Amino Acid Pathways Research Articles

Harnessing amino acid pathways to influence myeloid cell function in tumor immunity.

Amino acids are pivotal regulators of immune cell metabolism, signaling pathways, and gene expression. In myeloid cells, these processes underlie their functional plasticity, enabling shifts between pro-inflammatory, anti-inflammatory, pro-tumor, and anti-tumor activities. Within the tumor microenvironment, amino acid metabolism plays a crucial role in mediating the immunosuppressive functions of myeloid cells, contributing to tumor progression. This review delves into the mechanisms by which specific amino acids-glutamine, serine, arginine, and tryptophan-regulate myeloid cell function and polarization. Furthermore, we explore the therapeutic potential of targeting amino acid metabolism to enhance anti-tumor immunity, offering insights into novel strategies for cancer treatment.

Improved biosynthesis of tyrosol by epigenetic modification-based regulation and metabolic engineering in Saccharomyces cerevisiae.

Aromatic amino acids and their derivatives are high value chemicals widely used in food, pharmaceutical and feed industries. Current preparation methods for aromatic amino acid products are fraught with limitations. In this study, the efficient biosynthesis of aromatic amino acid compound tyrosol was investigated by epigenetic modification-based regulation and optimization of the biosynthetic pathway of aromatic amino acids. The production of tyrosol was significantly improved by the overexpression of m6A modification writer Ime4 and reader Pho92, and the positive regulator Gcr2. Introduction of Bbxfpk and deletion of Gpp1 further improved tyrosol production. Then the feedback inhibition of the shikimate pathway was relieved by the mutants Aro4K229L and Aro7G141S. The final tyrosol producing engineered strain was constructed by the deletion of PHA2, replacement of the native promoter of ARO10 with the strong promoter PGK1p, and introduction of tyrosine decarboxylase PcAAS. In the background of m6A modification regulation, this strain ultimately produced 954.69 ± 43.72 mg/L of tyrosol, promoted by 61.7-fold in shake-flask fermentation.

Physiological Responses and Metabolic Characteristics of Proso Millet Under Drought Stress During Germination Period.

To clarify the impact of drought stress during germination on proso millet's physiological responses and metabolic features, this study used physiological and targeted-like metabolomics methods. With Longmi No. 7 (drought-tolerant, L1) and Longmi No. 15 (drought-sensitive, L2) as materials, we studied the enzyme activities, osmotic adjustment substances, and differential metabolites of proso millet. Results showed that under drought stress, L1's enzyme activities and osmotic adjustment substance contents were significantly higher than L2's, especially at 48-h treatment. 1085 known metabolites were identified from 24 samples, under normal germination, L1's main differential metabolites (amino acids, flavonoids, phytohormone, lipids, sugars, etc.) were enriched in amino acid, lipid, sugar, and energy metabolism pathways. L2's (amino acids, sugars, flavonoids, etc.) were in sugar, lipid metabolism, secondary metabolite biosynthesis, and amino acid metabolism pathways. At 24-h treatment, the metabolic pathways of L1 were mainly concentrated in carbohydrate and nucleotide metabolism, while those of L2 were mainly in carbohydrate and lipid metabolism. At 48 h, the metabolic pathways of L1 were mainly in carbohydrate, energy and lipid metabolism, and those of L2 were mainly in carbohydrate, lipid metabolism, biosynthesis of other secondary metabolites and amino acid metabolism. Under stress, L1's main differential metabolites were organic acids, sugars, flavonoids, amino acids, etc.; L2's were phytohormones, organic acids, sugars, flavonoids, amino acids. This study provides a new direction for the development of proso millet sprouts. Meanwhile, it offers new ideas and theoretical bases for the development of functional foods and the regulation of nutritional components of proso millet.

Abstract TP362: Estrogen Receptor-Beta Activation Reduces Cognitive Deficits After Stroke in Middle-Aged Female Rats

Introduction: Menopause increases the risk and severity of ischemic stroke (IS), while endogenous 17β-estradiol (E2) naturally protects premenopausal women against IS. The female sex hormone E2 is a potent neuro- and cognitive-protective agent. Studies have shown that periodic E2 or estrogen receptor subtype-beta (ER-β) agonist pre-treatments every 48 hours before an ischemic episode ameliorated ischemic brain damage in young ovariectomized or reproductively senescent (RS) aged female rats. The current study investigates the underlying mechanism of ER-β agonist-mediated neuroprotection. Methods: Retired breeder (9–10 months) Sprague–Dawley female rats were considered RS after remaining in constant diestrus phase for more than a month. The RS rats were exposed to transient middle cerebral artery occlusion (tMCAO; 90 mins) and treated with either ER-β agonist (beta 2, 3-bis(4-hydroxyphenyl) propionitrile; DPN; 1 mg/kg; s.c.) or DMSO vehicle at 4.5 hours after induction of tMCAO. Subsequently, rats were treated with either ER-β agonist or DMSO vehicle every 48 hours (48-h) for ten injections. Forty-eight hours after the last treatment, animals were tested for cognitive deficits via the Morris water maze. At 1-month post-tMCAO, brains were collected for histopathological analysis. A second cohort of RS rats underwent DPN or DMSO treatment for a month; 48-h after last injection, brains were collected for unbiased global metabolomic analysis (conducted by Metabolon Inc.). The metabolomic study was complemented with western blot analysis and enzyme activity measurements of key altered pathways. Results: Data showed significant (p<0.05) decreases in glucose-6-phosphate and increases in 5-phosphyribosyl diphosphate, UDP-galactose, and N-acetylglucoseamine-6-phosphate in the brain of DPN-treated RS female rats as compared to DMSO-treated controls. DPN treatment also changes the enzymatic activity of glycolytic rate limiting enzyme hexokinase. Metabolomics data also showed significant increase in choline and arginine levels in the brain of DPN-treated RS female rats as compared to DMSO-treated controls. Conclusion: The observed changes in glycolytic and amino acid pathway metabolites could enhance brain energy metabolism and increase choline availability, potentially contributing to the improved post-stroke cognitive outcomes in RS rats.

Gene networks and metabolomic screening analysis revealed specific pathways of amino acid and acylcarnitine profile alterations in blood plasma of patients with Parkinson’s disease and vascular parkinsonism

Parkinson’s disease (PD) and vascular parkinsonism (VP) are characterized by similar neurological syndromes but differ in pathogenesis, morphology, and therapeutic approaches. The molecular genetic mechanisms of these pathologies are multifactorial and involve multiple biological processes. To comprehensively analyze the pathophysiology of PD and VP, the methods of systems biology and gene network reconstruction are essential. In the current study, we performed metabolomic screening of amino acids and acylcarnitines in blood plasma of three groups of subjects: PD patients, VP patients and the control group. Comparative statistical analysis of the metabolic profiles identified significantly altered metabolites in the PD and the VP group. To identify potential mechanisms of amino acid and acylcarnitine metabolism disorders in PD and VP, regulatory gene networks were reconstructed using ANDSystem, a cognitive system. Regulatory pathways to the enzymes converting significant metabolites were found from PD­specific genetic markers, VP­specific genetic markers, and the group of genetic markers common to the two diseases. Comparative analysis of molecular genetic pathways in gene networks allowed us to identify both specific and non­specific molecular mechanisms associated with changes in the metabolomic profile in PD and VP. Regulatory pathways with potentially impaired function in these pathologies were discovered. The regulatory pathways to the enzymes ALDH2, BCAT1, AL1B1, and UD11 were found to be specific for PD, while the pathways regulating OCTC, FURIN, and S22A6 were specific for VP. The pathways regulating BCAT2, ODPB and P4HA1 were associated with genetic markers common to both diseases. The results obtained deepen the understanding of pathological processes in PD and VP and can be used for application of diagnostic systems based on the evaluation of the amino acids and acylcarnitines profile in blood plasma of patients with PD and VP.

Metabolic shifts in glioblastoma: unraveling altered pathways and exploring novel therapeutic avenues.

Metabolic reprogramming stands out as a defining characteristic of cancer, including glioblastoma (GB), enabling tumor cells to overcome growth and survival challenges in adverse conditions. The dysregulation of metabolic processes in GB is crucial to its pathogenesis, influencing both tumorigenesis and the disease's invasive tendencies. This altered metabolism supplies essential energy substrates for uncontrolled cell proliferation and also creates an immunosuppressive microenvironment, complicating conventional therapies. A comprehensive understanding of the complexities of metabolic dysregulation in carbohydrate, amino acid, lipid and nucleotide pathways in GB holds promise for effective therapeutic interventions. Key metabolic enzymes, transporters, and signaling pathways and mitochondrial metabolism have been examined for their roles in GB pathology and their possible therapeutic potential. Addressing these metabolic targets has shown efficacy in preclinical models and is currently being evaluated in clinical trials. Combination therapies that exploit metabolic vulnerabilities alongside conventional treatments hold the promise of improving patient outcomes. This review explores the dynamic interplay between glioblastoma's aggressiveness and altered metabolism, offering insights into potential therapeutic strategies. Moreover, this review discusses the recent advancements in drug development aimed at targeting these dysregulated metabolic pathways.

In silico, in vitro and in vivo characterisation of thiamin binding proteins from plant seeds.

Thiamin, an essential micronutrient, is a cofactor for enzymes involved in the central carbon metabolism and amino acids pathways. Despite efforts to enhance thiamin content in rice by incorporating thiamin biosynthetic genes, increasing thiamin content in endosperm remains challenging, possibly due to a lack of thiamin stability and/or a local sink. The introduction of storage proteins has been successful in biofortification strategies and similar efforts targeting thiamin led to a 3-4-fold increase in white rice. However, only one thiamin-binding protein (TBP) sequence has been described in plants, more specifically from sesame seeds. Therefore, we aimed to identify and characterize TBPs, as well as to evaluate the effect of their expression on thiamin concentration, using an approach integrating in silico, in vitro and in vivo methods. We identified putative TBPs from Oryza sativa (rice), Fagopyrum esculentum (buckwheat) and Zea mays (maize) and pinpointed the thiamin-binding pockets through molecular docking. FeTBP and OsTBP contained one pocket with binding affinities similar to E. coli TBP, a well-characterized thiamin-binding protein, supporting their function. In vivo expression studies of TBPs in tobacco leaves and rice callus resulted in increased thiamin levels, with FeTBP and OsTBP showing the most pronounced effects. Additionally, thermal shift assays confirmed the thiamin binding capabilities of FeTBP and OsTBP, as observed by the significant increases in melting temperatures upon thiamin binding, indicating protein stabilization. These findings offer new insights into diversity and function of plant TBPs and highlight the potential of FeTBP and OsTBP to modulate thiamin levels in crop plants.

Impact of Enzymatic Degradation Treatment on Physicochemical Properties, Antioxidant Capacity, and Prebiotic Activity of Lilium Polysaccharides.

In order to overcome the bioavailability limitation of Lilium polysaccharide (LPS) caused by its high molecular weight and complex structure, two low-molecular-weight degraded polysaccharides, namely G-LPS(8) and G-LPS(16), were prepared through enzymatic degradation. The molecular weight of LPS was significantly reduced by enzymolysis, leading to increased exposure of internal functional groups and altering the molar ratio of its constituent monosaccharides. The results of antioxidant experiments showed that enzymatic hydrolysis had the potential to enhance the antioxidant performance of LPS. In vitro fermentation experiments revealed that LPS and its derivatives exerted different prebiotic effects on intestinal microbial communities. Specifically, LPS mainly inhibited the growth of harmful bacteria such as Fusobacterium, while G-LPS(8) and G-LPS(16) tended to promote the growth of beneficial bacteria like Megamonas, Bacteroides, and Parabacteroides. Metabolomic analysis revealed that LPSs with varying molecular weights exerted comparable promoting effects on multiple amino acid and carbohydrate metabolic pathways. Importantly, with the reduction in molecular weight, G-LPS(16) also particularly stimulated sphingolipid metabolism, nucleotide metabolism, as well as ascorbic acid and uronic acid metabolism, leading to the significant increase in specific metabolites such as sphingosine. Therefore, this study suggests that properly degraded LPS components have greater potential as a prebiotic for improving gut health.

Exploring metabolic reprogramming in esophageal cancer: the role of key enzymes in glucose, amino acid, and nucleotide pathways and targeted therapies.

Esophageal cancer (EC) is one of the most common malignancies worldwide with the character of poor prognosis and high mortality. Despite significant advancements have been achieved in elucidating the molecular mechanisms of EC, for example, in the discovery of new biomarkers and metabolic pathways, effective treatment options for patients with advanced EC are still limited. Metabolic heterogeneity in EC is a critical factor contributing to poor clinical outcomes. This heterogeneity arises from the complex interplay between the tumor microenvironment and genetic factors of tumor cells, which drives significant metabolic alterations in EC, a process known as metabolic reprogramming. Understanding the mechanisms of metabolic reprogramming is essential for developing new antitumor therapies and improving treatment outcomes. Targeting the distinct metabolic alterations in EC could enable more precise and effective therapies. In this review, we explore the complex metabolic changes in glucose, amino acid, and nucleotide metabolism during the progression of EC, and how these changes drive unique nutritional demands in cancer cells. We also evaluate potential therapies targeting key metabolic enzymes and their clinical applicability. Our work will contribute to enhancing knowledge of metabolic reprogramming in EC and provide new insights and approaches for the clinical treatment of EC.

Mid-life anti-inflammatory metabolites are inversely associated with long-term cardiovascular disease events.

Preclinical data have shown that low levels of metabolites with anti-inflammatory properties may impact metabolic disease processes. However, the association between mid-life levels of such metabolites and long-term ASCVD risk is not known. We characterised the plasma metabolomic profile (1228 metabolites) of 1852 participants (58.1±7.5 years old, 69.6% female, 43.6% self-identified as Black) enrolled in the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study. Logistic regression was used to assess the impact of metabolite levels on ASCVD risk (nonfatal MI, revascularisation, and cardiac mortality). We additionally explored the effect of genetic variants neighbouring ASCVD-related genes on the levels of metabolites predictive of ASCVD events. The Atherosclerosis Risk in Communities (ARIC) study (n=4790; 75.5±5.1 years old, 57.4% female, 19.5% self-identified as Black) was used as an independent validation cohort. In fully adjusted models, alpha-ketobutyrate [AKB] (OR 0.62 [95% CI, 0.49-0.80]; p<0.001), and 1-palmitoyl-2-linoleoyl-GPI [OR, 0.62, 95% CI, 0.47-0.83; p<0.001], two metabolites in amino acid and phosphatidylinositol lipid pathways, respectively, showed a significant protective association with incident ASCVD risk in both Heart SCORE and ARIC cohorts. Three plasmalogens and a bilirubin derivative, whose levels were regulated by genetic variants neighbouring FADS1 and UGT1A1, respectively, exhibited a significant protective association with ASCVD risk in the Heart SCORE only. Higher mid-life levels of AKB and 1-palmitoyl-2-linoleoyl-GPI metabolites may be associated with lower risk late-life ASCVD events. Further research can determine the causality and therapeutic potential of these metabolites in ASCVD. This study was funded by the Pennsylvania Department of Health (ME-02-384). The department specifically disclaims responsibility for any analyses, interpretations, or conclusions. Additional funding was provided by National Institutes of Health (NIH) grant R01HL089292 and UL1 TR001857 (Steven Reis). Further, NIH funded R01HL141824 and R01HL168683 were used for the ARIC study validation (Bing Yu).

Enhanced undecylprodigiosin production using collagen hydrolysate: a cost-effective and high-efficiency synthesis strategy.

Undecylprodigiosin (UDP), a desirable pyrrole-based biomaterial, holds significant promise in pharmaceutical and medical applications due to its diverse biological activities. However, its application is usually hampered by low synthesis efficiency and high production costs. Here, we developed a high-efficiency and cost-effective strategy for UDP synthesis using collagen hydrolysate (COH) as a readily available and abundant precursor source in conjunction with Streptomyces sp. SLL-523. COH obviously accelerated the proliferation of Streptomyces sp. SLL-523. Replacing muscle hydrolysate with COH resulted in a 7-fold increase in UDP yield and a 10-fold reduction in fermentation time, indicating that COH significantly enhanced the synthesis efficiency of UDP. Besides, COH remarkably increased the intracellular levels of UDP precursor amino acids (AAs). Whole-genome analysis of Streptomyces sp. SLL-523 revealed the gene clusters responsible for UDP synthesis and COH utilization. COH markedly stimulated the expression of genes involved in the metabolism pathways of energy, transporters, peptides, and AAs, ultimately promoting the UDP synthesis. Significantly, COH efficiently triggered and boosted the expression of key genes in the UDP biosynthesis pathway, including redQ, redM, redN, and redL, leading to highly efficient UDP synthesis. Thus, this innovative approach provides a novel framework for the high-efficiency synthesis of natural pyrrole biomedical materials based on renewable nitrogen-contained biomass.

Arabidopsis 3-Deoxy-d-Arabino-Heptulosonate 7-Phosphate (DAHP) Synthases of the Shikimate Pathway Display Both Manganese- and Cobalt-Dependent Activities.

The plant shikimate pathway directs a significant portion of photosynthetically assimilated carbon into the downstream biosynthetic pathways of aromatic amino acids (AAA) and aromatic natural products. 3-Deoxy-d-arabino-heptulosonate 7-phosphate (DAHP) synthase (hereafter DHS) catalyzes the first step of the shikimate pathway, playing a critical role in controlling the carbon flux from central carbon metabolism into the AAA biosynthesis. Previous biochemical studies suggested the presence of manganese- and cobalt-dependent DHS enzymes (DHS-Mn and DHS-Co, respectively) in various plant species. Unlike well-studied DHS-Mn, however, the identity of DHS-Co is still unknown. Here, we show that all three DHS isoforms of Arabidopsis thaliana exhibit both DHS-Mn and DHS-Co activities invitro. A phylogenetic analysis of various DHS orthologs and related sequences showed that Arabidopsis 3-deoxy-D-manno-octulosonate-8-phosphate synthase (KDOPS) proteins were closely related to microbial Type I DHSs. Despite their sequence similarity, these Arabidopsis KDOPS proteins showed no DHS activity. Meanwhile, optimization of the DHS assay conditions led to the successful detection of DHS-Co activity from Arabidopsis DHS recombinant proteins. Compared with DHS-Mn, DHS-Co activity displayed the same redox dependency but distinct optimal pH and cofactor sensitivity. Our work provides biochemical evidence that the DHS isoforms of Arabidopsis possess DHS-Co activity.

New insights into the neurophysiological effects of heat stress on the Chinese mitten crab (Eriocheir sinensis).

Climate warming and frequent incidents of extreme high temperatures are serious global concerns. Heat stress induced by high temperature has many adverse effects on animal physiology, especially in aquatic poikilotherms. Chinese mitten crab (Eriocheir sinensis) is sensitive to high temperatures, this study evaluated the harmful effects of heat stress on the neurotoxicity, intestinal health, microbial diversity, and metabolite profiles. The results showed that heat stress caused histopathological damages and altered the ultrastructure of lesions in the cranial ganglia. Heat stress significantly upregulated the mRNA expression of apoptosis-related genes, and significantly altered the expression of neurotransmitter receptors. In addition, heat stress induced significant intestinal damages that mainly manifested as a significant increase in the activity of diamine oxidase in the serum and contents of histamine in the intestine. The diversity and abundance of intestinal microbiota altered abnormally in E. sinensis exposed to heat stress, and the bacteria that exhibited significant variations in abundance were closely related to the production of neurotransmitters and neuromodulators. Heat stress caused significant changes in the intestinal metabolite profiles, which mainly involved the amino acid and lipid metabolism pathways. Analysis of the correlation showed that the abnormal changes in metabolites were closely related to differences in the abundance of intestinal microbiota. Therefore, this study showed that heat stress could cause neurophysiological toxic effects, which may be related to intestinal ecological imbalance.

PH-dependent medium-chain fatty acid synthesis in waste activated sludge fermentation: Metabolic pathway regulation.

Transforming waste activated sludge (WAS) into medium-chain fatty acids (MCFAs) via chain elongation (CE) technology is sustainable, yet pH effects on this process are poorly understood. In this study, semi-continuous flow experiments demonstrated that WAS degradation was highest under alkaline pH (10) but unsuitable for CE. Continuous output of MCFAs indicated that CE could be successfully performed under acidic pH (5) and neutral pH (7). Moreover, neutral pH optimized MCFAs production, achieving higher MCFAs yield (8.9±1.2g COD/L), MCFAs selectivity (51.2±7.3%), and WAS degradation (25.4±0.4%) than acidic pH. Further metagenomic and metatranscriptomic analysis revealed that the reverse β-oxidation cycle was the primary CE pathway. The absence of CE-related microorganisms and enzymes under alkaline pH hindered MCFAs synthesis, while under acidic pH, carboxylate accumulation may reduce cellular protection capabilities and affect energy metabolism, thereby inhibiting anaerobic fermentation. Conversely, neutral pH enhanced amino acid and butyrate metabolic pathways, facilitating WAS degradation and SCFAs production, providing precursor substrates for MCFAs production. Additionally, neutral pH promoted the enrichment and activity of CE-related microorganisms and enzymes, contributing to the accumulation of high-concentration MCFAs. Notably, Clostridium_kluyveri and Sporanaerobacter_acetigenes were key CE-functional bacteria at neutral pH.

Foliar Application of Zinc Oxide Nanoparticles Alleviates Phenanthrene and Cadmium-Induced Phytotoxicity in Lettuce: Regulation of Plant-Rhizosphere-Microbial Long Distance.

Foliar application of beneficial nanoparticles exhibits potential in mitigating combined stresses from heavy metals and polycyclic aromatic hydrocarbons (PAHs) in crops, necessitating a comprehensive understanding of plant-rhizosphere-microbial processes to promote sustainable nanotechnology in agriculture. Herein, we investigated the mitigating mechanisms of foliar application of zinc oxide nanoparticles (nZnO) on lettuce growth under phenanthrene (Phe) and cadmium (Cd) costress. Compared to Phe + Cd treatment, low (L-nZnO) and high (H-nZnO) concentration of nZnO increased fresh biomass (27.2% and 8.42%) and root length (20.4% and 39.6%) and decreased MDA (35.0% and 40.0%) and H2O2 (29.0% and 15.6%) levels. L-nZnO and H-nZnO decreased Cd in roots (26.8% and 41.8%) and enhanced Zn in roots (19.9% and 107%), stems (221% and 2510%), and leaves (233% and 1500%), suggesting the long-distance migration of Zn from leaves to roots and subsequently regulating the metabolic pathways and microbial communities. Metabolomics revealed that nZnO modulated leaf glycerophospholipid metabolism and amino acid pathways and promoted rhizosphere soil carbon and phosphorus metabolism. Additionally, nZnO enriched the plant-growth-promoting, extreme, and stress-resistant bacteria in roots and leaves and heavy-metal-resistant and PAH-degrading bacteria in rhizosphere soil. These findings underscore the promising nanostrategy of nZnO to benefit plant growth in soil cocontaminated with heavy metals and PAHs.

New insights into the combined effects of aflatoxin B1 and Eimeria ovinoidalis on uterine function by disrupting the gut–blood–reproductive axis in sheep

BackgroundSheep coccidiosis is an infectious parasitic disease that primarily causes diarrhea and growth retardation in young animals, significantly hindering the development of the sheep breeding industry. Cereal grains and animal feeds are frequently contaminated with mycotoxins worldwide, with aflatoxin B1 (AFB1) being the most common form. AFB1 poses a serious threat to gastrointestinal health upon ingestion and affects the function of parenteral organs, thus endangering livestock health. However, the impact of the combined effects of coccidia and AFB1 on the reproductive system of sheep has not been reported. Therefore, this study utilized sheep as an animal model to investigate the mechanisms underlying the reproductive toxicity induced by the individual or combined effects of AFB1 and Eimeria ovinoidalis (E. ovinoidalis) on the gut–blood–reproductive axis.ResultsThe results showed that AFB1 and coccidia adversely affect the reproductive system defense of sheep by altering uterine histopathology and hormone levels and triggering inflammation, which is associated with changes in the gut microbiota and metabolites. Moreover, co-exposure to AFB1 and coccidia disrupted the intestinal structure of the colon, resulting in reduced crypt depth. The impaired barrier function of the colon manifests primarily through the suppression of barrier protein expression, changes in the gut microbiome composition, and disruptions in gut metabolism. Importantly, the levels of blood inflammatory factors (IL-6, IL-10, TNF-α, and LPS) increased, suggesting that exposure to AFB1 and coccidia compromises the function of uterine organs in sheep by perturbing the gut–blood–reproductive axis. Blood metabolomics analysis further revealed that the differential metabolites predominantly concentrate in the amino acid pathway, particularly N-acetyl-L-phenylalanine. This metabolite is significantly correlated with IL-6, TNF-α, LPS, ERα, and ERβ, and it influences hormone levels while inducing uterine damage through the regulation of the downstream genes PI3K, AKT, and eNOS in the relaxin signaling pathway, as demonstrated by RNA sequencing.ConclusionsThese findings reveal for the first time that the combined effects of AFB1 and E. ovinoidalis on sheep uterine function operate at the level of the gut–blood–reproductive axis. This suggests that regulating gut microbiota and its metabolites may represent a potential therapeutic strategy for addressing mycotoxins and coccidia-co-induced female reproductive toxicity.Graphical

Is anthranil acid subject to deamination in animals?

All metabolic pathways of natural amino acids lead to the Krebs cycle. However, only nitrogen-free acyclic compounds can enter the Krebs cycle. In animals, however, the products of deamination and decyclization of amino acids are not only oxidized to end products in the Krebs cycle, but are also converted to glucose and ketone bodies. Consequently, every natural amino acid has a glucogenic or ketogenic effect, and some amino acids have a glucoketogenic or mixed effect, because they form both a glucogenic and a ketogenic product in the process of degradation. Tryptophan is such an amino acid. One of the degradation products of tryptophan is anthranilic acid. While the conversion of another degradation product of tryptophan, 3-hydroxyanthranilic acid, has long been known and is the cause of the ketogenic effect of tryptophan, the conversion of anthranilic acid has long remained unclear. This has led to various judgments that have not allowed true conclusions about the action of anthranilic acid (glucogenic or ketogenic) and, consequently, the final judgments about the action of tryptophan in animals. The article analyzes the conversion of anthranilic acid in animals, which allows us to conclude about the metabolic pathway of tryptophan through it. The article shows the impossibility of direct deamination of anthranilic acid in animals with the glucogenic effect of anthranilic acid resulting from direct deamination, and also shows the ketogenic effect of anthranilic acid due to its oxidation to 3-hydroxyanthranilic acid. Since both acids are intermediates in the degradation of the protein amino acid tryptophan, this fact should be taken into account in the diets of normal and pathological animals.

Characterisation of the Plasma and Faecal Metabolomes in Participants with Functional Gastrointestinal Disorders.

There is evidence of perturbed microbial and host processes in the gastrointestinal tract of individuals with functional gastrointestinal disorders (FGID) compared to healthy controls. The faecal metabolome provides insight into the metabolic processes localised to the intestinal tract, while the plasma metabolome highlights the overall perturbances of host and/or microbial responses. This study profiled the faecal (n = 221) and plasma (n = 206) metabolomes of individuals with functional constipation (FC), constipation-predominant irritable bowel syndrome (IBS-C), functional diarrhoea (FD), diarrhoea-predominant IBS (IBS-D) and healthy controls (identified using the Rome Criteria IV) using multimodal LC-MS technologies. Discriminant analysis separated patients with the 'all constipation' group (FC and IBS-C) from the healthy control group and 'all diarrhoea' group (FD and IBS-D) from the healthy control group in both sample types. In plasma, almost all multimodal metabolite analyses separated the 'all constipation' or 'all diarrhoea' group from the healthy controls, and the IBS-C or IBS-D group from the healthy control group. Plasma phospholipids and metabolites linked to several amino acid and nucleoside pathways differed (p < 0.05) between healthy controls and IBS-C. In contrast, metabolites involved in bile acid and amino acid metabolism were the key differentiating classes in the plasma of subjects with IBS-D from healthy controls. Faecal lipids, particularly ceramides, diglycerides, and triglycerides, varied (p < 0.05) between healthy controls and the 'all constipation' group and between healthy controls and 'all diarrhoea' group. The faecal and plasma metabolomes showed perturbations between constipation, diarrhoea and healthy control groups that may reflect processes and mechanisms linked to FGIDs.

Cytochrome c levels link mitochondrial function to plant growth and stress responses through changes in SnRK1 pathway activity.

Energy is required for growth as well as for multiple cellular processes. During evolution, plants developed regulatory mechanisms to adapt energy consumption to metabolic reserves and cellular needs. Reduced growth is often observed under stress, leading to a growth-stress trade-off that governs plant performance under different conditions. In this work, we report that plants with reduced levels of the mitochondrial respiratory chain component cytochrome c (CYTc), required for electron transport coupled to oxidative phosphorylation and ATP production, show impaired growth and increased global expression of stress-responsive genes, similar to those observed after inhibiting the respiratory chain or the mitochondrial ATP synthase. CYTc-deficient plants also show activation of the SnRK1 pathway, which regulates growth, metabolism, and stress responses under carbon starvation conditions, even though their carbohydrate levels are not significantly different from wild-type. Notably, loss-of-function of the gene encoding the SnRK1α1 subunit restores the growth of CYTc-deficient plants, as well as autophagy, free amino acid and TOR pathway activity levels, which are affected in these plants. Moreover, increasing CYTc levels decreases SnRK1 pathway activation, reflected in reduced SnRK1α1 phosphorylation, with no changes in total SnRK1α1 protein levels. Under stress imposed by mannitol, the growth of CYTc-deficient plants is relatively less affected than that of wild-type plants, which is also related to the activation of the SnRK1 pathway. Our results indicate that SnRK1 function is affected by CYTc levels, thus providing a molecular link between mitochondrial function and plant growth under normal and stress conditions.

Response of soybean root exudates and related metabolic pathways to low phosphorus stress.

Phosphorus (P) is an essential elemental nutrient required in high abundance for robust soybean growth and development. Low P stress negatively impacts plant physiological and biochemical processes, such as photosynthesis, respiration, and energy transfer. Soybean roots play key roles in plant adaptive responses to P stress and other soil-related environmental stressors. Study the changes in soybean root exudates and differences in related metabolic pathways under low phosphorus stress, analyzing the response mechanism of soybean roots to phosphorus stress from the perspective of root exudates, which provide a theoretical basis for further analyzing the physiological mechanism of phosphorus stress on soybean. In this study, soybean roots were exposed to three phosphate levels: 1 mg/L (P stress), 11 mg/L (P stress) and 31 mg/L (Normal P) for 10 days and 20 days, then root exudates were analyzed via ultra-high-performance liquid chromatography-mass spectrometry to identify effects of P stress on root metabolite profiles and associated metabolic pathways. Our results revealed that with increasing P stress severity and/or duration, soybean roots produced altered types, quantities, and increased numbers of exudate metabolites (DMs in the P1 group were primarily upregulated, whereas those in the P11 group were predominately downregulated) caused by changes in regulation of activities of numerous metabolic pathways. These pathways had functions related to environmental adaptation, energy metabolism, and scavenging of reactive oxygen species and primarily included amino acid, flavonoid, and nicotinate and nicotinamide metabolic pathways and pathways related to isoquinoline alkaloid biosynthesis, sugar catabolism, and phospholipid metabolism. These metabolites and metabolic pathways lay a foundation to support further investigations of physiological mechanisms underlying the soybean root response to P deficiency.