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Neuroscience Aug 2023Understanding the role and mechanism of astrocytes in inflammation and oxidative response is crucial for developing therapeutic strategies to reduce inflammation and...
Downregulated Phosphoglycerate Kinase 1 Attenuates Cerebral Ischemia-Reperfusion Injury by Reversing Neuroinflammation and Oxidative Stress through the Nuclear Factor Erythroid 2 Related Factor 2/ARE Pathway.
Understanding the role and mechanism of astrocytes in inflammation and oxidative response is crucial for developing therapeutic strategies to reduce inflammation and oxidative injury in cerebral ischemia-reperfusion injury (CIRI). In this study, we investigated the regulatory effects of phosphoglycerate kinase 1 (PGK1) on inflammation and oxidative response after CIRI in male adult Sprague-Dawley (SD) rats and using primary astrocytes obtained from neonatal SD rats, and explored its related mechanisms. We established a rat model of middle cerebral artery occlusion-reperfusion (MCAO/R) by suture occlusion, and an oxygen-glucose deprivation/reoxygenation model of astrocytes using oxygen-free, glucose-free, and serum-free cultures. AAV8-PGK1-GFP was injected into the left ventricle 24 h before modeling. Real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, co-immunoprecipitation (CoIP) assay, fluorescence in situ hybridization (FISH), and western blotting were used to elucidate the in-depth mechanisms of PGK1 in CIRI. PGK1 overexpression significantly exacerbated neurological deficits, increased cerebral infarct volume, and aggravated nerve cell injury in rats after MCAO/R. Using FISH and CoIP assays, we verified the localization of PGK1 and Nrf2 in primary astrocytes. Further rescue experiments showed that Nrf2 knockdown eliminated the protective effect of CBR-470-1 (a PGK1 inhibitor) on CIRI. Lastly, we confirmed that PGK1 aggravates CIRI by inhibiting the Nrf2/ARE pathway. In conclusion, our findings suggest that inhibiting PGK1 attenuates CIRI by reducing the release of inflammatory and oxidative factors from astrocytes by activating the Nrf2/ARE signaling pathway.
Topics: Rats; Male; Animals; Rats, Sprague-Dawley; Phosphoglycerate Kinase; Neuroinflammatory Diseases; NF-E2-Related Factor 2; In Situ Hybridization, Fluorescence; Oxidative Stress; Infarction, Middle Cerebral Artery; Reperfusion Injury; Brain Ischemia
PubMed: 37295596
DOI: 10.1016/j.neuroscience.2023.05.019 -
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 -
BMC Microbiology Aug 2023Colorectal cancer (CRC) is a public health concern and the second most common disease worldwide. This is due to genetic coding and is influenced by environmental...
BACKGROUND
Colorectal cancer (CRC) is a public health concern and the second most common disease worldwide. This is due to genetic coding and is influenced by environmental aspects, in which the gut microbiota plays a significant role. The purpose of this study was to compare the microbiota makeup of CRC patients with that of healthy control and to identify upregulated and downregulated proteins and metabolites in CRC patients. Using a next-generation sequencing approach, fecal samples of five females (4 CRC patients and one healthy control) were analyzed by BGI DNBSEQ-T7, Hong Kong, China. Furthermore, proteomics and metabolomics analysis were performed using LC-MS/MS technique.
RESULTS
Dysbiosis of gut microbiota has been observed in patients with CRC, with an increase in microbiota diversity at all taxonomic levels relative to healthy control. Where, at the functional level the bacterial species participate in many different pathways among them de novo nucleotide synthesis and amino acids pathways were aberrantly upregulated in CRC patients. Proteomics and metabolomics profiles of CRC patients showed different proteins and metabolites, a total of 360 and 158 proteins and metabolites, respectively were highly expressed compared to healthy control with fold change ≥ 1.2. Among the highly expressed proteins were transketolase, sushi domain-containing protein, sulfide quinone oxidoreductase protein, AAA family ATPase protein, carbonic anhydrase, IgG Fc-binding protein, nucleoside diphosphate kinase protein, arylsulfatase, alkaline phosphatase protein, phosphoglycerate kinase, protein kinase domain-containing protein, non-specific serine/threonine protein kinase, Acyl-CoA synthetase and EF-hand domain-containing protein. Some of the differential metabolites, Taurine, Taurocholic acid, 7-ketodeoxycholic acid, Glycochenodeoxycholic acid, Glycocholic acid, and Taurochenodeoxycholic acid that belong to bile acids metabolites.
CONCLUSIONS
Some bacterial species, proteins, and metabolites could be used as diagnostic biomarkers for CRC. Our study paves an insight into using multi-omics technology to address the relationship between gut microbiota and CRC.
Topics: Female; Humans; Pilot Projects; Chromatography, Liquid; Multiomics; Tandem Mass Spectrometry; Protein Kinases; Colorectal Neoplasms
PubMed: 37644393
DOI: 10.1186/s12866-023-02991-x -
Scientific Reports Oct 2023Numerous studies have been conducted on long non-coding RNAs (lncRNAs) in human tumors like gastric cancer (GC). Our research uncovers how aerobic glycolysis and cell...
Numerous studies have been conducted on long non-coding RNAs (lncRNAs) in human tumors like gastric cancer (GC). Our research uncovers how aerobic glycolysis and cell proliferation in gastric cancer cells are related to H19. We discovered that H19 was highly expressed in tumor tissues and that patients with higher H19 expression have a poorer prognosis. Intriguingly, we applied the subcellular isolation, luciferase reporter, western blot analysis, MTT, colony formation experiments, and CDX Model in Mice to verify that H19 regulates aerobic glycolysis towards GC cell growth by H19/microRNA (miR)-19a-3p/phosphoglycerate kinase 1 (PGK1) axis. Together, our research offers proof that the H19/miR-19a-3p/PGK1 pathway aids in the regulation of aerobic glycolysis and cell proliferation in GC. This may offer an opportunity for novel therapeutic approaches to the treatment of GC.
Topics: Animals; Humans; Mice; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Glycolysis; MicroRNAs; Phosphoglycerate Kinase; RNA, Long Noncoding; Stomach Neoplasms
PubMed: 37821504
DOI: 10.1038/s41598-023-43744-0 -
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 -
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 -
Frontiers in Bioscience (Landmark... Mar 2024Phosphoglycerate kinase 1 (PGK1) serves as a pivotal enzyme in the cellular glycolysis pathway, facilitating adenosine-triphosphate (ATP) production in tumor cells and... (Review)
Review
Phosphoglycerate kinase 1 (PGK1) serves as a pivotal enzyme in the cellular glycolysis pathway, facilitating adenosine-triphosphate (ATP) production in tumor cells and driving the Warburg effect. PGK1 generates ATP through the reversible phosphorylation reaction of 1,3-bisphosphoglycerate (1,3-BPG) to Mg-adenosine-5'-diphosphate (Mg-ADP). In addition to its role in regulating cellular metabolism, PGK1 plays a pivotal role in autophagy induction, regulation of the tricarboxylic acid cycle (TCA), and various mechanisms including tumor cell drug resistance, and so on. Given its multifaceted functions within cells, the involvement of PGK1 in many types of cancer, including breast cancer, astrocytoma, metastatic colon cancer, and pancreatic ductal adenocarcinoma, is intricate. Notably, PGK1 can function as an intracellular protein kinase to coordinate tumor growth, migration, and invasion via posttranslational modifications (PTMs). Furthermore, elevated expression levels of PGK1 have been observed in cancer tissues, indicating its association with unfavorable treatment outcomes and prognosis. This review provides a comprehensive summary of PGK1's expression pattern, structural features, functional properties, involvement in PTMs, and interaction with tumors. Additionally highlighted are the prospects for developing and applying related inhibitors that confirm the indispensable value of PGK1 in tumor progression.
Topics: Humans; Adenosine; Adenosine Triphosphate; Cell Line, Tumor; Colonic Neoplasms; Phosphoglycerate Kinase; Phosphorylation
PubMed: 38538272
DOI: 10.31083/j.fbl2903092 -
Food Chemistry: X Mar 2024The objective of this work was to investigate the influence of phosphoglycerate kinase-1 (PGK1) and pyruvate kinase-M2 (PKM2) activity on glycolysis, myofibrillar...
The objective of this work was to investigate the influence of phosphoglycerate kinase-1 (PGK1) and pyruvate kinase-M2 (PKM2) activity on glycolysis, myofibrillar proteins, calpain system, and apoptosis pathways of postmortem muscle. The activity of PGK1 and PKM2 was regulated by their inhibitors and activators to construct the postmortem glycolysis model and then incubated at 4 °C for 24 h. The results showed that compared to PGK1 and PKM2 inhibitors groups, the addition of PGK1 and PKM2 activators could accelerate glycogen consumption, ATP and lactate production, while declining pH value. Moreover, the addition of PGK1 and PKM2 activators could increase desmin degradation, μ-calpain activity, and caspase-3 abundance. Interestingly, troponin-T degradation was significantly increased both in PKM2 inhibitor and activator groups. It was suggested that PGK1 and PKM2 might be used as robust indicators to regulate meat quality by affecting the glycolysis, myofibrillar proteins, μ-calpain and apoptosis pathways in postmortem muscle.
PubMed: 38292674
DOI: 10.1016/j.fochx.2024.101125 -
Pharmacological Research Nov 2023Hypoxia is a key feature of tumor microenvironment that contributes to the development of breast cancer stem cells (BCSCs) with strong self-renewal properties. However,...
Hypoxia is a key feature of tumor microenvironment that contributes to the development of breast cancer stem cells (BCSCs) with strong self-renewal properties. However, the specific mechanism underlying hypoxia in BCSC induction is not completely understood. Herein, we provide evidence that a novel hypoxia-specific circSTT3A is significantly upregulated in clinical breast cancer (BC) tissues, and is closely related to the clinical stage and poor prognosis of patients with BC. The study revealed that hypoxia-inducible factor 1 alpha (HIF1α)-regulated circSTT3A has a remarkable effect on mammosphere formation in breast cancer cells. Mechanistically, circSTT3A directly interacts with nucleotide-binding domain of heat shock protein 70 (HSP70), thereby facilitating the recruitment of phosphoglycerate kinase 1 (PGK1) via its substrate-binding domain, which reduces the ubiquitination and increases the stability of PGK1. The enhanced levels of PGK1 catalyze 1,3-diphosphoglycerate (1,3-BPG) into 3-phosphoglycerate (3-PG) leading to 3-PG accumulation and increased serine synthesis, S-adenosylmethionine (SAM) accumulation, and trimethylation of histone H3 lysine 4 (H3K4me3). The activation of the H3K4me3 contributes to BCSCs by increasing the transcriptional level of stemness-related factors. Especially, our work reveals that either loss of circSTT3A or PGK1 substantially suppresses tumor initiation and tumor growth, which dramatically increases the sensitivity of tumors to doxorubicin (DOX) in mice. Injection of PGK1-silenced spheroids with 3-PG can significantly reverse tumor initiation and growth in mice, thereby increasing tumor resistance to DOX. In conclusion, our study sheds light on the functional role of hypoxia in the maintenance of BCSCs via circSTT3A/HSP70/PGK1-mediated serine synthesis, which provides new insights into metabolic reprogramming, tumor initiation and growth. Our findings suggest that targeting circSTT3A alone or in combination with chemotherapy has potential clinical value for BC management.
Topics: Humans; Mice; Animals; Female; Breast Neoplasms; Histones; Hypoxia; Cell Transformation, Neoplastic; Neoplastic Stem Cells; Cell Line, Tumor; Tumor Microenvironment
PubMed: 37865128
DOI: 10.1016/j.phrs.2023.106964 -
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