Nucleotide Metabolism Pathways Research Articles

Metabolic Characteristics of Gut Microbiota and Insomnia: Evidence from a Mendelian Randomization Analysis.

Insomnia is a common sleep disorder that significantly impacts individuals' sleep quality and daily life. Recent studies have suggested that gut microbiota may influence sleep through various metabolic pathways. This study aims to explore the causal relationships between the abundance of gut microbiota metabolic pathways and insomnia using Mendelian randomization (MR) analysis. This two-sample MR study used genetic data from the OpenGWAS database (205 gut bacterial pathway abundance) and the FinnGen database (insomnia-related data). We identified single nucleotide polymorphisms (SNPs) associated with gut bacterial pathway abundance as instrumental variables (IVs) and ensured their validity through stringent selection criteria and quality control measures. The primary analysis employed the inverse variance-weighted (IVW) method, supplemented by other MR methods, to estimate causal effects. The MR analysis revealed significant positive causal effects of specific carbohydrate, amino acid, and nucleotide metabolism pathways on insomnia. Key pathways, such as gluconeogenesis pathway (GLUCONEO.PWY) and TCA cycle VII acetate producers (PWY.7254), showed positive associations with insomnia (B > 0, p < 0.05). Conversely, pathways like hexitol fermentation to lactate, formate, ethanol and acetate pathway (P461.PWY) exhibited negative causal effects (B < 0, p < 0.05). Multivariable MR analysis confirmed the independent causal effects of these pathways (p < 0.05). Sensitivity analyses indicated no significant pleiotropy or heterogeneity, ensuring the robustness of the results. This study identifies specific gut microbiota metabolic pathways that play critical roles in the development of insomnia. These findings provide new insights into the biological mechanisms underlying insomnia and suggest potential targets for therapeutic interventions. Future research should further validate these causal relationships and explore how modulating gut microbiota or its metabolic products can effectively improve insomnia symptoms, leading to more personalized and precise treatment strategies.

Toxicity of soil leaching liquor from coking plant in developmental zebrafish embryos/larvae model.

The coking industry in China is the largest coke supplier in the world. Contaminated soil in industrial areas poses a serious threat to human and ecosystems. Most of the studies investigated the toxicity of soil from coking plant on soil microorganisms, while the toxic effects of soil leaching liquor on aquatics are limited. In this study, the composition of soil leaching liquor from a coking plant in Taiyuan (TY) was analyzed, and the developmental toxicity on zebrafish was evaluated. The results showed that a total of 91 polycyclic aromatic hydrocarbons were detected in the leaching liquor, followed by phenols and benzene series. The leaching liquor induced developmental impairment in zebrafish larvae, including delayed incubation, deficits in locomotor behavior, vascular and cardiac dysplasia, and impaired neurodevelopment. The results of metabolomics analysis showed that TY soil leaching liquor induced significant metabolic profile disturbances in zebrafish embryos/larvae. The developmental toxicity of the leaching liquor metabolic disorders may be associated with the leaching liquor-induced abnormalities in zebrafish embryonic development. Metabolic pathways were identified by arginine and proline metabolism, phosphotransferase system, starch and sucrose metabolism, steroid biosynthesis, beta-alanine metabolism, and nucleotide metabolism pathways.

Multi-omics analysis reveals genes and metabolites involved in Streptococcus suis biofilm formation

BackgroundStreptococcus suis is an important zoonotic pathogen. Biofilm formation largely explains the difficulty in preventing and controlling S. suis. However, little is known about the molecular mechanism of S. suis biofilm formation.ResultsIn this study, transcriptomic and metabolomic analyses of S. suis in biofilm and planktonic states were performed to identify key genes and metabolites involved in biofilm formation. A total of 789 differential genes and 365 differential metabolites were identified. By integrating transcriptomics and metabolomics, five main metabolic pathways were identified, including amino acid pathway, nucleotide metabolism pathway, carbon metabolism pathway, vitamin and cofactor metabolism pathway, and aminoacyl-tRNA biosynthesis metabolic pathway.ConclusionsThese results provide new insights for exploring the molecular mechanism of S. suis biofilm formation.

Association of Succinate and Adenosine Nucleotide Metabolic Pathways with Diabetic Kidney Disease in Patients with Type 2 Diabetes Mellitus

Association of Succinate and Adenosine Nucleotide Metabolic Pathways with Diabetic Kidney Disease in Patients with Type 2 Diabetes Mellitus

Metabolic differences in MSTN and FGF5 dual-gene edited sheep muscle cells during myogenesis

Dynamic metabolic reprogramming occurs at different stages of myogenesis and contributes to the fate determination of skeletal muscle satellite cells (MuSCs). Accumulating evidence suggests that mutations in myostatin (MSTN) have a vital role in regulating muscle energy metabolism. Here, we explored the metabolic reprogramming in MuSCs and myotube cells in MSTN and FGF5 dual-gene edited sheep models prepared previously, and also focused on the metabolic alterations during myogenic differentiation of MuSCs. Our study revealed that the pathways of nucleotide metabolism, pantothenate and CoA biosynthesis were weakened, while the unsaturated fatty acids biosynthesis were strengthened during myogenic differentiation of sheep MuSCs. The MSTN and FGF5 dual-gene editing mainly inhibited nucleotide metabolism and biosynthesis of unsaturated fatty acids in sheep MuSCs, reduced the number of lipid droplets in per satellite cell, and promoted the pentose phosphate pathway, and the interconversion of pentose and glucuronate. The MSTN and FGF5 dual-gene editing also resulted in the inhibition of nucleotide metabolism and TCA cycle pathway in differentiated myotube cells. The differential metabolites we identified can be characterized as biomarkers of different cellular states, and providing a new reference for MSTN and FGF5 dual-gene editing in regulation of muscle development. It may also provide a reference for the development of muscle regeneration drugs targeting biomarkers.

NagZ modulates the virulence of E. cloacae by acting through the gene of unknown function, ECL_03795

ABSTRACT β-N-acetylglucosaminidase (NagZ), a cytosolic glucosaminidase, plays a pivotal role in peptidoglycan recycling. Previous research demonstrated that NagZ knockout significantly eradicated AmpC-dependent β-lactam resistance in Enterobacter cloacae. However, NagZ’s role in the virulence of E. cloacae remains unclear. Our study, incorporating data on mouse and Galleria mellonella larval mortality rates, inflammation markers, and histopathological examinations, revealed a substantial reduction in the virulence of E. cloacae following NagZ knockout. Transcriptome sequencing uncovered differential gene expression between NagZ knockout and wild-type strains, particularly in nucleotide metabolism pathways. Further investigation demonstrated that NagZ deletion led to a significant increase in cyclic diguanosine monophosphate (c-di-GMP) levels. Additionally, transcriptome sequencing and RT-qPCR confirmed significant differences in the expression of ECL_03795, a gene with an unknown function but speculated to be involved in c-di-GMP metabolism due to its EAL domain known for phosphodiesterase activity. Interestingly, in ECL_03795 knockout strains, a notable reduction in the virulence was observed, and virulence was rescued upon complementation with ECL_03795. Consequently, our study suggests that NagZ’s function on virulence is partially mediated through the ECL_03795→c-di-GMP pathway, providing insight into the development of novel therapies and strongly supporting the interest in creating highly efficient NagZ inhibitors.

426-P: Association of Succinate and Adenosine Nucleotide Metabolic Pathways with the Progression of Diabetic Kidney Disease in Patients with Type 2 Diabetes Mellitus

426-P: Association of Succinate and Adenosine Nucleotide Metabolic Pathways with the Progression of Diabetic Kidney Disease in Patients with Type 2 Diabetes Mellitus

Dehydroabietylamine exerts antitumor effects by affecting nucleotide metabolism in gastric cancer.

Nucleotide metabolism is the ultimate and most critical link in the self-replication process of tumors, including gastric cancer (GC). However, in clinical treatment, classic anti-tumor drugs such as 5-fluorouracil (5-FU) are mostly metabolic analogues of purines or pyrimidines, which lack specificity for tumor cells and therefore have significant side effects. It is unclear whether there are other drugs that can target nucleotide metabolism, except for nucleic acid analogues. Here, we found that a natural compound, dehydroabietylamine (DHAA), significantly reduced the viability and proliferation of GC cells and organoids. DHAA disrupts purine and pyrimidine metabolism of GC cells, causing DNA damage and further inducing apoptosis. DHAA treatment decreased transcription and protein levels of key enzymes involved in nucleotide metabolism pathway, with significant reductions in the expression of pyrimidine metabolism key enzymes CAD, DHODH, and purine metabolism key enzymes PAICS. We also found that DHAA directly binds to and reduces the expression of Forkhead box K2 (FOXK2), a common transcription factor for these metabolic enzymes. Ultimately, DHAA was shown to delay tumorigenesis in K19-Wnt1/C2mE transgenic mice model and reduce levels of CAD, DHODH, and PAICS in vivo. We demonstrate that DHAA exerts an anticancer effect on GC by targeting transcription factor FOXK2, reducing transcription of key genes for nucleotide metabolism and impairing nucleotide biosynthesis, thus DHAA is a promising candidate for GC therapy.

Nucleotide metabolism-related host proteins RNA polymerase II subunit and uridine phosphorylase 1 interacting with porcine epidemic diarrhea virus N proteins affect viral replication.

Porcine epidemic diarrhea virus (PEDV) is a highly infectious pathogen that targets pig intestines to cause disease. It is globally widespread and causes huge economic losses to the pig industry. PEDV N protein is the protein that constitutes the core of PEDV virus particles, and most of it is expressed in the cytoplasm, and a small part can also be expressed in the nucleus. However, the role of related proteins in host nucleotide metabolic pathways in regulating PEDV replication have not been fully elucidated. In this study, PEDV-N-labeled antibodies were co-immunoprecipitated and combined with LC-MS to screen for host proteins that interact with N proteins. Bioinformatics analyses showed that the selected host proteins were mainly enriched in metabolic pathways. Moreover, co-immunoprecipitation and confocal microscopy confirmed that the second-largest subunit of RNA polymerase II (RPB2) and uridine phosphorylase 1 (UPP1) interacted with the N protein. RPB2 is the main subunit of RNA polymerase II and plays an important role in eukaryotic transcription. UPP1 is an enzyme that catalyzes reversible phosphorylation of uridine to uracil and ribo-1-phosphate to promote catabolism and bio anabolism. RPB2 overexpression significantly promoted viral replication, whereas UPP1 overexpression significantly inhibited viral replication. Studies on interactions between the PEDV N and host proteins are helpful in elucidating the pathogenesis and immune escape mechanism of PEDV.

Transcriptome-metabolome reveals the molecular changes in meat production and quality in the hybrid populations of Sichuan white goose

Hybrid breeding has proven to enhance meat quality and is extensively utilized in goose breeding. Nevertheless, there is a paucity of research investigating the molecular mechanisms that underlie the meat quality of hybrid geese. In this study, we employed the Sichuan White Goose as the maternal line for hybridization with the Zhedong White Goose and Tianfu Meat Goose P3 line. We assessed the growth and slaughter meat quality performance of 10-wk-old hybrid offspring in comparison to Sichuan white goose purebred offspring. The results indicate that hybrid geese have significantly improved performance in growth and slaughter meat quality. Furthermore, we conducted a comprehensive analysis of the chest muscles of hybrid offspring through transcriptomics and metabolomics to unravel the effects of hybrid breeding on growth and meat quality. A total of 673 differentially expressed genes (DEGs), and 93 differentially expressed metabolites were identified. The joint analysis highlighted the significant enrichment of DEGs AMPD1, AMPD3, RRM2, ENTPD3, and the metabolite UMP in the nucleotide metabolism pathway. These findings underscore the crucial role of these genetic and metabolic factors in regulating muscle growth and meat quality in hybrid populations.

Comparative metabolomics study on the quality of Antarctic krill (Euphausia superba) stored at different temperatures

SummaryIn this study, the effect of short‐term storage at different temperatures (0, 4 and −8 °C) on the quality of Antarctic krill was investigated using the main quality indicators as a reference, combined with electronic nose and untargeted metabolomics. Antarctic krill stored at lower temperatures (−8 °C) were of better quality and had a flavour similar to that of the original Antarctic krill. Metabolomics analyses showed that differential metabolites (DMS) were more abundant in Antarctic krill at higher temperatures (4 °C), with sixty‐five metabolites having reduced expression and forty‐five metabolites having increased expression; Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that amino acid metabolism and nucleotide metabolism pathways were the Five DMS, including α‐ketoglutarate, glutamate, succinate, sucrose and glutarate, can be used as potential biomarkers to monitor quality changes during short‐term storage of Antarctic krill. In addition, the association between quality indicators and differential metabolites remains to be explored.

Toxic effects of acaricide fenazaquin on development, hemolymph metabolome, and gut microbiome of honeybee (Apis mellifera) larvae

Fenazaquin, a potent insecticide widely used to control phytophagous mites, has recently emerged as a potential solution for managing Varroa destructor mites in honeybees. However, the comprehensive impact of fenazaquin on honeybee health remains insufficiently understood. Our current study investigated the acute and chronic toxicity of fenazaquin to honeybee larvae, along with its influence on larval hemolymph metabolism and gut microbiota. Results showed that the acute median lethal dose (LD50) of fenazaquin for honeybee larvae was 1.786 μg/larva, and the chronic LD50 was 1.213 μg/larva. Although chronic exposure to low doses of fenazaquin exhibited no significant effect on larval development, increasing doses of fenazaquin resulted in significant increases in larval mortality, developmental time, and deformity rates. At the metabolic level, high doses of fenazaquin inhibited nucleotide, purine, and lipid metabolism pathways in the larval hemolymph, leading to energy metabolism disorders and physiological dysfunction. Furthermore, high doses of fenazaquin reduced gut microbial diversity and abundance, characterized by decreased relative abundance of functional gut bacterium Lactobacillus kunkeei and increased pathogenic bacterium Melissococcus plutonius. The disrupted gut microbiota, combined with the observed gut tissue damage, could potentially impair food digestion and nutrient absorption in the larvae. Our results provide valuable insights into the complex and diverse effects of fenazaquin on honeybee larvae, establishing an important theoretical basis for applying fenazaquin in beekeeping.

Altered mucosal bacteria and metabolomics in patients with Peutz–Jeghers syndrome

BackgroundPeutz–Jeghers syndrome (PJS) is a rare genetic disorder characterized by the development of pigmented spots, gastrointestinal polyps and increased susceptibility to cancers. Currently, most studies have investigated intestinal microbiota through fecal microbiota, and there are few reports about mucosa-associated microbiota. It remains valuable to search for the key intestinal microbiota or abnormal metabolic pathways linked to PJS.AimThis study aimed to assess the structure and composition of mucosa-associated microbiota in patients with PJS and to explore the potential influence of intestinal microbiota disorders and metabolite changes on PJS.MethodsThe bacterial composition was analyzed in 13 PJS patients and 12 controls using 16S rRNA gene sequencing (Illumina MiSeq) for bacteria. Differential analyses of the intestinal microbiota were performed from the phylum to species level. Liquid chromatography-tandem mass spectrometry (LC‒MS) was used to detect the differentially abundant metabolites of PJS patients and controls to identify different metabolites and metabolic biomarkers of small intestinal mucosa samples.ResultsHigh-throughput sequencing confirmed the special characteristics and biodiversity of the mucosa microflora in patients with PJS. They had lower bacterial biodiversity than controls. The abundance of intestinal mucosal microflora was significantly lower than that of fecal microflora. In addition, lipid metabolism, amino acid metabolism, carbohydrate metabolism, nucleotide metabolism and other pathways were significantly different from those of controls, which were associated with the development of the enteric nervous system, intestinal inflammation and development of tumors.ConclusionThis is the first report on the mucosa-associated microbiota and metabolite profile of subjects with PJS, which may be meaningful to provide a structural basis for further research on intestinal microecology in PJS.

Establishment of a cholangiocarcinoma risk evaluation model based on mucin expression levels.

Cholangiocarcinoma (CCA) is a highly malignant cancer, characterized by frequent mucin overexpression. MUC1 has been identified as a critical oncogene in the progression of CCA. However, the comprehensive understanding of how the mucin family influences CCA progression and prognosis is still incomplete. To investigate the functions of mucins on the progression of CCA and to establish a risk evaluation formula for stratifying CCA patients. Single-cell RNA sequencing data from 14 CCA samples were employed for elucidating the roles of mucins, complemented by bioinformatic analyses. Subsequent validations were conducted through spatial transcriptomics and immunohistochemistry. The construction of a risk evaluation model utilized the least absolute shrinkage and selection operator regression algorithm, which was further confirmed by independent cohorts and diverse data types. CCA tumor cells with elevated levels of MUC1 and MUC4 showed activated nucleotide metabolic pathways and increased invasiveness. MUC5AC-high cells were found to promote CCA progression through WNT signaling. MUC5B-high cells exhibited robust cellular oxidation activities, leading to resistance against antitumoral treatments. MUC13-high cells were observed to secret chemokines, recruiting and transforming macrophages into the M2-polarized state, thereby suppressing antitumor immunity. MUC16-high cells were found to promote tumor progression through interleukin-1/nuclear factor kappa-light-chain-enhancer of activated B cells signaling upon interaction with neutrophils. Utilizing the expression levels of these mucins, a risk factor evaluation formula for CCA was developed and validated across multiple cohorts. CCA samples with higher risk factors exhibited stronger metastatic potential, chemotherapy resistance, and poorer prognosis. Our study elucidates the functional mechanisms through which mucins contribute to CCA development, and provides tools for risk stratification in CCA.

Targeting nucleotide metabolic pathways in colorectal cancer by integrating scRNA-seq, spatial transcriptome, and bulk RNA-seq data

BackgroundColorectal cancer is a malignant tumor of the digestive system originating from abnormal cell proliferation in the colon or rectum, often leading to gastrointestinal symptoms and severe health issues. Nucleotide metabolism, which encompasses the synthesis of DNA and RNA, is a pivotal cellular biochemical process that significantly impacts both the progression and therapeutic strategies of colorectal cancerMethodsFor single-cell RNA sequencing (scRNA-seq), five functions were employed to calculate scores related to nucleotide metabolism. Cell developmental trajectory analysis and intercellular interaction analysis were utilized to explore the metabolic characteristics and communication patterns of different epithelial cells. These findings were further validated using spatial transcriptome RNA sequencing (stRNA-seq). A risk model was constructed using expression profile data from TCGA and GEO cohorts to optimize clinical decision-making. Key nucleotide metabolism-related genes (NMRGs) were functionally validated by further in vitro experiments.ResultsIn both scRNA-seq and stRNA-seq, colorectal cancer (CRC) exhibited unique cellular heterogeneity, with myeloid cells and epithelial cells in tumor samples displaying higher nucleotide metabolism scores. Analysis of intercellular communication revealed enhanced signaling pathways and ligand-receptor interactions between epithelial cells with high nucleotide metabolism and fibroblasts. Spatial transcriptome sequencing confirmed elevated nucleotide metabolism states in the core region of tumor tissue. After identifying differentially expressed NMRGs in epithelial cells, a risk prognostic model based on four genes effectively predicted overall survival and immunotherapy outcomes in patients. High-risk group patients exhibited an immunosuppressive microenvironment and relatively poorer prognosis and responses to chemotherapy and immunotherapy. Finally, based on data analysis and a series of cellular functional experiments, ACOX1 and CPT2 were identified as novel therapeutic targets for CRC.ConclusionIn this study, a comprehensive analysis of NMRGs in CRC was conducted using a combination of single-cell sequencing, spatial transcriptome sequencing, and high-throughput data. The prognostic model constructed with NMRGs shows potential as a standalone prognostic marker for colorectal cancer patients and may significantly influence the development of personalized treatment approaches for CRC.

Analysis of blood biochemistry and non-targeted metabolomics of endometritis in dairy cows

The incidence of bovine endometritis, which has a negative impact on the reproduction of dairy cows, has been recently increasing. In this study, the differential markers and metabolites of healthy cows and cows with endometritis were analyzed by measuring blood biochemical indicators and immune factors using biochemical and enzyme-linked immunosorbent assay kits combined with nontargeted metabolomics. The LC-QTOF platform was used to evaluate the serum metabolomics of healthy cows and cows with endometritis after 21–27 days of calving. The results showed that glucose, free fatty acid, calcium, sodium, albumin, and alanine aminotransferase levels were significantly lower in the serum of cows with endometritis than in healthy cows (P < 0.05). However, the serum potassium, interleukin-1, interleukin-6, and tumor necrosis factor levels were significantly higher in cows with endometritis (P < 0.05). In addition, the serum metabolome data analysis of the two groups showed that the expression of 468 metabolites was significantly different (P < 0.05), of which 291 were upregulated and 177 were downregulated. These metabolites were involved in 78 metabolic pathways, including amino acid, nucleotide, carbohydrate, lipid, and vitamin metabolism pathways; signal transduction pathways, and other biological pathways. Taken together, negative energy balance and immune activation, which are related to local abnormalities in amino acid, lipid, and carbohydrate metabolism, were the important causes of endometritis in dairy cows. Metabolites such as glucose, carnosine, dehydroascorbic acid, L-malic acid, tetrahydrofolic acid, and UDP-glucose may be used as key indicators in the hematological diagnosis and treatment of endometritis in dairy cows.

Abstract 4426: Targeting MCT1 and PFKFB3 provokes synthetic lethality in small cell lung cancer

Abstract Small cell lung cancer (SCLC) is the third most common lung cancer and is extremely aggressive and highly metastatic. SCLC responds to radiation and standard platinum-based chemotherapy, yet this is invariably followed by relapse and the rapid emergence of lethal chemoresistant disease. Hence, SCLC has been declared a recalcitrant malignancy by NCI, and there is an urgent need to identify new and actionable therapeutic vulnerabilities. Unbiased metabolomic and shotgun and activity-based proteomic analyses of NSCLC and SCLC patient derived tumor tissues, PDX and a panel of cell lines revealed marked upregulation of glycolytic and nucleotide metabolic pathways in SCLC. Further, unbiased screens with metabolic inhibitors revealed selective sensitivity of SCLC cells to the MCT1 lactate transporter inhibitor SR13800 and to the PFKFB3 inhibitor PFK15, and that combined treatment provokes rapid apoptosis. Metabolic, flux and molecular analyses revealed that MCT1 inhibition (MCT1i) or loss in SCLC cells impairs glycolysis and triggers rapid increases in intracellular lactate that then diminish, and this is driven by the induction of lactate dehydrogenase-B (LDH-B) that oxidizes lactate into pyruvate. This is accompanied by a marked shift in the NAD+ to NADH ratio towards NADH, and increased pyruvate dehydrogenase (PDH) activity and OXPHOS. Further, MCT1 inhibition provoked increases in the Aspartate-Malate and DHAP-SnG3P shuttles, which restored the NAD+/NADH balance in the cytosol. In contrast, treatment of SCLC cells with PFKFB3 inhibitors (PFKFB3i) leads to inhibition of PDH activity, a collapse in OXPHOS and increases in lactate efflux that are due to flux of glucose through pentose phosphate pathway and re-entry into glycolysis via 3-phosphoglygerate (3-PGA). Combined MCT1/PFKFB3 inhibition amplifies metabolic alterations provoked by both MCT1i and PFKFB3i, triggering a collapse in both glycolysis and OXPHOS. Similarly, inhibition or silencing of enzymes that drive the Aspartate-Malate and DHAP-SnG3P shuttles, or inhibition of the mitochondrial pyruvate transporter, provoked metabolic collapse and cell death following inhibition or loss of MCT1. Finally, SCLC xenografts and primary SCLC CDX treated with a combination of SR13800 and PFK15 showed improved survival compared to vehicle or monotherapy treatments. Thus, co-targeting adaptive metabolic circuits provoked by inhibition of MCT1 and PFKFB3 provokes synthetic lethality in SCLC, supporting the notion that inhibition of these metabolic chokepoints will be an effective strategy for treatment of this lethal malignancy. Citation Format: Antony Herold Prabhu, Kristen Scott, Paul Stewart, Daniel Grass, Mario Fernandez, Dalia Ercan, John Koomen, Thomas Bannister, Charles Rudin, Gina DeNicola, Eric Haura, John Cleveland. Targeting MCT1 and PFKFB3 provokes synthetic lethality in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4426.

Rare red cell enzymopathies in the Indian population: A comprehensive review

Red blood cell enzyme deficiencies are a rare category of hemolytic anaemia that typically present in children with varying degrees of hemolysis, indirect hyperbilirubinemia and splenomegaly. Glucose 6-phosphate dehydrogenase (G6PD) is the most common enzyme deficiency, followed by pyruvate kinase deficiency (PKD). This article aims to understand the pathophysiology of the rare enzymopathies due to deficiencies in the Embden-Meyerhoff pathway, glutathione metabolism, hexose monophosphate shunt and nucleotide metabolism pathway, and to study the incidence, clinical symptoms, diagnostic strategy, and management of enzyme deficiencies in the Indian patients. Most red blood cell (RBC) enzyme deficiencies are inherited in an autosomal recessive fashion except for G6PD, and phosphoglycerate kinase deficiency which has X-linked inheritance. Presentation depends on the representation of the enzyme on different tissues of the body, hence some enzyme deficiencies may present with neurological or muscular manifestations. In patients with suspected hemolytic anaemia, complete blood count and peripheral smear help in differentiating from hemoglobinopathies, etc. To clinch the diagnosis enzyme levels and genetic testing may be required. These tests guide antenatal diagnosis in subsequent pregnancies. Management of RBC enzymopathies depends on the predominant symptoms and severity of hemolysis. Patients with marked hemolysis require regular blood transfusions and hence appropriate chelation therapy. Hematopoeitic stem cell transplant is attempted in patients with severe spectrum with variable results. Newer drugs, including mitapivat have proven to be beneficial in adults with PKD and ongoing trials in children are showing promising results.

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.

Multi-omics analyses uncover metabolic signatures and gene expression profiles of interstitial cystitis/bladder pain syndrome.

We explore molecular and metabolic pathways involved in interstitial cystitis (IC) with integrating multi-omics analysis for identifying potential diagnostic and therapeutic targets. Mouse models of IC/bladder pain syndrome (BPS) were established by intraperitoneal injection of cyclophosphamide and bladder tissue samples were collected for metabolomics and transcriptome analysis. We found a total of 82 and 145 differential metabolites in positive ion modes and negative ion modes, respectively. Glycerophospholipid metabolism, choline metabolism in cancer, and nucleotide metabolism pathways were significantly enriched in the IC/BPS group. Transcriptome analysis demonstrated that 1069 upregulated genes and 1087 downregulated genes were detected. Importantly, the stronger enrichment for cell cycle pathway was observed in IC/BPS than that in normal bladder tissue, which may be involved in the process of bladder remodeling. Moreover, the inflammatory response and inflammatory factors related pathways were enriched in the IC/BPS group. Our findings provide critical directions for further exploration of the molecular pathology underlying IC/BPS.