-
Seizure Apr 2024
Topics: Humans; Phosphoglycerate Kinase; Male; Joint Instability; Female; Spinal Diseases; Metabolism, Inborn Errors; Genetic Diseases, X-Linked
PubMed: 38432079
DOI: 10.1016/j.seizure.2024.02.010 -
Cell Death & Disease Feb 2024Many types of cancer cells, including colorectal cancer cells (CRC), can simultaneously enhance glycolysis and repress the mitochondrial tricarboxylic acid (TCA) cycle,...
Many types of cancer cells, including colorectal cancer cells (CRC), can simultaneously enhance glycolysis and repress the mitochondrial tricarboxylic acid (TCA) cycle, which is called the Warburg effect. However, the detailed mechanisms of abnormal activation of the glycolysis pathway in colorectal cancer are largely unknown. In this study, we reveal that the protein arginine methyltransferase 1 (PRMT1) promotes glycolysis, proliferation, and tumorigenesis in CRC cells. Mechanistically, PRMT1-mediated arginine asymmetric dimethylation modification of phosphoglycerate kinase 1 (PGK1, the first ATP-producing enzyme in glycolysis) at R206 (meR206-PGK1) enhances the phosphorylation level of PGK1 at S203 (pS203-PGK1), which inhibits mitochondrial function and promotes glycolysis. We found that PRMT1 and meR206-PGK1 expression were positively correlated with pS203-PGK1 expression in tissues from colorectal cancer patients. Furthermore, we also confirmed that meR206-PGK1 expression is positively correlated with the poor survival of patients with colorectal cancer. Our findings show that PRMT1 and meR206-PGK1 may become promising predictive biomarkers for the prognosis of patients with CRC and that arginine methyltransferase inhibitors have great potential in colorectal cancer treatment.
Topics: Humans; Phosphoglycerate Kinase; Arginine; Cell Line, Tumor; Carcinogenesis; Cell Transformation, Neoplastic; Methylation; Colorectal Neoplasms; Glycolysis; Protein-Arginine N-Methyltransferases; Repressor Proteins
PubMed: 38402202
DOI: 10.1038/s41419-024-06544-6 -
Genes Feb 2024L. is an economically valuable plant with tolerance to drought and salinity. Its leaves are utilized in tea production and pharmaceuticals, while the stem bark serves...
L. is an economically valuable plant with tolerance to drought and salinity. Its leaves are utilized in tea production and pharmaceuticals, while the stem bark serves as a high-quality fiber material. To gain insights into the gene expression patterns of using quantitative real-time PCR (qRT-PCR), it is crucial to identify appropriate reference genes. This study selected nine candidate genes, including α-tubulin (), β-tubulin (), actin (), cyclophilin (), elongation factor-1α (), the B family of regulatory subunits of protein phosphatase (, , and ), and phosphoglycerate kinase (), to determine the most appropriate reference genes in the leaf, stem, and root tissues of . A comprehensive ranking by geNorm, NormFinder, BestKeeper, and RefFinder software and Venn diagrams was used to screen more stable reference genes in different tissues. The two most stable reference genes were and in leaves, and in stems, and and in roots, respectively. The relative expression values of the four genes involved in proline metabolism under polyethylene glycol treatment were used to validate the screened reference genes, and they exhibited highly stable expression levels. These findings represent the first set of stable reference genes for future gene expression studies in . They significantly contribute to enhancing the accuracy and reliability of gene expression analyses in this economically important plant species.
Topics: Real-Time Polymerase Chain Reaction; Peptide Elongation Factor 1; Apocynum; Reproducibility of Results; Genes, Plant
PubMed: 38397220
DOI: 10.3390/genes15020231 -
Proceedings of the National Academy of... Feb 2024The drug terazosin (TZ) binds to and can enhance the activity of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) and can increase ATP levels. That finding...
The drug terazosin (TZ) binds to and can enhance the activity of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) and can increase ATP levels. That finding prompted studies of TZ in Parkinson's disease (PD) in which decreased neuronal energy metabolism is a hallmark feature. TZ was neuroprotective in cell-based and animal PD models and in large epidemiological studies of humans. However, how TZ might increase PGK1 activity has remained a perplexing question because structural data revealed that the site of TZ binding to PGK1 overlaps with the site of substrate binding, predicting that TZ would competitively inhibit activity. Functional data also indicate that TZ is a competitive inhibitor. To explore the paradoxical observation of a competitive inhibitor increasing enzyme activity under some conditions, we developed a mass action model of TZ and PGK1 interactions using published data on PGK1 kinetics and the effect of varying TZ concentrations. The model indicated that TZ-binding introduces a bypass pathway that accelerates product release. At low concentrations, TZ binding circumvents slow product release and increases the rate of enzymatic phosphotransfer. However, at high concentrations, TZ inhibits PGK1 activity. The model explains stimulation of enzyme activity by a competitive inhibitor and the biphasic dose-response relationship for TZ and PGK1 activity. By providing a plausible mechanism for interactions between TZ and PGK1, these findings may aid development of TZ or other agents as potential therapeutics for neurodegenerative diseases. The results may also have implications for agents that interact with the active site of other enzymes.
Topics: Humans; Animals; Phosphoglycerate Kinase; Prazosin; Parkinson Disease; Glycolysis
PubMed: 38377207
DOI: 10.1073/pnas.2318956121 -
European Journal of Medicinal Chemistry Mar 2024Our previous research has revealed phosphoglycerate kinase 1 (PGK1) enhances tumorigenesis and sorafenib resistance of kidney renal clear cell carcinoma (KIRC) by...
Our previous research has revealed phosphoglycerate kinase 1 (PGK1) enhances tumorigenesis and sorafenib resistance of kidney renal clear cell carcinoma (KIRC) by regulating glycolysis, so that PGK1 is a promising drug target. Herein we performed structure-based virtual screening and series of anticancer pharmaceutical experiments in vitro and in vivo to identify novel small-molecule PGK1-targeted compounds. As results, the compounds CHR-6494 and Z57346765 were screened and confirmed to specifically bind to PGK1 and significantly reduced the metabolic enzyme activity of PGK1 in glycolysis, which inhibited KIRC cell proliferation in a dose-dependent manner. While CHR-6494 showed greater anti-KIRC efficacy and fewer side effects than Z57346765 on nude mouse xenograft model. Mechanistically, CHR-9464 impeded glycolysis by decreasing the metabolic enzyme activity of PGK1 and suppressed histone H3T3 phosphorylation to inhibit KIRC cell proliferation. Z57346765 induced expression changes of genes related to cell metabolism, DNA replication and cell cycle. Overall, we screened two novel PGK1 inhibitors, CHR-6494 and Z57346765, for the first time and discovered their potent anti-KIRC effects by suppressing PGK1 metabolic enzyme activity in glycolysis.
Topics: Mice; Animals; Humans; Phosphoglycerate Kinase; Phosphorylation; Glycolysis; Carcinoma; Kidney; Cell Line, Tumor
PubMed: 38354523
DOI: 10.1016/j.ejmech.2024.116209 -
Molecular Therapy. Methods & Clinical... Mar 2024Friedreich's ataxia (FRDA) is an autosomal-recessive disorder primarily attributed to biallelic GAA repeat expansions that reduce expression of the mitochondrial protein...
Friedreich's ataxia (FRDA) is an autosomal-recessive disorder primarily attributed to biallelic GAA repeat expansions that reduce expression of the mitochondrial protein frataxin (FXN). FRDA is characterized by progressive neurodegeneration, with many patients developing cardiomyopathy that progresses to heart failure and death. The potential to reverse or prevent progression of the cardiac phenotype of FRDA was investigated in a mouse model of FRDA, using an adeno-associated viral vector (AAV8) containing the coding sequence of the gene. The Fxn::MCK-Cre conditional knockout mouse (-MCK) has an gene ablation that prevents FXN expression in cardiac and skeletal muscle, leading to cardiac insufficiency, weight loss, and morbidity. MCK mice received a single intravenous injection of an AAV8 vector containing human (hFXN) or mouse (mFXN) genes under the control of a phosphoglycerate kinase promoter. Compared to vehicle-treated MCK control mice, AAV-treated MCK mice displayed increases in body weight, reversal of cardiac deficits, and increases in survival without apparent toxicity in the heart or liver for up to 12 weeks postdose. FXN protein expression in heart tissue was detected in a dose-dependent manner, exhibiting wide distribution throughout the heart similar to wild type, but more speckled. These results support an AAV8-based approach to treat FRDA-associated cardiomyopathy.
PubMed: 38352270
DOI: 10.1016/j.omtm.2024.101193 -
Movement Disorders Clinical Practice May 2024Genetic underpinnings in Parkinson's disease (PD) and parkinsonian syndromes are challenging, and recent discoveries regarding their genetic pathways have led to... (Review)
Review
BACKGROUND
Genetic underpinnings in Parkinson's disease (PD) and parkinsonian syndromes are challenging, and recent discoveries regarding their genetic pathways have led to potential gene-specific treatment trials.
CASES
We report 3 X-linked levodopa (l-dopa)-responsive parkinsonism-epilepsy syndrome cases due to a hemizygous variant in the phosphoglycerate kinase 1 (PGK1) gene. The likely pathogenic variant NM_000291.4 (PGK1):c.950G > A;p.(Gly317Asp) was identified in a hemizygous state.
LITERATURE REVIEW
Only 8 previous cases have linked this phenotype to PGK1, a gene more commonly associated with hemolytic anemia and myopathy. The unusual association of epilepsy, psychiatric symptoms, action tremor, limb dystonia, cognitive symptoms, and l-dopa-responsive parkinsonism must draw attention to PGK1 mutations, especially because this gene is absent from most commercial hereditary parkinsonism panels.
CONCLUSIONS
This report aims to shed light on an overlooked gene that causes hereditary parkinsonian syndromes. Further research regarding genetic pathways in PD may provide a better understanding of its pathophysiology and open possibilities for new disease-modifying trials, such as SNCA, LRRK2, PRKN, PINK1, and DJ-1 genes.
Topics: Adult; Humans; Male; Middle Aged; Epilepsy; Genetic Diseases, X-Linked; Levodopa; Mutation; Parkinsonian Disorders; Phosphoglycerate Kinase
PubMed: 38341651
DOI: 10.1002/mdc3.13992 -
Nature Communications Feb 2024The epidermal growth factor receptor (EGFR) plays important roles in multiple cellular events, including growth, differentiation, and motility. A major mechanism of...
The epidermal growth factor receptor (EGFR) plays important roles in multiple cellular events, including growth, differentiation, and motility. A major mechanism of downregulating EGFR function involves its endocytic transport to the lysosome. Sorting of proteins into intracellular pathways involves cargo adaptors recognizing sorting signals on cargo proteins. A dileucine-based sorting signal has been identified previously for the sorting of endosomal EGFR to the lysosome, but a cargo adaptor that recognizes this signal remains unknown. Here, we find that phosphoglycerate kinase 1 (PGK1) is recruited to endosomal membrane upon its phosphorylation, where it binds to the dileucine sorting signal in EGFR to promote the lysosomal transport of this receptor. We also elucidate two mechanisms that act in concert to promote PGK1 recruitment to endosomal membrane, a lipid-based mechanism that involves phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and a protein-based mechanism that involves hepatocyte growth factor receptor substrate (Hrs). These findings reveal an unexpected function for a metabolic enzyme and advance the mechanistic understanding of how EGFR is transported to the lysosome.
Topics: Phosphoglycerate Kinase; ErbB Receptors; Endosomes; Proteins; Lysosomes; Protein Transport; Endosomal Sorting Complexes Required for Transport
PubMed: 38310114
DOI: 10.1038/s41467-024-45443-4 -
Diabetes & Metabolic Syndrome Feb 2024In this narrative review, we have analyzed and synthesized current studies relating to the effects of anti-diabetic drugs on traumatic brain injury (TBI) complications. (Review)
Review
AIMS
In this narrative review, we have analyzed and synthesized current studies relating to the effects of anti-diabetic drugs on traumatic brain injury (TBI) complications.
METHODS
Eligible studies were collected from Scopus, Google Scholar, PubMed, and Cochrane Library for clinical, in-vivo, and in-vitro studies published on the impact of anti-diabetic drugs on TBI.
RESULTS
Traumatic brain injury (TBI) is a serious brain disease that is caused by any type of trauma. The pathophysiology of TBI is not yet fully understood, though physical injury and inflammatory events have been implicated in TBI progression. Several signaling pathways are known to play pivotal roles in TBI injuries, including Nuclear factor erythroid 2-related factor 2 (Nrf2), High mobility group box 1 protein/Nuclear factor kappa B (HMGB1/NF-κB), Adiponectin, Mammalian Target of Rapamycin (mTOR), Toll-Like Receptor (TLR), Wnt/β-catenin, Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT), Nod-like receptor protein3 (NLRP3) inflammasome, Phosphoglycerate kinase 1/Kelch-like ECH-associated protein 1 (PGK1/KEAP1)/Nrf2, and Mitogen-activated protein kinase (MAPK) . Recent studies suggest that oral anti-diabetic drugs such as biguanides, thiazolidinediones (TZDs), sulfonylureas (SUs), sodium-glucose cotransporter-2 inhibitors (SGLT2is), dipeptidyl peptidase-4 inhibitors (DPPIs), meglitinides, and alpha-glucosidase inhibitors (AGIs) could have beneficial effects in the management of TBI complications. These drugs may downregulate the inflammatory pathways and induce antioxidant signaling pathways, thus alleviating complications of TBI.
CONCLUSION
Based on this comprehensive literature review, antidiabetic medications might be considered in the TBI treatment protocol. However, evidence from clinical trials in patients with TBI is still warranted.
Topics: Humans; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Sodium-Glucose Transporter 2 Inhibitors; Inflammation; Brain Injuries, Traumatic
PubMed: 38308863
DOI: 10.1016/j.dsx.2024.102949 -
Oncology Letters Mar 2024Hepatocellular carcinoma (HCC), a common type of liver cancer, is increasing in incidence worldwide. An early diagnosis of hepatocellular carcinoma (HCC) is still...
Hepatocellular carcinoma (HCC), a common type of liver cancer, is increasing in incidence worldwide. An early diagnosis of hepatocellular carcinoma (HCC) is still challenging: Currently, few biomarkers are available to diagnose the early stage of HCC, therefore, additional prognostic biomarkers are required to identify potential risk factors. The present study analyzed gene expression levels of HCC tissue samples and the protein expression levels obtained from the GSE46408 HCC dataset using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. The metabolically associated differentially expressed genes (DEGs), including DEGs involved in the glucose metabolism pathway, were selected for further analysis. Phosphoglycerate kinase 1 (PGK1), a glycolytic enzyme, was determined as a potential prognostic biomarker through Kaplan-Meier curve and clinical association variable analyses. This was also verified based on the expression levels of PGK1 in tumor tissue and protein expression levels in several liver cancer cell lines. PGK1 mRNA demonstrated a high level of expression in HCC tissue and was significantly associated with a poor prognosis, showing a negative association with survival time. In addition, as an independent risk factor, PGK1 may potentially be a valuable prognostic biomarker for patients with HCC. Furthermore, expression of PGK1 was associated with the early stages (stage I and T1) of HCC. Moreover, PGK1 mRNA expression levels demonstrated a positive association with progression of liver cancer. The results suggested that PGK1 mRNA may be involved in the degree of HCC malignancy and may be a future potential prognostic biomarker for HCC progression.
PubMed: 38304170
DOI: 10.3892/ol.2024.14242