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Frontiers in Microbiology 2024causes listeriosis, an infectious and potentially fatal disease of animals and humans. A diverse network of transcriptional regulators, including LysR-type catabolite...
causes listeriosis, an infectious and potentially fatal disease of animals and humans. A diverse network of transcriptional regulators, including LysR-type catabolite control protein C (CcpC), is critical for the survival of and its ability to transition into the host environment. In this study, we explored the physiological and genetic consequences of deleting and the effects of such deletion on the ability of to cause disease. We found that deletion did not impact hemolytic activity, whereas it resulted in significant reductions in phospholipase activities. Western blotting revealed that the Δ strain produced significantly reduced levels of the cholesterol-dependent cytolysin LLO relative to the wildtype F2365 strain. However, the Δ mutant displayed no significant intracellular growth defect in macrophages. Furthermore, Δ strain exhibited reduction in plaque numbers in fibroblasts compared to F2365, but plaque size was not significantly affected by deletion. In a murine model system, the Δ strain exhibited a significantly reduced bacterial burden in the liver and spleen compared to the wildtype F2365 strain. Interestingly, the deletion of this gene also enhanced the survival of under conditions of HO-induced oxidative stress. Transcriptomic analyses performed under HO-induced oxidative stress conditions revealed that DNA repair, cellular responses to DNA damage and stress, metalloregulatory proteins, and genes involved in the biosynthesis of peptidoglycan and teichoic acids were significantly induced in the deletion strain relative to F2365. In contrast, genes encoding internalin, 1-phosphatidylinositol phosphodiesterase, and genes associated with sugar-specific phosphotransferase system components, porphyrin, branched-chain amino acids, and pentose phosphate pathway were significantly downregulated in the deletion strain relative to F2365. This finding highlights CcpC as a key factor that regulates physiology and responses to oxidative stress by controlling the expression of important metabolic pathways.
PubMed: 38881664
DOI: 10.3389/fmicb.2024.1403694 -
The Journal of Biological Chemistry Jun 2024Obesity is a major risk factor for liver and cardiovascular diseases. However, obesity-driven mechanisms that contribute to the pathogenesis of multiple organ diseases...
Obesity is a major risk factor for liver and cardiovascular diseases. However, obesity-driven mechanisms that contribute to the pathogenesis of multiple organ diseases are still obscure and treatment is inadequate. We hypothesized that increased glucose-6-phosphate dehydrogenase (G6PD), the key rate-limiting enzyme in the pentose shunt, is critical in evoking metabolic reprogramming in multiple organs and is a significant contributor to the pathogenesis of liver and cardiovascular diseases. G6PD is induced by carbohydrate-rich diet and insulin. Long-term (8 months) high-fat diet (HFD) feeding increased body weight and elicited metabolic reprogramming in visceral fat, liver, and aorta, of the wild-type rats. In addition, HFD increased inflammatory chemokines in visceral fat. Interestingly, CRISPR-edited loss-of-function Mediterranean G6PD variant (G6PD) rats, which mimic human polymorphism, moderated HFD-induced weight gain and metabolic reprogramming in visceral fat, liver, and aorta. The G6PD variant prevented HFD-induced CCL7 and adipocyte hypertrophy. Furthermore, the G6PD variant increased Magel2 - a gene encoding circadian clock-related protein that suppresses obesity associated with Prader-Willi syndrome - and reduced HFD-induced non-alcoholic fatty liver. Additionally, the G6PD variant reduced aging-induced aortic stiffening. Our findings suggest G6PD is a regulator of HFD-induced obesity, adipocyte hypertrophy, and fatty liver.
PubMed: 38876306
DOI: 10.1016/j.jbc.2024.107460 -
Cell Metabolism Jun 2024Mitochondria house many metabolic pathways required for homeostasis and growth. To explore how human cells respond to mitochondrial dysfunction, we performed...
Mitochondria house many metabolic pathways required for homeostasis and growth. To explore how human cells respond to mitochondrial dysfunction, we performed metabolomics in fibroblasts from patients with various mitochondrial disorders and cancer cells with electron transport chain (ETC) blockade. These analyses revealed extensive perturbations in purine metabolism, and stable isotope tracing demonstrated that ETC defects suppress de novo purine synthesis while enhancing purine salvage. In human lung cancer, tumors with markers of low oxidative mitochondrial metabolism exhibit enhanced expression of the salvage enzyme hypoxanthine phosphoribosyl transferase 1 (HPRT1) and high levels of the HPRT1 product inosine monophosphate. Mechanistically, ETC blockade activates the pentose phosphate pathway, providing phosphoribosyl diphosphate to drive purine salvage supplied by uptake of extracellular bases. Blocking HPRT1 sensitizes cancer cells to ETC inhibition. These findings demonstrate how cells remodel purine metabolism upon ETC blockade and uncover a new metabolic vulnerability in tumors with low respiration.
PubMed: 38876105
DOI: 10.1016/j.cmet.2024.05.014 -
Biomedicine & Pharmacotherapy =... Jul 2024Breast cancer is one of the most common malignant tumors in women and is a serious threat to women's health. The pentose phosphate pathway (PPP) is a mode of oxidative... (Review)
Review
Breast cancer is one of the most common malignant tumors in women and is a serious threat to women's health. The pentose phosphate pathway (PPP) is a mode of oxidative breakdown of glucose that can be divided into oxidative (oxPPP) and non-oxidative (non-oxPPP) stages and is necessary for cell and body survival. However, abnormal activation of PPP often leads to proliferation, migration, invasion, and chemotherapy resistance in breast cancer. Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme in PPP oxidation. Nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) produced by G6PD is the raw material for cholesterol and lipid synthesis and can resist the production of oxygen species (ROS) and reduce oxidative stress damage to tumor cells. Transketolase (TKT) is a key enzyme in non-oxPPP. Ribose 5-phosphate (R5P), produced by TKT, is a raw material for DNA and RNA synthesis, and is essential for tumor cell proliferation and DNA damage repair. In this review, we describe the role and specific mechanism of the PPP and the two most important enzymes of the PPP, G6PD and TKT, in the malignant progression of breast cancer, providing strategies for future clinical treatment of breast cancer and a theoretical basis for breast cancer research.
Topics: Transketolase; Humans; Breast Neoplasms; Female; Glucosephosphate Dehydrogenase; Disease Progression; Pentose Phosphate Pathway; Animals
PubMed: 38876050
DOI: 10.1016/j.biopha.2024.116935 -
Redox Biology Aug 2024The pathogenesis of epilepsy remains unclear; however, a prevailing hypothesis suggests that the primary underlying cause is an imbalance between neuronal excitability...
Glucose-6-phosphate dehydrogenase alleviates epileptic seizures by repressing reactive oxygen species production to promote signal transducer and activator of transcription 1-mediated N-methyl-d-aspartic acid receptors inhibition.
The pathogenesis of epilepsy remains unclear; however, a prevailing hypothesis suggests that the primary underlying cause is an imbalance between neuronal excitability and inhibition. Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme in the pentose phosphate pathway, which is primarily involved in deoxynucleic acid synthesis and antioxidant defense mechanisms and exhibits increased expression during the chronic phase of epilepsy, predominantly colocalizing with neurons. G6PD overexpression significantly reduces the frequency and duration of spontaneous recurrent seizures. Furthermore, G6PD overexpression enhances signal transducer and activator of transcription 1 (STAT1) expression, thus influencing N-methyl-d-aspartic acid receptors expression, and subsequently affecting seizure activity. Importantly, the regulation of STAT1 by G6PD appears to be mediated primarily through reactive oxygen species signaling pathways. Collectively, our findings highlight the pivotal role of G6PD in modulating epileptogenesis, and suggest its potential as a therapeutic target for epilepsy.
Topics: Glucosephosphate Dehydrogenase; Reactive Oxygen Species; Animals; Receptors, N-Methyl-D-Aspartate; Seizures; STAT1 Transcription Factor; Epilepsy; Signal Transduction; Mice; Humans; Neurons; Male; Rats; Disease Models, Animal
PubMed: 38875958
DOI: 10.1016/j.redox.2024.103236 -
Frontiers in Microbiology 2024is a popular edible fungus with high economic and nutritional value. However, the rot disease caused by , pose a serious threat to the quality and yield of . Biological...
INTRODUCTION
is a popular edible fungus with high economic and nutritional value. However, the rot disease caused by , pose a serious threat to the quality and yield of . Biological control is one of the effective ways to control fungal diseases.
METHODS AND RESULTS
In this study, an effective endophytic A9 for the control of rot disease was screened, and its biocontrol mechanism was studied by transcriptome analysis. In total, 122 strains of endophytic bacteria from , of which the antagonistic effect of A9 on G1 reached 72.2% tests. Biological characteristics and genomic features of A9 were analyzed, and key antibiotic gene clusters were detected. Scanning electron microscope (SEM) observation showed that A9 affected the mycelium and spores of G1. In field experiments, the biological control effect of A9 reached to 62.5%. Furthermore, the transcritome profiling provides evidence of A9 bicontrol at the molecular level. A total of 1,246 differentially expressed genes (DEGs) were identified between the treatment and control group. Gene Ontology (GO) enrichment analysis showed that a large number of DEGs were related to antioxidant activity related. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the main pathways were Nitrogen metabolism, Pentose Phosphate Pathway (PPP) and Mitogen-Activated Protein Kinases (MAPK) signal pathway. Among them, some important genes such as carbonic anhydrase CA (H6S33_007248), catalase CAT (H6S33_001409), tRNA dihydrouridine synthase DusB (H6S33_001297) and NAD(P)-binding protein NAD(P) BP (H6S33_000823) were found. Furthermore, A9 considerably enhanced the activity of Polyphenol oxidase (POD), Superoxide dismutase (SOD), Phenylal anineammonia lyase (PAL) and Catalase (CAT).
CONCLUSION
This study presents the innovative utilization of A9, for effectively controlling rot disease. This will lay a foundation for biological control in , which may lead to the improvement of new biocontrol agents for production.
PubMed: 38873148
DOI: 10.3389/fmicb.2024.1388669 -
Experimental and Therapeutic Medicine Aug 2024Excessive alcohol consumption is considered to be a major risk factor of alcohol-induced osteonecrosis of the femoral head (AONFH). The gut microbiota (GM) has been...
Excessive alcohol consumption is considered to be a major risk factor of alcohol-induced osteonecrosis of the femoral head (AONFH). The gut microbiota (GM) has been reported to aid in the regulation of human physiology and its composition can be altered by alcohol consumption. The aim of the present study was to improve the understanding of the GM and its metabolites in patients with AONFH. Metabolomic sequencing and 16S rDNA analysis of fecal samples were performed using liquid chromatography-mass spectrometry to characterize the GM of patients with AONFH and healthy normal controls (NCs). Metagenomic sequencing of fecal samples was performed to identify whether GM changes on the species level were associated with the expression of gut bacteria genes or their associated functions in patients with AONFH. The abundance of 58 genera was found to differ between the NC group and the AONFH group. Specifically, , , and were significantly more abundant in the AONFH group compared with those in the NC group. Metagenomic sequencing demonstrated that the majority of the bacterial species that exhibited significantly different abundance in patients with AONFH belonged to the genus . Fecal metabolomic analysis demonstrated that several metabolites were present at significantly different concentrations in the AONFH group compared with those in the NC group. These metabolites were products of vitamin B6 metabolism, retinol metabolism, pentose and glucuronate interconversions and glycerophospholipid metabolism. In addition, these changes in metabolite levels were observed to be associated with the altered abundance of specific bacterial species, such as , and . According to the results of the present study, a comprehensive landscape of the GM and metabolites in patients with AONFH was revealed, suggesting the existence of interplay between the gut microbiome and metabolome in AONFH pathogenesis.
PubMed: 38873043
DOI: 10.3892/etm.2024.12599 -
Scientific Reports Jun 2024Cervical cancer, one of the most common gynecological cancers, is primarily caused by human papillomavirus (HPV) infection. The development of resistance to chemotherapy...
Cervical cancer, one of the most common gynecological cancers, is primarily caused by human papillomavirus (HPV) infection. The development of resistance to chemotherapy is a significant hurdle in treatment. In this study, we investigated the mechanisms underlying chemoresistance in cervical cancer by focusing on the roles of glycogen metabolism and the pentose phosphate pathway (PPP). We employed the cervical cancer cell lines HCC94 and CaSki by manipulating the expression of key enzymes PCK1, PYGL, and GYS1, which are involved in glycogen metabolism, through siRNA transfection. Our analysis included measuring glycogen levels, intermediates of PPP, NADPH/NADP ratio, and the ability of cells to clear reactive oxygen species (ROS) using biochemical assays and liquid chromatography-mass spectrometry (LC-MS). Furthermore, we assessed chemoresistance by evaluating cell viability and tumor growth in NSG mice. Our findings revealed that in drug-resistant tumor stem cells, the enzyme PCK1 enhances the phosphorylation of PYGL, leading to increased glycogen breakdown. This process shifts glucose metabolism towards PPP, generating NADPH. This, in turn, facilitates ROS clearance, promotes cell survival, and contributes to the development of chemoresistance. These insights suggest that targeting aberrant glycogen metabolism or PPP could be a promising strategy for overcoming chemoresistance in cervical cancer. Understanding these molecular mechanisms opens new avenues for the development of more effective treatments for this challenging malignancy.
Topics: Humans; Female; Uterine Cervical Neoplasms; Reactive Oxygen Species; Drug Resistance, Neoplasm; Neoplastic Stem Cells; Animals; Mice; Cell Line, Tumor; Phosphoenolpyruvate Carboxykinase (GTP); Glycogen; Intracellular Signaling Peptides and Proteins; Glycogenolysis; Pentose Phosphate Pathway; Cell Survival
PubMed: 38871968
DOI: 10.1038/s41598-024-64255-6 -
The Journal of Clinical Investigation Jun 2024Neutrophil hyperactivity and neutrophil extracellular trap release (NETosis) appear to play important roles in the pathogenesis of the thromboinflammatory autoimmune...
Neutrophil hyperactivity and neutrophil extracellular trap release (NETosis) appear to play important roles in the pathogenesis of the thromboinflammatory autoimmune disease known as antiphospholipid syndrome (APS). The understanding of neutrophil metabolism has advanced tremendously in the past decade, and accumulating evidence suggests that a variety of metabolic pathways guide neutrophil activities in health and disease. Our previous work characterizing the transcriptome of APS neutrophils revealed that genes related to glycolysis, glycogenolysis, and the pentose phosphate pathway (PPP) were significantly upregulated. Here, we found that APS patient neutrophils used glycolysis more avidly than healthy control neutrophils, especially when the neutrophils were from APS patients with a history of microvascular disease. In vitro, inhibiting either glycolysis or the PPP tempered phorbol myristate acetate- and APS IgG-induced NETosis, but not NETosis triggered by a calcium ionophore. In mice, inhibiting either glycolysis or the PPP reduced neutrophil reactive oxygen species production and suppressed APS IgG-induced NETosis ex vivo. When APS-associated thrombosis was evaluated in mice, inhibiting either glycolysis or the PPP markedly suppressed thrombosis and circulating NET remnants. In summary, these data identify a potential role for restraining neutrophil glucose flux in the treatment of APS.
PubMed: 38869951
DOI: 10.1172/JCI169893 -
Environmental Science & Technology Jun 2024Microbial organic matter turnover is an important contributor to the terrestrial carbon dioxide (CO) budget. Partitioning of organic carbons into biomass relative to CO...
Microbial organic matter turnover is an important contributor to the terrestrial carbon dioxide (CO) budget. Partitioning of organic carbons into biomass relative to CO efflux, termed carbon-use efficiency (CUE), is widely used to characterize organic carbon cycling by soil microorganisms. Recent studies challenge proposals of CUE dependence on the oxidation state of the substrate carbon and implicate instead metabolic strategies. Still unknown are the metabolic mechanisms underlying variability in CUE. We performed a multiomics investigation of these mechanisms in , a versatile soil bacterium of the Gammaproteobacteria, processing a mixture of plant matter derivatives. Our C-metabolomics data captured substrate carbons into different metabolic pathways: cellulose-derived sugar carbons in glycolytic and pentose-phosphate pathways; lignin-related aromatic carbons in the tricarboxylic acid cycle. Subsequent C-metabolic flux analysis revealed a 3-fold lower investment of sugar carbons in CO efflux compared to aromatic carbons, in agreement with reported substrate-dependent CUE. Proteomics analysis revealed enzyme-level regulation only for substrate uptake and initial catabolism, which dictated downstream fluxes through CO-producing versus biomass-synthesizing reactions. Metabolic partitioning as shown here explained the substrate-dependent CUE calculated from reported metabolic flux analyses of other bacteria, further supporting a metabolism-guided perspective for predicting the microbial conversion of accessible organic matter to CO efflux.
Topics: Carbon Dioxide; Carbon; Metabolic Networks and Pathways; Pseudomonas putida; Biomass
PubMed: 38860668
DOI: 10.1021/acs.est.4c01328