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Antioxidants (Basel, Switzerland) Dec 2023Inflammation plays a crucial role in tumorigenesis, primarily mediated by NF-κB. RhoA GTPases are instrumental in regulating the activation of NF-κB. Specifically, the...
Inflammation plays a crucial role in tumorigenesis, primarily mediated by NF-κB. RhoA GTPases are instrumental in regulating the activation of NF-κB. Specifically, the phosphorylation of Tyrosine 42 on RhoA ensures the activation of NF-κB by directly activating the IKKβ associated with IKKγ (NEMO). This study aimed to uncover the molecular mechanism through which p-Tyrosine 42 RhoA, in conjunction with NF-κB, promotes tumorigenesis. Notably, we observed that p-Tyrosine 42 RhoA co-immunoprecipitated with the p-Ser 536 p65/RelA subunit in NF-κB in response to LPS. Moreover, both p-Tyrosine 42 RhoA and p-p65/RelA translocated to the nucleus, where they formed a protein complex associated with the promoter of phosphoglycerate kinase 1 (PGK1) and regulated the expression of PGK1. In addition, p-p65/RelA and p-Tyr42 RhoA co-immunoprecipitated with p300 histone acetyltransferase. Intriguingly, PGK1 exhibited an interaction with β-catenin, PKM1 and PKM2. Of particular interest, si-PGK1 led to a reduction in the levels of β-catenin and phosphorylated pyruvate dehydrogenase A1 (p-PDHA1). We also found that PGK1 phosphorylated β-catenin at the Thr551 and Ser552 residues. These findings discovered that PGK1 may play a role in transcriptional regulation, alongside other transcription factors.
PubMed: 38136210
DOI: 10.3390/antiox12122090 -
Parasites & Vectors Dec 2023The durable oocyst wall formed from the contents of wall-forming bodies (WFBs) protects Eimeria parasites from harsh conditions and enhances parasite transmission....
BACKGROUND
The durable oocyst wall formed from the contents of wall-forming bodies (WFBs) protects Eimeria parasites from harsh conditions and enhances parasite transmission. Comprehending the contents of WFBs and proteins involved in oocyst wall formation is pivotal to understanding the mechanism of the oocyst wall formation and the search for novel targets to disrupt parasite transmission.
METHODS
Total proteins extracted from WFBs and the oocyst wall of Eimeria necatrix were subjected to comparative proteomic analysis using tandem mass tag in conjunction with liquid chromatography tandem-mass spectrometry techniques. After functional clustering analysis of the identified proteins, three proteins, including E. necatrix disulfide isomerase (EnPDI), thioredoxin (EnTrx) and phosphoglycerate kinase (EnPGK), were selected for further study to confirm their potential roles in oocyst wall formation.
RESULTS
A total of 3009 and 2973 proteins were identified from WFBs and the oocyst wall of E. necatrix, respectively. Among these proteins, 1102 were identified as differentially expressed proteins, of which 506 were upregulated and 596 downregulated in the oocyst wall compared to the WFBs. A total of 108 proteins, including compositional proteins of the oocyst wall, proteases, oxidoreductases, proteins involved in glycosylation, proteins involved in synthesis of the acid-fast lipid layer and proteins related to transport, were proposed to be involved in oocyst wall formation. The approximate molecular sizes of native EnPDI, EnTrx and EnPGK proteins were 55, 50 and 45 kDa, respectively. EnPDI was present in both type 1 and type 2 WFBs, EnTrx was present only in type 2 WFB2 and EnPGK was present only in type 1 WFBs, whereas all of them were localized to the outer layer of the oocyst wall, indicating that all of them participate in the formation of the oocyst wall.
CONCLUSIONS
To the best of our knowledge, this is the first report on the proteomes of WFBs and the oocyst wall of E. necatrix. The data obtained from this study form a basis for deciphering the molecular mechanisms underlying oocyst wall formation of Eimeria parasites. They also provide valuable resources for future studies on the development of novel therapeutic agents and vaccines aimed at combating coccidian transmission.
Topics: Animals; Oocysts; Eimeria; Proteomics; Protozoan Proteins; Chickens
PubMed: 38111000
DOI: 10.1186/s13071-023-06076-6 -
Brain Research Feb 2024Phosphoglycerate kinase 1 (PGK1) is extensively located in the cytosol and mitochondria. The role of PGK1 in ischemic neuronal injury remains elusive. In the in vitro...
Phosphoglycerate kinase 1 (PGK1) is extensively located in the cytosol and mitochondria. The role of PGK1 in ischemic neuronal injury remains elusive. In the in vitro model of oxygen-glucose deprivation/reoxygenation (OGD/R), we showed that PGK1 expression was increased in cortical neurons. Knockdown of PGK1 led to a reduction of OGD/R-induced neuronal death. The expression of cytosolic PGK1 was reduced, but the levels of mitochondrial PGK1 were increased in OGD/R-insulted neurons. Inhibiting the activity of mitochondrial PGK1 alleviated the neuronal injury after OGD/R insult. We further showed that the protein levels of TBC domain family member 15 (TBC1D15) were decreased in OGD/R-insulted neurons. Knockdown of TBC1D15 led to increased levels of mitochondrial PGK1 after OGD/R insult in cortical neurons. Moreover, increased reactive oxygen species (ROS) resulted in a reduction of TBC1D15 in OGD/R-insulted neurons. These results suggest that the upregulation of mitochondrial PGK1 by ROS-TBC1D15 signaling pathway promotes neuronal death after OGD/R injury. Mitochondrial PGK1 may act as a regulator of neuronal survival and interventions in the PGK1-dependent pathway may be a potential therapeutic strategy.
Topics: Humans; Oxygen; Reactive Oxygen Species; Up-Regulation; Glucose; Mitochondria; Apoptosis; Reperfusion Injury; GTPase-Activating Proteins; Phosphoglycerate Kinase
PubMed: 38110073
DOI: 10.1016/j.brainres.2023.148724 -
Journal of Experimental & Clinical... Dec 2023Cancer cells undergo cellular adaptation through metabolic reprogramming to sustain survival and rapid growth under various stress conditions. However, how brain tumors...
BACKGROUND
Cancer cells undergo cellular adaptation through metabolic reprogramming to sustain survival and rapid growth under various stress conditions. However, how brain tumors modulate their metabolic flexibility in the naturally serine/glycine (S/G)-deficient brain microenvironment remain unknown.
METHODS
We used a range of primary/stem-like and established glioblastoma (GBM) cell models in vitro and in vivo. To identify the regulatory mechanisms of S/G deprivation-induced metabolic flexibility, we employed high-throughput RNA-sequencing, transcriptomic analysis, metabolic flux analysis, metabolites analysis, chromatin immunoprecipitation (ChIP), luciferase reporter, nuclear fractionation, cycloheximide-chase, and glucose consumption. The clinical significances were analyzed in the genomic database (GSE4290) and in human GBM specimens.
RESULTS
The high-throughput RNA-sequencing and transcriptomic analysis demonstrate that the de novo serine synthesis pathway (SSP) and glycolysis are highly activated in GBM cells under S/G deprivation conditions. Mechanistically, S/G deprivation rapidly induces reactive oxygen species (ROS)-mediated AMP-activated protein kinase (AMPK) activation and AMPK-dependent hypoxia-inducible factor (HIF)-1α stabilization and transactivation. Activated HIF-1α in turn promotes the expression of SSP enzymes phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH). In addition, the HIF-1α-induced expression of glycolytic genes (GLUT1, GLUT3, HK2, and PFKFB2) promotes glucose uptake, glycolysis, and glycolytic flux to fuel SSP, leading to elevated de novo serine and glycine biosynthesis, NADPH/NADP ratio, and the proliferation and survival of GBM cells. Analyses of human GBM specimens reveal that the levels of overexpressed PHGDH, PSAT1, and PSPH are positively correlated with levels of AMPK T172 phosphorylation and HIF-1α expression and the poor prognosis of GBM patients.
CONCLUSION
Our findings reveal that metabolic stress-enhanced glucose-derived de novo serine biosynthesis is a critical metabolic feature of GBM cells, and highlight the potential to target SSP for treating human GBM.
Topics: Humans; AMP-Activated Protein Kinases; Glioblastoma; Serine; Glucose; Glycine; RNA; Hypoxia-Inducible Factor 1, alpha Subunit; Cell Line, Tumor; Tumor Microenvironment; Phosphofructokinase-2
PubMed: 38098117
DOI: 10.1186/s13046-023-02927-3 -
Journal of Experimental & Clinical... Dec 2023Within the tumor immune microenvironment (TME), tumor-associated macrophages (TAMs) are crucial in modulating polarization states to influence cancer development through...
BACKGROUND
Within the tumor immune microenvironment (TME), tumor-associated macrophages (TAMs) are crucial in modulating polarization states to influence cancer development through metabolic reprogramming. While long non-coding RNAs (lncRNAs) have been shown to play a pivotal role in the progression of various cancers, the underlying mechanisms by which lncRNAs alter M2 polarization through macrophage metabolism remodeling remain unelucidated.
METHODS
RNA sequencing was used to screen for differentially expressed lncRNAs in TAMs and normal tissue-resident macrophages (NTRMs) isolated from pancreatic ductal adenocarcinoma (PDAC) tissues, whilst RT-qPCR and FISH were employed to detect the expression level of SNHG17. Moreover, a series of in vivo and in vitro experiments were conducted to assess the functions of SNHG17 from TAMs in the polarization and glycolysis of M2-like macrophages and in the proliferation and metastasis of pancreatic cancer cells (PCs). Furthermore, Western blotting, RNA pull-down, mass spectrometry, RIP, and dual-luciferase assays were utilized to explore the underlying mechanism through which SNHG17 induces pro-tumor macrophage formation.
RESULTS
SNHG17 was substantially enriched in TAMs and was positively correlated with a worse prognosis in PDAC. Meanwhile, functional assays determined that SNHG17 promoted the malignant progression of PCs by enhancing M2 macrophage polarization and anaerobic glycolysis. Mechanistically, SNHG17 could sponge miR-628-5p to release PGK1 mRNA and concurrently interact with the PGK1 protein, activating the pro-tumorigenic function of PGK1 by enhancing phosphorylation at the T168A site of PGK1 through ERK1/2 recruitment. Lastly, SNHG17 knockdown could reverse the polarization status of macrophages in PDAC.
CONCLUSIONS
The present study illustrated the essential role of SNHG17 and its molecular mechanism in TAMs derived from PDAC, indicating that SNHG17 might be a viable target for PDAC immunotherapy.
Topics: Humans; Phosphorylation; RNA, Long Noncoding; Anaerobiosis; Cell Line, Tumor; Cell Proliferation; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Macrophages; Glycolysis; MicroRNAs; Tumor Microenvironment; Phosphoglycerate Kinase
PubMed: 38098044
DOI: 10.1186/s13046-023-02890-z -
Journal of the American Pharmacists... 2024Alpha-1-adrenergic receptor antagonists (AARAs) are used in the treatment of benign prostatic hypertrophy. Some AARAs, such as terazosin, stimulate glycolysis and...
BACKGROUND
Alpha-1-adrenergic receptor antagonists (AARAs) are used in the treatment of benign prostatic hypertrophy. Some AARAs, such as terazosin, stimulate glycolysis and increase cellular adenosine triphosphate levels through activation of phosphoglycerate kinase 1 (PGK1), which has been suggested to be of therapeutic benefit in patients with Parkinson disease (PD).
OBJECTIVE
This study aimed to determine whether exposure to PGK1-activating AARAs was associated with slower PD progression.
METHODS
National Veterans Affairs administrative data were used to identify patients who initiated PD-related pharmacotherapy during 2000 to 2019 and were concurrently prescribed an AARA. Using a retrospective cohort design, the count of incident PD-related outcome events within 1 year of follow-up was contrasted between patients prescribed a PGK1-activating AARA versus tamsulosin (an AARA without PKG1 stimulation), using multivariable negative binomial regression. PD-related outcome events were identified using ICD codes indicating motor symptoms, nonmotor symptoms, and other potential complications as clinical markers for the progression of PD.
RESULTS
A total of 127,142 patients initiated drug therapy for PD during the observation period, of whom 24,539 concurrently received an AARA. Incident PD-related events were observed significantly less often in patients receiving a PGK1 AARA (n = 14,571) than tamsulosin (n = 9968) (incidence rate ratio [IRR] 0.80 [95% CI 0.77-0.83]). These results remained significant after adjustment for confounding factors (IRR 0.85 [95% CI 0.81-0.88]) and in sensitivity analyses.
CONCLUSION
Patients prescribed a PGK1-activating AARA experienced fewer PD-related outcome events than patients prescribed tamsulosin. These results may indicate a role for terazosin and other PGK1 activators in slowing disease progression of PD; however, randomized controlled trials are needed.
Topics: Male; Humans; Tamsulosin; Adrenergic alpha-Antagonists; Parkinson Disease; Retrospective Studies; Prostatic Hyperplasia
PubMed: 38097174
DOI: 10.1016/j.japh.2023.12.008 -
Metabolic Brain Disease Mar 2024Circular RNAs (circRNAs) can play essential roles in tumor development, including glioblastoma (GBM). The current study was performed to explore the function and...
Circular RNAs (circRNAs) can play essential roles in tumor development, including glioblastoma (GBM). The current study was performed to explore the function and mechanism of circ_0027446 in GBM progression. Circ_0027446, microRNA-346 (miR-346) and Phosphoglycerate kinase 1 (PGK1) levels were detected using reverse transcription-quantitative polymerase chain reaction assay. Cell behaviors were examined using Cell Counting Kit-8 assay, colony formation assay, EdU assay, flow cytometry, and transwell assay. Glycolytic metabolism was analyzed by commercial kits. The protein level was determined via western blot. The target interaction was analyzed by dual-luciferase reporter assay. Circ_0027446 function in vivo was explored by tumor xenograft assay. Circ_0027446 expression was significantly up-regulated in GBM samples and cells. Circ_0027446 down-regulation suppressed proliferation, invasion, glycolytic metabolism and enhanced apoptosis of GBM cells. MiR-346 was a target of circ_0027446, and circ_0027446 promoted GBM progression by sponging miR-346. PGK1 acted as a target gene of miR-346, and circ_0027446 interacted with miR-346 to regulate PGK1 expression. Overexpression of miR-346 inhibited malignant behaviors of GBM cells through down-regulating PGK1. Circ_0027446 contributed to tumor growth in vivo via miR-346/PGK1 axis. The current evidences demonstrated that circ_0027446 facilitated malignant progression of GBM through binding to miR-346 to up-regulate PGK1.
Topics: Humans; Glioblastoma; Apoptosis; Cell Count; Down-Regulation; MicroRNAs; Cell Proliferation; Cell Line, Tumor; Phosphoglycerate Kinase
PubMed: 38091240
DOI: 10.1007/s11011-023-01332-1 -
Discovery Medicine Dec 2023Ischemic stroke is an acute cerebrovascular disease with high mortality rates and poor prognoses. The influence of ischemic stroke includes a heavy economic burden to...
BACKGROUND
Ischemic stroke is an acute cerebrovascular disease with high mortality rates and poor prognoses. The influence of ischemic stroke includes a heavy economic burden to patients and society, making the exploration of new therapeutic targets for preventing and treating ischemic stroke urgent. This study aimed to explore the effect of phosphoglycerate mutase family member 5 () on oxidative stress and mitochondrial dysfunction in ischemic stroke.
METHODS
The model of ischemic neuronal brain injury was established through culturing purchased human neuroblastoma cells (SH-SY5Y) by oxygen-glucose deprivation/reoxygenation (OGD/R). There were six experimental groups, including the OGD/R model group (SH-cells of OGD/R model), OE-NC group (cells of OGD/R model transfected with scramble cDNA), OE- group (cells of OGD/R model transfected with full-length sequence of ), si-NC group (cells of OGD/R model transfected with negative control small interference (si)RNA), si- group (cells of OGD/R model transfected with siRNA for knockdown), and a control group (cells cultured normally). Cell counting kit-8 (CCK-8) and flow cytometry were used to determine the activity and apoptosis of cells. Subsequently, the effects of expression on oxidative stress and mitochondrial dysfunction were analyzed. Mitochondrial morphology was observed by transmission electron microscopy (TEM), and mitochondrial membrane potential (MMP) was determined by JC-1 fluorescent probe. The levels of reactive oxygen species (ROS) were measured by flow cytometry, and levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were measured by enzyme-linked immunosorbent assay (ELISA) assay. The expression of light chain (LC)3-II/I and autophagy-related gene 5 (ATG5) proteins were measured, and the regulation of expression on -induced putative protein kinase 1 ()/ pathway was also explored.
RESULTS
overexpression in OGD/R cells decreased the cell viability ( < 0.001) while increasing cell apoptosis ( < 0.01) compared to the OGD/R group. Inhibition of expression reversed the decreased cell viability ( < 0.001) and the increased cell apoptosis ( < 0.01). The JC-1 fluorescence showed that OGD/R treatment reduced mitochondrial membrane potential ( < 0.001) and TEM showed an obvious increase in phagosomes. In addition, OGD/R treatment enhanced oxidative stress (increased ROS, < 0.01; increased MDA, < 0.001; decreased SOD, < 0.001), which could be further enhanced by overexpression of (ROS, < 0.001; MDA, < 0.001; SOD, < 0.001) while reversed by the inhibition of (ROS, < 0.01; MDA, < 0.001; SOD, < 0.001). The OGD/R-activated / pathway was inhibited by the knockdown of ( < 0.01) but promoted by the overexpression of ( < 0.05).
CONCLUSIONS
stimulates oxidative stress and impairs mitochondrial function in ischemic stroke, and regulates the / signaling pathway. Therefore, is likely to be a target for the therapy of ischemic stroke.
Topics: Humans; Reactive Oxygen Species; Ischemic Stroke; Neuroblastoma; Oxygen; Protein Kinases; Ubiquitin-Protein Ligases; Superoxide Dismutase; Mitochondrial Diseases; Glucose; Apoptosis; Phosphoprotein Phosphatases; Mitochondrial Proteins
PubMed: 38058078
DOI: 10.24976/Discov.Med.202335179.109 -
Revue Neurologique Nov 2023According to recent findings, Phosphoglycerate Kinase 1 (pgk-1) enzyme is linked to Parkinson's disease (PD). Mutations in the PGK-1 gene lead to decreases in the pgk-1... (Review)
Review
Importance of glucose and its metabolism in neurodegenerative disorder, as well as the combination of multiple therapeutic strategies targeting α-synuclein and neuroprotection in the treatment of Parkinson's disease.
According to recent findings, Phosphoglycerate Kinase 1 (pgk-1) enzyme is linked to Parkinson's disease (PD). Mutations in the PGK-1 gene lead to decreases in the pgk-1 enzyme which causes an imbalance in the levels of energy demand and supply. An increase in glycolytic adenosine triphosphate (ATP) production would help alleviate energy deficiency and sustain the acute energetic need of neurons. Neurodegeneration is caused by an imbalance or reduction in ATP levels. Recent data suggest that medications that increase glycolysis and neuroprotection can be used to treat PD. The current study focuses on treatment options for disorders associated with the pgk-1 enzyme, GLP-1, and A receptor which can be utilized to treat PD. A combination of metformin and terazosin, exenatide and meclizine, istradefylline and salbutamol treatments may benefit parkinsonism. The review also looked at potential target-specific new techniques that might assist in satisfying unfulfilled requirements in the treatment of PD.
PubMed: 38040547
DOI: 10.1016/j.neurol.2023.08.011 -
Cancer Genomics & Proteomics Dec 2023Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cancer worldwide, with a high recurrence rate and a low cure rate. Phosphoglycerate kinase 1 (PGK1),...
BACKGROUND/AIM
Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cancer worldwide, with a high recurrence rate and a low cure rate. Phosphoglycerate kinase 1 (PGK1), an essential enzyme in the aerobic glycolysis pathway, is a prognostic marker for a variety of cancers. However, it remains unclear whether a PGK1-based immune signature can be used as a prognostic biomarker in HNSCC patients.
MATERIALS AND METHODS
We explored the potential oncogenic mechanisms of PGK1 by multiple bioinformatics analyses combined with multiple databases, including the correlation between PGK1 and prognosis, and the infiltration of immune cells in HNSCC. Functional enrichment analyses were further performed to investigate the potential role of PGK1 in HNSCC.
RESULTS
The expression of PGK1 was significantly higher in HNSCC tissues compared to normal tissues. High expression of PGK1 was associated with poor prognosis in HNSCC, and multivariate cox regression analysis showed that PGK1 could be an independent prognostic factor in HNSCC. Pathway analysis revealed that PGK1 may regulate the pathogenesis of HNSCC through the immune signaling pathway. Moreover, PGK1 expression significantly correlated with the infiltration level of 16 types of immune cells.
CONCLUSION
The current study reports that PGK1 expression was increased in HNSCC and that high PGK1 expression was closely associated with poor prognosis and immune cell infiltration, which could serve as a promising independent prognostic biomarker and potential immunotherapeutic target for HNSCC.
Topics: Humans; Biomarkers; Head and Neck Neoplasms; Prognosis; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; Phosphoglycerate Kinase
PubMed: 38035710
DOI: 10.21873/cgp.20419