Integration of microbiome, metabolomics and transcriptome for in-depth understanding of berberine attenuates AOM/DSS-induced colitis-associated colorectal cancer.

A type of colorectal cancer (CRC)，Colitis-associated colorectal cancer (CAC)， is closely associated with chronic inflammation and gut microbiota dysbiosis. Berberine (BBR) has a long history in the treatment of intestinal diseases, which has been reported to inhibit colitis and CRC. However, the mechanism of its action is still unclear. Here, this study aimed to explore the potential protective effects of BBR on azoxymethane (AOM)/dextransulfate sodium (DSS)-induced colitis and tumor mice, and to elucidate its potential molecular mechanisms by microbiota, genes and metabolic alterations. The results showed that BBR inhibited the gut inflammation and improved the function of mucosal barrier to ameliorate AOM/DSS-induced colitis. And BBR treatment significantly reduced intestinal tumor development and ki-67 expression of intestinal tissue along with promoted apoptosis. Through microbiota analysis based on the 16 S rRNA gene, we found that BBR treatment improved intestinal microbiota imbalance in AOM/DSS-induced colitis and tumor mice, which were characterized by an increase of beneficial bacteria, for instance Akkermanisa, Lactobacillus, Bacteroides uniformis and Bacteroides acidifaciens. In addition, transcriptome analysis showed that BBR regulated colonic epithelial signaling pathway in CAC mice particularly by tryptophan metabolism and Wnt signaling pathway. Notably, BBR treatment resulted in the enrichment of amino acids metabolism and microbiota-derived SCFA metabolites. In summary, our research findings suggest that the gut microbiota-amino acid metabolism-Wnt signaling pathway axis plays critical role in maintaining intestinal homeostasis, which may provide new insights into the inhibitory effects of BBR on colitis and colon cancer.

Endothelial specific LAT1 ablation normalizes tumor vasculature.

Some endothelial cells in the tumor vasculature expressed a system L amino acid transporter LAT1. To elucidate the role of LAT1 in tumor related endothelial cells, tumor cells were injected into endothelial specific LAT1 conditional knockout mice (Slc7a5flox/flox; Cdh5-Cre-ERT2) and found that the shape of the tumor vasculature was normalized and that the size and numbers of lung metastasis was reduced. TNFα-induced expression of VCAM1 and E-selectin at the surface of HUVEC, both of which are responsible for enhanced monocyte attachment and pre-metastatic niche formation, was reduced in the presence of LAT1 inhibitor, nanvuranlat. Deprivation of tryptophan, an LAT1 substrate, mimicked LAT1 inhibition, which led to activation of MEK1/2-ERK1/2 pathway and subsequent cystathionine γ lyase (CTH) induction. Increased production of hydrogen sulfide (H2S) by CTH was at least partially responsible for tumor vascular normalization, leading to decreased leakiness and enhanced delivery of chemotherapeutic agents to the tumor.

ABCC2 induces metabolic vulnerability and cellular ferroptosis via enhanced glutathione efflux in gastric cancer.

BACKGROUND: Although it is traditionally believed that ATP binding cassette subfamily C member 2 (ABCC2) is a multidrug resistance-associated protein correlated with a worse prognosis, our previous and several other studies demonstrated the contrary to be true in gastric cancer (GC). We aim to explore the underlying mechanism of this discovery. METHODS: Our study utilized whole-exome sequencing (WES), RNA sequencing, and droplet digital PCR (ddPCR) analysis of 80 gastric cancer samples, along with comprehensive immunohistochemical (IHC) analysis of 1044 human GC tissue samples.By utilizing CRISPRCas9 to genetically modify cell lines with the ABCC2-24C > T (rs717620) point mutation and conducting dual-luciferase reporter assays, we identified that transcription factors SOX9 and ETS1 serve as negative regulators of ABCC2 expression. Seahorse assay and mass spectrometry were used to discover altered metabolic patterns. Gain and loss-of-function experiments in GC cell lines and preclinical models were carried out to validate ABCC2 biological function. RESULTS: ABCC2 high expression correlated with better prognosis, and rs717620 can influence ABCC2 expression by disrupting the binding of ETS1 and SOX9. Gain and loss-of-function experiments in GC cell lines demonstrated amino acid deprivation reduces proliferation, migration, and drug resistance in ABCC2-high GC cells. ABCC2 leads to reduced intracellular amino acid pools and disruption of cellular energy metabolism. This phenomenon depended on ABCC2-mediated GSH extrusion, resulting in alterations in redox status, thereby increasing the cell's susceptibility to ferroptosis. Furthermore, patient-derived organoids and patient-derived tumor-like cell clusters were used to observe impact of ABCC2 on therapeutic effect. In the xenograft model with high ABCC2 expression, we observed that constricting amino acid intake in conjunction with GPX4 inactivation resulted in notable tumor regression. CONCLUSIONS: Our findings demonstrate a significant role of ABCC2 in amino acid metabolism and ferroptosis by mediating GSH efflux in GC. This discovery underlines the potential of combining multiple ferroptosis targets as a promising therapeutic strategy for GC with high ABCC2 expression. HIGHLIGHTS: ABCC2 plays a crucial role in inducing metabolic vulnerability and ferroptosis in gastric cancer through enhanced glutathione efflux. The ABCC2 24C > T polymorphism is a key factor influencing its expression. These results highlight the potential of ABCC2 as a predictive biomarker and therapeutic target in gastric cancer.

Targeting dysregulated intracellular immunometabolism within synovial microenvironment in rheumatoid arthritis with natural products.

Immunometabolism has been an emerging hotspot in the fields of tumors, obesity, and atherosclerosis in recent decades, yet few studies have investigated its connection with rheumatoid arthritis (RA). In principle, intracellular metabolic pathways upstream regulated by nutrients and growth factors control the effector functions of immune cells. Dynamic communication and hypermetabolic lesions of immune cells within the inflammatory synovial microenvironment contributes to the development and progression of RA. Hence, targeting metabolic pathways within immune subpopulations and pathological cells may represent novel therapeutic strategies for RA. Natural products constitute a great potential treasury for the research and development of novel drugs targeting RA. Here, we aimed to delineate an atlas of glycolysis, lipid metabolism, amino acid biosynthesis, and nucleotide metabolism in the synovial microenvironment of RA that affect the pathological processes of synovial cells. Meanwhile, therapeutic potentials and pharmacological mechanisms of natural products that are demonstrated to inhibit related key enzymes in the metabolic pathways or reverse the metabolic microenvironment and communication signals were discussed and highlighted.

Effect of biochar addition on the anaerobic digestion of food waste: microbial community structure and methanogenic pathways.

This study assessed the effects of the addition of biochar prepared at 700 °C with different dosages on the anaerobic digestion of food waste. The biochar addition at a concentration of 10.0 g/L increased the cumulative methane yield by 128%, and daily methane production was also significantly promoted. The addition of biochar derived from poplar sawdust significantly increased the relative abundance of dominant bacteria for anaerobic digestion by 85.54-2530% and promoted the degradation of refractory organic matter and the transfer of materials between the hydrolysis and acid production stages. Further analysis has demonstrated that Bathyarchaeia and hydrogenotrophic methanogens were enriched by the biochar addition. Meanwhile, the relative abundances of functional genes, including C5-branched dibasic acid metabolism, and pyruvate metabolism, were increased by 11.38-26.27%. The relative abundances of genes related to major amino acid metabolism, including histidine metabolism, lysine biosynthesis, and phenylalanine, tyrosine, and tryptophan biosynthesis, were increased by 11.96-15.71%. Furthermore, the relative abundances of genes involved in major replication and repair were increased by 14.76-22.76%, and the major folding, sorting, degradation, and translation were increased by 14.47-19.95%, respectively. The relative abundances of genes related to major membrane transport and cell motility were increased by 10.02 and 83.09%, respectively.

Serum metabolome analysis reveals medicinal fungi Phellinus igniarius ameliorated type 2 diabetes mellitus indications in rats via modulation of amino acid and carbohydrate metabolism.

Medicinal fungi Phellinus igniarius exhibited hypoglycemic effects; however, the protective mechanisms of P. igniarius on type 2 diabetes are not yet fully understood. Herein, the anti-diabetic effect of P. igniarius was investigated via gas chromatography-mass spectrometry (GC/MS)-based metabolome analysis. The rats were divided into normal group; model group; positive group; and groups treated with low, medium, and high dose of P. igniarius. After the treatments, a significant decrease in blood glucose concentration was observed. The levels of total cholesterol and triglyceride were dramatically decreased, whereas the level of insulin was increased. Multivariate statistical analysis revealed 31 differential endogenous metabolites between model group and normal group. A total of 14, 28, and 31 biomarkers were identified for low, medium, and high dose of P. igniarius treated groups, respectively. Twenty-one of the biomarkers were validated by using standard substances. The linear correlation coefficients ranged from 0.9990 to 1.0000. The methodology exhibited good repeatability, recoveries, and stability. The major intervened metabolic pathways covered glyoxylate and dicarboxylic acid metabolism; alanine, aspartate, and glutamate metabolism; and glycine, serine, and threonine metabolism. Our metabolome analysis has provided insights into the underlying mechanism of P. igniarius on type 2 diabetes.

Breastfeeding in PKU and Other Amino Acid Metabolism Disorders-A Single Centre Experience.

In addition to the numerous immunological and nutritional benefits that breast milk offers to infants, its proportion in the diet must be limited or even excluded in the case of inborn errors of amino acid metabolism (IEM). The objective of the study was to expand knowledge about breastfeeding and the degree of contribution of breast milk to the feeding of infants with IEM before and after the introduction of expanded newborn screening. A retrospective single-centre study was conducted on 127 infants born between 1997 and 2020: 66 with phenylketonuria (PKU), 45 with other IEM (non-PKU), all diagnosed through newborn screening (NBS), and 16 non-PKU diagnosed through selective screening (SS). The time of initiation of dietary treatment and the proportion of breast milk in the diet, both expressed and breastfed, with or without intake control, were analysed at 1, 3, and 6 months after birth. For 47% of the newborns in Groups 1 and 2, the dietary treatment was started before the 10th day of life; in Group 3, the dietary treatment was started after the 10th day of life for all children. During the first month of life, the proportion of infants receiving breast milk was higher in the NBS-PKU (74%) and the NBS non-PKU (80%) groups, compared with 38% in the SS non-PKU infants. In the subsequent months of life, the proportion of infants receiving human milk (either from the breast or a bottle) declined in all groups. This decline occurred more in bottle-fed rather than directly breast-fed infants. Our observations indicate that the model of feeding from a bottle with expressed milk may have had an adverse effect on maintaining lactation and may have contributed to a faster transition to formula milk. Maintaining lactation and extending the period of feeding the infant with human milk in the first 6 months of life is possible by breastfeeding on demand, under regular biochemical monitoring: preferably weekly in PKU infants, and at least every 2-4 weeks in infants with other IEM.

Explore the mechanisms of triterpenoids from Ganoderma lucidum in the protection against Alzheimer's disease via microbiota-gut-brain axis with the aid of network pharmacology.

Ganoderma lucidum (Curtis) P. Karst.(G. lucidum) is a kind of fungi, which also a traditional Chinese medicine used for "wisdom growth" in China. Triterpenoids from G. lucidum (GLTs) are one of the main active ingredients. Based on the strategy of early intervention on Alzheimer's disease (AD) and the inextricable association between disordered gut microbiota and metabolites with AD, this study aimed to explore the mechanisms of GLTs in the protection against AD via microbiota-gut-brain axis with the aid of network pharmacology. In this study, LC-MS/MS was used to identify the main active ingredients of GLTs. Network pharmacology was used to predict the potential target and validated with Caco-2 cell model. D-galactose was used to induce the slow-onset AD on rats. Metabolomics methods basing on GC-MS combined with 16S rRNA sequencing technology was used to carry out microbiota-gut-metabolomics analysis in order to reveal the potential mechanisms of GLTs in the protection of AD. As results, GLTs showed a protection against AD effect on rats by intervening administration. The mechanisms were inextricably linked to GLTs interference with the balance of gut microbiota and metabolites. The main fecal metabolites involved were short-chain fatty acids and aromatic amino acid metabolites.

Amino acid metabolic reprogramming in the tumor microenvironment and its implication for cancer therapy.

Amino acids are essential building blocks for proteins, crucial energy sources for cell survival, and key signaling molecules supporting the resistant growth of tumor cells. In tumor cells, amino acid metabolic reprogramming is characterized by the enhanced uptake of amino acids as well as their aberrant synthesis, breakdown, and transport, leading to immune evasion and malignant progression of tumor cells. This article reviews the altered amino acid metabolism in tumor cells and its impact on tumor microenvironment, and also provides an overview of the current clinical applications of amino acid metabolism. Innovative drugs targeting amino acid metabolism hold great promise for precision and personalized cancer therapy.

Molecular mechanisms and drug therapy of metabolism disorders in psoriasis.

Psoriasis is a prevalent skin disease affecting approximately 1%-3% of the population and imposes significant medical, social and economic burdens. Psoriasis involves multiple organs and is often complicated with obesity, diabetes, dyslipidemia, and hypertension. Because of the benefits of lipid-lowering agents and antidiabetic medications for psoriasis, metabolic abnormalities possibly play a pathogenic role in psoriasis.This review focuses on the impacts of a variety of metabolic disorders on psoriasis and the underlying mechanisms.In psoriasis, enhanced glycolysis, glutamine metabolism and altered fatty acid composition in the psoriatic lesion and plasma result in the excessive proliferation of keratinocytes and secretion of inflammatory cytokines. Altered metabolism is associated with the activation of MTORC signaling pathway and transcription factors such as HIF and S6K1. Therefore, MTORC1 can be a target for the treatment of psoriasis. Additionally, there are diabetes drugs and lipid-lowering drugs including TZDs, GLP-1 RAs, Metformin, statins and fibrates, which improve both metabolic levels and psoriasis symptoms.

A novel amino acid metabolism-related gene signature to predict the overall survival of esophageal squamous cell carcinoma patients.

Background: Esophageal squamous cell carcinoma (ESCC) has a poor early detection rate, prognosis, and survival rate. Effective prognostic markers are urgently needed to assist in the prediction of ESCC treatment outcomes. There is accumulating evidence of a strong relationship between cancer cell growth and amino acid metabolism. This study aims to determine the relationship between amino acid metabolism and ESCC prognosis. Methods: This study comprehensively evaluates the association between amino acid metabolism-related gene (AAMRG) expression profiles and the prognosis of ESCC patients based on data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to verify the expression of prognosis-related genes. Results: A univariate Cox regression analysis of TCGA data identified 18 prognosis-related AAMRGs. The gene expression profiles of 90 ESCC tumor and normal tissues were obtained from the GSE20347 and GSE67269 datasets. Two differently expressed genes (DEGs) were considered as ESCC prognosis-related genes; and they were branched-chain amino acid transaminase 1 (BCAT1) and methylmalonic aciduria and homocystinuria type C protein (MMACHC). These two AAMRGs were used to develop a novel AAMRG-related gene signature to predict 1- and 2-year prognostic risk in ESCC patients. Both BCAT1 and MMACHC expression were verified by RT-qPCR. A prognostic nomogram that incorporated clinical factors and BCAT1 and MMACHC gene expression was constructed, and the calibration plots showed that it had good prognostic performance. Conclusions: The AAMRG signature established in our study is efficient and could be used in clinical settings to predict the early prognosis of ESCC patients.

Therapeutic effects of Lingguizhugan decoction in a rat model of high-fat diet-induced insulin resistance.

BACKGROUND: Lingguizhugan (LGZG) decoction is a widely used classic Chinese medicine formula that was recently shown to improve high-fat diet (HFD)-induced insulin resistance (IR) in animal studies. AIM: To assess the therapeutic effect of LGZG decoction on HFD-induced IR and explore the potential underlying mechanism. METHODS: To establish an IR rat model, a 12-wk HFD was administered, followed by a 4-wk treatment with LGZG. The determination of IR status was achieved through the use of biochemical tests and oral glucose tolerance tests. Using a targeted meta-bolomics platform to analyze changes in serum metabolites, quantitative real-time PCR (qRT-PCR) was used to assess the gene expression of the ribosomal protein S6 kinase beta 1 (S6K1). RESULTS: In IR rats, LGZG decreased body weight and indices of hepatic steatosis. It effectively controlled blood glucose and food intake while protecting islet cells. Metabolite analysis revealed significant differences between the HFD and HFD-LGZG groups. LGZG intervention reduced branched-chain amino acid levels. Levels of IR-related metabolites such as tryptophan, alanine, taurine, and asparagine decreased significantly. IR may be linked to amino acids due to the contemporaneous increase in S6K1 expression, as shown by qRT-PCR. CONCLUSIONS: Our study strongly suggests that LGZG decoction reduces HFD-induced IR. LGZG may activate S6K1 via metabolic pathways. These findings lay the groundwork for the potential of LGZG as an IR treatment.

Effect of Dietary Crude Protein and Apparent Metabolizable Energy Levels on Growth Performance, Nitrogen Utilization, Serum Parameter, Protein Synthesis, and Amino Acid Metabolism of 1- to 10-Day-Old Male Broilers.

This research compared how different levels of dietary crude protein (CP) and apparent metabolizable energy (AME) affect the growth performance, nitrogen utilization, serum parameters, protein synthesis, and amino acid (AA) metabolism in broilers aged 1 to 10 days. In a 4 × 3 factorial experimental design, the broilers were fed four levels of dietary CP (20%, 21%, 22%, and 23%) and three levels of dietary AME (2800 kcal/kg, 2900 kcal/kg, and 3000 kcal/kg). A total of 936 one-day-old male Arbor Acres broilers were randomly allocated to 12 treatments with 6 replications each. Growth performance, nitrogen utilization, serum parameter, gene expression of protein synthesis, and AA metabolism were evaluated at 10 d. The results revealed no interaction between dietary CP and AME levels on growth performance (p > 0.05). However, 22% and 23% CP enhanced body weight gain (BWG), the feed conversion ratio (FCR), total CP intake, and body protein deposition but had a detrimental effect on the protein efficiency ratio (PER) compared to 20% or 21% CP (p < 0.05). Broilers fed diets with 2800 kcal/kg AME showed increased feed intake (FI) and inferior PER (p < 0.05). Broilers fed diets with 3000 kcal/kg AME showed decreased muscle mRNA expression of mammalian target of the rapamycin (mTOR) and Atrogin-1 compared to those fed diets with 2800 kcal/kg and 2900 kcal/kg AME (p < 0.05). Increasing dietary CP level from 20% to 23% decreased muscle mTOR and increased S6K1 mRNA expression, respectively (p < 0.05). The muscle mRNA expression of Atrogin-1 was highest for broilers fed 23% CP diets (p < 0.05). The mRNA expression of betaine homocysteine methyltransferase (BHMT) and Liver alanine aminotransferase of the 22% and 23% CP groups were higher than those of 20% CP (p < 0.05). Significant interactions between dietary CP and AME levels were observed for muscle AMPK and liver lysine-ketoglutarate reductase (LKR) and branched-chain alpha-keto acid dehydrogenase (BCKDH) mRNA expression (p < 0.05). Dietary AME level had no effect on muscle AMPK mRNA expression for broilers fed 21% and 22% CP diets (p > 0.05), whereas increasing dietary AME levels decreased AMPK mRNA expression for broilers fed 23% CP diets (p < 0.05). The mRNA expression of LKR and BCKDH was highest for broilers fed the diet with 2800 kcal/kg AME and 22% CP, while it was lowest for broilers fed the diet with 3000 kcal/kg AME and 20% CP. The findings suggest that inadequate energy density hindered AA utilization for protein synthesis, leading to increased AA catabolism for broilers aged 1 to 10 days, and a dietary CP level of 22% and an AME level of 2900 to 3000 kcal/kg may be recommended based on performance and dietary protein utilization.

Activating the iNOS regulatory pathway by arginine deprivation targets energy metabolism to induce autophagy-dependent apoptosis against spinal echinococcosis.

Spinal echinococcosis is one of the most overlooked zoonotic parasitic diseases worldwide. There is currently no safe and effective treatment to eradicate it, and research based on the physiological-metabolic signature of the disease is lacking. Herein, we repurposed agrimol B as a potent anti-hydatid compound and validated its pharmacological mechanism based on arginine uptake as a target through multi-omics sequencing. This herbal component suppressed energy metabolism and activated ROS aggregation by inducing mitochondrial membrane potential depolarization, which subsequently triggered autophagy-dependent apoptosis leading to parasite death. Moreover, we discovered that arginine deprivation induced metabolic changes led to a shift from ornithine to nitrogen oxide synthesis, thus boosting the iNOS enzyme-regulated dominant metabolic pathway. The excess NO targeted the mitochondrial respiratory chain complex IV to disrupt energy metabolic homeostasis and induced a downstream pathological waterfall effect to kill the hydatid. A novel metabolic regulatory mechanism targeting mitochondrial damage for arginine starvation therapy was discovered. Finally, arginine depletion was found to be superior to the anti-spinal echinococcosis effect of albendazole and accompanied by the potential for disc protection. This study unveils the role of arginine in the physiological metabolism of Echinococcus granulosus and reveals the value of targeting arginine metabolism as a potential therapy. In addition, agrimol B is proposed as a promising therapeutic strategy for spinal echinococcosis to block arginine uptake and break this parasite's metabolic balance.

Deceased donor kidney function and branched chain amino acid metabolism during ex vivo normothermic perfusion.

Current kidney perfusion protocols are not optimized for addressing the ex vivo physiological and metabolic needs of the kidney. Ex vivo normothermic perfusion may be utilized to distinguish high-risk kidneys to determine suitability for transplantation. Here, we assessed the association of tissue metabolic changes with changes in a kidney injury biomarker and functional parameters in eight deceased donor kidneys deemed unsuitable for transplantation during a 12-hour ex vivo normothermic perfusion. The kidneys were grouped into good and poor performers based on blood flow and urine output. The mean age of the deceased kidney donors was 43 years with an average cold ischemia time of 37 hours. Urine output and creatinine clearance progressively increased and peaked at six hours post-perfusion among good performers. Poor performers had 71 ng/ml greater (95% confidence interval 1.5, 140) urinary neutrophil gelatinase-associated lipocalin at six hours compared to good performers corresponding to peak functional differences. Organ performance was distinguished by tissue metabolic differences in branched chain amino acid metabolism and that their tissue levels negatively correlated with urine output among all kidneys at six hours. Tissue lipid profiling showed poor performers were highlighted by the accumulation of membrane structure components including glycerolipids and sphingolipids at early perfusion time points. Thus, we showed that six hours is needed for kidney function recovery during ex vivo normothermic perfusion and that branched chain amino acid metabolism may be a major determinant of organ function and resilience.

Photosynthesis, Anatomy, and Metabolism as a Tool for Assessing Physiological Modulation in Five Native Species of the Brazilian Atlantic Forest.

The Brazilian Atlantic Forest, renowned for its exceptional species richness and high endemism, acts as a vital reservoir of terrestrial biodiversity, often referred to as a biodiversity hotspot. Consequently, there is an urgent need to restore this forest to safeguard certain species and to unravel the ecophysiological adaptations of others. This study aims to integrate some physiological parameters, including gas exchange and chlorophyll a fluorescence, with anatomical and metabolic techniques to elucidate how five different native species (Paubrasilia echinata, Chorisia glaziovii, Clusia nemorosa, Licania tomentosa, and Schinus terebinthifolius), each occupying distinct ecological niches, respond to seasonal variations in rainfall and their consequences. Our investigation has revealed that C. nemorosa and P. echinata exhibit robust mechanisms to mitigate the adverse effects of drought. In contrast, others demonstrate greater adaptability (e.g., S. terebinthifolia and C. glaziovii). In this context, exploring metabolic pathways has proven invaluable in comprehending the physiological strategies and their significance in species acclimatization. This study provides a comprehensive overview of the impact of water restrictions and their consequential effects on various species, defining the strategies each species uses to mitigate water privation during the dry season.

Amino acid metabolomics and machine learning-driven assessment of future liver remnant growth after hepatectomy in livers of various backgrounds.

Accurate assessment of future liver remnant growth after partial hepatectomy (PH) in patients with different liver backgrounds is a pressing clinical issue. Amino acid (AA) metabolism plays a crucial role in liver regeneration. In this study, we combined metabolomics and machine learning (ML) to develop a generalized future liver remnant assessment model for multiple liver backgrounds. The liver index was calculated at 0, 6, 24, 48, 72 and 168 h after 70 % PH in healthy mice and mice with nonalcoholic steatohepatitis or liver fibrosis. The serum levels of 39 amino acids (AAs) were measured using UPLC-MS/MS. The dataset was randomly divided into training and testing sets at a 2:1 ratio, and orthogonal partial least squares regression (OPLS) and minimally biased variable selection in R (MUVR) were used to select a metabolite signature of AAs. To assess liver remnant growth, nine ML models were built, and evaluated using the coefficient of determination (R2), mean absolute error (MAE), and root mean square error (RMSE). The post-Pareto technique for order preference by similarity to the ideal solution (TOPSIS) was employed for ranking the ML algorithms, and a stacking technique was utilized to establish consensus among the superior algorithms. Compared with those of OPLS, the signature AAs set identified by MUVR (Thr, Arg, EtN, Phe, Asa, 3MHis, Abu, Asp, Tyr, Leu, Ser, and bAib) are more concise. Post-Pareto TOPSIS ranking demonstrated that the majority of ML algorithm in combinations with MUVR outperformed those with OPLS. The established SVM-KNN consensus model performed best, with an R2 of 0.79, an MAE of 0.0029, and an RMSE of 0.0035 for the testing set. This study identified a metabolite signature of 12 AAs and constructed an SVM-KNN consensus model to assess future liver remnant growth after PH in mice with different liver backgrounds. Our preclinical study is anticipated to establish an alternative and generalized assessment method for liver regeneration.

The significant role of amino acid metabolic reprogramming in cancer.

Amino acid metabolism plays a pivotal role in tumor microenvironment, influencing various aspects of cancer progression. The metabolic reprogramming of amino acids in tumor cells is intricately linked to protein synthesis, nucleotide synthesis, modulation of signaling pathways, regulation of tumor cell metabolism, maintenance of oxidative stress homeostasis, and epigenetic modifications. Furthermore, the dysregulation of amino acid metabolism also impacts tumor microenvironment and tumor immunity. Amino acids can act as signaling molecules that modulate immune cell function and immune tolerance within the tumor microenvironment, reshaping the anti-tumor immune response and promoting immune evasion by cancer cells. Moreover, amino acid metabolism can influence the behavior of stromal cells, such as cancer-associated fibroblasts, regulate ECM remodeling and promote angiogenesis, thereby facilitating tumor growth and metastasis. Understanding the intricate interplay between amino acid metabolism and the tumor microenvironment is of crucial significance. Expanding our knowledge of the multifaceted roles of amino acid metabolism in tumor microenvironment holds significant promise for the development of more effective cancer therapies aimed at disrupting the metabolic dependencies of cancer cells and modulating the tumor microenvironment to enhance anti-tumor immune responses and inhibit tumor progression.

Aspartate aminotransferase of Rhizobium leguminosarum has extended substrate specificity and metabolizes aspartate to enable N2 fixation in pea nodules.

Rhizobium leguminosarum aspartate aminotransferase (AatA) mutants show drastically reduced symbiotic nitrogen fixation in legume nodules. Whilst AatA reversibly transaminates the two major amino-donor compounds aspartate and glutamate, the reason for the lack of N2 fixation in the mutant has remained unclear. During our investigations into the role of AatA, we found that it catalyses an additional transamination reaction between aspartate and pyruvate, forming alanine. This secondary reaction runs at around 60 % of the canonical aspartate transaminase reaction rate and connects alanine biosynthesis to glutamate via aspartate. This may explain the lack of any glutamate-pyruvate transaminase activity in R. leguminosarum, which is common in eukaryotic and many prokaryotic genomes. However, the aspartate-to-pyruvate transaminase reaction is not needed for N2 fixation in legume nodules. Consequently, we show that aspartate degradation is required for N2 fixation, rather than biosynthetic transamination to form an amino acid. Hence, the enzyme aspartase, which catalyses the breakdown of aspartate to fumarate and ammonia, suppressed an AatA mutant and restored N2 fixation in pea nodules.

Metabolic reprogramming and heterogeneity during the decidualization process of endometrial stromal cells.

The human endometrial decidualization is a transformative event in the pregnant uterus that involves the differentiation of stromal cells into decidual cells. While crucial to the establishment of a successful pregnancy, the metabolic characteristics of decidual cells in vivo remain largely unexplored. Here, we integrated the single-cell RNA sequencing (scRNA-seq) datasets on the endometrium of the menstrual cycle and the maternal-fetal interface in the first trimester to comprehensively decrypt the metabolic characteristics of stromal fibroblast cells. Our results revealed that the differentiation of stromal cells into decidual cells is accompanied by increased amino acid and sphingolipid metabolism. Furthermore, metabolic heterogeneity exists in decidual cells with differentiation maturity disparities. Decidual cells with high metabolism exhibit higher cellular activity and show a strong propensity for signaling. In addition, significant metabolic reprogramming in amino acids and lipids also occurs during the transition from non-pregnancy to pregnancy in the uteri of pigs, cattle, and mice. Our analysis provides comprehensive insights into the dynamic landscape of stromal fibroblast cell metabolism, contributing to our understanding of the metabolism at the molecular dynamics underlying the decidualization process in the human endometrium.