Nucleoside Metabolism Research Articles

Совершенствование маршрутизации в системе расширенного неонатального скрининга для диагностики первичных иммунодефицитов

Expanded neonatal screening (ENS) system is a crucial invention that was aimed at reducing infant mortality by enabling the early detection and treatment of severe and life-threatening conditions. Since its Russia-wide implementation in 2023 ENS had successfully identified hundreds of cases of newborns at risk allowing further timely medical intervention that often happened even at a pre-symptomatic stage. However, further optimization of patient routing algorithms within ENS is necessary in order to enhance the identification of newborns at risk and expedite their diagnosis and treatment. This manuscript focuses on optimizing of the routing algorithms specifically for newborns with suspected adenosine deaminase (ADA) deficiency, a severe form of primary immunodeficiency. Given the unique therapeutic and preventive measures required for these patients, the proposed guidelines expand the criteria for referring newborns for confirmatory diagnostics based on nucleoside metabolism data obtained from tandem mass spectrometry of dried blood spots. These improvements are aimed to the earliest detection and targeted treatment of newborns with ADA deficiency thereby enhancing the overall efficiency of primary immunodeficiency screening in Russia.

CX43-mediated mitochondrial transfer maintains stemness of KG-1a leukemia stem cells through metabolic remodeling

BackgroundAcute myeloid leukemia (AML) is characterized by abundant immature myeloid cells, relapse and refractory due to leukemia stem cells (LSCs). Bone marrow mesenchymal stem/ stromal cells (BMSCs) supported LSCs survival, meanwhile, chemotherapy improved connexin43 (CX43) expression. CX43, as the most intercellular gap junction, facilitated transmit mitochondria from BMSCs into AML. We hypothesized that increased mitochondria transferred from BMSCs supported metabolic remodeling in LSCs to sustain their stemness.MethodsPrimary BMSCs from AML patients were isolated. CX43-BMSCs, overexpressing CX43, were cocultured with KG-1a cells. Fluorescence and confocal microscopy observed mitochondrial transfer. Flow cytometry, EdU assay, and clonogenicity evaluated cell cycle, proliferation, and clonogenic potential. Xenograft mouse models were used to evaluate the tumorigenicity of KG-1a in vivo. Seahorse, RNA-seq, and LC-MS assessed mitochondrial function, transcriptomes, and metabolites post-coculture.ResultsCX43-BMSCs promoted unidirectional mitochondrial transfer, enhancing KG-1a adhesion and proliferation to maintain LSCs stemness in vitro and vivo. RNA-seq revealed coculture with CX43-BMSCs upregulated genes related to adhesion, proliferation, and migration in KG-1a cells. Elevated CX43 expression strengthened BMSCs-KG-1a interaction, facilitating mitochondrial transfer and nucleoside metabolism, fueling KG-1a cells. This enhanced mitochondrial energy metabolism, promoting metabolic reprogramming and clonogenicity.ConclusionCX43-mediated mitochondrial transfer from BMSCs to KG-1a enhances LSCs adhesion, proliferation, clonogenicity, and metabolic reprogramming. CX43 emerges as a potential therapeutic target for AML by sustaining LSCs stemness through metabolic remodeling.

Nutritional vitamin B12 regulates RAS/MAPK-mediated cell fate decisions through one-carbon metabolism

Vitamin B12 is an essential nutritional co-factor for the folate and methionine cycles, which together constitute one-carbon metabolism. Here, we show that dietary uptake of vitamin B12 modulates cell fate decisions controlled by the conserved RAS/MAPK signaling pathway in C. elegans. A bacterial diet rich in vitamin B12 increases vulval induction, germ cell apoptosis and oocyte differentiation. These effects are mediated by different one-carbon metabolites in a tissue-specific manner. Vitamin B12 enhances via the choline/phosphatidylcholine metabolism vulval induction by down-regulating fat biosynthesis genes and increasing H3K4 tri-methylation, which results in increased expression of RAS/MAPK target genes. Furthermore, the nucleoside metabolism and H3K4 tri-methylation positively regulate germ cell apoptosis and oocyte production. Using mammalian cells carrying different activated KRAS and BRAF alleles, we show that the effects of methionine on RAS/MAPK-regulated phenotype are conserved in mammals. Our findings suggest that the vitamin B12-dependent one-carbon metabolism is a limiting factor for diverse RAS/MAPK-induced cellular responses.

Purines and pyrimidines in the trophoblast; ontogeny of genes involved in their metabolism and effect of nucleosides on gene regulation and cytotrophoblast proliferation

Purines and pyrimidines in the trophoblast; ontogeny of genes involved in their metabolism and effect of nucleosides on gene regulation and cytotrophoblast proliferation

Urine metabolomics signature reveals novel determinants of adrenal suppression in children taking inhaled corticosteroids to control asthma symptoms.

Asthma is routinely treated with inhaled corticosteroids (ICS). Asthma patients on ICS are at increased risk of adrenal suppression, a potentially serious effect of long-term glucocorticoid exposure; however, this relationship is poorly understood. Therefore, this study aims to identify metabolite biomarkers related to adrenal suppression in asthma patients taking ICS. A total of 571 urine metabolites from 200 children with asthma on ICS in the Pharmacogenetics of Adrenal Suppression with Inhaled Steroids (PASS) cohort were profiled. Samples were grouped by peak plasma cortisol measurement as adrenal sufficient (>350 nmol/L) or insufficient (≤350 nmol/L) (outcome). Regression and discriminant-based statistical models combined with network analyses were utilized to assess relationships between metabolites and the outcome. Finally, prioritized metabolites were validated using data from an ancillary study of the Childhood Asthma Management (CAMP) cohort with similar characteristics to PASS. Ninety metabolites were significantly associated with adrenal suppression, of which 57 also could discriminate adrenal status. While 26 metabolites (primarily steroids) were present at lower levels in the adrenal insufficient patients, 14 were significantly elevated in this group; the top metabolite, mannitol/sorbitol, was previously associated with asthma exacerbations. Network analyses identified unique clusters of metabolites related to steroids, fatty acid oxidation, and nucleoside metabolism, respectively. Four metabolites including urocanic acid, acetylcarnitine, uracil, and sorbitol were validated in CAMP cohort for adrenal suppression. Urinary metabolites differ among asthma patients on ICS, by adrenal status. While steroid metabolites were reduced in patients with poor adrenal function, our findings also implicate previously unreported metabolites involved in amino acid, lipid, and nucleoside metabolism.

Advances in next-generation sequencing for relapsed pediatric acute lymphoblastic leukemia: current insights and future directions.

Leukemia is one of the most common cancers in children; and its genetic diversity in the landscape of acute lymphoblastic leukemia (ALL) is important for diagnosis, risk assessment, and therapeutic approaches. Relapsed ALL remains the leading cause of cancer deaths among children. Almost 20% of children who are treated for ALL and achieve complete remission experience disease recurrence. Relapsed ALL has a poor prognosis, and relapses are more likely to have mutations that affect signaling pathways, chromatin patterning, tumor suppression, and nucleoside metabolism. The identification of ALL subtypes has been based on genomic alterations for several decades, using the molecular landscape at relapse and its clinical significance. Next-generation sequencing (NGS), also known as massive parallel sequencing, is a high-throughput, quick, accurate, and sensitive method to examine the molecular landscape of cancer. This has undoubtedly transformed the study of relapsed ALL. The implementation of NGS has improved ALL genomic analysis, resulting in the recent identification of various novel molecular entities and a deeper understanding of existing ones. Thus, this review aimed to consolidate and critically evaluate the most current information on relapsed pediatric ALL provided by NGS technology. In this phase of targeted therapy and personalized medicine, identifying the capabilities, benefits, and drawbacks of NGS will be essential for healthcare professionals and researchers offering genome-driven care. This would contribute to precision medicine to treat these patients and help improve their overall survival and quality of life.

Gallein potentiates isoniazid's ability to suppress Mycobacterium tuberculosis growth.

Mycobacterium tuberculosis (Mtb), the bacterium that causes tuberculosis (TB), can be difficult to treat because of drug tolerance. Increased intracellular polyphosphate (polyP) in Mtb enhances tolerance to antibiotics, and capsular polyP in Neisseria gonorrhoeae potentiates resistance to antimicrobials. The mechanism by which bacteria utilize polyP to adapt to antimicrobial pressure is not known. In this study, we found that Mtb adapts to the TB frontline antibiotic isoniazid (INH) by enhancing the accumulation of cellular, extracellular, and cell surface polyP. Gallein, a broad-spectrum inhibitor of the polyphosphate kinase that synthesizes polyP, prevents this INH-induced increase in extracellular and cell surface polyP levels. Gallein and INH work synergistically to attenuate Mtb's ability to grow in in vitro culture and within human macrophages. Mtb when exposed to INH, and in the presence of INH, gallein inhibits cell envelope formation in most but not all Mtb cells. Metabolomics indicated that INH or gallein have a modest impact on levels of Mtb metabolites, but when used in combination, they significantly reduce levels of metabolites involved in cell envelope synthesis and amino acid, carbohydrate, and nucleoside metabolism, revealing a synergistic effect. These data suggest that gallein represents a promising avenue to potentiate the treatment of TB.

Engineering Substrate Promiscuity of Nucleoside Phosphorylase Via an Insertions-Deletions Strategy.

Nucleoside phosphorylases (NPs) are the key enzymes in the nucleoside metabolism pathway and are widely employed for the synthesis of nucleoside analogs, which are difficult to access via conventional synthetic methods. NPs are generally classified as purine nucleoside phosphorylase (PNP) and pyrimidine or uridine nucleoside phosphorylase (PyNP/UP), based on their substrate preference. Here, based on the evolutionary information on the NP-I family, we adopted an insertions-deletions (InDels) strategy to engineer the substrate promiscuity of nucleoside phosphorylase AmPNPΔS2V102K, which exhibits both PNP and UP activities from a trimeric PNP (AmPNP) of Aneurinibacillus migulanus. Furthermore, the AmPNPΔS2V102K exerted phosphorylation activities toward arabinose nucleoside, fluorosyl nucleoside, and dideoxyribose, thereby broadening the unnatural-ribose nucleoside substrate spectrum of AmPNP. Finally, six purine nucleoside analogues were successfully synthesized, using the engineered AmPNPΔS2V102K instead of the traditional "two-enzymes PNP/UP" approach. These results provide deep insights into the catalytic mechanisms of the PNP and demonstrate the benefits of using the InDels strategy to achieve substrate promiscuity in an enzyme, as well as broadening the substrate spectrum of the enzyme.

The identification of a correlation between lipid content in the model diatom Phaeodactylum tricornutum and pH treatment strategies

pH treatment promotes single-cell lipid accumulation and significantly affects microalgae growth. This study investigates the correlation between lipid content and environmental pH using the model diatom Phaeodactylum tricornutum (P. tricornutum). We compared three distinct pH treatment strategies—continuous, intermittent, and a two-phase culture—in P. tricornutum. Rigorous analysis of chlorophyll content, cell density, and lipid content indicated that ongoing pH treatment at pH 9.5 (CHES) emerged as the most effective approach for lipid accumulation in P. tricornutum. The CHES buffer treatment significantly boosted total lipid yield and led to a reduction in protein content. Carbohydrate content experienced a slight decline under CHES buffer treatment, but changes were observed in the activities of key enzymes. Specifically, [acyl-carrier-protein] S-malonyltransferase (MAT) activity decreased after 3 days in the control treatment, while no significant change was noted under the CHES buffer treatment. In contrast, diacylglycerol O-acyltransferase (DGAT) activity showed upregulation 2 and 3 days post-CHES buffer treatment. Moreover, the study identified differentially expressed genes enriched in Gene Ontology (GO) terms associated with protein biosynthesis, photosynthesis, nucleoside metabolism, and transferase activity. These outcomes underscore the pivotal role of CHES buffer in orchestrating primary metabolism, potentially steering carbon flux towards lipogenesis. As a result, the potential of microalgae as a sustainable source of biofuels contributes significantly to the transition towards a more environmentally friendly energy landscape.

Clinical metabolomics of Zicuiyin in treatment of diabetic kidney disease

This study aimed to analyze the therapeutic effect of Zicuiyin on diabetic kidney disease(DKD) and explore the possible targets of this formula. Eighteen DKD patients treated in the endocrine department or nephrology department of Second Affilia-ted Hospital of Tianjin University of Traditional Chinese Medicine from January to December in 2019 were enrolled and assigned into a test group(n=10) and a control group(n=8). Both groups received routine chemical medicine treatment. In addition, the test group was treated with Zicuiyin and the control group with Huangkui Capsules for 8 weeks. The clinical trial was approved by the Ethics Committee of Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, with the ethical approval No. 2017-023-01, and all the patients signed the informed consent form. The results showed that the 8-week treatment with Zicuiyin lowered the level of glycosylated hemoglobin(HbA1c) and recovered the 24 h urinary protein(24hUP), 24 h urinary microalbumin(24hmAlb), urine albumin-to-creatinine ratio(UACR), and estimated glomerular filtration rate(eGFR) of the patients with 24hUP<3.5 g. According to the different levels in 24hUP, all the patients were divided into two subgroups(subgroup A with 24hUP<3.5 g and subgroup B with 24hUP≥3.5 g). The ultra-high performance liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS/MS)-based non-targeted metabolomics analysis was conducted on the baseline serum samples from diffe-rent subgroups of patients. Nineteen biomarker candidates were identified to distinguish the metabolic differences between the two subgroups, and their correlations with clinical indicators were analyzed. Zicuiyin lowered the levels of phenylalanine, pseudouridine, and adenosine [fold change(FC)<0.5, P<0.05] in subgroup A. The results indicated that Zicuiyin was more effective on the DKD patients with low urinary protein levels, and its targets were involved in phenylalanine metabolism and nucleoside metabolism.

Molecular and functional profiling of chemotolerant cells unveils nucleoside metabolism-dependent vulnerabilities in medulloblastoma

Chemotherapy resistance is considered one of the main causes of tumor relapse, still challenging researchers for the identification of the molecular mechanisms sustaining its emergence. Here, we setup and characterized chemotherapy-resistant models of Medulloblastoma (MB), one of the most lethal pediatric brain tumors, to uncover targetable vulnerabilities associated to their resistant phenotype. Integration of proteomic, transcriptomic and kinomic data revealed a significant deregulation of several pathways in resistant MB cells, converging to cell metabolism, RNA/protein homeostasis, and immune response, eventually impacting on patient outcome. Moreover, resistant MB cell response to a large library of compounds through a high-throughput screening (HTS), highlighted nucleoside metabolism as a relevant vulnerability of chemotolerant cells, with peculiar antimetabolites demonstrating increased efficacy against them and even synergism with conventional chemotherapeutics. Our results suggest that drug-resistant cells significantly rewire multiple cellular processes, allowing their adaptation to a chemotoxic environment, nevertheless exposing alternative actionable susceptibilities for their specific targeting.

Tubular dysfunction impairs renal excretion of pseudouridine in diabetic kidney disease.

Plasma nucleosides-pseudouridine (PU) and N2N2-dimethyl guanosine (DMG) predict the progression of type 2 diabetic kidney disease (DKD) to end-stage renal disease, but the mechanisms underlying this relationship are not well understood. We used a well-characterized model of type 2 diabetes (db/db mice) and control nondiabetic mice (db/m mice) to characterize the production and excretion of PU and DMG levels using liquid chromatography-mass spectrometry. The fractional excretion of PU and DMG was decreased in db/db mice compared with control mice at 24 wk before any changes to renal function. We then examined the dynamic changes in nucleoside metabolism using in vivo metabolic flux analysis with the injection of labeled nucleoside precursors. Metabolic flux analysis revealed significant decreases in the ratio of urine-to-plasma labeling of PU and DMG in db/db mice compared with db/m mice, indicating significant tubular dysfunction in diabetic kidney disease. We observed that the gene and protein expression of the renal tubular transporters involved with nucleoside transport in diabetic kidneys in mice and humans was reduced. In conclusion, this study strongly suggests that tubular handling of nucleosides is altered in early DKD, in part explaining the association of PU and DMG with human DKD progression observed in previous studies.NEW & NOTEWORTHY Tubular dysfunction explains the association between the nucleosides pseudouridine and N2N2-dimethyl guanosine and diabetic kidney disease.

In situ analysis of metabolic changes under hypoxic-ischemic encephalopathy via MALDI mass spectrometry imaging

Hypoxic-ischemic encephalopathy (HIE) is a leading cause of neurological disability and even more serious fetal or neonatal asphyxia death. As the therapeutic time window is limited and timely intervention could have a better prognosis, elucidating the mechanisms underlying HIE and developing novel therapeutic strategies is of great importance. In the present study, 1, 5-Diaminonaphthalene hydrochloride (1, 5-DANHCl) assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) was applied to the neonatal rat model of HIE to investigate metabolic changes during hypoxic-ischemic period. Seventy-three metabolites involved in various metabolic pathways such as glycolysis, tricarboxylic acid (TCA) cycle, nucleoside metabolism, lipid metabolism, oxidative stress and ionic homeostasis demonstrated significant changes. It is worth mentioning that we have detected neutral triglycerides (TGs) that are difficult to ionize and observed their accumulation in the ischemic region, which has been rarely reported in previous studies. The results not only help us discover biomarkers but also provide new insights into its mechanism for us to understand the pathological and physiological processes of the disease.

The dynamic change of flavor characteristics in Pacific oyster (Crassostrea gigas) during depuration uncovered by mass spectrometry-based metabolomics combined with gas chromatography-ion mobility spectrometry (GC-IMS)

The flavor of Pacific oyster (Crassostrea gigas) significantly changed during the depuration process. This work aimed to explore the mechanism of flavor changes during the 72 h depuration by metabolomics combined with gas chromatography-ion mobility spectrometry (GC-IMS). The metabolomics analysis indicated that carbohydrate metabolism was more affected in the early stage of depuration, including the citrate cycle, glyoxylae and dicarboxylate metabolism, etc. After 72 h depuration, it affected mainly the metabolism of global and overview maps and nucleoside metabolism, etc. The equivalent umami concentration (EUC) value was calculated and exhibited a gradual increase following a 48 h depuration. The GC–MS results revealed that the content of furans was the highest, and the content of aldehydes, ketones, and alcohols was the lowest after 48 h depuration, while the content of aldehydes, ketones, and alcohols increased after 72 h depuration. All these results suggested the depuration period was recommended to be controlled within 48 h.

Distinctive metabolic remodeling in TYMP deficiency beyond mitochondrial dysfunction.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is caused by mutations in the TYMP gene, which encodes thymidine phosphorylase (TP). As a cytosolic metabolic enzyme, TP defects affect biological processes that are thought to not be limited to the abnormal replication of mitochondrial DNA. This study aimed to elucidate the characteristic metabolic alterations and associated homeostatic regulation caused by TYMP deficiency. The pathogenicity of novel TYMP variants was evaluated in terms of clinical features, genetic analysis, and structural instability. We analyzed plasma samples from three patients with MNGIE; three patients with m.3243A > G mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS); and four healthy controls (HC) using both targeted and untargeted metabolomics techniques. Transcriptomics analysis and bioenergetic studies were performed on skin fibroblasts from participants in these three groups. A TYMP overexpression experiment was conducted to rescue the observed changes. Compared with controls, specific alterations in nucleosides, bile acids, and steroid metabolites were identified in the plasma of MNGIE patients. Comparable mitochondrial dysfunction was present in fibroblasts from patients with TYMP deficiency and in those from patients with the m.3243A > G mutation. Distinctively decreased sterol regulatory element binding protein (SREBP) regulated cholesterol metabolism and fatty acid (FA) biosynthesis as well as reduced FA degradation were revealed in fibroblasts with TYMP deficiency. The restoration of thymidine phosphorylase activity rescued the observed changes in MNGIE fibroblasts. Our findings indicated that more widespread metabolic disturbance may be caused by TYMP deficiency in addition to mitochondrial dysfunction, which expands our knowledge of the biochemical outcome of TYMP deficiency. KEY MESSAGES: Distinct metabolic profiles in patients with TYMP deficiency compared to those with m.3243A > G mutation. TYMP deficiency leads to a global disruption of nucleoside metabolism. Cholesterol and fatty acid metabolism are inhibited in individuals with MNGIE. TYMP is functionally related to SREBP-regulated pathways. Potential metabolite biomarkers that could be valuable clinical tools to improve the diagnosis of MNGIE.

Increased renal elimination of endogenous and synthetic pyrimidine nucleosides in concentrative nucleoside transporter 1 deficient mice

Concentrative nucleoside transporters (CNTs) are active nucleoside influx systems, but their in vivo roles are poorly defined. By generating CNT1 knockout (KO) mice, here we identify a role of CNT1 in the renal reabsorption of nucleosides. Deletion of CNT1 in mice increases the urinary excretion of endogenous pyrimidine nucleosides with compensatory alterations in purine nucleoside metabolism. In addition, CNT1 KO mice exhibits high urinary excretion of the nucleoside analog gemcitabine (dFdC), which results in poor tumor growth control in CNT1 KO mice harboring syngeneic pancreatic tumors. Interestingly, increasing the dFdC dose to attain an area under the concentration-time curve level equivalent to that achieved by wild-type (WT) mice rescues antitumor efficacy. The findings provide new insights into how CNT1 regulates reabsorption of endogenous and synthetic nucleosides in murine kidneys and suggest that the functional status of CNTs may account for the optimal action of pyrimidine nucleoside analog therapeutics in humans.

(088) The Essential Role of O-GlcNAcylation in the Testis Aging

Abstract Introduction With the delay of reproductive age, reproductive disorders related to advanced age have gradually attracted widespread attention. Studies have shown that the decline in male fertility due to aging is manifested as a decrease in semen parameters and spermatogenetic cells histologically. O-GlcNAc (O-acetylglucosamine) glycosylation is a post-translational modification that exists widely in cells. The level of UDP-GlcNAc, which is the substrate of O-GlcNAcylation, changes rapidly with various nutrients and external factors. Therefore, O-GlcNAcylation can respond to glucose, amino acid, fatty acid, and nucleoside metabolism, and is considered to be an important sensor of cellular metabolism. The previous study of our project found that the level of O-GlcNAc modification in aged testis tissue was significantly increased, so this study aimed to explore the specific mechanism of O-GlcNAc modification involved in testicular aging. Objective 1.Explore the modification pattern of O-GlcNAcylation in testis 2.Mimic the high O-GlcNAcylation state of aging mice in young mice, to study the effect of elevated high O-GlcNAcylation level on testis. 3.Reveal the role of key proteins modified by O-GlcNAc in testicular aging Methods Mice were injected intraperitoneally with OGA inhibitor Thiamet-G for 35 days to increase the level of O-GlcNAc to simulate aging. CASA system was used to detect semen parameters, and chromosome spreading technology was used to study mouse testis meiosis. Using protein profiling technology, the differentially modified O-GlcNAc proteins in aged testis and young testis were screened, and point mutations were made at their O-GlcNAc sites to study the specific mechanism of key O-GlcNAc proteins involved in testis aging. Results The O-GlcNAc modification level in the testis of aged mice was significantly increased. After intraperitoneally injecting Thiamet-G into mice for 35 days, the level of O-GlcNAcylation in the testis tissue was significantly increased. High level of O-GlcNAcylation in testis damaged the sperm parameter, decreased the thickness of seminiferous epithelium and increased apoptosis in testis. Chromosome spreading experiments showed that, γH2Ax, which is the marker of DNA double strand breaks, stained unusually at autosomes in pachytene spermatocytes. The elevation of γH2Ax affected the transition of pachytene spermatocytes to diplotene. Importantly, we found that the O-GlcNAcylation of Hyou1 protein was significantly increased in the testis of aged mice. O-GlcNAcylation of Hyou1 promotes the degradation of Hyou1. An O-GlcNAc site of Hyou1 was identified at S634 and mutation of this site decreased the O-GlcNAcylation, increased the protein stability and exerts protective roles in aging testis. Conclusions In the testis of aged mice, the level of O-GlcNAcylation is increased, which leads to the arrest of spermatocyte meiosis by affecting the DNA damage repair pathway. Hyou1 is the key O-GlcNAc protein in testicular aging and mutation of this site exerts protective roles. This study revealed for the first time the specific mechanism of O-GlcNAc involved in testicular aging, and provided a new therapeutic target for clinically delaying testicular aging and treating male infertility. Disclosure No

Repurposing degradation pathways for modular metabolite biosynthesis in nematodes.

Recent studies have revealed that Caenorhabditis elegans and other nematodes repurpose products from biochemical degradation pathways for the combinatorial assembly of complex modular structures that serve diverse signaling functions. Building blocks from neurotransmitter, amino acid, nucleoside and fatty acid metabolism are attached to scaffolds based on the dideoxyhexose ascarylose or glucose, resulting in hundreds of modular ascarosides and glucosides. Genome-wide association studies have identified carboxylesterases as the key enzymes mediating modular assembly, enabling rapid compound discovery via untargeted metabolomics and suggesting that modular metabolite biosynthesis originates from the 'hijacking' of conserved detoxification mechanisms. Modular metabolites thus represent a distinct biosynthetic strategy for generating structural and functional diversity in nematodes, complementing the primarily polyketide synthase- and nonribosomal peptide synthetase-derived universe of microbial natural products. Although many aspects of modular metabolite biosynthesis and function remain to be elucidated, their identification demonstrates how phenotype-driven compound discovery, untargeted metabolomics and genomic approaches can synergize to facilitate the annotation of metabolic dark matter.

Regulation of metabolism in pancreatic ductal adenocarcinoma via nanotechnology-enabled strategies

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal malignancy with insidious onset and early distal metastasis. Metabolic reprogramming, the autonomous changes in cellular bioenergetics driven by aberrant genetic events and crosstalk between cancer and non-cancer cells in the desmoplastic microenvironment, is pivotal for the rapid progression of PDAC. As an attractive therapeutic target, nucleoside metabolism is regulated by various anti-metabolic drugs for the clinical treatment of PDAC. Despite various challenges, such as poor drug delivery efficiency and off-target side effects, metabolic modification and intervention are emerging as promising strategies for PDAC therapy, enabled by the rapid development of nanotechnology-based drug delivery strategies. In this review, we discuss the metabolic characteristics of PDAC and highlight how the development of nanomedicine has boosted the development of new therapeutics for PDAC by modulating critical targets in metabolic reprogramming.

Changes in Liver Lipidomic Profile in G2019S-LRRK2 Mouse Model of Parkinson's Disease.

The identification of Parkinson's disease (PD) biomarkers has become a main goal for the diagnosis of this neurodegenerative disorder. PD has not only been intrinsically related to neurological problems, but also to a series of alterations in peripheral metabolism. The purpose of this study was to identify metabolic changes in the liver in mouse models of PD with the scope of finding new peripheral biomarkers for PD diagnosis. To achieve this goal, we used mass spectrometry technology to determine the complete metabolomic profile of liver and striatal tissue samples from WT mice, 6-hydroxydopamine-treated mice (idiopathic model) and mice affected by the G2019S-LRRK2 mutation in LRRK2/PARK8 gene (genetic model). This analysis revealed that the metabolism of carbohydrates, nucleotides and nucleosides was similarly altered in the liver from the two PD mouse models. However, long-chain fatty acids, phosphatidylcholine and other related lipid metabolites were only altered in hepatocytes from G2019S-LRRK2 mice. In summary, these results reveal specific differences, mainly in lipid metabolism, between idiopathic and genetic PD models in peripheral tissues and open up new possibilities to better understand the etiology of this neurological disorder.