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Frontiers in Immunology 2023Gut-microbiota-brain axis is a potential treatment to decrease the risk of chronic traumatic encephalopathy following traumatic brain injury (TBI). Phosphoglycerate...
INTRODUCTION
Gut-microbiota-brain axis is a potential treatment to decrease the risk of chronic traumatic encephalopathy following traumatic brain injury (TBI). Phosphoglycerate mutase 5 (PGAM5), a mitochondrial serine/threonine protein phosphatase, resides in mitochondrial membrane and regulates mitochondrial homeostasis and metabolism. Mitochondria mediates intestinal barrier and gut microbiome.
OBJECTIVES
This study investigated the association between PGAM5 and gut microbiota in mice with TBI.
METHODS
The controlled cortical impact injury was established in mice with genetically-ablated () or wild type, and WT male mice were treated with fecal microbiota transplantation (FMT) from male mice or (). Then the gut microbiota abundance, blood metabolites, neurological function, and nerve injury were detected.
RESULTS
Treated with antibiotics for suppressing gut microbiota in mice partially relieved the role of deficiency in the improvement of initial inflammatory factors and motor dysfunction post-TBI. knockout exhibited an increased abundance of in mice. FMT from male mice enabled better maintenance of amino acid metabolism and peripherial environment than that in TBI-vehicle mice, which suppressed neuroinflammation and improved neurological deficits, and was negatively associated with intestinal mucosal injury and neuroinflammation post-TBI. Moreover, treatment ameliorated neuroinflammation and nerve injury by regulating Nlrp3 inflammasome activation in cerebral cortex with TBI.
CONCLUSION
Thus, the present study provides evidence that Pgam5 is involved in gut microbiota-mediated neuroinflammation and nerve injury, with -Nlrp3 contributing to peripheral effects.
Topics: Male; Animals; Mice; Neuroprotection; Neuroinflammatory Diseases; Phosphoglycerate Mutase; Verrucomicrobia; Brain Injuries, Traumatic; NLR Family, Pyrin Domain-Containing 3 Protein
PubMed: 37287985
DOI: 10.3389/fimmu.2023.1172710 -
FEMS Microbiology Letters Jan 2023Actinobacillus seminis is the causal agent of epididymitis and has other effects on the reproductive tracts of small ruminants and bovines. This bacterium causes...
Actinobacillus seminis is the causal agent of epididymitis and has other effects on the reproductive tracts of small ruminants and bovines. This bacterium causes infection when luteinizing (LH) or follicle-stimulating hormones increase, and hosts reach sexual maturity. LH induces female ovulation and male testosterone production, suggesting that these hormones affect A. seminis pathogenicity. In the present study, we evaluated the effect of testosterone (1-5 ng/ml) or estradiol (5-25 pg/ml) added to culture medium on the in vitro growth, biofilm production, and adhesin expression of A. seminis. Estradiol does not promote the growth of this bacterium, whereas testosterone increased A. seminis planktonic growth 2-fold. Both hormones induced the expression of the elongation factor thermo unstable (EF-Tu) and phosphoglycerate mutase (PGM), proteins that A. seminis uses as adhesins. Estradiol (5 or 10 pg/ml) decreased biofilm formation by 32%, whereas testosterone, even at 5 ng/ml, showed no effect. Both hormones modified the concentrations of carbohydrates and eDNA in biofilms by 50%. Amyloid proteins are characterized by their capacity to bind Congo red (CR) dye. Actinobacillus seminis binds CR dye, and this binding increases in the presence of 5-20 pg/ml estradiol or 4 ng/ml testosterone. The A. seminis EF-Tu protein was identified as amyloid-like protein (ALP). The effect of sexual hormones on the growth and expression of virulence factors of A. seminis seems to be relevant for its colonization and permanence in the host.
Topics: Female; Male; Animals; Cattle; Actinobacillus seminis; Estradiol; Actinobacillus Infections; Testosterone; Peptide Elongation Factor Tu; Adhesins, Bacterial; Biofilms
PubMed: 37279906
DOI: 10.1093/femsle/fnad048 -
Cell & Bioscience May 2023Patients suffered from severe traumatic brain injury (TBI) have twice the risk of developing into neurodegenerative diseases later in their life. Thus, early...
BACKGROUND
Patients suffered from severe traumatic brain injury (TBI) have twice the risk of developing into neurodegenerative diseases later in their life. Thus, early intervention is needed not only to treat TBI but also to reduce neurodegenerative diseases in the future. Physiological functions of neurons highly depend on mitochondria. Thus, when mitochondrial integrity is compromised by injury, neurons would initiate a cascade of events to maintain homeostasis of mitochondria. However, what protein senses mitochondrial dysfunction and how mitochondrial homeostasis is maintained during regeneration remains unclear.
RESULTS
We found that TBI-increased transcription of a mitochondrial protein, phosphoglycerate mutase 5 (PGAM5), during acute phase was via topological remodeling of a novel enhancer-promoter interaction. This up-regulated PGAM5 correlated with mitophagy, whereas presenilins-associated rhomboid-like protein (PARL)-dependent PGAM5 cleavage at a later stage of TBI enhanced mitochondrial transcription factor A (TFAM) expression and mitochondrial mass. To test whether PGAM5 cleavage and TFAM expression were sufficient for functional recovery, mitochondrial oxidative phosphorylation uncoupler carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP) was used to uncouple electron transport chain and reduce mitochondrial function. As a result, FCCP triggered PGAM5 cleavage, TFAM expression and recovery of motor function deficits of CCI mice.
CONCLUSIONS
Findings from this study implicate that PGAM5 may act as a mitochondrial sensor for brain injury to activate its own transcription at acute phase, serving to remove damaged mitochondria through mitophagy. Subsequently, PGAM5 is cleaved by PARL, and TFAM expression is increased for mitochondrial biogenesis at a later stage after TBI. Taken together, this study concludes that timely regulation of PGAM5 expression and its own cleavage are required for neurite re-growth and functional recovery.
PubMed: 37221611
DOI: 10.1186/s13578-023-01052-0 -
Biochemical and Biophysical Research... Jul 2023Bacillus anthracis Ser/Thr protein kinase PrkC is necessary for phenotypic memory and spore germination, and the loss of PrkC-dependent phosphorylation events affect the...
Bacillus anthracis Ser/Thr protein kinase PrkC is necessary for phenotypic memory and spore germination, and the loss of PrkC-dependent phosphorylation events affect the spore development. During sporulation, Bacillus sp. can store 3-Phosphoglycerate (3-PGA) that will be required at the onset of germination when ATP will be necessary. The Phosphoglycerate mutase (Pgm) catalyzes the isomerization of 2-PGA and 3-PGA and is important for spore germination as a key metabolic enzyme that maintains 3-PGA pool at later events. Therefore, regulation of Pgm is important for an efficient spore germination process and metabolic switching. While the increased expression of Pgm in B. anthracis decreases spore germination efficiency, it remains unexplored if PrkC could directly influence Pgm activity. Here, we report the phosphorylation and regulation of Pgm by PrkC and its impact on Pgm stability and catalytic activity. Mass spectrometry revealed Pgm phosphorylation on seven threonine residues. In silico mutational analysis highlighted the role of Thr residue towards metal and substrate binding. Altogether, we demonstrated that PrkC-mediated Pgm phosphorylation negatively regulates its activity that is essential to maintain Pgm in its apo-like isoform before germination. This study advances the role of Pgm regulation that represents an important switch for B. anthracis resumption of metabolism and spore germination.
Topics: Phosphorylation; Protein Kinases; Bacillus anthracis; Phosphoglycerate Mutase; Threonine; Spores, Bacterial; Bacterial Proteins
PubMed: 37149987
DOI: 10.1016/j.bbrc.2023.04.039 -
Advanced Science (Weinheim,... Jun 2023Herein, we observed that nuclear localization of phosphoglycerate dehydrogenase (PHGDH) is associated with poor prognosis in liver cancer, and Phgdh is required for...
Herein, we observed that nuclear localization of phosphoglycerate dehydrogenase (PHGDH) is associated with poor prognosis in liver cancer, and Phgdh is required for liver cancer progression in a mouse model. Unexpectedly, impairment of Phgdh enzyme activity exerts a slight effect in a liver cancer model. In liver cancer cells, the aspartate kinase-chorismate mutase-tyrA prephenate dehydrogenase (ACT) domain of PHGDH binds nuclear cMyc to form a transactivation axis, PHGDH/p300/cMyc/AF9, which drives chemokine CXCL1 and IL8 gene expression. Then, CXCL1 and IL8 promote neutrophil recruitment and enhance tumor-associated macrophage (TAM) filtration in the liver, thereby advancing liver cancer. Forced cytosolic localization of PHGDH or destruction of the PHGDH/cMyc interaction abolishes the oncogenic function of nuclear PHGDH. Depletion of neutrophils by neutralizing antibodies greatly hampers TAM filtration. These findings reveal a nonmetabolic role of PHGDH with altered cellular localization and suggest a promising drug target for liver cancer therapy by targeting the nonmetabolic region of PHGDH.
Topics: Animals; Mice; Phosphoglycerate Dehydrogenase; Cell Line, Tumor; Interleukin-8; Liver Neoplasms; Tumor Microenvironment
PubMed: 37078828
DOI: 10.1002/advs.202205818 -
PeerJ 2023PGAM1 plays a critical role in cancer cell metabolism through glycolysis and different biosynthesis pathways to promote cancer. It is generally known as a crucial target...
PGAM1 plays a critical role in cancer cell metabolism through glycolysis and different biosynthesis pathways to promote cancer. It is generally known as a crucial target for treating pancreatic ductal adenocarcinoma, the deadliest known malignancy worldwide. In recent years different studies have been reported that strived to find inhibitory agents to target PGAM1, however, no validated inhibitor has been reported so far, and only a small number of different inhibitors have been reported with limited potency at the molecular level. Our studies aimed to identify potential new PGAM1 inhibitors that could bind at the allosteric sites. At first, shape and feature-based models were generated and optimized by performing receiver operating characteristic (ROC) based enrichment studies. The best query model was then employed for performing shape, color, and electrostatics complementarity-based virtual screening of the ChemDiv database. The top two hundred and thirteen hits with greater than 1.2 TanimotoCombo score were selected and then subjected to structure-based molecular docking studies. The hits yielded better docking scores than reported compounds, were selected for subsequent structural similarity-based clustering analysis to select the best hits from each cluster. Molecular dynamics simulations and binding free energy calculations were performed to validate their plausible binding modes and their binding affinities with the PGAM1 enzyme. The results showed that these compounds were binding in the reported allosteric site of the enzyme and can serve as a good starting point to design better active selective scaffolds against PGAM1enzyme.
Topics: Humans; Molecular Docking Simulation; Phosphoglycerate Mutase; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Molecular Dynamics Simulation
PubMed: 37051414
DOI: 10.7717/peerj.14936 -
Drug Resistance Updates : Reviews and... May 2023Resistance to epidermal growth factor receptor (EGFR) inhibitors, from the first-generation erlotinib to the third generation osimertinib, is a clinical challenge in the...
A phosphoglycerate mutase 1 allosteric inhibitor overcomes drug resistance to EGFR-targeted therapy via disrupting IL-6/JAK2/STAT3 signaling pathway in lung adenocarcinoma.
Resistance to epidermal growth factor receptor (EGFR) inhibitors, from the first-generation erlotinib to the third generation osimertinib, is a clinical challenge in the treatment of patients with EGFR-mutant lung adenocarcinoma. Our previous work found that a novel allosteric inhibitor of phosphoglycerate mutase 1 (PGAM1), HKB99, restrains erlotinib resistance in lung adenocarcinoma cells. However, the role of HKB99 in osimertinib resistance and its underlying molecular mechanism remains to be elucidated. Herein, we found that IL-6/JAK2/STAT3 signaling pathway is aberrantly activated in both erlotinib and osimertinib resistant cells. Importantly, HKB99 significantly blocks the interaction of PGAM1 with JAK2 and STAT3 via the allosteric sites of PGAM1, which leads to inactivation of JAK2/STAT3 and thereby disrupts IL-6/JAK2/STAT3 signaling pathway. Consequently, HKB99 remarkably restores EGFR inhibitor sensitivity and exerts synergistic tumoricidal effect. Additionally, HKB99 alone or in combination with osimertinib down-regulated the level of p-STAT3 in xenograft tumor models. Collectively, this study identifies PGAM1 as a key regulator in IL-6/JAK2/STAT3 axis in the development of resistance to EGFR inhibitors, which could serve as a therapeutic target in lung adenocarcinoma with acquired resistance to EGFR inhibitors.
Topics: Humans; Erlotinib Hydrochloride; Lung Neoplasms; Interleukin-6; Phosphoglycerate Mutase; Drug Resistance, Neoplasm; Adenocarcinoma of Lung; ErbB Receptors; Signal Transduction; Protein Kinase Inhibitors; Mutation; Cell Line, Tumor; Janus Kinase 2
PubMed: 36990047
DOI: 10.1016/j.drup.2023.100957 -
Annals of Translational Medicine Feb 2023Recent evidence shows that COL3A1 promotes the progression of many types of cancer. The purpose of our study is to explore the correlation between COL3A1 and the...
BACKGROUND
Recent evidence shows that COL3A1 promotes the progression of many types of cancer. The purpose of our study is to explore the correlation between COL3A1 and the prognosis of patients with head and neck squamous cell carcinoma (HNSCC) and its potential mechanism.
METHODS
We initially screened the differentially expressed gene COL3A1 in The Cancer Genome Atlas (TCGA) database, and the association between the expression level of COL3A1, prognosis, and the clinical parameters of HNSCC patients was verified. A nomogram was constructed according to the multivariate analysis results. Next, a heatmap of COL3A1 co-expressed genes was constructed in TCGA database. The TargetScan database is used to explore the microRNAs (miRNA) related to COL3A1. The starBase database was used to explore and predict the long non-coding RNAs (lncRNAs) that the candidate miRNAs might bind to. Finally, the potential mechanism of action was investigated using Gene Set Enrichment Analysis (GSEA).
RESULTS
COL3A1 expression is elevated in HNSCC tumor tissues, and HNSCC patients with high COL3A1 expression have worse prognostic factors. COL3A1 was positively correlated with the central carbon metabolism-related proteins: epidermal growth factor receptor (EGFR), phosphoglycerate mutase 1 (PGAM1), hexokinase 3 (HK3), and phosphofructokinase, platelet (PFKP). The TargetScan database showed that the best candidate miRNA for binding to the three prime untranslated region (3'UTR) end of COL3A1 mRNA was , which was negatively correlated with COL3A1. The starBase database showed that the lncRNA X Inactive Specific Transcript (lncRNA XIST) was the best candidate upstream non-coding RNA for regulating . GSEA showed that COL3A1 may be involved in the poor prognosis of HNSCC by participating in carbon metabolism, glucose metabolism, oxidative stress, and the Wingless-Type MMTV Integration Site Family (Wnt) and vascular endothelial growth factor A-vascular endothelial growth factor receptor 2 (VEGFA-VEGFR2) pathways.
CONCLUSIONS
Low COL3A1 expression can be employed as a new HNSCC predictive biomarker, and the prognosis of HNSCC patients with lower COL3A1 expression can be greatly improved. At the same time, we found that the lncRNA XIST//COL3A1 axis may regulate the central carbon metabolism of HNSCC and is associated with poor prognosis. These findings point to a potential target for developing HNSCC anticancer therapies.
PubMed: 36923098
DOI: 10.21037/atm-23-30 -
European Journal of Pharmacology Jun 2023Metabolic reprogramming of cancer cells is a common hallmark of malignant transformation. The preference for aerobic glycolysis over oxidative phosphorylation in tumors... (Review)
Review
Metabolic reprogramming of cancer cells is a common hallmark of malignant transformation. The preference for aerobic glycolysis over oxidative phosphorylation in tumors is a well-studied phenomenon known as the Warburg effect. Importantly, metabolic transformation of cancer cells also involves alterations in signaling cascades contributing to lipid metabolism, amino acid flux and synthesis, and utilization of ketone bodies. Also, redox regulation interacts with metabolic reprogramming during malignant transformation. Flavonoids, widely distributed phytochemicals in plants, exert various beneficial effects on human health through modulating molecular cascades altered in the pathological cancer phenotype. Recent evidence has identified numerous flavonoids as modulators of critical components of cancer metabolism and associated pathways interacting with metabolic cascades such as redox balance. Flavonoids affect lipid metabolism by regulating fatty acid synthase, redox balance by modulating nuclear factor-erythroid factor 2-related factor 2 (Nrf2) activity, or amino acid flux and synthesis by phosphoglycerate mutase 1. Here, we discuss recent preclinical evidence evaluating the impact of flavonoids on cancer metabolism, focusing on lipid and amino acid metabolic cascades, redox balance, and ketone bodies.
Topics: Humans; Amino Acids; Lipid Metabolism; NF-E2-Related Factor 2; Ketone Bodies; Flavonoids; Neoplasms; Oxidation-Reduction; Cell Transformation, Neoplastic
PubMed: 36921709
DOI: 10.1016/j.ejphar.2023.175655