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Conservation Physiology 2024Bumblebee populations across the globe are experiencing substantial declines due to climate change, with major consequences for pollination services in both natural and...
Bumblebee populations across the globe are experiencing substantial declines due to climate change, with major consequences for pollination services in both natural and agricultural settings. Using an economically important species, , we explored the physiological mechanisms that may cause susceptibility to extreme heat events. We tested the hypothesis that heat exposure limits the activity of the pentose phosphate pathway (PPP)-a parallel pathway to glycolysis that can use nectar sugar to generate antioxidant potential and combat oxidative stress. Using isotopically labelled glucose, we tracked PPP activity in at rest, during exercise and during a post-exercise recovery period under two different temperature regimes (22°C and 32°C). We found that the PPP is routinely used by at moderate temperatures, but that its activity is markedly reduced when ATP demands are high, such as during periods of exercise and heat exposure. We also exposed to either 22°C or 32°C for 5 hours and assessed levels of oxidative damage (lipid peroxidation, protein carbonyls) and antioxidant potential [reduced (GSH) and oxidized (GSSG) glutathione concentrations]. Interestingly, bees exhibited little oxidative damage after the thermal exposure, but we found a lower GSH:GSSG ratio in 32°C-exposed bees, reflecting lower antioxidant potential. Overall, our study demonstrates that acute heat stress severely limits PPP activity and may constrain antioxidant potential in . The repeated attenuation of this pathway in a warming climate may have more severe physiological consequences for this species, with potential implications for pollination services across North America.
PubMed: 38812726
DOI: 10.1093/conphys/coae031 -
Frontiers in Microbiology 2024Higher alcohols are volatile compounds produced during alcoholic fermentation that affect the quality and safety of the final product. This study used a correlation...
INTRODUCTION
Higher alcohols are volatile compounds produced during alcoholic fermentation that affect the quality and safety of the final product. This study used a correlation analysis of transcriptomics and metabolomics to study the impact of the initial addition of SO (30, 60, and 90 mg/L) on the synthesis of higher alcohols in EC1118a and to identify key genes and metabolic pathways involved in their metabolism.
METHODS
Transcriptomics and metabolomics correlation analyses were performed and differentially expressed genes (DEGs) and differential metabolites were identified. Single-gene knockouts for targeting genes of important pathways were generated to study the roles of key genes involved in the regulation of higher alcohol production.
RESULTS
We found that, as the SO concentration increased, the production of total higher alcohols showed an overall trend of first increasing and then decreasing. Multi-omics correlation analysis revealed that the addition of SO affected carbon metabolism (ko01200), pyruvate metabolism (ko00620), glycolysis/gluconeogenesis (ko00010), the pentose phosphate pathway (ko00030), and other metabolic pathways, thereby changing the precursor substances. The availability of SO indirectly affects the formation of higher alcohols. In addition, excessive SO affected the growth of the strain, leading to the emergence of a lag phase. We screened the ten most likely genes and constructed recombinant strains to evaluate the impact of each gene on the formation of higher alcohols. The results showed that , and are important genes of alcohol metabolism in . The isoamyl alcohol content of the EC1118a strain decreased by 21.003%; The isobutanol content of the EC1118a strain was reduced by 71.346%; and the 2-phenylethanol content of EC1118a strain was reduced by 25.198%.
CONCLUSION
This study lays a theoretical foundation for investigating the mechanism of initial addition of SO in the synthesis of higher alcohols in , uncovering DEGs and key metabolic pathways related to the synthesis of higher alcohols, and provides guidance for regulating these mechanisms.
PubMed: 38803372
DOI: 10.3389/fmicb.2024.1394880 -
Frontiers in Endocrinology 2024Emerging data suggests liver disease may be initiated during development when there is high genome plasticity and the molecular pathways supporting liver function are...
Early life exposure to vitamin D deficiency impairs molecular mechanisms that regulate liver cholesterol biosynthesis, energy metabolism, inflammation, and detoxification.
INTRODUCTION
Emerging data suggests liver disease may be initiated during development when there is high genome plasticity and the molecular pathways supporting liver function are being developed.
METHODS
Here, we leveraged our Collaborative Cross mouse model of developmental vitamin D deficiency (DVD) to investigate the role of DVD in dysregulating the molecular mechanisms underlying liver disease. We defined the effects on the adult liver transcriptome and metabolome and examined the role of epigenetic dysregulation. Given that the parental origin of the genome (POG) influences response to DVD, we used our established POG model [POG1-(CC011xCC001)F1 and POG2-(CC001xCC011)F1] to identify interindividual differences.
RESULTS
We found that DVD altered the adult liver transcriptome, primarily downregulating genes controlling liver development, response to injury/infection (detoxification & inflammation), cholesterol biosynthesis, and energy production. In concordance with these transcriptional changes, we found that DVD decreased liver cell membrane-associated lipids (including cholesterol) and pentose phosphate pathway metabolites. Each POG also exhibited distinct responses. POG1 exhibited almost 2X more differentially expressed genes (DEGs) with effects indicative of increased energy utilization. This included upregulation of lipid and amino acid metabolism genes and increased intermediate lipid and amino acid metabolites, increased energy cofactors, and decreased energy substrates. POG2 exhibited broader downregulation of cholesterol biosynthesis genes with a metabolomics profile indicative of decreased energy utilization. Although DVD primarily caused loss of liver DNA methylation for both POGs, only one epimutation was shared, and POG2 had 6.5X more differentially methylated genes. Differential methylation was detected at DEGs regulating developmental processes such as amino acid transport (POG1) and cell growth & differentiation (e.g., Wnt & cadherin signaling, POG2).
CONCLUSIONS
These findings implicate a novel role for maternal vitamin D in programming essential offspring liver functions that are dysregulated in liver disease. Importantly, impairment of these processes was not rescued by vitamin D treatment at weaning, suggesting these effects require preventative measures. Substantial differences in POG response to DVD demonstrate that the parental genomic context of exposure determines offspring susceptibility.
Topics: Animals; Mice; Liver; Energy Metabolism; Vitamin D Deficiency; Cholesterol; Female; Inflammation; Male; Mice, Inbred C57BL; Transcriptome; Epigenesis, Genetic
PubMed: 38800476
DOI: 10.3389/fendo.2024.1335855 -
Nature Communications May 2024Virulence and metabolism are often interlinked to control the expression of essential colonisation factors in response to host-associated signals. Here, we identified an...
Virulence and metabolism are often interlinked to control the expression of essential colonisation factors in response to host-associated signals. Here, we identified an uncharacterised transporter of the dietary monosaccharide ʟ-arabinose that is widely encoded by the zoonotic pathogen enterohaemorrhagic Escherichia coli (EHEC), required for full competitive fitness in the mouse gut and highly expressed during human infection. Discovery of this transporter suggested that EHEC strains have an enhanced ability to scavenge ʟ-arabinose and therefore prompted us to investigate the impact of this nutrient on pathogenesis. Accordingly, we discovered that ʟ-arabinose enhances expression of the EHEC type 3 secretion system, increasing its ability to colonise host cells, and that the underlying mechanism is dependent on products of its catabolism rather than the sensing of ʟ-arabinose as a signal. Furthermore, using the murine pathogen Citrobacter rodentium, we show that ʟ-arabinose metabolism provides a fitness benefit during infection via virulence factor regulation, as opposed to supporting pathogen growth. Finally, we show that this mechanism is not restricted to ʟ-arabinose and extends to other pentose sugars with a similar metabolic fate. This work highlights the importance integrating central metabolism with virulence regulation in order to maximise competitive fitness of enteric pathogens within the host-niche.
Topics: Arabinose; Animals; Mice; Citrobacter rodentium; Humans; Virulence; Enterohemorrhagic Escherichia coli; Gene Expression Regulation, Bacterial; Virulence Factors; Enterobacteriaceae Infections; Escherichia coli Proteins; Type III Secretion Systems; Escherichia coli Infections; Female
PubMed: 38796512
DOI: 10.1038/s41467-024-48933-7 -
Viruses May 2024Recent studies highlight the crucial role of the gut microbiome in post-infectious complications, especially in patients recovering from severe COVID-19. Our research...
Recent studies highlight the crucial role of the gut microbiome in post-infectious complications, especially in patients recovering from severe COVID-19. Our research aimed to explore the connection between gut microbiome changes and the cytokine profile of patients with post-COVID syndrome. Using 16S rRNA amplicon sequencing, we analyzed the composition of the gut microbiome in 60 COVID-19 patients over the course of one year. We also measured the levels of serum cytokines and chemokines using the Milliplex system. Our results showed that severe SARS-CoV-2 infection cases, especially those complicated by pneumonia, induce a pro-inflammatory microbial milieu with heightened presence of , , and . Furthermore, we found that post-COVID syndrome is characterized by a cross-correlation of various cytokines and chemokines MDC, IL-1b, Fractalkine, TNFa, FGF-2, EGF, IL-1RA, IFN-a2, IL-10, sCD40L, IL-8, Eotaxin, IL-12p40, and MIP-1b as well as a shift in the gut microbiome towards a pro-inflammatory profile. At the functional level, our analysis revealed associations with post-COVID-19 in homolactic fermentation, pentose phosphate, NAD salvage, and flavin biosynthesis. These findings highlight the intricate interplay between the gut microbiota, their metabolites, and systemic cytokines in shaping post-COVID symptoms. Unraveling the gut microbiome's role in post-infectious complications opens avenues for new treatments for those patients with prolonged symptoms.
Topics: Humans; COVID-19; Cytokines; Gastrointestinal Microbiome; Male; Female; Middle Aged; SARS-CoV-2; Aged; Adult; RNA, Ribosomal, 16S; Post-Acute COVID-19 Syndrome; Feces
PubMed: 38793604
DOI: 10.3390/v16050722 -
Genes May 2024is the primary active compound of . However, the definitive genetic mechanism governing cordycepin synthesis in fruiting body growth and development remains elusive,...
is the primary active compound of . However, the definitive genetic mechanism governing cordycepin synthesis in fruiting body growth and development remains elusive, necessitating further investigation. This study consists of 64 strains collected from northeast China. The high-yielding cordycepin strain CMS19 was selected for the analysis of cordycepin production and the genetic basis of cordycepin anabolism. First, the whole-genome sequencing of CMS19 yielded a final size of 30.96 Mb with 8 contigs and 9781 protein-coding genes. The genome component revealed the presence of four additional secondary metabolite gene clusters compared with other published genomes, suggesting the potential for the production of new natural products. The analyses of evolutionary and genetic differentiation revealed a close relationship between and . The population of strains distributed in northeast China exhibited the significant genetic variation. Finally, functional genes associated with cordycepin synthesis were identified using a combination of genomic and transcriptomic analyses. A large number of functional genes associated with energy and purine metabolism were significantly enriched, facilitating the reconstruction of a hypothetical cordycepin metabolic pathway. Therefore, our speculation of the cordycepin metabolism pathway involved 24 genes initiating from the glycolysis and pentose phosphate pathways, progressing through purine metabolism, and culminating in the core region of cordycepin synthesis. These findings could offer fundamental support for scientific utilizations of germplasm resources and standardized cultivation for cordycepin production.
Topics: Cordyceps; Deoxyadenosines; Transcriptome; Genome, Fungal; Gene Expression Profiling; Genomics; Multigene Family; Gene Expression Regulation, Fungal; Whole Genome Sequencing; Phylogeny
PubMed: 38790255
DOI: 10.3390/genes15050626 -
Metabolic Engineering May 2024Metabolic engineering for high productivity and increased robustness is needed to enable sustainable biomanufacturing of lactic acid from lignocellulosic biomass. Lactic...
Metabolic engineering for high productivity and increased robustness is needed to enable sustainable biomanufacturing of lactic acid from lignocellulosic biomass. Lactic acid is an important commodity chemical used for instance as a monomer for production of polylactic acid, a biodegradable polymer. Here, rational and model-based optimization was used to engineer a diploid, xylose fermenting Saccharomyces cerevisiae strain to produce L-lactic acid. The metabolic flux was steered towards lactic acid through the introduction of multiple lactate dehydrogenase encoding genes while deleting ERF2, GPD1, and CYB2. A production of 93 g/L of lactic acid with a yield of 0.84 g/g was achieved using xylose as the carbon source. To increase xylose utilization and reduce acetic acid synthesis, PHO13 and ALD6 were also deleted from the strain. Finally, CDC19 encoding a pyruvate kinase was overexpressed, resulting in a yield of 0.75 g lactic acid/g sugars consumed, when the substrate used was a synthetic lignocellulosic hydrolysate medium, containing hexoses, pentoses and inhibitors such as acetate and furfural. Notably, modeling also provided leads for understanding the influence of oxygen in lactic acid production. High lactic acid production from xylose, at oxygen-limitation could be explained by a reduced flux through the oxidative phosphorylation pathway. On the contrast, higher oxygen levels were beneficial for lactic acid production with the synthetic hydrolysate medium, likely as higher ATP concentrations are needed for tolerating the inhibitors therein. The work highlights the potential of S. cerevisiae for industrial production of lactic acid from lignocellulosic biomass.
PubMed: 38788894
DOI: 10.1016/j.ymben.2024.05.003 -
Metabolites Apr 2024The metabolic reprogramming that promotes tumorigenesis in glioblastoma is induced by dynamic alterations in the hypoxic tumor microenvironment, as well as in... (Review)
Review
The metabolic reprogramming that promotes tumorigenesis in glioblastoma is induced by dynamic alterations in the hypoxic tumor microenvironment, as well as in transcriptional and signaling networks, which result in changes in global genetic expression. The signaling pathways PI3K/AKT/mTOR and RAS/RAF/MEK/ERK stimulate cell metabolism, either directly or indirectly, by modulating the transcriptional factors p53, HIF1, and c-Myc. The overexpression of HIF1 and c-Myc, master regulators of cellular metabolism, is a key contributor to the synthesis of bioenergetic molecules that mediate glioma cell transformation, proliferation, survival, migration, and invasion by modifying the transcription levels of key gene groups involved in metabolism. Meanwhile, the tumor-suppressing protein p53, which negatively regulates HIF1 and c-Myc, is often lost in glioblastoma. Alterations in this triad of transcriptional factors induce a metabolic shift in glioma cells that allows them to adapt and survive changes such as mutations, hypoxia, acidosis, the presence of reactive oxygen species, and nutrient deprivation, by modulating the activity and expression of signaling molecules, enzymes, metabolites, transporters, and regulators involved in glycolysis and glutamine metabolism, the pentose phosphate cycle, the tricarboxylic acid cycle, and oxidative phosphorylation, as well as the synthesis and degradation of fatty acids and nucleic acids. This review summarizes our current knowledge on the role of HIF1, c-Myc, and p53 in the genic regulatory network for metabolism in glioma cells, as well as potential therapeutic inhibitors of these factors.
PubMed: 38786726
DOI: 10.3390/metabo14050249 -
Journal of Fungi (Basel, Switzerland) Apr 2024Gray mold, caused by , poses significant threats to various crops, while it can be remarkably inhibited by ε-poly-L-lysine (ε-PL). A previous study found that...
Gray mold, caused by , poses significant threats to various crops, while it can be remarkably inhibited by ε-poly-L-lysine (ε-PL). A previous study found that extracts could stimulate the ε-PL biosynthesis of , while it is unclear whether the impact of the signal on ε-PL biosynthesis is direct or indirect. This study evaluated the role of elevated reactive oxygen species (ROS) in efficient ε-PL biosynthesis after induction, and its underlying mechanism was disclosed with a transcriptome analysis. The microbial call from could arouse ROS elevation in cells, which fall in a proper level that positively influenced the ε-PL biosynthesis. A systematic transcriptional analysis revealed that this proper dose of intracellular ROS could induce a global transcriptional promotion on key pathways in ε-PL biosynthesis, including the embden-meyerhof-parnas pathway, the pentose phosphate pathway, the tricarboxylic acid cycle, the diaminopimelic acid pathway, ε-PL accumulation, cell respiration, and energy synthesis, in which sigma factor HrdD and the transcriptional regulators of TcrA, TetR, FurA, and MerR might be involved. In addition, the intracellular ROS elevation also resulted in a global modification of secondary metabolite biosynthesis, highlighting the secondary signaling role of intracellular ROS in ε-PL production. This work disclosed the transcriptional mechanism of efficient ε-PL production that resulted from an intracellular ROS elevation after elicitors' induction, which was of great significance in industrial ε-PL production as well as the biocontrol of gray mold disease.
PubMed: 38786679
DOI: 10.3390/jof10050324 -
The EMBO Journal Jul 2024During infection viruses hijack host cell metabolism to promote their replication. Here, analysis of metabolite alterations in macrophages exposed to poly I:C recognises...
During infection viruses hijack host cell metabolism to promote their replication. Here, analysis of metabolite alterations in macrophages exposed to poly I:C recognises that the antiviral effector Protein Kinase RNA-activated (PKR) suppresses glucose breakdown within the pentose phosphate pathway (PPP). This pathway runs parallel to central glycolysis and is critical to producing NADPH and pentose precursors for nucleotides. Changes in metabolite levels between wild-type and PKR-ablated macrophages show that PKR controls the generation of ribose 5-phosphate, in a manner distinct from its established function in gene expression but dependent on its kinase activity. PKR phosphorylates and inhibits the Ribose 5-Phosphate Isomerase A (RPIA), thereby preventing interconversion of ribulose- to ribose 5-phosphate. This activity preserves redox control but decreases production of ribose 5-phosphate for nucleotide biosynthesis. Accordingly, the PKR-mediated immune response to RNA suppresses nucleic acid production. In line, pharmacological targeting of the PPP during infection decreases the replication of the Herpes simplex virus. These results identify an immune response-mediated control of host cell metabolism and suggest targeting the RPIA as a potential innovative antiviral treatment.
Topics: Animals; Ribosemonophosphates; Mice; Pentose Phosphate Pathway; eIF-2 Kinase; Macrophages; Aldose-Ketose Isomerases; RNA; Poly I-C; Nucleic Acids; Virus Replication; Phosphorylation
PubMed: 38778156
DOI: 10.1038/s44318-024-00100-w