|
1
|
Cao Y, Hong J, Wang H, Lin M, Cai Y, Liao L, Li X, Han Y. Beyond glycolysis: multifunctional roles of glyceraldehyde-3-phosphate dehydrogenases in plants. HORTICULTURE RESEARCH 2025; 12:uhaf070. [PMID: 40303431 PMCID: PMC12038228 DOI: 10.1093/hr/uhaf070] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 02/25/2025] [Indexed: 05/02/2025]
Abstract
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a highly conserved enzyme in the glycolytic pathway, also acts as a moonlighting protein, performing various functions beyond its classical role in glycolysis, such as regulating gene expression, participating in cell signal transduction, and responding to environmental stress. By interacting with various signaling molecules, GAPDH plays a regulatory role in hormone signaling pathways, influencing plant growth and development. Functional plasticity in GAPDH is modulated mainly through redox-driven post-translational modifications, which alter the enzyme's catalytic activity and influence its subcellular distribution. This review explores the diverse functionalities of GAPDHs in plants, highlighting their significance in plant metabolic processes and stress adaptation.
Collapse
Affiliation(s)
- Yunpeng Cao
- State Key Laboratory of Plant Diversity and Specialty Crops, Wuhan Botanical Garden, Chinese Academy of Sciences, Wuhan 430074, China
| | - Jiayi Hong
- College of Life Sciences, Anhui Agricultural University, Hefei 230036, China
| | - Han Wang
- Institute of Horticulture, Anhui Academy of Agricultural Sciences, Hefei 230000, China
| | - Mengfei Lin
- Jiangxi Provincial Key Laboratory of Plantation and High Valued Utilization of Specialty Fruit Tree and Tea, Institute of Biological Resources, Jiangxi Academy of Sciences, Nanchang 330224 Jiangxi, China
| | - Yongping Cai
- College of Life Sciences, Anhui Agricultural University, Hefei 230036, China
| | - Liao Liao
- State Key Laboratory of Plant Diversity and Specialty Crops, Wuhan Botanical Garden, Chinese Academy of Sciences, Wuhan 430074, China
| | - Xiaoxu Li
- Beijing Life Science Academy, Beijing 102209, China
- Tobacco Chemistry Research Institute of Technology Center, China Tobacco Hunan Industrial Co., Ltd., Changsha, China
| | - Yuepeng Han
- State Key Laboratory of Plant Diversity and Specialty Crops, Wuhan Botanical Garden, Chinese Academy of Sciences, Wuhan 430074, China
| |
Collapse
|
|
2
|
Wang P, Guo W, Liu S, Li S, Li J, Ding B, Yin F, Yang Y, Li X, Cao P, Ma C, Zhang W, Song Y, Geng Y, Liu L, Hu J, Hao J, Feng Y. Novel Pt@PCN-Cu-induced cuproptosis amplifies αPD-L1 immunotherapy in pancreatic ductal adenocarcinoma through mitochondrial HK2-mediated PD-L1 upregulation. J Exp Clin Cancer Res 2025; 44:149. [PMID: 40382627 DOI: 10.1186/s13046-025-03409-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2025] [Accepted: 05/06/2025] [Indexed: 05/20/2025] Open
Abstract
BACKGROUND Copper accumulation triggers mitochondrial-driven cell death, known as cuproptosis, offering a promising mechanism for targeted cancer therapy. Recent studies have highlighted the critical role of intratumoral copper levels in regulating the expression of programmed cell death ligand-1 (PD-L1), suggesting that copper-induced cuproptosis not only enhances cancer cell death but may also amplify the effects of anti-PD-L1 antibodies (αPD-L1). However, in tumors where monotherapy with αPD-L1 shows limited efficacy, particularly in pancreatic ductal adenocarcinoma (PDAC), the role of copper-induced cuproptosis in enhancing αPD-L1 treatment efficacy and its underlying mechanisms remain unclear. Meanwhile, inadequate tumor drug accumulation and glycolysis significantly restrict the efficacy of cuproptosis. To address these challenges, we have synthesized a novel nanozyme, Pt@PCN-Cu, designed to stabilize intracellular copper accumulation and effectively induce cuproptosis. Additionally, we aim to determine whether this strong induction of cuproptosis can synergize with αPD-L1 to enhance cancer therapy, ultimately paving the way for novel strategies to improve PDAC treatment. METHODS Pt@PCN-Cu was synthesized via a one-pot method, and its therapeutic potential was assessed in combination with αPD-L1 for the treatment of PDAC. Initially, the material's properties were characterized, and its efficient cellular uptake was confirmed. Anti-tumor efficacy was evaluated by inducing cuproptosis in PDAC cell lines and xenograft models. RNA sequencing (RNA-seq) was utilized to identify key regulators involved in the modulation of PD-L1 expression by cuproptosis. Lastly, the therapeutic efficacy of Pt@PCN-Cu combined with αPD-L1 was evaluated in vivo, focusing on tumor growth inhibition and immune modulation within the tumor microenvironment (TME). RESULTS Pt@PCN-Cu demonstrates excellent physicochemical properties and remarkable cascade catalytic activity, providing a solid foundation for further in vitro and in vivo studies. In vitro, Pt@PCN-Cu efficiently transports copper and induces cuproptosis primarily through mitochondrial dysfunction. Mechanistic studies show that Pt@PCN-Cu triggers the dissociation of hexokinase 2 (HK2) from mitochondria, leading to a reduction in HK2 activity. This decline in HK2 activity impairs glycolysis, a metabolic pathway essential for tumor energy metabolism, which in turn results in elevated PD-L1 levels. In vivo, Pt@PCN-Cu demonstrates excellent safety and accumulates at the tumor site in a subcutaneous PDAC mouse model, inducing cuproptosis. Moreover, the combination of Pt@PCN-Cu with αPD-L1 further enhanced its therapeutic efficacy and effectively reprogrammed the immunosuppressive TME. CONCLUSION This study presents strong evidence confirming the safety and therapeutic potential of Pt@PCN-Cu in PDAC treatment. Importantly, Pt@PCN-Cu not only induces cuproptosis but also significantly enhances antitumor efficacy in combination with αPD-L1 by regulating PD-L1 expression through HK2 modulation. These findings underscore a more effective and innovative approach for treating PDAC.
Collapse
Affiliation(s)
- Pengyu Wang
- Pancreas Center, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Weihua Guo
- Pancreas Center, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Shuyue Liu
- Pancreas Center, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Shouyi Li
- Pancreas Center, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Jiaqi Li
- Pancreas Center, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Bowen Ding
- Pancreas Center, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Fengyi Yin
- Pancreas Center, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Yang Yang
- Pancreas Center, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Xingjiang Li
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, 157011, China
| | - Pei Cao
- Pancreas Center, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Chaozhe Ma
- Pancreas Center, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Wanying Zhang
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, 157011, China
| | - Yidan Song
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, 157011, China
| | - Yating Geng
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, 157011, China
| | - Lantao Liu
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, 157011, China.
| | - Jing Hu
- School of Basic Medicine, Tianjin Medical University, Tianjin, 300070, China.
| | - Jihui Hao
- Pancreas Center, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China.
| | - Yukuan Feng
- Pancreas Center, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China.
| |
Collapse
|
|
3
|
She F, Liu K, Anderson BW, Pisithkul T, Li Y, Fung DK, McCue T, Mulhern W, Amador-Noguez D, Wang JD. Pyruvate kinase directly generates GTP in glycolysis, supporting growth and contributing to guanosine toxicity. mBio 2025; 16:e0379824. [PMID: 39998177 PMCID: PMC11980595 DOI: 10.1128/mbio.03798-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 01/28/2025] [Indexed: 02/26/2025] Open
Abstract
Guanosine triphosphate (GTP) is essential for macromolecular biosynthesis, and its intracellular levels are tightly regulated in bacteria. Loss of the alarmone (p)ppGpp disrupts GTP regulation in Bacillus subtilis, causing cell death in the presence of exogenous guanosine and underscoring the critical importance of GTP homeostasis. To investigate the basis of guanosine toxicity, we performed a genetic selection for spontaneous mutations that suppress this effect, uncovering an unexpected link between GTP synthesis and glycolysis. In particular, we identified suppressor mutations in pyk, which encodes pyruvate kinase, a glycolytic enzyme. Metabolomic analysis revealed that inactivating pyruvate kinase prevents guanosine toxicity by reducing GTP levels. Although traditionally associated with ATP generation via substrate-level phosphorylation, B. subtilis pyruvate kinase in vitro was found to produce GTP and UTP approximately 10 and three times more efficiently than ATP, respectively. This efficient GTP/UTP synthesis extends to Enterococcus faecalis and Listeria monocytogenes, challenging the conventional understanding of pyruvate kinase's primary role in ATP production. These findings support a model in which glycolysis directly contributes to GTP synthesis, fueling energy-demanding processes, such as protein translation. Finally, we observed a synergistic essentiality of the Δndk Δpyk double mutant specifically on glucose, indicating that pyruvate kinase and nucleoside diphosphate kinase are the major contributors to nucleoside triphosphate production and complement each other during glycolysis. Our work highlights the critical role of nucleotide selectivity in pyruvate kinase and its broader implications in cellular physiology. IMPORTANCE In this study, we reveal that pyruvate kinase, a key glycolytic enzyme, primarily generates GTP from GDP in Bacillus subtilis, relative to other nucleotide triphosphates, such as ATP. This finding, uncovered through genetic selection for mutants that suppress toxic GTP overaccumulation, challenges the conventional understanding that pyruvate kinase predominantly produces ATP via substrate-level phosphorylation. The substantial role of GTP production by pyruvate kinase suggests a model where glycolysis rapidly and directly supplies GTP as the energy currency to power high GTP-demanding processes such as protein synthesis. Our results underscore the importance of nucleotide selectivity (ATP vs GTP vs UTP) in shaping the physiological state and fate of the cell, prompting further exploration into the mechanisms and broader implications of this selective nucleotide synthesis.
Collapse
Affiliation(s)
- Fukang She
- Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Kuanqing Liu
- Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, USA
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
| | - Brent W. Anderson
- Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Tippapha Pisithkul
- Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Yanxiu Li
- Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Danny K. Fung
- Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Tyler McCue
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
| | - William Mulhern
- Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Daniel Amador-Noguez
- Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Jue D. Wang
- Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| |
Collapse
|
|
4
|
Yuan W, Lu G, Zhao Y, He X, Liao S, Wang Z, Lei X, Xie Z, Yang X, Tang S, Tang G, Deng X. Intranuclear TCA and mitochondrial overload: The nascent sprout of tumors metabolism. Cancer Lett 2025; 613:217527. [PMID: 39909232 DOI: 10.1016/j.canlet.2025.217527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/19/2025] [Accepted: 02/02/2025] [Indexed: 02/07/2025]
Abstract
Abnormal glucose metabolism in tumors is a well-known form of metabolic reprogramming in tumor cells, the most representative of which, the Warburg effect, has been widely studied and discussed since its discovery. However, contradictions in a large number of studies and suboptimal efficacy of drugs targeting glycolysis have prompted us to further deepen our understanding of glucose metabolism in tumors. Here, we review recent studies on mitochondrial overload, nuclear localization of metabolizing enzymes, and intranuclear TCA (nTCA) in the context of the anomalies produced by inhibition of the Warburg effect. We provide plausible explanations for many of the contradictory points in the existing studies, including the causes of the Warburg effect. Furthermore, we provide a detailed prospective discussion of these studies in the context of these new findings, providing new ideas for the use of nTCA and mitochondrial overload in tumor therapy.
Collapse
Affiliation(s)
- Weixi Yuan
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Guozhong Lu
- 922nd Hospital of Hengyang, 421001, Hunan, China
| | - Yin Zhao
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Xiang He
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Senyi Liao
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Zhe Wang
- The Second Affiliated Hospital, Department of Pharmacy, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Xiaoyong Lei
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; Department of Pharmacy, Xiangnan University, Chenzhou, 423000, China
| | - Zhizhong Xie
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Xiaoyan Yang
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; Department of Pharmacy, Xiangnan University, Chenzhou, 423000, China
| | - Shengsong Tang
- Hunan Province Key Laboratory for Antibody-based Drug and Intelligent Delivery Systems (2018TP1044), Hunan, 410007, China.
| | - Guotao Tang
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
| | - Xiangping Deng
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
| |
Collapse
|
|
5
|
Meng Y, Ding J, Wang Y, Wang J, Huang W, Jiang W, Li J, Lang X, Zhang S, Liu Y, Liu X, Li H, Sun B. The transcriptional repressor Ctbp2 as a metabolite sensor regulating cardiomyocytes proliferation and heart regeneration. Mol Med 2025; 31:119. [PMID: 40140769 PMCID: PMC11948641 DOI: 10.1186/s10020-025-01168-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 03/13/2025] [Indexed: 03/28/2025] Open
Abstract
BACKGROUND C-terminal binding protein-2 (Ctbp2) is an evolutionarily conserved transcriptional repressor that regulates fundamental processes such as cell proliferation and apoptosis. However, the potential role of Ctbp2 in cardiomyocyte proliferation and heart regeneration remains unclear. In this study, we aim to explore the important role of Ctbp2 in cardiomyocyte proliferation and the regeneration of injured adult hearts. METHODS AND RESULTS In this study, we found that the expression of Ctbp2 in cardiomyocytes is downregulated after adulthood. Silencing Ctbp2 in cardiomyocytes on the post-natal day 1 (P1) reduced the proliferation ability of cardiomyocytes, whereas overexpressing Ctbp2 enhanced the proliferation ability of cardiomyocytes. Additionally, overexpressing Ctbp2 via adeno-associated virus-9 (AAV9) had no effect on the hearts of normal adult mice, but in the case of heart injury, overexpression of Ctbp2 in adult mice cardiomyocytes promoted cardiomyocyte proliferation. Mechanistically, the transcriptional repressor Ctbp2 acts as a metabolite sensor, and its regulation of cardiomyocyte proliferation is influenced by the metabolites NADH/NAD+ and fatty acyl-CoAs. Ctbp2 is activated by the intracellular accumulation of NADH during cardiomyocyte ischemia and hypoxia, inhibiting the transcriptional activity of the transcription factor FoxO1, thereby repressing the expression of the target genes and cell cycle negative regulators p21 and p27, allowing cardiomyocytes to re-enter the cell cycle. In contrast, normal adult cardiomyocytes mainly use fatty acid oxidation metabolism as their primary energy source, and the intracellular production of fatty acyl-CoAs inactivates Ctbp2, thus preventing it from inhibiting FoxO1 mediated cell cycle arrest. CONCLUSION In conclusion, this study demonstrates that the Ctbp2-FoxO1-p21/p27 axis can promote cardiomyocyte proliferation and heart regeneration. As a metabolite sensor, Ctbp2 is activated during cardiomyocyte ischemia and hypoxia, while it is inactivated under normal conditions. This controllable and transient regulation of cardiomyocyte proliferation can avoid the detrimental effects on cardiac function caused by long-term regulation of cardiomyocyte proliferation, such as hypertrophic cardiomyopathy or heart failure. This provides new targets and new ideas for addressing the issues of cardiomyocyte proliferation and heart regeneration.
Collapse
Affiliation(s)
- Yanting Meng
- Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, 157 Health Road, Nangang District, Harbin, 150081, Heilongjiang, China
| | - Jianwen Ding
- Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, 157 Health Road, Nangang District, Harbin, 150081, Heilongjiang, China
| | - Yanping Wang
- Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, 157 Health Road, Nangang District, Harbin, 150081, Heilongjiang, China
| | - Jing Wang
- Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, 157 Health Road, Nangang District, Harbin, 150081, Heilongjiang, China
| | - Wei Huang
- Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, 157 Health Road, Nangang District, Harbin, 150081, Heilongjiang, China
| | - Wenkang Jiang
- Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, 157 Health Road, Nangang District, Harbin, 150081, Heilongjiang, China
| | - Jiayi Li
- Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, 157 Health Road, Nangang District, Harbin, 150081, Heilongjiang, China
| | - Xiujuan Lang
- Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, 157 Health Road, Nangang District, Harbin, 150081, Heilongjiang, China
| | - Sifan Zhang
- Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, 157 Health Road, Nangang District, Harbin, 150081, Heilongjiang, China
| | - Yumei Liu
- Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, 157 Health Road, Nangang District, Harbin, 150081, Heilongjiang, China
| | - Xijun Liu
- Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, 157 Health Road, Nangang District, Harbin, 150081, Heilongjiang, China
| | - Hulun Li
- Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, 157 Health Road, Nangang District, Harbin, 150081, Heilongjiang, China
- The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, 157 Health Road, Nangang District, Harbin, 150081, Heilongjiang, China
| | - Bo Sun
- Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, 157 Health Road, Nangang District, Harbin, 150081, Heilongjiang, China.
| |
Collapse
|
|
6
|
Xie C, Lu C, Lv N, Kong W, Liu Y. Identification and analysis of oxidative stress-related genes in endometriosis. Front Immunol 2025; 16:1515490. [PMID: 40124382 PMCID: PMC11925871 DOI: 10.3389/fimmu.2025.1515490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 02/18/2025] [Indexed: 03/25/2025] Open
Abstract
Background Early diagnosis and treatment of endometriosis (EM) remain challenging because of the lack of knowledge about EM development. While oxidative stress (OS) has been associated with EM, the link is unclear. We explored OS-related genes (OSRGs) and their role in EM pathogenesis. Material and methods We combined two ectopic endometrium (EC) and eutopic endometrium (EU) datasets (GSE11691 and GSE25628) into a dataset for analysis. Bioinformatic analyses were used to identify differentially expressed genes (DEGs), OS-related genes (OSRGs), enriched pathways, competitive endogenous RNA network, and immune cell infiltration. Finally, real time-quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB) were used to validate the expression of key OSRGs in clinical patient samples. Results Bioinformatic analysis identified 459 DEGs between EC and EU samples, including 67 OSRGs. A ceRNA network was established, encompassing 28 DE-OSRGs, 32 miRNAs, and 53 lncRNAs. Four key OSRGs (CYP17A1, NR3C1, ENO2, and NGF) were selected from protein-protein interaction network analysis. The RT-qPCR and WB analysis showed that these genes' abnormal changes in RNA and protein levels were consistent with data in public databases. Weighted gene co-expression network analysis identified three immune-related OSRGs (CYP17A1, NR3C1, and NGF) and 20 lncRNAs that may regulate NR3C1 through 10 miRNAs. Conclusion The key OSRGs may function via multilayered networks in EM. We provide insights into EM and underscore the potential significance of OSRGs and the immune environment for diagnostic and prognosis evaluation.
Collapse
Affiliation(s)
| | | | | | | | - Yong Liu
- Department of Gynecology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, China
| |
Collapse
|
|
7
|
She F, Liu K, Anderson BW, Pisithkul T, Li Y, Fung DK, McCue T, Mulhern W, Amador-Noguez D, Wang JD. Pyruvate Kinase Directly Generates GTP in Glycolysis, Supporting Growth and Contributing to Guanosine Toxicity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.17.629031. [PMID: 39763737 PMCID: PMC11702619 DOI: 10.1101/2024.12.17.629031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Guanosine triphosphate (GTP) is essential for macromolecular biosynthesis, and its intracellular levels are tightly regulated in bacteria. Loss of the alarmone (p)ppGpp disrupts GTP regulation in Bacillus subtilis , causing cell death in the presence of exogenous guanosine and underscoring the critical importance of GTP homeostasis. To investigate the basis of guanosine toxicity, we performed a genetic selection for spontaneous mutations that suppress this effect, uncovering an unexpected link between GTP synthesis and glycolysis. In particular, we identified suppressor mutations in pyk , which encodes pyruvate kinase, a glycolytic enzyme. Metabolomic analysis revealed that inactivating pyruvate kinase prevents guanosine toxicity by reducing GTP levels. Although traditionally associated with ATP generation via substrate-level phosphorylation, B. subtilis pyruvate kinase in vitro was found to produce GTP and UTP approximately ten and three times more efficiently than ATP, respectively. This efficient GTP/UTP synthesis extends to Enterococcus faecalis and Listeria monocytogenes , challenging the conventional understanding of pyruvate kinase's primary role in ATP production. These findings support a model in which glycolysis directly contributes to GTP synthesis, fueling energy-demanding processes such as protein translation. Finally, we observed a synergistic essentiality of the Δ ndk Δ pyk double mutant specifically on glucose, indicating that pyruvate kinase and nucleoside diphosphate kinase are the major contributors of NTP production and complement each other during glycolysis. Our work highlights the critical role of nucleotide selectivity in pyruvate kinase and its broader implications in cellular physiology. Importance In this study, we reveal pyruvate kinase, a key glycolytic enzyme, primarily generates GTP from GDP in Bacillus subtilis , relatively to other trinucleotides such as ATP. This finding, uncovered through genetic selection for mutants that suppress toxic GTP overaccumulation, challenges the conventional understanding that pyruvate kinase predominantly produces ATP via substrate-level phosphorylation. The substantial role of GTP production by pyruvate kinase suggests a model where glycolysis rapidly and directly supplies GTP as the energy currency to power high GTP-demanding processes such as protein synthesis. Our results underscore the importance of nucleotide selectivity (ATP vs. GTP vs UTP) in shaping the physiological state and fate of the cell, prompting further exploration into the mechanisms and broader implications of this selective nucleotide synthesis.
Collapse
|
|
8
|
Li Y, Zhu W, Qian Y, Yang H, Wu Y, Meng J, Huang X, Liu Z, Mu L. Transcriptomic profiling of day 3 human embryos of poor quality reveals molecular links to divergent developmental trajectories. Cell Rep 2024; 43:114888. [PMID: 39487990 DOI: 10.1016/j.celrep.2024.114888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 07/21/2024] [Accepted: 10/02/2024] [Indexed: 11/04/2024] Open
Abstract
Poor-quality (PQ) embryos are commonly formed in assisted reproduction and often discarded, but emerging evidence suggests that some can develop into healthy children. Here, we performed single-embryo transcriptome profiling of day 3 human embryos of both good quality (GQ) and PQ. Our analyses revealed that day 3 PQ embryos can be categorized into two distinct subgroups: genuine PQ (gPQ) and morphological PQ (mPQ) embryos. This was further supported by additional transcriptomic data of GQ and PQ embryos donated by the same individuals. gPQ embryos showed greater impairments in both RNA decay and zygotic genome activation (ZGA) compared to mPQ embryos. Blastocysts that emerged from PQ embryos, more likely from mPQ embryos, demonstrated transcriptomic similarity to normal blastocysts. We also identified genes highly upregulated in day 3 gPQ embryos. These molecular insights may improve embryo selection and offer valuable clues for enhancing embryo quality in the future.
Collapse
Affiliation(s)
- Yan Li
- Reproductive Medicine Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Wencheng Zhu
- Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, CAS Key Laboratory of Primate Neurobiology, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yuchen Qian
- Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, CAS Key Laboratory of Primate Neurobiology, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Haiyan Yang
- Reproductive Medicine Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Yonggen Wu
- Reproductive Medicine Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Juan Meng
- Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, CAS Key Laboratory of Primate Neurobiology, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xuefeng Huang
- Reproductive Medicine Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
| | - Zhen Liu
- Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, CAS Key Laboratory of Primate Neurobiology, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai 200031, China; Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai 200031, China.
| | - Liangshan Mu
- Reproductive Medicine Center, Zhongshan Hospital, Fudan University, Shanghai 200031, China.
| |
Collapse
|
|
9
|
Hou N, Zhou H, Li J, Xiong X, Deng H, Xiong S. Macrophage polarization and metabolic reprogramming in abdominal aortic aneurysm. Immun Inflamm Dis 2024; 12:e1268. [PMID: 39530309 PMCID: PMC11555488 DOI: 10.1002/iid3.1268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 04/03/2024] [Accepted: 04/22/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Abdominal aortic aneurysm (AAA) is a macrovascular disease with high morbidity and mortality in the elderly. The limitation of the current management is that most patients can only be followed up until the AAA diameter increases to a threshold, and surgical intervention is recommended. The development of preventive and curative drugs for AAA is urgently needed. Macrophage-mediated immune inflammation is one of the key pathological links in the occurrence and development of AAA. AIMS This review article aims to evaluate the impact of immunometabolism on macrophage biology and its role in AAA. METHODS We analyze publications focusing on the polarization and metabolic reprogramming in macrophages as well as their potential impact on AAA, and summarize the potential interventions that are currently available to regulate these processes. RESULTS The phenotypic and functional changes in macrophages are accompanied by significant alterations in metabolic pathways. The interaction between macrophage polarization and metabolic pathways significantly influences the progression of AAA. CONCLUSION Macrophage polarization is a manifestation of the gross dichotomy of macrophage function into pro-inflammatory killing and tissue repair, that is, classically activated M1 macrophages and alternatively activated M2 macrophages. Macrophage functions are closely linked to metabolic changes, and the emerging field of immunometabolism is providing unique insights into the role of macrophages in AAA. It is essential to further investigate the precise metabolic changes and their functional consequences in AAA-associated macrophages.
Collapse
Affiliation(s)
- Ningxin Hou
- Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Hongmin Zhou
- Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Jun Li
- Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Xiaoxing Xiong
- Department of NeurosurgeryRenmin Hospital of Wuhan UniversityWuhanChina
| | - Hongping Deng
- Department of Vascular SurgeryRenmin Hospital of Wuhan UniversityWuhanChina
| | - Sizheng Xiong
- Department of Vascular SurgeryRenmin Hospital of Wuhan UniversityWuhanChina
| |
Collapse
|
|
10
|
Kierans SJ, Taylor CT. Glycolysis: A multifaceted metabolic pathway and signaling hub. J Biol Chem 2024; 300:107906. [PMID: 39442619 PMCID: PMC11605472 DOI: 10.1016/j.jbc.2024.107906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 10/07/2024] [Accepted: 10/14/2024] [Indexed: 10/25/2024] Open
Abstract
Glycolysis is a highly conserved metabolic pathway responsible for the anaerobic production of adenosine triphosphate (ATP) from the breakdown of glucose molecules. While serving as a primary metabolic pathway in prokaryotes, glycolysis is also utilized by respiring eukaryotic cells, providing pyruvate to fuel oxidative metabolism. Furthermore, glycolysis is the primary source of ATP production in multiple cellular states (e.g., hypoxia) and is particularly important in maintaining bioenergetic homeostasis in the most abundant cell type in the human body, the erythrocyte. Beyond its role in ATP production, glycolysis also functions as a signaling hub, producing several metabolic intermediates which serve roles in both signaling and metabolic processes. These signals emanating from the glycolytic pathway can profoundly impact cell function, phenotype, and fate and have previously been overlooked. In this review, we will discuss the role of the glycolytic pathway as a source of signaling molecules in eukaryotic cells, emphasizing the newfound recognition of glycolysis' multifaceted nature and its importance in maintaining cellular homeostasis, beyond its traditional role in ATP synthesis.
Collapse
Affiliation(s)
- Sarah J Kierans
- Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland; UCD School of Medicine, University College Dublin, Dublin, Ireland
| | - Cormac T Taylor
- Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland; UCD School of Medicine, University College Dublin, Dublin, Ireland.
| |
Collapse
|
|
11
|
Sikder S, Bhattacharya A, Agrawal A, Sethi G, Kundu TK. Micro-RNAs in breast cancer progression and metastasis: A chromatin and metabolic perspective. Heliyon 2024; 10:e38193. [PMID: 39386816 PMCID: PMC11462366 DOI: 10.1016/j.heliyon.2024.e38193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 09/06/2024] [Accepted: 09/19/2024] [Indexed: 10/12/2024] Open
Abstract
Breast cancer is a highly complex disease with multiple subtypes. While many of the breast cancer cases are sporadic some can be familial or hereditary. Genomic integrity is closely monitored by several mechanisms, such as DNA damage machinery and mitotic checkpoints. Any defect in the key genes involved in the regulation of these mechanisms often results in genomic instability, predisposing the cells to malignancy. This results in altered expression of many coding and noncoding genes. The noncoding RNAs especially the long noncoding RNA (lncRNAs) and microRNA (miRNAs) act as key regulators of cancer gene networks. Some miRNAs repress the expression of the heterochromatin-associated proteins, inducing the formation of open chromatin, and promoting the expression of genes required for oncogenesis. Additionally, specific miRNAs may also favour cancer progression and metastasis by regulating the expression of genes that support the metabolic microenvironment essential for cancer cell growth and proliferation. Understanding how these noncoding RNAs contribute to breast cancer development opens potential avenues for therapeutic intervention, targeting their dysregulated activity.
Collapse
Affiliation(s)
- Sweta Sikder
- Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, 560064, India
| | - Aditya Bhattacharya
- Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, 560064, India
| | - Aayushi Agrawal
- Division of Cancer Biology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, UP, India
- Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, 117600, Singapore
| | - Tapas K. Kundu
- Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, 560064, India
| |
Collapse
|
|
12
|
Stacpoole PW, Dirain CO. The pyruvate dehydrogenase complex at the epigenetic crossroads of acetylation and lactylation. Mol Genet Metab 2024; 143:108540. [PMID: 39067348 DOI: 10.1016/j.ymgme.2024.108540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 06/25/2024] [Accepted: 07/15/2024] [Indexed: 07/30/2024]
Abstract
The pyruvate dehydrogenase complex (PDC) is remarkable for its size and structure as well as for its physiological and pathological importance. Its canonical location is in the mitochondrial matrix, where it primes the tricarboxylic acid (TCA) cycle by decarboxylating glycolytically-derived pyruvate to acetyl-CoA. Less well appreciated is its role in helping to shape the epigenetic landscape, from early development throughout mammalian life by its ability to "moonlight" in the nucleus, with major repercussions for human healthspan and lifespan. The PDC's influence on two crucial modifiers of the epigenome, acetylation and lactylation, is the focus of this brief review.
Collapse
Affiliation(s)
- Peter W Stacpoole
- University of Florida, College of Medicine Department of Medicine, Department of Biochemistry & Molecular Biology, Gainesville, FL, United States.
| | - Carolyn O Dirain
- University of Florida, College of Medicine Department of Medicine, Gainesville, FL, United States
| |
Collapse
|
|
13
|
Aodah AH, Alkholifi FK, Alharthy KM, Devi S, Foudah AI, Yusufoglu HS, Alam A. Effects of kaempherol-3-rhamnoside on metabolic enzymes and AMPK in the liver tissue of STZ-induced diabetes in mice. Sci Rep 2024; 14:16167. [PMID: 39003280 PMCID: PMC11246446 DOI: 10.1038/s41598-024-66426-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 07/01/2024] [Indexed: 07/15/2024] Open
Abstract
Diabetes mellitus (DM) is a chronic metabolic disorder characterized by persistent hyperglycemia. It involves disturbances in carbohydrate, fat, and protein metabolism due to defects in insulin secretion, insulin action, or both. Novel therapeutic approaches are continuously being explored to enhance metabolic control and prevent complications associated with the disease. This study investigates the therapeutic potential of kaempherol-3-rhamnoside, a flavonoid, in managing diabetes by modulating the AMP-activated protein kinase (AMPK) pathway and improving metabolic enzyme activities in streptozotocin (STZ) -induced diabetic mice. Diabetic mice were treated with varying doses of kaempherol-3-rhamnoside and/or insulin over a 28-day period. Glycolytic and gluconeogenesis enzyme activities in the liver, fasting blood glucose levels, serum insulin levels, lipid profiles and oxidative stress markers were assessed. Treatment with kaempherol-3-rhamnoside significantly improved glycolytic enzyme activities, reduced fasting blood glucose, and enhanced insulin levels compared to diabetic controls. The compound also normalized lipid profiles and reduced oxidative stress in the liver, suggesting its potential in reversing diabetic dyslipidemia and oxidative damage. Furthermore, kaempherol-3-rhamnoside activated the AMPK pathway, indicating a mechanism through which it could exert its effects. Kaempherol-3-rhamnoside exhibits promising antidiabetic properties, potentially through AMPK pathway activation and metabolic enzyme modulation. These findings support its potential use as an adjunct therapy for diabetes management. Further clinical studies are warranted to validate these results in human subjects.
Collapse
Affiliation(s)
- Alhussain H Aodah
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, 11942, Al Kharj, Saudi Arabia
| | - Faisal K Alkholifi
- Department of Pharmacology and Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, 11942, Al Kharj, Saudi Arabia
| | - Khalid M Alharthy
- Department of Pharmacology and Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, 11942, Al Kharj, Saudi Arabia
| | - Sushma Devi
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India.
| | - Ahmed I Foudah
- Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, 11942, Al Kharj, Saudi Arabia
| | - Hasan S Yusufoglu
- Department of Pharmacognosy and Pharmaceutical Chemistry, College of Dentistry and Pharmacy, Buraydah Private Colleges, 51418, Buraydah, Saudi Arabia
| | - Aftab Alam
- Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, 11942, Al Kharj, Saudi Arabia.
| |
Collapse
|
|
14
|
Xu J, Lu W, Wei X, Zhang B, Yang H, Tu M, Chen X, Wu S, Guo T. Single-cell transcriptomics reveals the aggressive landscape of high-grade serous carcinoma and therapeutic targets in tumor microenvironment. Cancer Lett 2024; 593:216928. [PMID: 38714290 DOI: 10.1016/j.canlet.2024.216928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 03/29/2024] [Accepted: 04/26/2024] [Indexed: 05/09/2024]
Abstract
High-grade serous carcinoma (HGSC) is characterized by early abdominal metastasis, leading to a dismal prognosis. In this study, we conducted single-cell RNA sequencing on 109,573 cells from 34 tumor samples of 18 HGSC patients, including both primary tumors and their metastatic sites. Our analysis revealed a distinct S100A9+ tumor cell subtype present in both primary and metastatic sites, strongly associated with poor overall survival. This subtype exhibited high expression of S100A8, S100A9, ADGRF1, CEACAM6, CST6, NDRG2, MUC4, PI3, SDC1, and C15orf48. Individual knockdown of these ten marker genes, validated through in vitro and in vivo models, significantly inhibited ovarian cancer growth and invasion. Around S100A9+ tumor cells, a population of HK2+_CAF was identified, characterized by activated glycolysis metabolism, correlating with shorter overall survival in patients. Notably, similar to CAFs, immunosuppressive tumor-associated macrophage (TAM) subtypes underwent glycolipid metabolism reprogramming via PPARgamma regulation, promoting tumor metastasis. These findings shed light on the mechanisms driving the aggressiveness of HGSC, offering crucial insights for the development of novel therapeutic targets against this formidable cancer.
Collapse
Affiliation(s)
- Junfen Xu
- Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China; Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou, 310006, Zhejiang, China.
| | - Weiguo Lu
- Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China; Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou, 310006, Zhejiang, China
| | - Xinyi Wei
- Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China
| | - Bo Zhang
- Novel Bioinformatics Co., Ltd, Shanghai, China
| | - Haihua Yang
- Novel Bioinformatics Co., Ltd, Shanghai, China
| | - Mengyan Tu
- Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China
| | - Xin Chen
- Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China
| | - Shenglong Wu
- Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China
| | - Tianchen Guo
- Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China
| |
Collapse
|
|
15
|
Luís C, Fernandes R, Soares R. Exploring variations in glycolytic and gluconeogenic enzymes and isoforms across breast cancer cell lines and tissues. Carbohydr Res 2024; 541:109169. [PMID: 38838492 DOI: 10.1016/j.carres.2024.109169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 05/07/2024] [Accepted: 05/29/2024] [Indexed: 06/07/2024]
Abstract
It is well established that tumour cells undergo metabolic changes to acquire biological advantage over normal cells with activation of the glycolytic pathway, a process termed "Warburg effect". Enzyme isoforms are alternative enzymatic forms with the same function but with different biochemical or epigenetic features. Moreover, isoforms may have varying impacts on different metabolic pathways. We challenge ourselves to analyse the glycolytic and gluconeogenic enzymes and isoforms in breast cancer, a complex and heterogeneous pathology, associated with high incidence and mortality rates especially among women. We analysed epithelial and tumour cell lines by RT-PCR and compared values to a publicly available database for the expression profile of normal and tumour tissues (Gepia) of enzymes and enzymatic isoforms from glycolytic and gluconeogenic pathways. Additionally, GeneMANIA was used to evaluate interactions, pathways, and attributes of each glycolytic/gluconeogenic steps. The findings reveal that the enzymes and enzymatic isoforms expressed in cell culture were somewhat different from those in breast tissue. We propose that the tumor microenvironment plays a crucial role in the expression of glycolytic and gluconeogenic enzymes and isoforms in tumour cells. Nonetheless, they not only participate in glycolytic and gluconeogenic enzymatic activities but may also influence other pathways, such as the Pentose-Phosphate-Pathway, TCA cycle, as well as other carbohydrate, lipid, and amino acid metabolism.
Collapse
Affiliation(s)
- Carla Luís
- Biochemistry Unit, Department of Biomedicine, Faculty of Medicine, University of Porto (FMUP), Porto, Portugal; i3S - Instituto de Inovação e Investigação em Saúde, Universidade do Porto, Porto, Portugal.
| | - Rúben Fernandes
- Faculty of Health Sciences, University Fernando Pessoa, Fernando Pessoa Hospital School (FCS/HEFP/UFP), Porto, Portugal
| | - Raquel Soares
- Biochemistry Unit, Department of Biomedicine, Faculty of Medicine, University of Porto (FMUP), Porto, Portugal; i3S - Instituto de Inovação e Investigação em Saúde, Universidade do Porto, Porto, Portugal
| |
Collapse
|
|
16
|
Koltai T, Fliegel L. Dichloroacetate for Cancer Treatment: Some Facts and Many Doubts. Pharmaceuticals (Basel) 2024; 17:744. [PMID: 38931411 PMCID: PMC11206832 DOI: 10.3390/ph17060744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 05/23/2024] [Accepted: 06/04/2024] [Indexed: 06/28/2024] Open
Abstract
Rarely has a chemical elicited as much controversy as dichloroacetate (DCA). DCA was initially considered a dangerous toxic industrial waste product, then a potential treatment for lactic acidosis. However, the main controversies started in 2008 when DCA was found to have anti-cancer effects on experimental animals. These publications showed contradictory results in vivo and in vitro such that a thorough consideration of this compound's in cancer is merited. Despite 50 years of experimentation, DCA's future in therapeutics is uncertain. Without adequate clinical trials and health authorities' approval, DCA has been introduced in off-label cancer treatments in alternative medicine clinics in Canada, Germany, and other European countries. The lack of well-planned clinical trials and its use by people without medical training has discouraged consideration by the scientific community. There are few thorough clinical studies of DCA, and many publications are individual case reports. Case reports of DCA's benefits against cancer have been increasing recently. Furthermore, it has been shown that DCA synergizes with conventional treatments and other repurposable drugs. Beyond the classic DCA target, pyruvate dehydrogenase kinase, new target molecules have also been recently discovered. These findings have renewed interest in DCA. This paper explores whether existing evidence justifies further research on DCA for cancer treatment and it explores the role DCA may play in it.
Collapse
Affiliation(s)
- Tomas Koltai
- Hospital del Centro Gallego de Buenos Aires, Buenos Aires 2199, Argentina
| | - Larry Fliegel
- Department of Biochemistry, University Alberta, Edmonton, AB T6G 2H7, Canada;
| |
Collapse
|
|
17
|
Sapkota S, Briski KP. Sex-Dimorphic Effects of Hypoglycemia on Metabolic Sensor mRNA Expression in Ventromedial Hypothalamic Nucleus-Dorsomedial Division (VMNdm) Growth Hormone-Releasing Hormone Neurons. ACS Chem Neurosci 2024; 15:2350-2358. [PMID: 38757688 DOI: 10.1021/acschemneuro.4c00206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/18/2024] Open
Abstract
Growth hormone-releasing hormone (Ghrh) neurons in the dorsomedial ventromedial hypothalamic nucleus (VMNdm) express the metabolic transcription factor steroidogenic factor-1 and hypoglycemia-sensitive neurochemicals of diverse chemical structures, transmission modes, and temporal signaling profiles. Ghrh imposes neuromodulatory control of coexpressed transmitters. Multiple metabolic sensory mechanisms are employed in the brain, including screening of the critical nutrient glucose or the energy currency ATP. Here, combinatory laser-catapult-microdissection/single-cell multiplex qPCR tools were used to investigate whether these neurons possess molecular machinery for monitoring cellular metabolic status and if these biomarkers exhibit sex-specific sensitivity to insulin-induced hypoglycemia. Data show that hypoglycemia up- (male) or downregulated (female) Ghrh neuron glucokinase (Gck) mRNA; Ghrh gene silencing decreased baseline and hypoglycemic patterns of Gck gene expression in each sex. Ghrh neuron glucokinase regulatory protein (Gckr) transcript levels were respectively diminished or augmented in hypoglycemic male vs female rats; this mRNA profile was decreased by Ghrh siRNA in both sexes. Gene transcripts encoding catalytic alpha subunits of the energy monitor 5-AMP-activated protein kinase (AMPK), i.e., Prkaa1 and 2, were increased by hypoglycemia in males, yet only the former mRNA was hypoglycemia-sensitive in females. Ghrh siRNA downregulated baseline and hypoglycemia-associated Prkaa subunit mRNAs in males but elicited divergent changes in Prkaa2 transcripts in eu- vs hypoglycemic females. Results provide unique evidence that VMNdm Ghrh neurons express the characterized metabolic sensor biomarkers glucokinase and AMPK and that the corresponding gene profiles exhibit distinctive sex-dimorphic transcriptional responses to hypoglycemia. Data further document Ghrh neuromodulation of baseline and hypoglycemic transcription patterns of these metabolic gene profiles.
Collapse
Affiliation(s)
- Subash Sapkota
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, Louisiana 71201, United States
| | - Karen P Briski
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, Louisiana 71201, United States
| |
Collapse
|
|
18
|
Horvat S, Kos J, Pišlar A. Multifunctional roles of γ-enolase in the central nervous system: more than a neuronal marker. Cell Biosci 2024; 14:61. [PMID: 38735971 PMCID: PMC11089681 DOI: 10.1186/s13578-024-01240-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Accepted: 04/27/2024] [Indexed: 05/14/2024] Open
Abstract
Enolase, a multifunctional protein with diverse isoforms, has generally been recognized for its primary roles in glycolysis and gluconeogenesis. The shift in isoform expression from α-enolase to neuron-specific γ-enolase extends beyond its enzymatic role. Enolase is essential for neuronal survival, differentiation, and the maturation of neurons and glial cells in the central nervous system. Neuron-specific γ-enolase is a critical biomarker for neurodegenerative pathologies and neurological conditions, not only indicating disease but also participating in nerve cell formation and neuroprotection and exhibiting neurotrophic-like properties. These properties are precisely regulated by cysteine peptidase cathepsin X and scaffold protein γ1-syntrophin. Our findings suggest that γ-enolase, specifically its C-terminal part, may offer neuroprotective benefits against neurotoxicity seen in Alzheimer's and Parkinson's disease. Furthermore, although the therapeutic potential of γ-enolase seems promising, the effectiveness of enolase inhibitors is under debate. This paper reviews the research on the roles of γ-enolase in the central nervous system, especially in pathophysiological events and the regulation of neurodegenerative diseases.
Collapse
Affiliation(s)
- Selena Horvat
- Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia
| | - Janko Kos
- Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia
- Department of Biotechnology, Jožef Stefan Institute, Jamova Cesta 39, 1000, Ljubljana, Slovenia
| | - Anja Pišlar
- Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia.
| |
Collapse
|
|
19
|
Pawłowska M, Mila-Kierzenkowska C. Effect of Alpha-1 Antitrypsin and Irisin on Post-Exercise Inflammatory Response: A Narrative Review. IRANIAN JOURNAL OF MEDICAL SCIENCES 2024; 49:205-218. [PMID: 38680225 PMCID: PMC11053258 DOI: 10.30476/ijms.2023.97480.2925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/12/2023] [Accepted: 02/16/2023] [Indexed: 05/01/2024]
Abstract
Physical activity has a positive effect on human health and emotional well-being. However, in both amateur and professional athletes, training poses a risk of acute or chronic injury through repetitive overloading of bones, joints, and muscles. Inflammation can be an adverse effect of intense exercise caused by several factors including oxidative stress. The present narrative review summarizes current knowledge on inflammatory markers induced by physical exercise. Post-exercise recovery may reduce inflammatory responses and is key to effective training and adaptation of muscle tissues to sustained physical exertion.
Collapse
Affiliation(s)
- Marta Pawłowska
- Department of Medical Biology and Biochemistry, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Poland
| | - Celestyna Mila-Kierzenkowska
- Department of Medical Biology and Biochemistry, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Poland
| |
Collapse
|
|
20
|
Sekiya M, Kainoh K, Saito K, Yamazaki D, Tsuyuzaki T, Chen W, Kobari Y, Nakata A, Babe H, Shimano H. C-Terminal Binding Protein 2 Emerges as a Critical Player Linking Metabolic Imbalance to the Pathogenesis of Obesity. J Atheroscler Thromb 2024; 31:109-116. [PMID: 37793810 PMCID: PMC10857841 DOI: 10.5551/jat.rv22014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 08/21/2023] [Indexed: 10/06/2023] Open
Abstract
Metabolism is one of the vital functions of cells and living organisms, and the systems to sense and respond to the metabolic alterations play pivotal roles in a plethora of biological processes, including cell proliferative activities, immune cell functions, aging processes, and neuronal functions. Recently, we have reported that a transcriptional cofactor, C-terminal binding protein 2 (CtBP2), serves as a critical metabolite sensor in this context. CtBP2 has a structural pocket called Rossmann fold to accommodate metabolites, and it has been reported to be activated upon binding to NADH/NAD＋. Owing to its preferential binding affinity for NADH compared with NAD＋, increased glycolysis activates CtBP2 by regenerating NADH from NAD＋. Furthermore, we recently reported that fatty acyl-CoAs, metabolites accumulated under the condition of lipid overload, as represented by obesity, can inactivate CtBP2. These observations suggest that CtBP2 monitors not only redox state but also energy substrate preference in the maintenance of metabolic homeostasis. In line with these metabolite-sensing capabilities, CtBP2 is activated in healthy subjects to protect against metabolic disturbances, whereas inactivation of CtBP2 in obesity contributes to the pathogeneses of obesity.This metabolic system orchestrated by CtBP2 can provide a novel framework for understanding how cells maintain their homeostasis through coordination of metabolism, and CtBP2 incapacitation can be a critical point of the obesogenic cascade.
Collapse
Affiliation(s)
- Motohiro Sekiya
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Kenta Kainoh
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Kenji Saito
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Daichi Yamazaki
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Tomomi Tsuyuzaki
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Wanpei Chen
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Yuto Kobari
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Ayumi Nakata
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Haruka Babe
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Hitoshi Shimano
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| |
Collapse
|
|
21
|
Vilfan M, Lampreht Tratar U, Milevoj N, Nemec Svete A, Čemažar M, Serša G, Tozon N. Comparison of Nucleosome, Ferritin and LDH Levels in Blood with Clinical Response before and after Electrochemotherapy Combined with IL-12 Gene Electrotransfer for the Treatment of Mast Cell Tumours in Dogs. Animals (Basel) 2024; 14:438. [PMID: 38338081 PMCID: PMC10854863 DOI: 10.3390/ani14030438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 01/19/2024] [Accepted: 01/25/2024] [Indexed: 02/12/2024] Open
Abstract
Electrochemotherapy (ECT) in combination with the gene electrotransfer of interleukin 12 (IL-12 GET) has been successfully used in veterinary medicine for the treatment of mast cell tumours (MCT), but the biomarkers that could predict response to this treatment have not yet been investigated. The aim of this study was to determine the plasma nucleosome and serum ferritin concentrations, as well as the lactate dehydrogenase (LDH) activity, in the serum of treated patients before and one and six months after treatment to evaluate their utility as potential biomarkers that could predict response to the combined treatment. The study was conducted in 48 patients with a total of 86 MCTs that we treated with the combined treatment. The blood samples used for analysing the potential predictive biomarkers were taken before treatment and one and six months after treatment, when the response to treatment was also assessed. The Nu. Q® Vet Cancer Test, the Canine Ferritin ELISA Kit, and the RX Daytona+ automated biochemical analyser were used to analyse the blood samples. The results showed that the plasma nucleosome concentration (before treatment (BT): 32.84 ng/mL (median); one month after treatment (1 M AT): 58.89 ng/mL (median); p = 0.010) and serum LDH activity (BT: 59.75 U/L (median); 1 M AT: 107.5 U/L (median); p = 0.012) increased significantly one month after treatment and that the increase correlated significantly with the presence of a more pronounced local reaction (necrosis, swelling, etc.) at that time point for both markers (nucleosome: BT (necrosis): 21.61 ng/mL (median); 1 M AT (necrosis): 69.92 ng/mL (median), p = 0.030; LDH: BT (necrosis): 54.75 U/L (median); 1 M AT (necrosis): 100.3 U/L (median), p = 0.048). Therefore, both the plasma nucleosome concentration and serum LDH activity could serve as early indicators of the effect of the treatment. In this context, the serum ferritin concentration showed no significant predictive potential for treatment response (p > 0.999 for all comparisons). In conclusion, this study provides some new and important observations on the use of predictive biomarkers in veterinary oncology. Furthermore, it emphasises the need for the continued identification and validation of potential predictive biomarkers in dogs with MCT and other malignancies undergoing ECT treatment in combination with IL-12 GET to ultimately improve treatment outcomes.
Collapse
Affiliation(s)
- Maša Vilfan
- Veterinary Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia (U.L.T.); (A.N.S.)
| | - Urša Lampreht Tratar
- Veterinary Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia (U.L.T.); (A.N.S.)
- Institute of Oncology Ljubljana, 1000 Ljubljana, Slovenia; (M.Č.); (G.S.)
| | - Nina Milevoj
- Veterinary Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia (U.L.T.); (A.N.S.)
| | - Alenka Nemec Svete
- Veterinary Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia (U.L.T.); (A.N.S.)
| | - Maja Čemažar
- Institute of Oncology Ljubljana, 1000 Ljubljana, Slovenia; (M.Č.); (G.S.)
- Faculty of Health Sciences, University of Primorska, 6310 Izola, Slovenia
| | - Gregor Serša
- Institute of Oncology Ljubljana, 1000 Ljubljana, Slovenia; (M.Č.); (G.S.)
| | - Nataša Tozon
- Veterinary Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia (U.L.T.); (A.N.S.)
| |
Collapse
|
|
22
|
Trejo-Solis C, Silva-Adaya D, Serrano-García N, Magaña-Maldonado R, Jimenez-Farfan D, Ferreira-Guerrero E, Cruz-Salgado A, Castillo-Rodriguez RA. Role of Glycolytic and Glutamine Metabolism Reprogramming on the Proliferation, Invasion, and Apoptosis Resistance through Modulation of Signaling Pathways in Glioblastoma. Int J Mol Sci 2023; 24:17633. [PMID: 38139462 PMCID: PMC10744281 DOI: 10.3390/ijms242417633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 12/11/2023] [Accepted: 12/14/2023] [Indexed: 12/24/2023] Open
Abstract
Glioma cells exhibit genetic and metabolic alterations that affect the deregulation of several cellular signal transduction pathways, including those related to glucose metabolism. Moreover, oncogenic signaling pathways induce the expression of metabolic genes, increasing the metabolic enzyme activities and thus the critical biosynthetic pathways to generate nucleotides, amino acids, and fatty acids, which provide energy and metabolic intermediates that are essential to accomplish the biosynthetic needs of glioma cells. In this review, we aim to explore how dysregulated metabolic enzymes and their metabolites from primary metabolism pathways in glioblastoma (GBM) such as glycolysis and glutaminolysis modulate anabolic and catabolic metabolic pathways as well as pro-oncogenic signaling and contribute to the formation, survival, growth, and malignancy of glioma cells. Also, we discuss promising therapeutic strategies by targeting the key players in metabolic regulation. Therefore, the knowledge of metabolic reprogramming is necessary to fully understand the biology of malignant gliomas to improve patient survival significantly.
Collapse
Affiliation(s)
- Cristina Trejo-Solis
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Laboratorio de Reprogramación Celular, Departamento de Neurofisiología, Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico 14269, Mexico; (D.S.-A.); (N.S.-G.); (R.M.-M.)
| | - Daniela Silva-Adaya
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Laboratorio de Reprogramación Celular, Departamento de Neurofisiología, Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico 14269, Mexico; (D.S.-A.); (N.S.-G.); (R.M.-M.)
| | - Norma Serrano-García
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Laboratorio de Reprogramación Celular, Departamento de Neurofisiología, Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico 14269, Mexico; (D.S.-A.); (N.S.-G.); (R.M.-M.)
| | - Roxana Magaña-Maldonado
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Laboratorio de Reprogramación Celular, Departamento de Neurofisiología, Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico 14269, Mexico; (D.S.-A.); (N.S.-G.); (R.M.-M.)
| | - Dolores Jimenez-Farfan
- Laboratorio de Inmunología, División de Estudios de Posgrado e Investigación, Facultad de Odontología, Universidad Nacional Autónoma de México, Ciudad de Mexico 04510, Mexico;
| | - Elizabeth Ferreira-Guerrero
- Centro de Investigación Sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública, Cuernavaca 62100, Mexico; (E.F.-G.); (A.C.-S.)
| | - Arturo Cruz-Salgado
- Centro de Investigación Sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública, Cuernavaca 62100, Mexico; (E.F.-G.); (A.C.-S.)
| | | |
Collapse
|
|
23
|
Liu R, Yang Z, Yang T, Wang Z, Chen X, Zhu J, Ren A, Shi L, Yu H, Zhao M. PRMT5 regulates the polysaccharide content by controlling the splicing of thaumatin-like protein in Ganoderma lucidum. Microbiol Spectr 2023; 11:e0290623. [PMID: 37882562 PMCID: PMC10715077 DOI: 10.1128/spectrum.02906-23] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 09/07/2023] [Indexed: 10/27/2023] Open
Abstract
IMPORTANCE PRMT5 contributes to secondary metabolite biosynthesis in Ganoderma lucidum. However, the mechanism through which PRMT5 regulates the biosynthesis of secondary metabolites remains unclear. In the current study, PRMT5 silencing led to a significant decrease in the biosynthesis of polysaccharides from G. lucidum through the action of the alternative splicing of TLP. A shorter TLP2 isoform can directly bind to PGI and regulated polysaccharide biosynthesis. These results suggest that PRMT5 enhances PGI activity by regulating TLP binding to PGI. The results of the current study reveal a novel target gene for PRMT5-mediated alternative splicing and provide a reference for the identification of PRMT5 regulatory target genes.
Collapse
Affiliation(s)
- Rui Liu
- Key Laboratory of Agricultural Environmental Microbiology, Ministry of Agriculture; Microbiology Department, College of Life Sciences, Nanjing Agricultural University, Nanjing, China
| | - Zhengyan Yang
- Key Laboratory of Agricultural Environmental Microbiology, Ministry of Agriculture; Microbiology Department, College of Life Sciences, Nanjing Agricultural University, Nanjing, China
| | - Tao Yang
- Key Laboratory of Agricultural Environmental Microbiology, Ministry of Agriculture; Microbiology Department, College of Life Sciences, Nanjing Agricultural University, Nanjing, China
| | - Zi Wang
- Key Laboratory of Agricultural Environmental Microbiology, Ministry of Agriculture; Microbiology Department, College of Life Sciences, Nanjing Agricultural University, Nanjing, China
| | - Xin Chen
- Key Laboratory of Agricultural Environmental Microbiology, Ministry of Agriculture; Microbiology Department, College of Life Sciences, Nanjing Agricultural University, Nanjing, China
| | - Jing Zhu
- Key Laboratory of Agricultural Environmental Microbiology, Ministry of Agriculture; Microbiology Department, College of Life Sciences, Nanjing Agricultural University, Nanjing, China
| | - Ang Ren
- Key Laboratory of Agricultural Environmental Microbiology, Ministry of Agriculture; Microbiology Department, College of Life Sciences, Nanjing Agricultural University, Nanjing, China
| | - Liang Shi
- Key Laboratory of Agricultural Environmental Microbiology, Ministry of Agriculture; Microbiology Department, College of Life Sciences, Nanjing Agricultural University, Nanjing, China
| | - Hanshou Yu
- Key Laboratory of Agricultural Environmental Microbiology, Ministry of Agriculture; Microbiology Department, College of Life Sciences, Nanjing Agricultural University, Nanjing, China
| | - Mingwen Zhao
- Key Laboratory of Agricultural Environmental Microbiology, Ministry of Agriculture; Microbiology Department, College of Life Sciences, Nanjing Agricultural University, Nanjing, China
| |
Collapse
|
|
24
|
Ahamed A, Hosea R, Wu S, Kasim V. The Emerging Roles of the Metabolic Regulator G6PD in Human Cancers. Int J Mol Sci 2023; 24:17238. [PMID: 38139067 PMCID: PMC10743588 DOI: 10.3390/ijms242417238] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 12/01/2023] [Accepted: 12/06/2023] [Indexed: 12/24/2023] Open
Abstract
Metabolic reprogramming, especially reprogrammed glucose metabolism, is a well-known cancer hallmark related to various characteristics of tumor cells, including proliferation, survival, metastasis, and drug resistance. Glucose-6-phosphate dehydrogenase (G6PD) is the first and rate-limiting enzyme of the pentose phosphate pathway (PPP), a branch of glycolysis, that converts glucose-6-phosphate (G6P) into 6-phosphogluconolactone (6PGL). Furthermore, PPP produces ribose-5-phosphate (R5P), which provides sugar-phosphate backbones for nucleotide synthesis as well as nicotinamide adenine dinucleotide phosphate (NADPH), an important cellular reductant. Several studies have shown enhanced G6PD expression and PPP flux in various tumor cells, as well as their correlation with tumor progression through cancer hallmark regulation, especially reprogramming cellular metabolism, sustaining proliferative signaling, resisting cell death, and activating invasion and metastasis. Inhibiting G6PD could suppress tumor cell proliferation, promote cell death, reverse chemoresistance, and inhibit metastasis, suggesting the potential of G6PD as a target for anti-tumor therapeutic strategies. Indeed, while challenges-including side effects-still remain, small-molecule G6PD inhibitors showing potential anti-tumor effect either when used alone or in combination with other anti-tumor drugs have been developed. This review provides an overview of the structural significance of G6PD, its role in and regulation of tumor development and progression, and the strategies explored in relation to G6PD-targeted therapy.
Collapse
Affiliation(s)
- Alfar Ahamed
- Key Laboratory of Biorheological Science and Technology of Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400045, China
- The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China
| | - Rendy Hosea
- Key Laboratory of Biorheological Science and Technology of Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400045, China
- The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China
| | - Shourong Wu
- Key Laboratory of Biorheological Science and Technology of Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400045, China
- The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing University, Chongqing 400030, China
| | - Vivi Kasim
- Key Laboratory of Biorheological Science and Technology of Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400045, China
- The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing University, Chongqing 400030, China
| |
Collapse
|
|
25
|
Ranjbar M, Khakdan F, Ghorbani A, Zargar M, Chen M. The variations in gene expression of GAPDH in Ocimum basilicum cultivars under drought-induced stress conditions. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:119187-119203. [PMID: 37919503 DOI: 10.1007/s11356-023-30549-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 10/14/2023] [Indexed: 11/04/2023]
Abstract
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) holds a pivotal role within the glycolytic pathway of higher plants. It has garnered attention as a significant target protein in instances of oxidative stress, where it can engage in thiolation reactions within its active site. Numerous genes encoding cytosolic iterations of GAPDH have been identified and analyzed in specific plant species. This investigation was conducted to gain insights into GAPDH's function amidst drought-induced stress. Within this framework, the basil plant (Ocimum basilicum) was chosen for focused exploration, encompassing the cloning of the comprehensive cDNA of basil GAPDH (ObGAPDH) and scrutinizing its patterns of expression. The complete sequence of Ob-GAPDH spanned 1315 base pairs. The resultant protein derived from this sequence comprised 399 amino acids, projecting a molecular weight of approximately 42.54 kDa and an isoelectric point (pI) of 6.01. An examination of the evolutionary connections among various GAPDH proteins unveiled ObGAPDH's shared lineage with GAPDH proteins sourced from other plants, such as Salvia splendens and Sesamum indicum. Furthermore, computational methodologies were harnessed to predict the potential oxidative role of ObGAPDH in response to external signals. Molecular docking simulations illuminated the interaction between ObGAPDH and hydrogen peroxide (H2O2) as a ligand. Scrutinizing the expression patterns of the ObGAPDH gene under conditions of water scarcity stress brought to light diverse levels of transcriptional activity. Collectively, these findings underscore the notion that the regulation of ObGAPDH expression is contingent upon both the specific plant cultivar and the presence of stress stemming from drought conditions.
Collapse
Affiliation(s)
- Mojtaba Ranjbar
- Microbial Biotechnology Department, Faculty of Biotechnology, Amol University of Special Modern Technologies, Amol, Iran
| | | | - Abazar Ghorbani
- National Key Laboratory of Green Pesticide, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Center for Research and Development of Fine Chemicals, Guizhou University, Guiyang, China
| | - Meisam Zargar
- Department of Agrobiotechnology, Institute of Agriculture, RUDN University, 117198, Moscow, Russia
| | - Moxian Chen
- National Key Laboratory of Green Pesticide, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Center for Research and Development of Fine Chemicals, Guizhou University, Guiyang, China
| |
Collapse
|
|
26
|
Sun L, Suo C, Zhang T, Shen S, Gu X, Qiu S, Zhang P, Wei H, Ma W, Yan R, Chen R, Jia W, Cao J, Zhang H, Gao P. ENO1 promotes liver carcinogenesis through YAP1-dependent arachidonic acid metabolism. Nat Chem Biol 2023; 19:1492-1503. [PMID: 37500770 DOI: 10.1038/s41589-023-01391-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 06/29/2023] [Indexed: 07/29/2023]
Abstract
Enolase 1 (ENO1) is a glycolytic enzyme that plays essential roles in various pathological activities including cancer development. However, the mechanisms underlying ENO1-contributed tumorigenesis are not well explained. Here, we uncover that ENO1, as an RNA-binding protein, binds to the cytosine-uracil-guanine-rich elements of YAP1 messenger RNA to promote its translation. ENO1 and YAP1 positively regulate alternative arachidonic acid (AA) metabolism by inverse regulation of PLCB1 and HPGD (15-hydroxyprostaglandin dehydrogenase). The YAP1/PLCB1/HPGD axis-mediated activation of AA metabolism and subsequent accumulation of prostaglandin E2 (PGE2) are responsible for ENO1-mediated cancer progression, which can be retarded by aspirin. Finally, aberrant activation of ENO1/YAP1/PLCB1 and decreased HPGD expression in clinical hepatocellular carcinoma samples indicate a potential correlation between ENO1-regulated AA metabolism and cancer development. These findings underline a new function of ENO1 in regulating AA metabolism and tumorigenesis, suggesting a therapeutic potential for aspirin in patients with liver cancer with aberrant expression of ENO1 or YAP1.
Collapse
Affiliation(s)
- Linchong Sun
- Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
| | - Caixia Suo
- Department of Colorectal Surgery, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China
| | - Tong Zhang
- Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
| | - Shengqi Shen
- Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xuemei Gu
- School of Medicine, South China University of Technology, Guangzhou, China
| | - Shiqiao Qiu
- School of Medicine, South China University of Technology, Guangzhou, China
| | - Pinggen Zhang
- Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Haoran Wei
- Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
| | - Wenhao Ma
- Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Ronghui Yan
- Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Rui Chen
- School of Medicine, South China University of Technology, Guangzhou, China
| | - Weidong Jia
- The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
| | - Jie Cao
- Department of Colorectal Surgery, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China
| | - Huafeng Zhang
- Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
- The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China.
| | - Ping Gao
- Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
- School of Medicine, South China University of Technology, Guangzhou, China.
| |
Collapse
|
|
27
|
Zhang J, Chen F, Tian Y, Xu W, Zhu Q, Li Z, Qiu L, Lu X, Peng B, Liu X, Gan H, Liu B, Xu X, Zhu WG. PARylated PDHE1α generates acetyl-CoA for local chromatin acetylation and DNA damage repair. Nat Struct Mol Biol 2023; 30:1719-1734. [PMID: 37735618 DOI: 10.1038/s41594-023-01107-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 08/21/2023] [Indexed: 09/23/2023]
Abstract
Chromatin relaxation is a prerequisite for the DNA repair machinery to access double-strand breaks (DSBs). Local histones around the DSBs then undergo prompt changes in acetylation status, but how the large demands of acetyl-CoA are met is unclear. Here, we report that pyruvate dehydrogenase 1α (PDHE1α) catalyzes pyruvate metabolism to rapidly provide acetyl-CoA in response to DNA damage. We show that PDHE1α is quickly recruited to chromatin in a polyADP-ribosylation-dependent manner, which drives acetyl-CoA generation to support local chromatin acetylation around DSBs. This process increases the formation of relaxed chromatin to facilitate repair-factor loading, genome stability and cancer cell resistance to DNA-damaging treatments in vitro and in vivo. Indeed, we demonstrate that blocking polyADP-ribosylation-based PDHE1α chromatin recruitment attenuates chromatin relaxation and DSB repair efficiency, resulting in genome instability and restored radiosensitivity. These findings support a mechanism in which chromatin-associated PDHE1α locally generates acetyl-CoA to remodel the chromatin environment adjacent to DSBs and promote their repair.
Collapse
Affiliation(s)
- Jun Zhang
- International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, China
| | - Feng Chen
- International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, China
| | - Yuan Tian
- International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, China
| | - Wenchao Xu
- International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, China
| | - Qian Zhu
- International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, China
| | - Zhenhai Li
- International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, China
| | - Lingyu Qiu
- International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, China
| | - Xiaopeng Lu
- International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, China
| | - Bin Peng
- Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Cell Biology and Medical Genetics, Shenzhen University Medical School, Shenzhen, China
| | - Xiangyu Liu
- International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, China
| | - Haiyun Gan
- Shenzhen Key Laboratory of Synthetic Genomics, Guangdong Provincial Key Laboratory of Synthetic Genomics, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Baohua Liu
- International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, China
- Shenzhen Key Laboratory for Systemic Aging and Intervention, National Engineering Research Center for Biotechnology (Shenzhen), Shenzhen University Medical School, Shenzhen, China
| | - Xingzhi Xu
- Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Cell Biology and Medical Genetics, Shenzhen University Medical School, Shenzhen, China
| | - Wei-Guo Zhu
- International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, China.
| |
Collapse
|
|
28
|
Li Z, Zhao L, Zhang Y, Zhu L, Mu W, Ge T, Jin J, Tan J, Cheng J, Wang J, Wang N, Zhou X, Chen L, Chang Z, Liu C, Bian Z, Liu B, Ye L, Lan Y, Huang L, Zhou J. Functional diversification and dynamics of CAR-T cells in patients with B-ALL. Cell Rep 2023; 42:113263. [PMID: 37851569 DOI: 10.1016/j.celrep.2023.113263] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 08/03/2023] [Accepted: 09/28/2023] [Indexed: 10/20/2023] Open
Abstract
Understanding of cellular evolution and molecular programs of chimeric antigen receptor-engineered (CAR)-T cells post-infusion is pivotal for developing better treatment strategies. Here, we construct a longitudinal high-precision single-cell transcriptomic landscape of 7,578 CAR-T cells from 26 patients with B cell acute lymphoblastic leukemia (B-ALL) post-infusion. We molecularly identify eight CAR-T cell subtypes, including three cytotoxic subtypes with distinct kinetics and three dual-identity subtypes with non-T cell characteristics. Remarkably, long-term remission is coincident with the dominance of cytotoxic subtypes, while leukemia progression is correlated with the emergence of subtypes with B cell transcriptional profiles, which have dysfunctional features and might predict relapse. We further validate in vitro that the generation of B-featured CAR-T cells is induced by excessive tumor antigen stimulation or suppressed TCR signaling, while it is relieved by exogenous IL-12. Moreover, we define transcriptional hallmarks of CAR-T cell subtypes and reveal their molecular changes along computationally inferred cellular evolution in vivo. Collectively, these results decipher functional diversification and dynamics of peripheral CAR-T cells post-infusion.
Collapse
Affiliation(s)
- Zongcheng Li
- State Key Laboratory of Experimental Hematology, Haihe Laboratory of Cell Ecosystem, Institute of Hematology, Senior Department of Hematology, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, China.
| | - Lei Zhao
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Yuanyuan Zhang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Li Zhu
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Wei Mu
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Tong Ge
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Jin Jin
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Jiaqi Tan
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Jiali Cheng
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Jue Wang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Na Wang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Xiaoxi Zhou
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Liting Chen
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Zhilin Chang
- State Key Laboratory of Proteomics, Academy of Military Medical Sciences, Academy of Military Sciences, Beijing 100850, China
| | - Chen Liu
- State Key Laboratory of Proteomics, Academy of Military Medical Sciences, Academy of Military Sciences, Beijing 100850, China
| | - Zhilei Bian
- Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450052, China
| | - Bing Liu
- State Key Laboratory of Experimental Hematology, Haihe Laboratory of Cell Ecosystem, Institute of Hematology, Senior Department of Hematology, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, China; State Key Laboratory of Proteomics, Academy of Military Medical Sciences, Academy of Military Sciences, Beijing 100850, China; Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou 510632, China.
| | - Lilin Ye
- Institute of Immunology, Third Military Medical University, Chongqing 400038, China.
| | - Yu Lan
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou 510632, China.
| | - Liang Huang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China.
| | - Jianfeng Zhou
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| |
Collapse
|
|
29
|
Shi J, Miao D, Lv Q, Tan D, Xiong Z, Zhang X. ENO2 as a Biomarker Regulating Energy Metabolism to Promote Tumor Progression in Clear Cell Renal Cell Carcinoma. Biomedicines 2023; 11:2499. [PMID: 37760940 PMCID: PMC10525605 DOI: 10.3390/biomedicines11092499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 08/18/2023] [Accepted: 09/01/2023] [Indexed: 09/29/2023] Open
Abstract
BACKGROUND Clear cell renal cell carcinoma (ccRCC) is the most common and metastatic type of renal cell carcinoma. Despite significant advancements, the current diagnostic biomarkers for ccRCC lack the desired specificity and sensitivity, necessitating the identification of novel biomarkers and elucidation of their underlying mechanisms. METHODS Three gene expression profile datasets were obtained from the GEO database, and differentially expressed genes (DEGs) were screened. Gene Ontology and KEGG pathway analysis were conducted in ccRCC. To clarify the diagnosis and prognostic role of ENO2, Kaplan-Meier analysis and Cox proportional hazards regression analysis were performed. Functional experiments were also carried out to verify the significant role of ENO2 in ccRCC. Finally, tumor mutational burden analysis was utilized to investigate the potential role of ENO2 in gene mutations in ccRCC. RESULTS The study showed that ENO2 is a potential biomarker for the diagnosis of ccRCC and can independently predict the clinical prognosis of ccRCC. Furthermore, we found that ENO2 can promote the occurrence and progression of ccRCC by affecting the glycolysis level of cells through the "Warburg effect". CONCLUSIONS These findings provide new theories for the occurrence and development of ccRCC and can help formulate new strategies for its diagnosis and treatment.
Collapse
Affiliation(s)
- Jian Shi
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China (D.M.); (D.T.)
- Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Daojia Miao
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China (D.M.); (D.T.)
- Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Qingyang Lv
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China (D.M.); (D.T.)
- Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Diaoyi Tan
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China (D.M.); (D.T.)
- Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zhiyong Xiong
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China (D.M.); (D.T.)
- Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiaoping Zhang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China (D.M.); (D.T.)
- Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| |
Collapse
|
|
30
|
Soultanas P, Janniere L. The metabolic control of DNA replication: mechanism and function. Open Biol 2023; 13:230220. [PMID: 37582405 PMCID: PMC10427196 DOI: 10.1098/rsob.230220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 07/26/2023] [Indexed: 08/17/2023] Open
Abstract
Metabolism and DNA replication are the two most fundamental biological functions in life. The catabolic branch of metabolism breaks down nutrients to produce energy and precursors used by the anabolic branch of metabolism to synthesize macromolecules. DNA replication consumes energy and precursors for faithfully copying genomes, propagating the genetic material from generation to generation. We have exquisite understanding of the mechanisms that underpin and regulate these two biological functions. However, the molecular mechanism coordinating replication to metabolism and its biological function remains mostly unknown. Understanding how and why living organisms respond to fluctuating nutritional stimuli through cell-cycle dynamic changes and reproducibly and distinctly temporalize DNA synthesis in a wide-range of growth conditions is important, with wider implications across all domains of life. After summarizing the seminal studies that founded the concept of the metabolic control of replication, we review data linking metabolism to replication from bacteria to humans. Molecular insights underpinning these links are then presented to propose that the metabolic control of replication uses signalling systems gearing metabolome homeostasis to orchestrate replication temporalization. The remarkable replication phenotypes found in mutants of this control highlight its importance in replication regulation and potentially genetic stability and tumorigenesis.
Collapse
Affiliation(s)
- Panos Soultanas
- Biodiscovery Institute, School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
| | - Laurent Janniere
- Génomique Métabolique, Genoscope, Institut François Jacob, CEA, CNRS, Université Evry, Université Paris-Saclay, 91057 Evry, France
| |
Collapse
|
|
31
|
Shegay PV, Shatova OP, Zabolotneva AA, Shestopalov AV, Kaprin AD. Moonlight functions of glycolytic enzymes in cancer. Front Mol Biosci 2023; 10:1076138. [PMID: 37449059 PMCID: PMC10337784 DOI: 10.3389/fmolb.2023.1076138] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 06/19/2023] [Indexed: 07/18/2023] Open
Abstract
Since an extensive genome research has started, basic principle "one gene-one protein-one function" was significantly revised. Many proteins with more than one function were identified and characterized as "moonlighting" proteins, which activity depend not only on structural peculiarities but also on compartmentation and metabolic environment. It turned out that "housekeeping" glycolytic enzymes show important moonlight functions such as control of development, proliferation, apoptosis, migration, regulation of transcription and cell signaling. Glycolytic enzymes emerged very early in evolution and because of the limited content of genomes, they could be used as ancient regulators for intercellular and intracellular communication. The multifunctionality of the constitutively expressed enzymes began to serve cancer cell survival and growth. In the present review we discuss some moonlight functions of glycolytic enzymes that important for malignant transformation and tumor growth.
Collapse
Affiliation(s)
- Petr V. Shegay
- Federal State Budget Institution, National Medical Research Radiology Center of the Ministry of Healthcare of the Russian Federation, Moscow, Russia
| | - Olga P. Shatova
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Pirogov Russian National Research Medical University, Moscow, Russia
- Biochemistry Department, Peoples’ Friendship University of Russia, Moscow, Russia
| | - Anastasia A. Zabolotneva
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Pirogov Russian National Research Medical University, Moscow, Russia
- National Medical Research Centre for Endocrinology, Laboratory of Biochemistry of Signaling Pathways, Moscow, Russia
| | - Aleksandr V. Shestopalov
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Pirogov Russian National Research Medical University, Moscow, Russia
- National Medical Research Centre for Endocrinology, Laboratory of Biochemistry of Signaling Pathways, Moscow, Russia
- Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - Andrei D. Kaprin
- Federal State Budget Institution, National Medical Research Radiology Center of the Ministry of Healthcare of the Russian Federation, Moscow, Russia
- Biochemistry Department, Peoples’ Friendship University of Russia, Moscow, Russia
| |
Collapse
|
|
32
|
Liu H, Zheng Y, Zhu B, Tong Y, Xin W, Yang H, Jin P, Hu Y, Huang M, Chang W, Ballarin F, Li S, Hou Z. Marine-montane transitions coupled with gill and genetic convergence in extant crustacean. SCIENCE ADVANCES 2023; 9:eadg4011. [PMID: 37352347 PMCID: PMC10289665 DOI: 10.1126/sciadv.adg4011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 05/17/2023] [Indexed: 06/25/2023]
Abstract
Marine-terrestrial transition represents an important aspect of organismal evolution that requires numerous morphological and genetic innovations and has been hypothesized to be caused by geological changes. We used talitrid crustaceans with marine-coastal-montane extant species at a global scale to investigate the marine origination and terrestrial adaptation. Using genomic data, we demonstrated that marine ancestors repeatedly colonized montane terrestrial habitats during the Oligocene to Miocene. Biological transitions were well correlated with plate collisions or volcanic island formation, and top-down cladogenesis was observed on the basis of a positive relationship between ancestral habitat elevation and divergence time for montane lineages. We detected convergent variations of convoluted gills and convergent evolution of SMC3 associated with montane transitions. Moreover, using CRISPR-Cas9 mutagenesis, we proposed that SMC3 potentially regulates the development of exites, such as talitrid gills. Our results provide a living model for understanding biological innovations and related genetic regulatory mechanisms associated with marine-terrestrial transitions.
Collapse
Affiliation(s)
- Hongguang Liu
- Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Southeast Asia Biodiversity Research Institute, Chinese Academy of Sciences, Yezin, Nay Pyi Taw 05282, Myanmar
| | - Yami Zheng
- Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Bingyue Zhu
- Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yan Tong
- Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Wenpei Xin
- Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Han Yang
- Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Pengyu Jin
- Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Yueyao Hu
- Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Mengyi Huang
- Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Wanjin Chang
- Xiamen University Malaysia, Jalan Sunsuria, Bandar Sunsuria, 43900 Sepang, Selangor, Malaysia
| | - Francesco Ballarin
- Systematic Zoology Laboratory, Department of Biological Sciences, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji-shi, 192-0397, Tokyo, Japan
| | - Shuqiang Li
- Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Zhonge Hou
- Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| |
Collapse
|
|
33
|
Chen L, Zhang H, Shi H, Li Z, Xue C. Application of multi-omics combined with bioinformatics techniques to assess salinity stress response and tolerance mechanisms of Pacific oyster (Crassostrea gigas) during depuration. FISH & SHELLFISH IMMUNOLOGY 2023; 137:108779. [PMID: 37120087 DOI: 10.1016/j.fsi.2023.108779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 04/13/2023] [Accepted: 04/26/2023] [Indexed: 05/13/2023]
Abstract
Depuration is a vital stage to ensure the safety of oyster consumption, and salinity had a great impact on the environmental adaptability of oysters, but the underlying molecular mechanism was poorly understood during depuration stage. Here, Crassostrea gigas was depurated for 72 h at different salinity (26, 29, 32, 35, 38 g/L, corresponding to ±20%, ±10% salinity fluctuation away from oyster's production area) and then analyzed by using transcriptome, proteome, and metabolome combined with bioinformatics techniques. The transcriptome showed that the salinity stress led to 3185 differentially expressed genes and mainly enriched in amino acid metabolism, carbohydrate metabolism, lipid metabolism, etc. A total of 464 differentially expressed proteins were screened by the proteome, and the number of up-regulated expression proteins was less than the down-regulated, indicating that the salinity stress would affect the regulation of metabolism and immunity in oysters. 248 metabolites significantly changed in response to depuration salinity stress in oysters, including phosphate organic acids and their derivatives, lipids, etc. The results of integrated omics analysis indicated that the depuration salinity stress induced abnormal metabolism of the citrate cycle (TCA cycle), lipid metabolism, glycolysis, nucleotide metabolism, ribosome, ATP-binding cassette (ABC) transport pathway, etc. By contrast with Pro-depuration, more radical responses were observed in the S38 group. Based on the results, we suggested that the 10% salinity fluctuation was suitable for oyster depuration and the combination of multi-omics analysis could provide a new perspective for the analysis of the mechanism changes.
Collapse
Affiliation(s)
- Lipin Chen
- College of Food Science and Engineering, Ocean University of China, No.5, Yu Shan Road, Qingdao, Shandong Province, 266003, PR China
| | - Hongwei Zhang
- Food and Agricultural Products Testing Agency, Technology Center of Qingdao Customs District, Qingdao, Shandong Province, 266237, PR China
| | - Haohao Shi
- College of Food Science and Technology, Hainan University, Hainan, 570228, PR China.
| | - Zhaojie Li
- College of Food Science and Engineering, Ocean University of China, No.5, Yu Shan Road, Qingdao, Shandong Province, 266003, PR China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116034, PR China.
| | - Changhu Xue
- College of Food Science and Engineering, Ocean University of China, No.5, Yu Shan Road, Qingdao, Shandong Province, 266003, PR China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116034, PR China
| |
Collapse
|
|
34
|
Gupta MN, Uversky VN. Moonlighting enzymes: when cellular context defines specificity. Cell Mol Life Sci 2023; 80:130. [PMID: 37093283 PMCID: PMC11073002 DOI: 10.1007/s00018-023-04781-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/13/2023] [Accepted: 04/15/2023] [Indexed: 04/25/2023]
Abstract
It is not often realized that the absolute protein specificity is an exception rather than a rule. Two major kinds of protein multi-specificities are promiscuity and moonlighting. This review discusses the idea of enzyme specificity and then focusses on moonlighting. Some important examples of protein moonlighting, such as crystallins, ceruloplasmin, metallothioniens, macrophage migration inhibitory factor, and enzymes of carbohydrate metabolism are discussed. How protein plasticity and intrinsic disorder enable the removing the distinction between enzymes and other biologically active proteins are outlined. Finally, information on important roles of moonlighting in human diseases is updated.
Collapse
Affiliation(s)
- Munishwar Nath Gupta
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology, Hauz Khas, New Delhi, 110016, India
| | - Vladimir N Uversky
- Department of Molecular Medicine and USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd., MDC07, Tampa, FL, 33612-4799, USA.
| |
Collapse
|
|
35
|
Cao L, Wang R, Liu G, Zhang Y, Thorne RF, Zhang XD, Li J, Xia Y, Guo L, Shao F, Gu H, Wu M. Glycolytic Pfkp acts as a Lin41 protein kinase to promote endodermal differentiation of embryonic stem cells. EMBO Rep 2023; 24:e55683. [PMID: 36660859 PMCID: PMC9986826 DOI: 10.15252/embr.202255683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 12/21/2022] [Accepted: 01/03/2023] [Indexed: 01/21/2023] Open
Abstract
Unveiling the principles governing embryonic stem cell (ESC) differentiation into specific lineages is critical for understanding embryonic development and for stem cell applications in regenerative medicine. Here, we establish an intersection between LIF-Stat3 signaling that is essential for maintaining murine (m) ESCs pluripotency, and the glycolytic enzyme, the platelet isoform of phosphofructokinase (Pfkp). In the pluripotent state, Stat3 transcriptionally suppresses Pfkp in mESCs while manipulating the cells to lift this repression results in differentiation towards the ectodermal lineage. Pfkp exhibits substrate specificity changes to act as a protein kinase, catalyzing serine phosphorylation of the developmental regulator Lin41. Such phosphorylation stabilizes Lin41 by impeding its autoubiquitination and proteasomal degradation, permitting Lin41-mediated binding and destabilization of mRNAs encoding ectodermal specification markers to favor the expression of endodermal specification genes. This provides new insights into the wiring of pluripotency-differentiation circuitry where Pfkp plays a role in germ layer specification during mESC differentiation.
Collapse
Affiliation(s)
- Leixi Cao
- Translational Research Institute, Henan Provincial People's Hospital, Academy of Medical ScienceZhengzhou UniversityZhengzhouChina
| | - Ruijie Wang
- Translational Research Institute, Henan Provincial People's Hospital, Academy of Medical ScienceZhengzhou UniversityZhengzhouChina
| | - Guangzhi Liu
- Translational Research Institute, Henan Provincial People's Hospital, Academy of Medical ScienceZhengzhou UniversityZhengzhouChina
| | - Yuwei Zhang
- Translational Research Institute, Henan Provincial People's Hospital, Academy of Medical ScienceZhengzhou UniversityZhengzhouChina
| | - Rick Francis Thorne
- Translational Research Institute, Henan Provincial People's Hospital, Academy of Medical ScienceZhengzhou UniversityZhengzhouChina
- School of Biomedical Sciences & PharmacyUniversity of NewcastleNewcastleNSWAustralia
| | - Xu Dong Zhang
- Translational Research Institute, Henan Provincial People's Hospital, Academy of Medical ScienceZhengzhou UniversityZhengzhouChina
- School of Environmental & Life SciencesUniversity of NewcastleNewcastleNSWAustralia
| | - Jinming Li
- Translational Research Institute, Henan Provincial People's Hospital, Academy of Medical ScienceZhengzhou UniversityZhengzhouChina
| | - Yang Xia
- Department of Immunology, School of Basic Medical SciencesAnhui Medical UniversityHefeiChina
| | - Lili Guo
- Department of Immunology, School of Basic Medical SciencesAnhui Medical UniversityHefeiChina
| | - Fengmin Shao
- Translational Research Institute, Henan Provincial People's Hospital, Academy of Medical ScienceZhengzhou UniversityZhengzhouChina
| | - Hao Gu
- Department of Immunology, School of Basic Medical SciencesAnhui Medical UniversityHefeiChina
| | - Mian Wu
- Translational Research Institute, Henan Provincial People's Hospital, Academy of Medical ScienceZhengzhou UniversityZhengzhouChina
- School of Clinical MedicineHenan UniversityZhengzhouChina
- CAS Centre for Excellence in Molecular Cell Sciencethe First Affiliated Hospital of University of Science and Technology of ChinaHefeiChina
| |
Collapse
|
|
36
|
Shatova OP, Shegay PV, Zabolotneva AA, Shestopalov AV, Kaprin AD. Evolutionary Acquisition of Multifunctionality by Glycolytic Enzymes. J EVOL BIOCHEM PHYS+ 2023. [DOI: 10.1134/s002209302301009x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/15/2023]
|
|
37
|
Spelat R, Ferro F, Contessotto P, Aljaabary A, Martin-Saldaña S, Jin C, Karlsson NG, Grealy M, Hilscher MM, Magni F, Chinello C, Kilcoyne M, Pandit A. Metabolic reprogramming and membrane glycan remodeling as potential drivers of zebrafish heart regeneration. Commun Biol 2022; 5:1365. [PMID: 36509839 PMCID: PMC9744865 DOI: 10.1038/s42003-022-04328-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 12/01/2022] [Indexed: 12/15/2022] Open
Abstract
The ability of the zebrafish heart to regenerate following injury makes it a valuable model to deduce why this capability in mammals is limited to early neonatal stages. Although metabolic reprogramming and glycosylation remodeling have emerged as key aspects in many biological processes, how they may trigger a cardiac regenerative response in zebrafish is still a crucial question. Here, by using an up-to-date panel of transcriptomic, proteomic and glycomic approaches, we identify a metabolic switch from mitochondrial oxidative phosphorylation to glycolysis associated with membrane glycosylation remodeling during heart regeneration. Importantly, we establish the N- and O-linked glycan structural repertoire of the regenerating zebrafish heart, and link alterations in both sialylation and high mannose structures across the phases of regeneration. Our results show that metabolic reprogramming and glycan structural remodeling are potential drivers of tissue regeneration after cardiac injury, providing the biological rationale to develop novel therapeutics to elicit heart regeneration in mammals.
Collapse
Affiliation(s)
- Renza Spelat
- CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Galway, Ireland ,grid.5970.b0000 0004 1762 9868Neurobiology Sector, International School for Advanced Studies (SISSA), Trieste, Italy
| | - Federico Ferro
- CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Galway, Ireland ,grid.5133.40000 0001 1941 4308Department of Medical Surgery and Health Science, University of Trieste, Trieste, Italy
| | - Paolo Contessotto
- CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Galway, Ireland ,grid.5608.b0000 0004 1757 3470Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Amal Aljaabary
- CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Galway, Ireland
| | - Sergio Martin-Saldaña
- CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Galway, Ireland
| | - Chunsheng Jin
- grid.8761.80000 0000 9919 9582Department of Medical Biochemistry, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Niclas G. Karlsson
- grid.8761.80000 0000 9919 9582Department of Medical Biochemistry, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Maura Grealy
- Pharmacology and Therapeutics, School of Medicine, University of Galway, Galway, Ireland
| | - Markus M. Hilscher
- grid.10548.380000 0004 1936 9377Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
| | - Fulvio Magni
- grid.7563.70000 0001 2174 1754Clinical Proteomics and Metabolomics Unit, School of Medicine and Surgery, University of Milano-Bicocca, Vedano al Lambro, Italy
| | - Clizia Chinello
- grid.7563.70000 0001 2174 1754Clinical Proteomics and Metabolomics Unit, School of Medicine and Surgery, University of Milano-Bicocca, Vedano al Lambro, Italy
| | - Michelle Kilcoyne
- CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Galway, Ireland ,Carbohydrate Signalling Group, Microbiology, School of Natural Sciences, University of Galway, Galway, Ireland
| | - Abhay Pandit
- CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Galway, Ireland
| |
Collapse
|
|
38
|
Guo J, Yue X, Chang J, Zhang Z, Li J, Liu X. First identification of Nocardia seriolae GapA adhesion function and its three B-cell epitopes with cell-binding activity. JOURNAL OF FISH DISEASES 2022; 45:1845-1855. [PMID: 36048577 DOI: 10.1111/jfd.13709] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 08/11/2022] [Accepted: 08/16/2022] [Indexed: 06/15/2023]
Abstract
Fish nocardiosis mainly caused by Nocardia seriolae (N. seriolae) is a serious threat to aquaculture. Bacterial adhesion to host cells mediated by adhesin is an initial step of pathogenesis. But it is not clear whether glyceraldehyde-3-phosphate dehydrogenase (GapA) is an adhesin of N. seriolae. Here, recombinant GapA protein (rGapA) was prokaryotic expressed, and its role in the bacterial adhesion to Ctenopharyngodon idella kidney cells was investigated by indirect immunofluorescence, protein-binding assay and adhesion inhibition assay. The results showed that an obvious green fluorescence was observed on the surface of the cells co-incubated with rGapA protein; the cytomembrane proteins of the cells pretreated with rGapA could react with anti-rGapA antibody; and the antibody significantly inhibited the adhesion ability of the bacteria. Subsequently, B-cell linear epitopes of GapA protein were identified by using a immunoinformatics approach combined with peptide ELISA and Western blot for the first time. It was found that four predicted epitopes (Ep58-69 , Ep139-150 , Ep186-197 , Ep318-329 ) could all react with anti-rGapA antibody and obviously inhibit the immunoreactivity between rGapA and anti-rGapA antibody, and they were confirmed as indeed B-cell linear epitopes of the protein. Furthermore, flow cytometry analysis found the percentage of positive cells co-incubated with FITC-labelled epitope peptides (Ep139-150 , Ep186-197 , Ep318-329 ) was significantly higher than those in the FITC-labelled Ep58-69 , unrelated control peptide and cell control. Collectively, GapA is an adhesin of N. seriolae, and epitope peptides (Ep139-150 , Ep186-197 , Ep318-329 ) possess cell-binding activity, which are potential candidates for developing a multiple epitopes-based adhesin vaccine against fish nocardiosis.
Collapse
Affiliation(s)
- Jiajing Guo
- Anhui Province Key Lab of Veterinary Pathobiology and Disease Control, College of Animal Science and Technology, Anhui Agricultural University, Hefei, P. R. China
| | - Xiaozhen Yue
- Anhui Province Key Lab of Veterinary Pathobiology and Disease Control, College of Animal Science and Technology, Anhui Agricultural University, Hefei, P. R. China
| | - Jiaojiao Chang
- Anhui Province Key Lab of Veterinary Pathobiology and Disease Control, College of Animal Science and Technology, Anhui Agricultural University, Hefei, P. R. China
| | - Zhenyuan Zhang
- Anhui Province Key Lab of Veterinary Pathobiology and Disease Control, College of Animal Science and Technology, Anhui Agricultural University, Hefei, P. R. China
| | - Jinnian Li
- Anhui Province Key Lab of Veterinary Pathobiology and Disease Control, College of Animal Science and Technology, Anhui Agricultural University, Hefei, P. R. China
| | - Xuelan Liu
- Anhui Province Key Lab of Veterinary Pathobiology and Disease Control, College of Animal Science and Technology, Anhui Agricultural University, Hefei, P. R. China
| |
Collapse
|
|
39
|
Konieczka P, Żelechowska E, Przybylski W, Jaworska D, Sałek P, Kinsner M, Jankowski J. The Sarcoplasmic Protein Profile of Breast Muscle in Turkeys in Response to Different Dietary Ratios of Limiting Amino Acids and Clostridium perfringens-Induced Inflammation. Poult Sci 2022; 101:102195. [PMID: 36257075 PMCID: PMC9574763 DOI: 10.1016/j.psj.2022.102195] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 09/15/2022] [Accepted: 09/16/2022] [Indexed: 12/23/2022] Open
Abstract
In this study, the effects of the Arginine/Lysine (Arg/Lys) ratio in low- and high-methionine (Met) diets on the sarcoplasmic protein profile of breast muscles from turkeys reared under optimal or challenge (Clostridium perfringens infection) conditions were determined. One-day-old Hybrid Converter female turkey poults (216 in total) obtained from a commercial hatchery on hatching day, and on the basis of their average initial body weight were randomly allocated to 12 pens (4 m2 each; 2.0 m × 2.0 m) containing litter bedding and were reared over a 42-day experimental period. Diets with high levels of Lys contained approximately 1.80% and 1.65% Lys and were offered in two successive feeding periods (days 1–28 and days 29–42). The supplemental levels of Lys were consistent with the nutritional specifications for birds at their respective ages as established in the Management Guidelines for Raising Commercial Turkeys. The experiment was based on a completely randomized 3 × 2 × 2 factorial design with three levels of Arg (90%, 100% and 110%) relative to the content of dietary Met (30 or 45%) and without (−) or with (+) C. perfringens challenge at 34, 36, or 37 d of age. Meat samples were investigated in terms of pH, color, and sarcoplasmic protein profile. The experimental factors did not influence meat quality but the dietary Arg content affected meat color. The sarcoplasmic protein profile was influenced by all studied factors, and glycolytic enzymes were the most abundant. This study evidenced strong association between the challenge conditions and the involvement of glycolytic enzymes in cell metabolism, particularly in inflammatory processes, and DNA replication and maintenance in turkeys. The results showed an effect of C. perfringens infection and feeding with different doses of Arg and Met may lead to significant consequences in cell metabolism.
Collapse
Affiliation(s)
- Paweł Konieczka
- Department of Poultry Science and Apiculture, University of Warmia and Mazury, Olsztyn, Poland.
| | - Elżbieta Żelechowska
- Institute of Human Nutrition Sciences, Warsaw University of Life Sciences, Warsaw, Poland
| | - Wiesław Przybylski
- Institute of Human Nutrition Sciences, Warsaw University of Life Sciences, Warsaw, Poland
| | - Danuta Jaworska
- Institute of Human Nutrition Sciences, Warsaw University of Life Sciences, Warsaw, Poland
| | - Piotr Sałek
- Institute of Human Nutrition Sciences, Warsaw University of Life Sciences, Warsaw, Poland
| | - Misza Kinsner
- Department of Animal Nutrition, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Jabłonna, Poland
| | - Jan Jankowski
- Department of Poultry Science and Apiculture, University of Warmia and Mazury, Olsztyn, Poland
| |
Collapse
|
|
40
|
Neusius D, Kleinknecht L, Teh JT, Ostermeier M, Kelterborn S, Eirich J, Hegemann P, Finkemeier I, Bohne AV, Nickelsen J. Lysine acetylation regulates moonlighting activity of the E2 subunit of the chloroplast pyruvate dehydrogenase complex in Chlamydomonas. THE PLANT JOURNAL : FOR CELL AND MOLECULAR BIOLOGY 2022; 111:1780-1800. [PMID: 35899410 DOI: 10.1111/tpj.15924] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 07/08/2022] [Accepted: 07/18/2022] [Indexed: 06/15/2023]
Abstract
The dihydrolipoamide acetyltransferase subunit DLA2 of the chloroplast pyruvate dehydrogenase complex (cpPDC) in the green alga Chlamydomonas reinhardtii has previously been shown to possess moonlighting activity in chloroplast gene expression. Under mixotrophic growth conditions, DLA2 forms part of a ribonucleoprotein particle (RNP) with the psbA mRNA that encodes the D1 protein of the photosystem II (PSII) reaction center. Here, we report on the characterization of the molecular switch that regulates shuttling of DLA2 between its functions in carbon metabolism and D1 synthesis. Determination of RNA-binding affinities by microscale thermophoresis demonstrated that the E3-binding domain (E3BD) of DLA2 mediates psbA-specific RNA recognition. Analyses of cpPDC formation and activity, as well as RNP complex formation, showed that acetylation of a single lysine residue (K197) in E3BD induces the release of DLA2 from the cpPDC, and its functional shift towards RNA binding. Moreover, Förster resonance energy transfer microscopy revealed that psbA mRNA/DLA2 complexes localize around the chloroplast's pyrenoid. Pulse labeling and D1 re-accumulation after induced PSII degradation strongly suggest that DLA2 is important for D1 synthesis during de novo PSII biogenesis.
Collapse
Affiliation(s)
- Daniel Neusius
- Molecular Plant Sciences, Faculty of Biology, LMU Munich, Großhaderner Str. 2-4, 82152 Planegg-, Martinsried, Germany
| | - Laura Kleinknecht
- Molecular Plant Sciences, Faculty of Biology, LMU Munich, Großhaderner Str. 2-4, 82152 Planegg-, Martinsried, Germany
| | - Jing Tsong Teh
- Molecular Plant Sciences, Faculty of Biology, LMU Munich, Großhaderner Str. 2-4, 82152 Planegg-, Martinsried, Germany
| | - Matthias Ostermeier
- Molecular Plant Sciences, Faculty of Biology, LMU Munich, Großhaderner Str. 2-4, 82152 Planegg-, Martinsried, Germany
| | - Simon Kelterborn
- Experimental Biophysics, Institute of Biology, Humboldt University of Berlin, Invalidenstr. 42, 10115, Berlin, Germany
| | - Jürgen Eirich
- Institute of Plant Biology and Biotechnology, University of Muenster, Schlossplatz 7, 48149, Münster, Germany
| | - Peter Hegemann
- Experimental Biophysics, Institute of Biology, Humboldt University of Berlin, Invalidenstr. 42, 10115, Berlin, Germany
| | - Iris Finkemeier
- Institute of Plant Biology and Biotechnology, University of Muenster, Schlossplatz 7, 48149, Münster, Germany
| | - Alexandra-Viola Bohne
- Molecular Plant Sciences, Faculty of Biology, LMU Munich, Großhaderner Str. 2-4, 82152 Planegg-, Martinsried, Germany
| | - Jörg Nickelsen
- Molecular Plant Sciences, Faculty of Biology, LMU Munich, Großhaderner Str. 2-4, 82152 Planegg-, Martinsried, Germany
| |
Collapse
|
|
41
|
Atalay B, Cesur A, Agirbasli M. Discrepancy between biomarkers of lung injury and 1-year mortality in COVID-19. Eur J Clin Invest 2022; 52:e13827. [PMID: 35753029 PMCID: PMC9350115 DOI: 10.1111/eci.13827] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 06/05/2022] [Accepted: 06/18/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND COVID-19 global pandemic started in late 2019 with the first wave. In this cross-sectional and observational study, we evaluated the associations between the biomarkers, COVID-19 pneumonia severity and 1-year mortality. METHODS A sample of 276 polymerase chain reaction (PCR)-positive patients for SARS-CoV-2 was included. Computerized tomography severity score (CT-SS) was used to assess the severity of COVID-19 pneumonia in 222 cases. Multivariate analyses were performed to find the predictors of CT-SS, severe CT-SS (≥20) and 1-year mortality. Biomarkers of ferritin, high-sensitive C-reactive protein (CRP), lactate dehydrogenase (LDH), cardiac troponin (cTn), neutrophil-to-lymphocyte ratio (NLR), uric acid (UA) and d-dimer were routinely measured. RESULTS Severe CT-SS (>20) was observed in 86 (31.2%) cases. Mortality was observed in 75 (27.2%) patients at 1 year. LDH displayed the highest predictive accuracy for severe CT-SS (AUC 0.741, sensitivity = 81% and specificity = 68%, cut-off value: 360 mg/dl). Linear regression analysis displayed that LDH predicted CT-SS [B = 11 (95% CI for B = 5-17, p < .001)]. Age was the most significant parameter that was associated with severe CT-SS (OR 0.96, 95% CI 0.92-0.99, p = .015). d-dimer was the only biomarker that predicted with 1-year mortality (OR 1.62, 95% CI 1.08-2.42, p = .020). CONCLUSION LDH is a sensitive and specific biomarker to determine patients with severe lung injury in COVID-19. d-dimer is the only biomarker that predicts 1-year mortality. Neither LDH nor CT-SS is associated with 1-year mortality.
Collapse
Affiliation(s)
- Basak Atalay
- Department of Radiology, School of Medicine, Istanbul Medeniyet University, Goztepe Prof. Dr. Suleyman Yalcin City Hospital, Istanbul, Turkey
| | | | - Mehmet Agirbasli
- Department of Cardiology, School of Medicine, Istanbul Medeniyet University, Goztepe Prof. Dr. Suleyman Yalcin City Hospital, Istanbul, Turkey
| |
Collapse
|
|
42
|
Bao C, Zhu S, Song K, He C. HK2: a potential regulator of osteoarthritis via glycolytic and non-glycolytic pathways. Cell Commun Signal 2022; 20:132. [PMID: 36042519 PMCID: PMC9426234 DOI: 10.1186/s12964-022-00943-y] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 05/20/2022] [Indexed: 01/10/2023] Open
Abstract
Osteoarthritis (OA) is an age-related chronic degenerative joint disease where the main characteristics include progressive degeneration of cartilage, varying degrees of synovitis, and periarticular osteogenesis. However, the underlying factors involved in OA pathogenesis remain elusive which has resulted in poor clinical treatment effect. Recently, glucose metabolism changes provide a new perspective on the pathogenesis of OA. Under the stimulation of external environment, the metabolic pathway of chondrocytes tends to change from oxidative phosphorylation (OXPHOS) to aerobic glycolysis. Previous studies have demonstrated that glycolysis of synovial tissue is increased in OA. The hexokinase (HK) is the first rate limiting enzyme in aerobic glycolysis, participating and catalyzing the main pathway of glucose utilization. An isoform of HKs, HK2 is considered to be a key regulator of glucose metabolism, promotes the transformation of glycolysis from OXPHOS to aerobic glycolysis. Moreover, the expression level of HK2 in OA synovial tissue (FLS) was higher than that in control group, which indicated the potential therapeutic effect of HK2 in OA. However, there is no summary to help us understand the potential therapeutic role of glucose metabolism in OA. Therefore, this review focuses on the properties of HK2 and existing research concerning HK2 and OA. We also highlight the potential role and mechanism of HK2 in OA.
|