Purine Nucleotide Metabolism Research Articles

Recent Advances in Xanthine Oxidase Inhibitors.

Uric acid is a product of purine nucleotide metabolism, and high concentrations of uric acid can lead to hyperuricemia, gout and other related diseases. Xanthine oxidase, the only enzyme that catalyzes xanthine and hypoxanthine into uric acid, has become a target for drug development against hyperuricemia and gout. Inhibition of xanthine oxidase can reduce the production of uric acid, so xanthine oxidase inhibitors are used to treat hyperuricemia and related diseases, including gout. In recent years, researchers have obtained new xanthine oxidase inhibitors through drug design, synthesis, or separation of natural products. This paper summarizes the research on xanthine oxidase inhibitors since 2015, mainly including natural products, pyrimidine derivatives, triazole derivatives, isonicotinamide derivatives, chalcone derivatives, furan derivatives, coumarin derivatives, pyrazole derivatives, and imidazole derivatives, hoping to provide valuable information for the research and development of novel xanthine oxidase inhibitors.

Identification of blood exosomal metabolomic profiling for high-altitude cerebral edema

High-altitude cerebral edema (HACE) is a severe neurological condition that can occur at high altitudes. It is characterized by the accumulation of fluid in the brain, leading to a range of symptoms, including severe headache, confusion, loss of coordination, and even coma and death. Exosomes play a crucial role in intercellular communication, and their contents have been found to change in various diseases. This study analyzed the metabolomic characteristics of blood exosomes from HACE patients compared to those from healthy controls (HCs) with the aim of identifying specific metabolites or metabolic pathways associated with the development of HACE conditions. A total of 21 HACE patients and 21 healthy controls were recruited for this study. Comprehensive metabolomic profiling of the serum exosome samples was conducted using ultraperformance liquid chromatography–tandem mass spectrometry (UPLC‒MS/MS). Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed to identify the metabolic pathways affected in HACE patients. Twenty-six metabolites, including ( +)-camphoric acid, choline, adenosine, adenosine 5′-monophosphate, deoxyguanosine 5′-monophosphate, guanosine, and hypoxanthine-9-β-D-arabinofuranoside, among others, exhibited significant changes in expression in HACE patients compared to HCs. Additionally, these differentially abundant metabolites were confirmed to be potential biomarkers for HACE. KEGG pathway enrichment analysis revealed several pathways that significantly affect energy metabolism regulation (such as purine metabolism, thermogenesis, and nucleotide metabolism), estrogen-related pathways (the estrogen signaling pathway, GnRH signaling pathway, and GnRH pathway), cyclic nucleotide signaling pathways (the cGMP-PKG signaling pathway and cAMP signaling pathway), and hormone synthesis and secretion pathways (renin secretion, parathyroid hormone synthesis, secretion and action, and aldosterone synthesis and secretion). In patients with HACE, adenosine, guanosine, and hypoxanthine-9-β-D-arabinofuranoside were negatively correlated with height. Deoxyguanosine 5′-monophosphate is negatively correlated with weight and BMI. Additionally, LPE (18:2/0:0) and pregnanetriol were positively correlated with age. This study identified potential biomarkers for HACE and provided valuable insights into the underlying metabolic mechanisms of this disease. These findings may lead to potential targets for early diagnosis and therapeutic intervention in HACE patients.

Unraveling genetic underpinnings of purine content in pork

The significance of purine base content as an important nutrition indicator in foods arises from its potential to trigger hyperuricemia or gout via high-purine diet. Livestock meats, including pork, generally contain moderate to high total purine content (TP). Recent research revealed substantial variations within and across pig breeds, implying genetic factors influencing this trait. Thus, this study aimed to unravel the genetic underpinnings governing purine base content in pork. The heritability estimates (h2) for the four purine traits ranged from 0.14 to 0.35. A total of 14, 36, 19 and 25 quantitative trait loci (QTLs) were identified for guanine, adenine, hypoxanthine, and TP, respectively. Our comprehensive gene set enrichment analysis and gene network analysis revealed 15 promising candidate genes intricately interwoven within diverse purine metabolism pathways, such as purine ribonucleotide metabolic process, purine nucleotide metabolism and transport, and purine salvage pathways, all contributing to TP. Strikingly, most genetic variants significantly associated with TP displayed analogous effects on multiple purine bases. Two distinct and highly significant QTLs (P < 10-12) emerged on Sus Scrofa chromosome (SSC) 12: one impacting guanine content and the other concurrently influencing adenine and hypoxanthine levels. The peak of the guanine QTL on SSC12 resided 1.1 kb downstream of the transmembrane protein 238 like (TMEM238L) gene and is encapsulated within a genomic segment characterized by the histone modification H3K27me3. Focused fine-mapping for the SSC12 QTL associated with adenine and hypoxanthine levels narrowed its scope to around 172 kb, encompassing the growth arrest specific 7 (GAS7) and myosin heavy chain 13 (MYH13) genes. However, the observed QTL effect was not attributed to any missense mutations within the two genes. This pioneering study unveils the genetic variations and candidate genes associated with purine content in livestock, laying a robust foundation for the selective breeding of pig lines with reduced purine base content.

Purinosomes involved in the regulation of tumor metabolism: current progress and potential application targets.

The core of tumor cell metabolism is the management of energy metabolism due to the extremely high energy requirements of tumor cells. The purine nucleotide synthesis pathway in cells uses the purinosomes as an essential spatial structural complex. In addition to serving a crucial regulatory role in the emergence and growth of tumors, it contributes to the synthesis and metabolism of purine nucleotides. The significance of purine metabolism in tumor cells is initially addressed in this current article. The role of purinosomes as prospective therapeutic targets is then reviewed, along with a list of the signaling pathways that play in the regulation of tumor metabolism. A thorough comprehension of the function of purinosomes in the control of tumor metabolism can generate fresh suggestions for the creation of innovative cancer treatment methods.

Metabolomics analysis of CEF cells infected with avian leukosis virus subgroup J based on UHPLC-QE-MS

Avian leukosis virus subgroup J (ALV-J) is a retrovirus that can cause immunosuppression and tumors in chicken. However, relative pathogenesis is still not clear. At present, metabolomics has shown great potential in the screening of tumor metabolic markers, prognostic evaluation, and drug target design. In this study, we utilize an untargeted metabolomics approach based on ultrahigh-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UHPLC-QTOF-MS) to analyze the metabolic changes in chicken embryo fibroblast (CEF) cells infected by ALV-J. We found that ALV-J infection significantly altered a wealth of metabolites compared with control group. Additionally, most of the differentially expressed metabolites belonged to lipid metabolism, purine nucleotide metabolism and amino acid metabolism. Among them, the proportion of lipid metabolites account for the highest proportion (around 31%). Results suggest that these changes may be conductive to the formation of virion, thereby promoting the replication of ALV-J. These data provided metabolic evidence and potential biomarkers for the cellular metabolic changes induced by ALV-J, and provided important insight for further understanding the replication needs and pathogenesis of ALV-J.

Comparative Transcriptome Profiles of the Response of Mycelia of the Genus Morchella to Temperature Stress: An Examination of Potential Resistance Mechanisms.

Temperature and moisture belong to the most important environmental factors affecting the growth and development of fungi. However, the effect of temperature on the mycelia of the edible Morchella mushrooms has not been determined. Here, a comprehensive analysis was performed to determine the influence of culture temperature on 13 strains of mycelia of three Morchella species (Morchella sextelata, Morchella septimelata, and Morchella importuna) at 5 °C, 10 °C, 15 °C, 20 °C, 25 °C, and 30 °C. The mycelial branching and growth rate data showed that 15-20 °C was a suitable temperature range for the mycelial growth of the 13 Morchella strains. RNA sequences revealed that a total of 2843, 2404, 1973, 1572, and 1866 differentially expressed genes (DEGs) were identified at 5 °C, 10 °C, 15 °C, 25 °C, and 30 °C compared with 20 °C. A Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis further indicated that the purine nucleotide and tyrosine metabolism pathways were crucial for mycelium development. Moreover, the enrichment of autophagy of mitochondria, regulation of cell morphogenesis, and piecemeal microautophagy of the nuclei at 25 °C (vs. 20 °C) indicated the damage caused by heat stress in Morchella mycelia. Notably, a total of four unique module eigengenes (MEs) were identified through a weighted gene coexpression network analysis (WGCNA). Among them, 2293 genes in the turquoise module were significantly positively correlated with temperature (r = 0.946, p < 0.001), whereas 739 genes in the blue module were significantly negatively correlated with temperature (r = -0.896, p < 0.001), suggesting that the effect of high temperatures on mycelial genes was significantly greater than that of low temperatures. Moreover, the coexpression network indicated that high culture temperatures accelerated the oxidative stress response and energy metabolism in mycelia, while upregulation of purine nucleotide catabolism and ribosomal protein-related genes were improved by low-temperature tolerance. In addition, the upregulated expression of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and heat shock protein (HSP) genes in mycelia was associated with reactive oxygen species (ROS)-mediated damage at high temperatures. Overall, this study provides an important theoretical basis and application value for optimizing Morchella cultivation techniques.

Evaluation on purine metabolism in human skin fibroblast cells exposed to oxygenated polycyclic aromatic hydrocarbons.

A rapid and sensitive assessment of the toxicity of oxygenated polycyclic aromatic hydrocarbons (OPAHs), widely distributed persistent organic pollutants in the environment, is crucial for human health. In this study, using high-performance liquid chromatography, the separation and detection of four purines, xanthine (X), guanine (G), adenine (A), and hypoxanthine (HX) in cells were performed. The aim was to evaluate the cytotoxicity of three OPAHs, namely 1,4-benzoquinone (1,4-BQ), 1,2-naphthoquinone (1,2-NQ) and 9,10-phenanthrenequinone (9,10-PQ), with higher environmental concentrations, from the perspective of purine nucleotide metabolism in human skin fibroblast cells (HFF-1). The results revealed that the levels of G and A were low in HFF-1 cells, while the levels of HX and X showed a dose-response relationship with persistent organic pollutants concentration. With increased concentration of the three persistent organic pollutants, the purine metabolism in HFF-1 cells weakened, and the impact of the three persistent organic pollutants on purine metabolism in cells was in the order of 9,10-PQ > 1,4-BQ > 1,2-NQ. This study provided valuable insights into the toxic mechanisms of 1,4-BQ, 1,2-NQ and 9,10-PQ, contributing to the formulation of relevant protective measures and the safeguarding of human health.

N6-methyladenosine modification of the mRNA for a key gene in purine nucleotide metabolism regulates virus proliferation in an insect vector

The titer of viruses that persist and propagate in their insect vector must be high enough for transmission yet not harm the insect, but the mechanism of this dynamic balance is unclear. Here, expression of inosine monophosphate dehydrogenase (LsIMPDH), a rate-limiting enzyme for guanosine triphosphate (GTP) synthesis, is shown to be downregulated by increased levels of N6-methyladenosine (m6A) on LsIMPDH mRNA in rice stripe virus (RSV)-infected small brown planthoppers (SBPHs; Laodelphax striatellus), the RSV vector, which decreases GTP content, thus limiting viral proliferation. Moreover, planthopper methyltransferase-like protein 3 (LsMETTL3) and m6A reader protein LsYTHDF3 are found to catalyze and recognize the m6A on LsIMPDH mRNA, respectively, and cooperate in destabilizing LsIMPDH transcripts. Co-silencing assays show that negative regulation of viral proliferation by both LsMETTL3 and LsYTHDF3 is partially dependent on LsIMPDH. This distinct mechanism limits virus replication in an insect vector, providing a potential gene target to block viral transmission.

Integrated Functions of Cardiac Energetics, Mechanics, and Purine Nucleotide Metabolism.

Purine nucleotides play central roles in energy metabolism in the heart. Most fundamentally, the free energy of hydrolysis of the adenine nucleotide adenosine triphosphate (ATP) provides the thermodynamic driving force for numerous cellular processes including the actin-myosin crossbridge cycle. Perturbations to ATP supply and/or demand in the myocardium lead to changes in the homeostatic balance between purine nucleotide synthesis, degradation, and salvage, potentially affecting myocardial energetics and, consequently, myocardial mechanics. Indeed, both acute myocardial ischemia and decompensatory remodeling of the myocardium in heart failure are associated with depletion of myocardial adenine nucleotides and with impaired myocardial mechanical function. Yet there remain gaps in the understanding of mechanistic links between adenine nucleotide degradation and contractile dysfunction in heart disease. The scope of this article is to: (i) review current knowledge of the pathways of purine nucleotide depletion and salvage in acute ischemia and in chronic heart disease; (ii) review hypothesized mechanisms linking myocardial mechanics and energetics with myocardial adenine nucleotide regulation; and (iii) highlight potential targets for treating myocardial metabolic and mechanical dysfunction associated with these pathways. It is hypothesized that an imbalance in the degradation, salvage, and synthesis of adenine nucleotides leads to a net loss of adenine nucleotides in both acute ischemia and under chronic high-demand conditions associated with the development of heart failure. This reduction in adenine nucleotide levels results in reduced myocardial ATP and increased myocardial inorganic phosphate. Both of these changes have the potential to directly impact tension development and mechanical work at the cellular level. © 2024 American Physiological Society. Compr Physiol 14:5345-5369, 2024.

Metabolic reprogramming driven by EZH2 inhibition depends on cell–matrix interactions

EZH2 (Enhancer of Zeste Homolog 2), a subunit of Polycomb Repressive Complex 2 (PRC2), catalyzes the trimethylation of histone H3 at lysine 27 (H3K27me3), which represses expression of genes. It also has PRC2-independent functions, including transcriptional coactivation of oncogenes, and is frequently overexpressed in lung cancers. Clinically, EZH2 inhibition can be achieved with the FDA-approved drug EPZ-6438 (tazemetostat). To realize the full potential of EZH2 blockade, it is critical to understand how cell-cell/cell-matrix interactions present in three-dimensional (3D) tissue and cell culture systems influences this blockade in terms of growth-related metabolic functions. Here, we show that EZH2 suppression reduced growth of human lung adenocarcinoma A549 cells in two-dimensional (2D) cultures but stimulated growth in 3D culture. To understand the metabolic underpinnings, we employed [13C6]-glucose Stable Isotope-Resolved Metabolomics (SIRM) to determine the effect of EZH2 suppression on metabolic networks in 2D versus 3D A549 cultures. The Krebs cycle, neoribogenesis, γ-aminobutyrate (GAB) metabolism, and salvage synthesis of purine nucleotides were activated by EZH2 suppression in 3D spheroids but not in 2D cells, consistent with the growth effect. Using simultaneous 2H7-glucose + 13C5,15N2-Gln tracers and EPZ-6438 inhibition of H3 trimethylation, we delineated the effects on the Krebs cycle, γ-aminobutyrate metabolism, gluconeogenesis, and purine salvage to be PRC2 dependent. Furthermore, the growth/metabolic effects differed for mouse Matrigel versus self-produced A549 extracellular matrix. Thus, our findings highlight the importance of the presence and nature of extracellular matrix in studying the function of EZH2 and its inhibitors in cancer cells for modeling the in vivo outcomes.

Purine metabolism-related genes and immunization in thyroid eye disease were validated using bioinformatics and machine learning

Thyroid eye disease (TED), an autoimmune inflammatory disorder affecting the orbit, exhibits a range of clinical manifestations. While the disease presentation can vary, cases that adhere to a prototypical pattern typically commence with mild symptoms that subsequently escalate in severity before entering a phase of stabilization. Notably, the metabolic activity of cells implicated in the disease substantially deviates from that of healthy cells, with purine metabolism representing a critical facet of cellular material metabolism by supplying components essential for DNA and RNA synthesis. Nevertheless, the precise involvement of Purine Metabolism Genes (PMGs) in the defensive mechanism against TED remains largely unexplored. The present study employed a bioinformatics approach to identify and validate potential PMGs associated with TED. A curated set of 65 candidate PMGs was utilized to uncover novel PMGs through a combination of differential expression analysis and a PMG dataset. Furthermore, GSEA and GSVA were employed to explore the biological functions and pathways associated with the newly identified PMGs. Subsequently, the Lasso regression and SVM-RFE algorithms were applied to identify hub genes and assess the diagnostic efficacy of the top 10 PMGs in distinguishing TED. Additionally, the relationship between hub PMGs and clinical characteristics was investigated. Finally, the expression levels of the identified ten PMGs were validated using the GSE58331 and GSE105149 datasets. This study revealed ten PMGs related with TED. PRPS2, PFAS, ATIC, NT5C1A, POLR2E, POLR2F, POLR3B, PDE3A, ADSS, and NTPCR are among the PMGs. The biological function investigation revealed their participation in processes such as RNA splicing, purine-containing chemical metabolism, and purine nucleotide metabolism. Furthermore, the diagnostic performance of the 10 PMGs in differentiating TED was encouraging. This study was effective in identifying ten PMGs linked to TED. These findings provide light on potential new biomarkers for TED and open up possibilities for tracking disease development.

Untargeted metabolomics revealed the effect of soybean metabolites on poly(γ-glutamic acid) production in fermented natto and its metabolic pathway.

Natto mucus is mainly composed of poly(γ-glutamic acid) (γ-PGA), which affects the sensory quality of natto and has some effective functional activities. The soybean metabolites that cause different γ-PGA contents in different fermented natto are unclear. In this study, we use untargeted metabolomics to analyze the metabolites of high-production γ-PGA natto and low-production γ-PGA natto and their fermented substrate soybean. A total of 257 main significantly different metabolites with the same trend among the three comparison groups were screened, of which 114 were downregulated and 143 were upregulated. Through the enrichment of metabolic pathways, the metabolic pathways with significant differences were purine metabolism, nucleotide metabolism, fructose and mannose metabolism, anthocyanin biosynthesis, isoflavonoid biosynthesis and the pentose phosphate pathway. For 114 downregulated main significantly different metabolites with the same trend among the three comparison groups, Bacillus subtilis (natto) may directly decompose them to synthesize γ-PGA. Adding downregulated substances before fermentation or cultivating soybean varieties with the goal of high production of such substances has a great effect on the production of γ-PGA by natto fermentation. The enrichment analysis results showed the main pathways affecting the production of γ-PGA by Bacillus subtilis (natto) using soybean metabolites, which provides a theoretical basis for the production of γ-PGA by soybean and promotes the diversification of natto products. © 2023 Society of Chemical Industry.

The two-component system WalKR provides an essential link between cell wall homeostasis and DNA replication in Staphylococcus aureus.

The opportunistic human pathogen Staphylococcus aureus uses an array of protein sensing systems called two-component systems (TCS) to sense environmental signals and adapt its physiology in response by regulating different genes. This sensory network is key to S. aureus versatility and success as a pathogen. Here, we reveal for the first time the full extent of the regulatory network of WalKR, the only staphylococcal TCS that is indispensable for survival under laboratory conditions. We found that WalKR is a master regulator of cell growth, coordinating the expression of genes from multiple, fundamental S. aureus cellular processes, including those involved in maintaining cell wall metabolism, protein biosynthesis, nucleotide metabolism, and the initiation of DNA replication.

Adenylosuccinic Acid Is a Non-Toxic Small Molecule In Vitro and In Vivo.

Adenylosuccinic acid (ASA) is a small molecule dicarboxylate that could be a strong clinical development candidate for inherited myopathies involving dysregulated purine nucleotide metabolism. Currently, there are no published pharmacokinetic/dynamic or toxicology data available, although 10-year clinical trial data on Duchenne muscular dystrophy patients suggests it is a chronically safe drug. In this study, we tested the toxicity of ASA to cultured myoblasts in vitro and its acute systemic toxicity in mice. ASA is a non-toxic small molecule with an LD50 > 5000 mg/kg. Some background necrotic foci in the liver, kidney and gastrointestinal tract were shown that are likely incidental but warrant follow-up sub-/chronic oral exposure studies.

The role of purine nucleotide metabolism in cardiac failure

Normal cardiac function requires ATP to be synthesized at a sufficient rate to drive the molecular processes underlying electromechanical coupling. Myocardial metabolic dysfunction observed during heart failure leads to reductions in the chemical potential at which ATP is synthesized. We have observed reductions in oxidative capacity, and total adenine nucleotide (TAN) levels in a rat aortic constriction (TAC) induced heart failure model that parallel changes seen in large mammal models and humans with heart failure. Computer simulations of cardiac mechano-energetics also predict a marked increase in inorganic phosphate levels in diseased hearts compared to healthy control hearts. Furthermore, simulations predict that restoring the impaired energetic dysfunction of TAC rats improves systolic function. Metabolomic and proteomic analysis reveal increases in purine degradation by-products and AMP deaminase 3 (AMPD3) levels in failing versus control hearts. AMPD activity has been hypothesized to play a role in skeletal muscle in type 2 diabetes, however, there is still a need to decern the role, if any, of AMPD3 in the heart and in failure. A cardiac ventricle specific AMPD3 conditional knock out (cKO) rat model was developed to test the hypothesis that decreasing AMPD3 activity in the failing heart will lead to a preservation of TAN and improvement in cardiac mechanical function. Cardiac hypertrophy and decomposition were induced by placing a clip (TAC) in three-week old female and male rats. In the cKO model, AMPD3 exon 6 is flanked by loxP sites, and are either heterozygous for cre recombinase driven by the cardiac myosin light chain promoter (cre+/-) or lack the cre enzyme (cre-/-). Tamoxifen was administered to all rats both pre-surgery and post-surgery to induce AMPD3 knock down. Echocardiography was performed at 2- and 18-weeks post-surgery. At 18 weeks post-surgery, hearts were harvested for mitochondrial capacity, metabolite measurements, AMPD activity, and protein and mRNA measurements. Knock down efficiency in cre +/- animals compared to cre -/- was assessed based on enzyme activity, mRNA expression, and protein abundance. There is a 45% decrease in total AMPD activity in the AMPD3 cKO rats, where measured AMPD activity reflects the sum activity of all present AMPD isoforms. Additionally, there is 52% decrease in protein abundance and a 72% reduction in AMPD3 mRNA expression. Preliminary observations reveal significant differences in oxidative capacity and in cardiac function between TAC and sham rats, consistent with the hypothesis that knock down of AMDP3, an enzyme that is upregulated during TAC induced heart failure in rodents, results in preservation of myocardial nucleotide pools and improve cardiac mechanical function. Research is supported by the NIH grants HL144657 and F31-HL154605 (RL). We are grateful for support from the post-baccalaureate research program (2R25GM086262-09), the Systems and Integrative Biology (T32-GM008322) training grant and the Cardiovascular Research and Entrepreneurship training grant (T32-HL125242) and the University of Michigan Rackham Merit Fellowship. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Impact of spatial metabolomics on immune-microenvironment in oral cancer prognosis: a clinical report.

MALDI imaging for metabolites and immunohistochemistry for 38 immune markers was used to characterize the spatial biology of 2 primary oral tumours, one from a patient with an early recurrence (Tumour R), and the other from a patient with no recurrence 2years after treatment completion (Tumour NR). Tumour R had an increased purine nucleotide metabolism in different regions of tumour and adenosine-mediated suppression of immune cells compared to Tumour NR. The differentially expressed markers in the different spatial locations in tumour R were CD33, CD163, TGF-β, COX2, PD-L1, CD8 and CD20. These results suggest that altered tumour metabolomics concomitant with a modified immune microenvironment could be a potential marker of recurrence.

Uncovering the Gene Regulatory Network of Endothelial Cells in Mouse Duchenne Muscular Dystrophy: Insights from Single-Nuclei RNA Sequencing Analysis.

Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disorder caused by mutations in the dystrophin gene, which leads to heart and respiratory failure. Despite the critical impact of DMD on endothelial cells (ECs), there is limited understanding of its effect on the endothelial gene network. The aim of this study was to investigate the impact of DMD on the gene regulatory network of ECs. To gain insights into the role of the dystrophin muscular dystrophy gene (DMD) in ECs from Duchenne muscular dystrophy; the study utilized single-nuclei RNA sequencing (snRNA-seq) to evaluate the transcriptomic profile of ECs from skeletal muscles in DMD mutant mice (DMDmut) and wild-type control mice. The analysis showed that the DMD mutation resulted in the suppression of several genes, including SPTBN1 and the upregulation of multiple long noncoding RNAs (lncRNAs). GM48099, GM19951, and GM15564 were consistently upregulated in ECs and skeletal muscle cells from DMDmut, indicating that these dysregulated lncRNAs are conserved across different cell types. Gene ontology (GO) enrichment analysis revealed that the DMD mutation activated the following four pathways in ECs: fibrillary collagen trimer, banded collagen fibril, complex of collagen trimers, and purine nucleotide metabolism. The study also found that the metabolic pathway activity of ECs was altered. Oxidative phosphorylation (OXPHOS), fatty acid degradation, glycolysis, and pyruvate metabolism were decreased while purine metabolism, pyrimidine metabolism, and one carbon pool by folate were increased. Moreover, the study investigated the impact of the DMD mutation on ECs from skeletal muscles and found a significant decrease in their overall number, but no change in their proliferation. Overall, this study provides new insights into the gene regulatory program in ECs in DMD and highlights the importance of further research in this area.

Mechanistic insights of soluble uric acid-induced insulin resistance: Insulin signaling and beyond.

Hyperuricemia is a metabolic disease caused by purine nucleotide metabolism disorder. The prevalence of hyperuricemia is increasing worldwide, with a growing trend in the younger populations. Although numerous studies have indicated that hyperuricemia may be an independent risk factor for insulin resistance, the causal relationship between the two is controversial. There are few reviews, however, focusing on the relationship between uric acid (UA) and insulin resistance from experimental studies. In this review, we summarized the experimental models related to soluble UA-induced insulin resistance in pancreas and peripheral tissues, including skeletal muscles, adipose tissue, liver, heart/cardiomyocytes, vascular endothelial cells and macrophages. In addition, we summarized the research advances about the key mechanism of UA-induced insulin resistance. Moreover, we attempt to identify novel targets for the treatment of hyperuricemia-related insulin resistance. Lastly, we hope that the present review will encourage further researches to solve the chicken-and-egg dilemma between UA and insulin resistance, and provide strategies for the pathogenesis and treatment of hyperuricemia related metabolic diseases.

HYPERURICEMIA AS AN INTERDISCIPLINARY PROBLEM

Introduction Uric acid is the end product of purine nucleotide metabolism in the human body. Elevation of uric acid in the blood is known as hyperuricemia. Its participation in the development of gout is well known. According to the latest reports, it plays a role in developing cardiovascular and central nervous diseases. Aim This review article discusses the mechanisms and risk factors of hyperuricemia, its complications, and treatments that highlight hyperuricemia as a multi-faceted disorder requiring optimal treatment and rehabilitation. Materials and methods Pubmed and ClinicalKeys databases were used for searching for relevant research results. We focused on studies published in less than 5 years, but older references were also analyzed, if they brought valuable reports to our work. Results The analysis of the presented articles can indicate the role of hyperuricemia not only in the formation of gout, but also in hypertension, cardiovascular and kidney diseases and neurological disorders. Conclusions Due to the increase in the incidence of hyperuricemia worldwide and its consequences, maintaining an adequate level of uric acid is an essential aspect of patient management for clinicians. In addition to pharmacological treatment of hyperuricemia, patients should be considered for diet modification and increased physical activity. Further studies are needed to improve guidelines and recommendations for treating hyperuricemia and patient education.

Integrated metabolomics and transcriptomics reveal metabolites difference between wild and cultivated Ophiocordyceps sinensis

Ophiocordyceps sinensis is a traditional medicinal fungus endemic to the alpine and high-altitude areas of the Qinghai-Tibet plateau. The scarcity of the wild resource has led to increased attention to artificially cultivated O. sinensis. However, little is known about the metabolic differences and the regulatory mechanisms between cultivated and wild O. sinensis. This study exploited untargeted metabolomics and transcriptomics to uncover the differences in accumulated metabolites and expressed genes between wild and cultivated O. sinensis. Metabolomics results revealed that 368 differentially accumulated metabolites were mainly enriched in biosynthesis of amino acids, biosynthesis of plant secondary metabolites and purine nucleotide metabolism. Cultivated O. sinensis contained more amino acids and derivatives, carbohydrates and derivatives, and phenolic acids than wild O. sinensis, whereas the contents of most nucleosides and nucleotides in wild O. sinensis were significantly higher than in cultivated O. sinensis. Transcriptome analysis indicated that 4430 annotated differentially expressed genes were identified between two types. Integrated metabolomics and transcriptomics analyses suggested that IMPDH, AK, ADSS, guaA and GUK genes might be related to the synthesis of purine nucleotides and nucleosides. Our findings will provide a new insight into the molecular basis of metabolic variations of this medicinal fungus.