Metabolic Reconfiguration Research Articles

Establishment and Verification of a Novel Gene Signature Connecting Hypoxia and Lactylation for Predicting Prognosis and Immunotherapy of Pancreatic Ductal Adenocarcinoma Patients by Integrating Multi-Machine Learning and Single-Cell Analysis.

Pancreatic ductal adenocarcinoma (PDAC) has earned a notorious reputation as one of the most formidable and deadliest malignant tumors. Within the tumor microenvironment, cancer cells have acquired the capability to maintain incessant expansion and increased proliferation in response to hypoxia via metabolic reconfiguration, leading to elevated levels of lactate within the tumor surroundings. However, there have been limited studies specifically investigating the association between hypoxia and lactic acid metabolism-related lactylation in PDAC. In this study, multiple machine learning approaches, including LASSO regression analysis, XGBoost, and Random Forest, were employed to identify hub genes and construct a prognostic risk signature. The implementation of the CERES score and single-cell analysis was used to discern a prospective therapeutic target for the management of PDAC. CCK8 assay, colony formation assays, transwell, and wound-healing assays were used to explore both the proliferation and migration of PDAC cells affected by CENPA. In conclusion, we discovered two distinct subtypes characterized by their unique hypoxia and lactylation profiles and developed a risk score to evaluate prognosis, as well as response to immunotherapy and chemotherapy, in PDAC patients. Furthermore, we indicated that CENPA may serve as a promising therapeutic target for PDAC.

Research progress in the biosynthesis of xylitol: feedstock evolution from xylose to glucose.

Xylitol, as an important food additive and fine chemical, has a wide range of applications, including food, medicine, chemical, and feed. This review paper focuses on the research progress of xylitol biosynthesis, from overcoming the limitations of traditional chemical hydrogenation and xylose bioconversion, to the full biosynthesis of xylitol production using green and non-polluting glucose as substrate. In the review, the molecular strategies of wild strains to increase xylitol yield, as well as the optimization strategies and metabolic reconfiguration during xylitol biosynthesis are discussed. Subsequently, on the basis of existing studies, the paper further discusses the current status of research and future perspectives of xylitol production using glucose as a single substrate. The evolution of raw materials from xylose-based five-carbon sugars to glucose is not only cost-saving, but also safe and environmentally friendly, which brings new opportunities for the green industrial chain of xylitol.

Microbial colonisation rewires the composition and content of poplar root exudates, root and shoot metabolomes

BackgroundTrees are associated with a broad range of microorganisms colonising the diverse tissues of their host. However, the early dynamics of the microbiota assembly microbiota from the root to shoot axis and how it is linked to root exudates and metabolite contents of tissues remain unclear. Here, we characterised how fungal and bacterial communities are altering root exudates as well as root and shoot metabolomes in parallel with their establishment in poplar cuttings (Populus tremula x tremuloides clone T89) over 30 days of growth. Sterile poplar cuttings were planted in natural or gamma irradiated soils. Bulk and rhizospheric soils, root and shoot tissues were collected from day 1 to day 30 to track the dynamic changes of fungal and bacterial communities in the different habitats by DNA metabarcoding. Root exudates and root and shoot metabolites were analysed in parallel by gas chromatography-mass spectrometry.ResultsOur study reveals that microbial colonisation triggered rapid and substantial alterations in both the composition and quantity of root exudates, with over 70 metabolites exclusively identified in remarkably high abundances in the absence of microorganisms. Noteworthy among these were lipid-related metabolites and defence compounds. The microbial colonisation of both roots and shoots exhibited a similar dynamic response, initially involving saprophytic microorganisms and later transitioning to endophytes and symbionts. Key constituents of the shoot microbiota were also discernible at earlier time points in the rhizosphere and roots, indicating that the soil constituted a primary source for shoot microbiota. Furthermore, the microbial colonisation of belowground and aerial compartments induced a reconfiguration of plant metabolism. Specifically, microbial colonisation predominantly instigated alterations in primary metabolism in roots, while in shoots, it primarily influenced defence metabolism.ConclusionsThis study highlighted the profound impact of microbial interactions on metabolic pathways of plants, shedding light on the intricate interplay between plants and their associated microbial communities.2SWtA3_gUD-Xt4Z7N25436Video

Exploring the mystery of tumor metabolism: Warburg effect and mitochondrial metabolism fighting side by side

The metabolic reconfiguration of tumor cells constitutes a pivotal aspect of tumor proliferation and advancement. This study delves into two primary facets of tumor metabolism: the Warburg effect and mitochondrial metabolism, elucidating their contributions to tumor dominance. The Warburg effect facilitates efficient energy acquisition by tumor cells through aerobic glycolysis and lactic acid fermentation, offering metabolic advantages conducive to growth and proliferation. Simultaneously, mitochondrial metabolism, serving as the linchpin of sustained tumor vitality, orchestrates the tricarboxylic acid cycle and electron transport chain, furnishing a steadfast and dependable wellspring of biosynthesis for tumor cells. Regarding targeted therapy, this discourse examines extant strategies targeting tumor glycolysis and mitochondrial metabolism, underscoring their potential efficacy in modulating tumor metabolism while envisaging future research trajectories and treatment paradigms in the realm of tumor metabolism. By means of a thorough exploration of tumor metabolism, this study aspires to furnish crucial insights into the regulation of tumor metabolic processes, thereby furnishing valuable guidance for the development of novel therapeutic modalities. This comprehensive deliberation is poised to catalyze advancements in tumor metabolism research and offer novel perspectives and pathways for the formulation of cancer treatment strategies in the times ahead.

Gut Microbiota Analysis in Silkworms (Bombyx mori) Provides Insights into Identifying Key Bacterials for Inclusion in Artificial Diet Formulations.

The gut microbiome significantly influences the health and productivity of silkworms (Bombyx mori), the cornerstone of sericulture. With the increasing use of cost-effective artificial diets in sericulture, it is crucial to understand how these diets impact the silkworm gut microbiomes. Here we employed 16S rRNA sequencing to delineate the impact of three distinct dietary regimens on the silkworm gut microbiomes: exclusive mulberry leaf diet (SY), exclusive artificial feed diet (SL), and a sequential transition from artificial feed to mulberry leaves (ZS). Our results unveiled stark differences in microbial diversity across the groups, with the ZS group displaying an intermediary complexity. LefSe and random forest analyses identified Methylobacteriaceae, Microbacterium, and Rhodococcus as significantly enriched in the ZS group, suggesting their potential to facilitate silkworms' adaptation to dietary transitions. Functional profiling revealed differential pathway regulation, indicating a metabolic reconfiguration in response to dietary modulations. Notably, the enrichment of Lactobacillus and Weissella in both the SL and ZS groups highlights their potential as probiotics in artificial diets. Our findings provide insights into the diet adaptation mechanisms of silkworm gut microbiota, paving the way for harnessing the intestinal bacteria to enhance silkworm health and silk production through targeted microbial interventions in sericulture practices.

Activation of immune pathways in common bed bugs, Cimex lectularius, in response to bacterial immune challenges - a transcriptomics analysis.

The common bed bug, Cimex lectularius, is an urban pest of global health significance, severely affecting the physical and mental health of humans. In contrast to most other blood-feeding arthropods, bed bugs are not major vectors of pathogens, but the underlying mechanisms for this phenomenon are largely unexplored. Here, we present the first transcriptomics study of bed bugs in response to immune challenges. To study transcriptional variations in bed bugs following ingestion of bacteria, we extracted and processed mRNA from body tissues of adult male bed bugs after ingestion of sterile blood or blood containing the Gram-positive (Gr+) bacterium Bacillus subtilis or the Gram-negative (Gr-) bacterium Escherichia coli. We analyzed mRNA from the bed bugs' midgut (the primary tissue involved in blood ingestion) and from the rest of their bodies (RoB; body minus head and midgut tissues). We show that the midgut exhibits a stronger immune response to ingestion of bacteria than the RoB, as indicated by the expression of genes encoding antimicrobial peptides (AMPs). Both the Toll and Imd signaling pathways, associated with immune responses, were highly activated by the ingestion of bacteria. Bacterial infection in bed bugs further provides evidence for metabolic reconfiguration and resource allocation in the bed bugs' midgut and RoB to promote production of AMPs. Our data suggest that infection with particular pathogens in bed bugs may be associated with altered metabolic pathways within the midgut and RoB that favors immune responses. We further show that multiple established cellular immune responses are preserved and are activated by the presence of specific pathogens. Our study provides a greater understanding of nuances in the immune responses of bed bugs towards pathogens that ultimately might contribute to novel bed bug control tactics.

Low Nitrogen Input Mitigates Quantitative but Not Qualitative Reconfiguration of Leaf Primary Metabolism in Brassica napus L. Subjected to Drought and Rehydration.

In the context of climate change and the reduction of mineral nitrogen (N) inputs applied to the field, winter oilseed rape (WOSR) will have to cope with low-N conditions combined with water limitation periods. Since these stresses can significantly reduce seed yield and seed quality, maintaining WOSR productivity under a wide range of growth conditions represents a major goal for crop improvement. N metabolism plays a pivotal role during the metabolic acclimation to drought in Brassica species by supporting the accumulation of osmoprotective compounds and the source-to-sink remobilization of nutrients. Thus, N deficiency could have detrimental effects on the acclimation of WOSR to drought. Here, we took advantage of a previously established experiment to evaluate the metabolic acclimation of WOSR during 14 days of drought, followed by 8 days of rehydration under high- or low-N fertilization regimes. For this purpose, we selected three leaf ranks exhibiting contrasted sink/source status to perform absolute quantification of plant central metabolites. Besides the well-described accumulation of proline, we observed contrasted accumulations of some "respiratory" amino acids (branched-chain amino acids, lysineand tyrosine) in response to drought under high- and low-N conditions. Drought also induced an increase in sucrose content in sink leaves combined with a decrease in source leaves. N deficiency strongly decreased the levels of major amino acids and subsequently the metabolic response to drought. The drought-rehydration sequence identified proline, phenylalanine, and tryptophan as valuable metabolic indicators of WOSR water status for sink leaves. The results were discussed with respect to the metabolic origin of sucrose and some amino acids in sink leaves and the impact of drought on source-to-sink remobilization processes depending on N nutrition status. Overall, this study identified major metabolic signatures reflecting a similar response of oilseed rape to drought under low- and high-N conditions.

Adaptive laboratory evolution of Naematelia aurantialba under high temperature for efficient production of exopolysaccharide

Liquid fermentation could revolutionize mushroom polysaccharide production, but the low temperature constraint hampers the process. This study implemented adaptive laboratory evolution (ALE) to enhance the thermotolerance of Naematelia aurantialba strains and increase expolysaccharide production. After 75 ALE cycles at 30 °C, the adaptive strain surpassed the wild-type strain by 5 °C. In a 7.5 L fermentor at 30 °C, the ALE strain yielded 17 % more exopolysaccharide than the wild type strain at 25 °C. Although the exopolysaccharide synthesized by both strains shares a consistent monosaccharide composition, infrared spectrum, and glycosidic bond composition, the ALE strain's exopolysaccharide has a larger molecular weight. Furthermore, the ALE strain's exopolysaccharide exhibits superior cryoprotection performance compared to that produced by the original strain. The adapted strain demonstrated lower ROS levels and increased activity of antioxidant enzymes, indicating improved performance. Fatty acid profiling and transcriptomics revealed reconfiguration of carbohydrate metabolism, amino acid metabolism, and membrane lipid synthesis in thermophilic strains, maintaining cellular homeostasis and productivity. This study provides efficient strains and fermentation methods for high-temperature mushroom polysaccharide production, reducing energy consumption and costs.

Mitochondria: the gatekeepers between metabolism and immunity.

Metabolism and immunity are crucial monitors of the whole-body homeodynamics. All cells require energy to perform their basic functions. One of the most important metabolic skills of the cell is the ability to optimally adapt metabolism according to demand or availability, known as metabolic flexibility. The immune cells, first line of host defense that circulate in the body and migrate between tissues, need to function also in environments in which nutrients are not always available. The resilience of immune cells consists precisely in their high adaptive capacity, a challenge that arises especially in the framework of sustained immune responses. Pubmed and Scopus databases were consulted to construct the extensive background explored in this review, from the Kennedy and Lehninger studies on mitochondrial biochemistry of the 1950s to the most recent findings on immunometabolism. In detail, we first focus on how metabolic reconfiguration influences the action steps of the immune system and modulates immune cell fate and function. Then, we highlighted the evidence for considering mitochondria, besides conventional cellular energy suppliers, as the powerhouses of immunometabolism. Finally, we explored the main immunometabolic hubs in the organism emphasizing in them the reciprocal impact between metabolic and immune components in both physiological and pathological conditions.

Metabolomic and Growth Responses of Houttyunia cordata to Varying Light Intensities and Subsequent Effects on Fermented Products

Suitable light intensities were studied to enable sustainable and efficient cultivation of Houttuynia cordata with a high yield of bioactive compounds which later can be a good quality material for fermentation. To achieve this goal, the evaluation of physiological adaptation and elucidation of the metabolic alterations of Houttuynia cordata in response to different light intensities were conducted. Four-month-old H. cordata was exposed to 3 different light intensities: high light, control, and low light (100, 50 and 20 % natural irradiances, respectively). Physiological responses were measured using leaf gas exchange. The same leaf samples were either methanolic extracted for LC-QTOF-MS analysis to generate metabolite fingerprints or fermented for 3 months prior to quercetin quantification. High light treatment had the greatest effects on both the physiology and metabolisms of H. cordata compared to control and low light treatments. Compared to the control, the key results observed in high-light-grown H. cordata were a significant increase in photosynthesis, a decrease in relative chlorophyll contents, the enrichment of the top 3 metabolic pathways (phenylpropanoid biosynthesis, pyruvate metabolism and fatty acid degradation) and increasing quercetin concentrations in both fresh and fermented leaves. Metabolite fingerprints of high light-grown H. cordata were distinctively different from those of the other 2 treatments according to PCA and hierarchical clustering analysis. In conclusion, H. cordata responded to high light intensity by enriching the phenylpropanoid biosynthetic pathway to elevate sunscreen pigments. Additional acetyl-CoA generated from pyruvate metabolism and fatty acid degradation was a key supporting factor in the above response. As high quercetin concentration was observed in both fresh and fermented leaves, this will lead to quality improvement of the fermented products. HIGHLIGHTS The remarkable effects of light intensities on Houttuynia cordata growth and abundance of bioactive compounds are substantial, but the underlying mechanism has never been investigated. Metabolomics technology was applied to gain insight into light-induced metabolic reconfiguration. GRAPHICAL ABSTRACT

Metabolic reconfiguration in vitiligo: progress and future

Metabolic reconfiguration in vitiligo: progress and future

Minimal aromatic aldehyde reduction (MARE) yeast platform for engineering vanillin production

BackgroundVanillin represents one of the most widely used flavoring agents in the world. However, microbial synthesis of vanillin is hindered by the host native metabolism that could rapidly degrade vanillin to the byproducts.ResultsHere, we report that the industrial workhorse Saccharomyces cerevisiae was engineered by systematic deletion of oxidoreductases to improve the vanillin accumulation. Subsequently, we harnessed the minimal aromatic aldehyde reduction (MARE) yeast platform for de novo synthesis of vanillin from glucose. We investigated multiple coenzyme-A free pathways to improve vanillin production in yeast. The vanillin productivity in yeast was enhanced by multidimensional engineering to optimize the supply of cofactors (NADPH and S-adenosylmethionine) together with metabolic reconfiguration of yeast central metabolism. The final yeast strain with overall 24 genetic modifications produced 365.55 ± 7.42 mg l−1 vanillin in shake-flasks, which represents the best reported vanillin titer from glucose in yeast.ConclusionsThe success of vanillin overproduction in budding yeast showcases the great potential of synthetic biology for the creation of suitable biocatalysts to meet the requirement in industry. Our work lays a foundation for the future implementation of microbial production of aromatic aldehydes in budding yeast.Graphical

Stem Cells Derived from Human Exfoliated Deciduous Teeth Functional Assessment: Exploring the Changes of Free Fatty Acids Composition during Cultivation.

The metabolic regulation of stemness is widely recognized as a crucial factor in determining the fate of stem cells. When transferred to a stimulating and nutrient-rich environment, mesenchymal stem cells (MSCs) undergo rapid proliferation, accompanied by a change in protein expression and a significant reconfiguration of central energy metabolism. This metabolic shift, from quiescence to metabolically active cells, can lead to an increase in the proportion of senescent cells and limit their regenerative potential. In this study, MSCs from human exfoliated deciduous teeth (SHEDs) were isolated and expanded in vitro for up to 10 passages. Immunophenotypic analysis, growth kinetics, in vitro plasticity, fatty acid content, and autophagic capacity were assessed throughout cultivation to evaluate the functional characteristics of SHEDs. Our findings revealed that SHEDs exhibit distinctive patterns of cell surface marker expression, possess high self-renewal capacity, and have a unique potential for neurogenic differentiation. Aged SHEDs exhibited lower proliferation rates, reduced potential for chondrogenic and osteogenic differentiation, an increasing capacity for adipogenic differentiation, and decreased autophagic potential. Prolonged cultivation of SHEDs resulted in changes in fatty acid composition, signaling a transition from anti-inflammatory to proinflammatory pathways. This underscores the intricate connection between metabolic regulation, stemness, and aging, crucial for optimizing therapeutic applications.

Modular bioengineering of whole-cell catalysis for sialo-oligosaccharide production: coordinated co-expression of CMP-sialic acid synthetase and sialyltransferase

BackgroundIn whole-cell bio-catalysis, the biosystems engineering paradigm shifts from the global reconfiguration of cellular metabolism as in fermentation to a more focused, and more easily modularized, optimization of comparably short cascade reactions. Human milk oligosaccharides (HMO) constitute an important field for the synthetic application of cascade bio-catalysis in resting or non-living cells. Here, we analyzed the central catalytic module for synthesis of HMO-type sialo-oligosaccharides, comprised of CMP-sialic acid synthetase (CSS) and sialyltransferase (SiaT), with the specific aim of coordinated enzyme co-expression in E. coli for reaction flux optimization in whole cell conversions producing 3′-sialyllactose (3SL).ResultsDifference in enzyme specific activity (CSS from Neisseria meningitidis: 36 U/mg; α2,3-SiaT from Pasteurella dagmatis: 5.7 U/mg) was compensated by differential protein co-expression from tailored plasmid constructs, giving balance between the individual activities at a high level of both (α2,3-SiaT: 9.4 × 102 U/g cell dry mass; CSS: 3.4 × 102 U/g cell dry mass). Finally, plasmid selection was guided by kinetic modeling of the coupled CSS-SiaT reactions in combination with comprehensive analytical tracking of the multistep conversion (lactose, N-acetyl neuraminic acid (Neu5Ac), cytidine 5′-triphosphate; each up to 100 mM). The half-life of SiaT in permeabilized cells (≤ 4 h) determined the efficiency of 3SL production at 37 °C. Reaction at 25 °C gave 3SL (40 ± 4 g/L) in ∼ 70% yield within 3 h, reaching a cell dry mass-specific productivity of ∼ 3 g/(g h) and avoiding intermediary CMP-Neu5Ac accumulation.ConclusionsCollectively, balanced co-expression of CSS and SiaT yields an efficient (high-flux) sialylation module to support flexible development of E. coli whole-cell catalysts for sialo-oligosaccharide production.

Modulation of angiogenic switch in reprogramming browning and lipid metabolism in white adipocytes

Thermogenic activation via trans-and de novo browning of white adipocytes is a promising strategy to accelerate lipid metabolism for regulating obesity-related disorders. In this study, we investigated the intricate interplay between angiogenic regulation and browning in white adipocytes using the bioactive compound, resveratrol (Rsv). Rsv has previously been documented for its regulatory influence on the trans and de novo browning of white adipocytes. Our findings revealed that concurrent activation of angiogenesis is prerequisite for inducing browning within the microenvironment of white adipocytes when exposed to browning activators. Additionally, we observed a significant browning effect on white adipocytes when the local adipose tissue environment was prompted to undergo angiogenesis, notably facilitated by a proangiogenic molecule known as Vascular endothelial growth factor (VEGF). Intriguingly, this effect was reversed when angiogenesis was inhibited by treatment with the antiangiogenic agent thalidomide. Furthermore, the study revealed the role of VEGF in paracrine activation of white adipocytes resulting in the induction of browning in both 3T3-L1 cell lines and primary mouse white adipocytes. The cross-talk between angiogenesis and browning was found to be initiated via the transcriptional activation of Estrogen receptor α (ERα) triggering the VEGF/VEGFR2 signaling pathway leading to browning and a reconfiguration of lipid metabolism within adipocytes. In conclusion, this study sheds light on the intricate cross-talk between angiogenesis and browning of white adipocytes. Notably, the findings underscore the reciprocal relationship between these processes, wherein inhibition of one process exerts discernible effects on the other.

AMPKα1 negatively regulates osteoclastogenesis and mitigates pathological bone loss

Osteoclasts are specialized cells responsible for bone resorption, a highly energy-demanding process. Focus on osteoclast metabolism could be a key for the treatment of osteolytic diseases including osteoporosis. In this context, AMP-activated protein kinase α1 (AMPKα1), an energy sensor highly expressed in osteoclasts, participates in the metabolic reconfiguration during osteoclast differentiation and activation. This study aimed to elucidate the role of AMPKα1 during osteoclastogenesis in vitro and its impact in bone loss in vivo. Using LysMcre/0AMPK⍺1f/f animals and LysMcre/0 as control, we evaluated how AMPKα1 interferes with osteoclastogenesis and bone resorption activity in vitro. We found that AMPKα1 is highly expressed in the early stages of osteoclastogenesis. Genetic deletion of AMPKα1 leads to increased gene expression of osteoclast differentiation and fusion markers. In addition, LysMcre/0AMPK⍺1f/f mice had an increased number and size of differentiated osteoclast. Accordingly, AMPKα1 negatively regulates bone resorption in vitro, as evidenced by the area of bone resorption in LysMcre/0AMPK⍺1f/f osteoclasts. Our data further demonstrated that AMPKα1 regulates mitochondrial fusion and fission markers upregulating Mfn2 and downregulating DRP1 (dynamics-related protein 1) and that Ctskcre/0AMPK⍺1f/f osteoclasts lead to an increase in the number of mitochondria in AMPK⍺1-deficient osteoclast. In our in vivo study, femurs from Ctskcre/0AMPK⍺1f/f animals exhibited bone loss associated with the increased number of osteoclasts, and there was no difference between Sham and ovariectomized group. Our data suggest that AMPKα1 acts as a negative regulator of osteoclastogenesis, and the depletion of AMPKα1 in osteoclast leads to a bone loss state similar to that observed after ovariectomy.

Metabolic proteins with crucial roles in Edwardsiella tarda antioxidative adaptation and intracellular proliferation.

Edwardsiella tarda is a severe fish pathogen, featured by its capacity to live inside host phagocytes. For intracellular survival, it is crucial for E. tarda to neutralize the deleterious effect of host reactive oxygen species (ROS). Accumulating evidence suggests that bacterial metabolism is closely connected to oxidative resistance. However, the roles of E. tarda metabolic proteins in antioxidative adaptation and intracellular proliferation remain elusive. In this study, we performed a proteomic analysis on E. tarda and identified 111 proteins responsive to H2O2-mediated oxidative stress. Based on this data, we further obtained eight crucial proteins, including seven metabolic proteins, for E. tarda antioxidation and intracellular infection. Among them, two C4-dicarboxylate transporters were found necessary for E. tarda to disseminate in fish tissues. Furthermore, the substrate of the two transporters was identified as L-aspartate, which was proven to be essential for the full antioxidative capacity of E. tarda. Our results indicate that reprogramming the metabolic flux to the production of pyruvate, a ketoacid capable of neutralizing ROS, was likely a pivotal strategy of E. tarda to survive the oxidative environments inside host cells. Together, the findings of this study highlight the significance of metabolic reprogramming for bacterial redox homeostasis and intracellular infection. IMPORTANCE Edwardsiella tarda is a significant fish pathogen that can live in challenging environments of reactive oxygen species (ROS), such as inside the phagocytes. Metabolic reconfiguration has been increasingly associated with bacterial oxidative tolerance and virulence. However, the metabolic proteins of E. tarda involved in such processes remain elusive. By proteomic analysis and functional characterization of protein null mutants, the present study identified eight crucial proteins for bacterial oxidative resistance and intracellular infection. Seven of them are metabolic proteins dictating the metabolic flux toward the generation of pyruvate, a key metabolite capable of scavenging ROS molecules. Furthermore, L-aspartate uptake, which can fuel the pyruvate generation, was found essential for the full antioxidative capacity of E. tarda. These findings identified seven metabolic proteins involved in bacterial oxidative adaptation and indicate that metabolic reprogramming toward pyruvate was likely a pivotal strategy of bacteria for antioxidative adaptation and intracellular survival.

Homoharringtonine as a PHGDH inhibitor: Unraveling metabolic dependencies and developing a potent therapeutic strategy for high-risk neuroblastoma

Neuroblastoma, a childhood cancer affecting the sympathetic nervous system, continues to challenge the development of potent treatments due to the limited availability of druggable targets for this aggressive illness. Recent investigations have uncovered that phosphoglycerate dehydrogenase (PHGDH), an essential enzyme for de novo serine synthesis, serves as a non-oncogene dependency in high-risk neuroblastoma. In this study, we show that homoharringtonine (HHT) acts as a PHGDH inhibitor, inducing intricate alterations in cellular metabolism, and thus providing an efficient treatment for neuroblastoma. We have experimentally verified the reliance of neuroblastoma on PHGDH and employed molecular docking, thermodynamic evaluations, and X-ray crystallography techniques to determine the bond interactions between HHT and PHGDH. Administering HHT to treat neuroblastoma resulted in effective cell elimination in vitro and tumor reduction in vivo. Metabolite and functional assessments additionally disclosed that HHT treatment suppressed de novo serine synthesis, initiating intricate metabolic reconfiguration and oxidative stress in neuroblastoma. Collectively, these discoveries highlight the potential of targeting PHGDH using HHT as a potent approach for managing high-risk neuroblastoma.

Systemic analysis of metabolome reconfiguration in Arabidopsis after abiotic stressors uncovers metabolites that modulate defense against pathogens

Understanding plant immune responses is complex because of the high interdependence among biological processes in homeostatic networks. Hence, the integration of environmental cues causes network rewiring that interferes with defense responses. Similarly, plants retain molecular signatures configured under abiotic stress periods to rapidly respond to recurrent stress, and these can alter immunity. Metabolome changes imposed by abiotic stressors are persistent, although their impact on defense remains to be clarified. In this study, we profiled metabolomes of Arabidopsis plants under several abiotic stress treatments applied individually or simultaneously to capture temporal trajectories in metabolite composition during adverse conditions and recovery. Further systemic analysis was performed to address the relevance of metabolome changes and extract central features to be tested in planta. Our results demonstrate irreversibility in major fractions of metabolome changes as a general pattern in response to abiotic stress periods. Functional analysis of metabolomes and co-abundance networks points to convergence in the reconfiguration of organic acid and secondary metabolite metabolism. Arabidopsis mutant lines for components related to these metabolic pathways showed altered defense capacities against different pathogens. Collectively, our data suggest that sustained metabolome changes configured in adverse environments can act as modulators of immune responses and provide evidence for a new layer of regulation in plant defense.

Metabolite profiling of susceptible and resistant wheat (Triticum aestivum) cultivars responding to Puccinia striiformis f. sp. tritici infection

BackgroundPuccinia striiformis f. sp. tritici (Pst) is an economically devasting disease that is prominent in cereal crops such as wheat (Triticum aestivum). The fungal pathogen can cause approximately 30–70% losses in crop productivity and yields. Pst has become difficult to manage due to its ease of transmission through wind dispersal over long distances, and intercontinental dispersal has been previously reported. The ease of transmission has resulted in further destruction because of new and more virulent strains infecting crops previously resistant to a different strain.ResultsIn this study, a liquid chromatography-mass spectrometry-based untargeted metabolomics approach, in combination with multivariate data analytical tools, was used to elucidate the mechanistic nature of the defence systems of a Pst-resistant and a susceptible wheat cultivar infected with P. striiformis. We also investigated the time-dependant metabolic reconfiguration of infected plants over a four-week period. The untargeted metabolomic analysis revealed a time-course metabolic reprogramming involving phenylpropanoids (majority flavonoids), amino acids, lipids, benzoic acids, TCA cycle intermediates and benzoxazinoids responding to Pst infection. Interestingly, the results do not show a linear course for the decrease and increase (up-/down-regulation) of said classes of metabolites, but rather the up- or down-regulation of specific metabolites in response to the pathogen infection. The resistant Koonap cultivar had an abundance of phenolic compounds such as rutin, isoorintin-7-O-glucoside and luteolin-6-C-hexoside-O-hexoside. These compounds showed a decrease over time in control Koonap plants compared to an increase in Pst-infected plants. These metabolites were down-regulated in the susceptible Gariep cultivar, which could serve as biomarkers for plant responses to biotic stress and resistance against Pst.ConclusionsOverall, an LC-MS-based metabolomics approach allowed for the metabolic profiling and analysis of the impact of plant-pathogen interactions on the overall plant metabolome and provided a real-time snapshot of the differential significant metabolic perturbations occurring in wheat plants responding to the Pst pathogen. The Pst-resistant Koonap cultivar showed a rapid accumulation of defence metabolites in response to pathogen infection compared to the susceptible Gariep cultivar. These findings provide insight into the mechanistic biochemical nature of plant-microbe interactions and the prospects of metabolic engineering for improved plant tolerance and resistance to biotic stresses.