzoate in the fall armyworm, Spodoptera frugiperda (J.E. Smith).

The fall armyworm (FAW) Spodoptera frugiperda (J.E. Smith) is a highly damaging invasive omnivorous pest that has developed varying degrees of resistance to commonly used insecticides. To investigate the molecular mechanisms of tolerance to tetraniliprole, spinetoram, and emamectin benzoate, the enzyme activity, synergistic effect, and RNA interference were implemented in S. frugiperda. The functions of cytochrome P450 monooxygenase (P450) in the tolerance to tetraniliprole, spinetoram, and emamectin benzoate in S. frugiperda was determined by analysing changes in detoxification metabolic enzyme activity and the effects of enzyme inhibitors on susceptibility to the three insecticides. 102 P450 genes were screened via transcriptome and genome, of which 67 P450 genes were differentially expressed in response to tetraniliprole, spinetoram, and emamectin benzoate and validated by quantitative real-time PCR. The expression patterns of CYP9A75, CYP340AA4, CYP340AX8v2, CYP340L16, CYP341B15v2, and CYP341B17v2 were analysed in different tissues and at different developmental stages in S. frugiperda. Silencing CYP340L16 significantly increased the susceptibility of S. frugiperda to tetraniliprole, spinetoram, and emamectin benzoate. Furthermore, knockdown of CYP340AX8v2, CYP9A75, and CYP341B17v2 significantly increased the sensitivity of S. frugiperda to tetraniliprole. Knockdown of CYP340AX8v2 and CYP340AA4 significantly increased mortality of S. frugiperda to spinetoram. Knockdown of CYP9A75 and CYP341B15v2 significantly increased the susceptibility of S. frugiperda to emamectin benzoate. These results may help to elucidate the mechanisms of tolerance to tetraniliprole, spinetoram and emamectin benzoate in S. frugiperda.

Labile assembly of a tardigrade protein induces biostasis.

Tardigrades are microscopic animals that survive desiccation by inducing biostasis. To survive drying tardigrades rely on intrinsically disordered CAHS proteins, which also function to prevent perturbations induced by drying in vitro and in heterologous systems. CAHS proteins have been shown to form gels both in vitro and in vivo, which has been speculated to be linked to their protective capacity. However, the sequence features and mechanisms underlying gel formation and the necessity of gelation for protection have not been demonstrated. Here we report a mechanism of fibrillization and gelation for CAHS D similar to that of intermediate filament assembly. We show that in vitro, gelation restricts molecular motion, immobilizing and protecting labile material from the harmful effects of drying. In vivo, we observe that CAHS D forms fibrillar networks during osmotic stress. Fibrillar networking of CAHS D improves survival of osmotically shocked cells. We observe two emergent properties associated with fibrillization; (i) prevention of cell volume change and (ii) reduction of metabolic activity during osmotic shock. We find that there is no significant correlation between maintenance of cell volume and survival, while there is a significant correlation between reduced metabolism and survival. Importantly, CAHS D's fibrillar network formation is reversible and metabolic rates return to control levels after CAHS fibers are resolved. This work provides insights into how tardigrades induce reversible biostasis through the self-assembly of labile CAHS gels.

Analysis of pharmacokinetic profile and ecotoxicological character of cefepime and its photodegradation products

An important problem is the impact of photodegradation on product toxicity in biological tests, which may be complex and context-dependent. Previous studies have described the pharmacology of cefepime, but the toxicological effects of its photodegradation products remain largely unknown. Therefore, photodegradation studies were undertaken in conditions similar to those occurring in biological systems insilico, in vitro, in vivo and ecotoxicological experiments. The structures of four cefepime photodegradation products were determined by UPLC-MS/MS method. The calculated in silico ADMET profile indicates that carcinogenic potential is expected for compounds CP-1, cefepime, CP-2 and CP-3. The Cell Line Cytomotovity Predictor 2.0 tool was used to predict the cytotoxic effects of cefepime and related compounds in non-transformed and cancer cell lines. The results indicate that possible actions include: non-small cell lung cancer, breast adenocarcinoma, prostate cancer and papillary renal cell carcinoma. OPERA models were used to predict absorption, distribution, metabolism and excretion (ADME) endpoints, and potential bioactivity of CP-2, cefepime and CP-4. The results obtained in silico show that after 96h of exposure, cefepime, CP-1, CP-2, and CP-3 are moderately toxic in the zebrafish model, while CP-4 is highly toxic. On the contrary, cefepime is more toxic to T. platyurus (highly toxic) compared to the zebrafish model, similar to products CP-4, CP-3 and CP-2. In vitro cytotoxicity studies were performed by MTT assay and in vivo acute embryo toxicity studies using Danio rerio embryos and larvae. In vitro showed an increase in the cytotoxicity of products with the longest exposure period i.e. for 8 h. Additionally, at a concentration of 200 μg/mL, statistically significant changes in metabolic activity were observed depending on the irradiation time. In vivo studies conducted with Zebrafish showed that both cefepime and its photodegradation products have only low toxicity. Assessment of potential ecotoxicity included Microbiotests on invertebrates (Thamnotoxkit F and Daphtoxkit F), and luminescence inhibition tests (LumiMara). The observed toxicity of the tested solutions towards both Thamnocephalus platyurus and Daphnia magna indicates that the parent substance (unexposed) has lower toxicity, which increases during irradiation. The acute toxicity (Lumi Mara) of nonirradiated cefepime solution is low for all tested strains (<10%), but mixtures of cefepime and its photoproducts showed growth inhibition against all tested strains (except #6, Photobacterium phoreum). Generally, it can be concluded that after UV–Vis irradiation, the mixture of cefepime phototransformation products shows a significant increase in toxicity.

Research on the Application and Mechanisms of Electroactive Microorganisms in Toxicants Monitoring: A Review.

A biological treatment is the core process for removing organic pollutants from industrial wastewater. However, industrial wastewater often contains large amounts of toxic and harmful pollutants, which can inhibit the activity of microorganisms in a treatment system, precipitate the deterioration of effluent quality, and threaten water ecological security from time to time. In most of the existing anaerobic biological treatment processes, toxic effects on microorganisms are determined according to the amounts of end-products of the biochemical reactions, and the evaluation results are relatively lacking. When microorganisms contact toxic substances, changes in biological metabolic activity precede the accumulation of reaction products. As sensitive units, electroactive microorganisms can generate electrical signals, a change in which can directly reflect the toxicity level. The applications of electroactive microorganisms for the toxicity monitoring of wastewater are very promising. Further attention needs to be paid to considering the appropriate evaluation index, the influence of the environment on test results, mechanisms, and other aspects. Therefore, we reviewed the literature regarding the above aspects in order to provide a research foundation for the practical application of electroactive microorganisms in toxicant monitoring.

The maturity, humus content, and microbial metabolic function of sheep manure compost on the Qinghai-Tibet Plateau can be significantly improved by reducing the moisture content.

The Qinghai-Tibet Plateau (QTP) is characterized by an extreme hypoxia, which may lead to lack of sufficient oxygen for compost production, and thus seriously affecting the compost quality. The moisture content (MC) has a direct effect on the oxygen content of composting pile. At present, the research on the optimum moisture content of compost production on the QTP is still lacking. This study aimed to investigate the influences of MC on fermentation quality of sheep manure composting on the QTP and to further analyze the changes of microbial metabolic function and enzyme activity under different MC. Composting experiment with low MC (45%) and conventional MC (60%) was conducted in both summer and autumn. The results showed that the composting efficiency of 45% MC was better than 60% in both seasons, which was mainly manifested as longer high-temperature period (summer:16d vs 14d, autumn: 7d vs 2d), higher germination index (summer:136.1% vs 128.6%, autumn:103.5% vs 81.2%), and more humus synthesis (summer:159.8g/kg vs 151.2g/kg, autumn:136.1k/kg vs 115.5k/kg). The 45% MC can improve microbial metabolism, including increasing the abundance of functional genes involved in carbohydrate metabolism, amino acid metabolism, and nucleotide metabolism and improving the activities of cellulase, β-glucosidase, protease, polyphenol oxidase, and peroxidase. In conclusion, 45% MC can improve the fermentation efficiency and products quality of sheep manure compost on QTP.

Monitoring drug metabolic pathways through extracellular vesicles in mouse plasma.

The ability to monitor the response of metabolic enzymes to drug exposure in individuals is highly appealing and critical to personalized medicine. Although pharmacogenomics assesses genotypic differences, it does not report changes in metabolic enzyme activities due to environmental factors such as drug interactions. Here, we report a quantitative proteomics strategy to monitor drug metabolic pathways by profiling metabolic enzymes in circulating extracellular vesicles (EVs) upon drug exposure. Mass spectrometry (MS)-based measurement revealed that changes in metabolic enzyme abundance in EVs paralleled those in hepatic cells isolated from liver tissue. Coupling with multiplexed isotopic labeling, we temporally quantified 34 proteins involved in drug absorption, distribution, metabolism, and excretion (ADME) pathways. Out of 44 known ADME proteins in plasma EVs, previously annotated mouse cytochrome P450 3A11 (Cyp3a11), homolog to human CYP3A4, and uridine 5'-diphospho (UDP) glucuronosyltransferase 2A3 (Ugt2a3), increased upon daily rifampicin dosage. Dasatinib, a tyrosine kinase inhibitor to treat leukemia, also elevated Cyp3a11 levels in plasma EVs, but to a lesser extent. Altogether, this study demonstrates that measuring drug enzymes in circulating EVs as an effective surrogate is highly feasible and may transform today's drug discovery and development for personalized medicine.

Revving the engine: PKB/AKT as a key regulator of cellular glucose metabolism.

Glucose metabolism is of critical importance for cell growth and proliferation, the disorders of which have been widely implicated in cancer progression. Glucose uptake is achieved differently by normal cells and cancer cells. Even in an aerobic environment, cancer cells tend to undergo metabolism through glycolysis rather than the oxidative phosphorylation pathway. Disordered metabolic syndrome is characterized by elevated levels of metabolites that can cause changes in the tumor microenvironment, thereby promoting tumor recurrence and metastasis. The activation of glycolysis-related proteins and transcription factors is involved in the regulation of cellular glucose metabolism. Changes in glucose metabolism activity are closely related to activation of protein kinase B (PKB/AKT). This review discusses recent findings on the regulation of glucose metabolism by AKT in tumors. Furthermore, the review summarizes the potential importance of AKT in the regulation of each process throughout glucose metabolism to provide a theoretical basis for AKT as a target for cancers.

The Potential Transcriptomic and Metabolomic Mechanisms of ATO and ATRA in Treatment of FLT3-ITD Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) with Fms-like tyrosine kinase 3 gene internal tandem duplication (FLT3-ITD) mutations has a poor prognosis. The combination of arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) has a synergistic killing effect on leukemia cells with FLT3-ITD mutation. However, the mechanism, especially the changes of gene expression and metabolic activity remain unclear. Here we explore the transcriptome and metabolomics changes of FLT3-ITD AML cells treated with ATO/ATRA. RNA-seq was used to identify differential expressed genes (DEGs), and ultra-high performance liquid chromatography-quadrupole electrostatic field orbital trap mass spectrometry (UHPLC-QE-MS) nontargeted metabolomics method was used to screen out the differential metabolites in FLT3-ITD mutant cell lines treated with ATRA and ATO. KEGG pathway database was utilized for pathway exploration and Seahorse XF24 was used to detect extracellular acidification rate (ECAR). Metabolic polymerase chain reaction (PCR) array and real-time quantitative PCR (RT-qPCR) were used to detect mRNA levels of key metabolic genes of glycolysis and fatty acid after drug treatment. A total of 3873 DEGs were identified and enriched in 281 Gene Ontology (GO) terms, among which 210 were related to biological processes, 43 were related to cellular components, and 28 were related to molecular functions. Besides, 1794 and 927 differential metabolites were screened in positive and negative ion mode separately, and 59 different metabolic pathways were involved, including alanine-aspartate-glutamate metabolic pathway, arginine, and proline metabolic pathway, glycerophospholipid metabolic pathways, etc. According to KEGG Pathway analysis of transcriptome combined with metabolome, glycolysis/gluconeogenesis pathway and fatty acid metabolism pathway were significantly founded enriched. ATRA + ATO may inhibit the glycolysis of FLT3-ITD AML cells by inhibiting FLT3 and its downstream AKT/HK2-VDAC1 signaling pathway. The gene transcription profile and metabolites of FLT3-ITD mutant cells changes significantly after treatment, which might be related to the anti-FLT3-ITD AML effect. The screened DEGs, differential metabolites pathway are helpful in studying the mechanism of anti-leukemia effects and drug targets.