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Sehrawat U. Exploiting Translation Machinery for Cancer Therapy: Translation Factors as Promising Targets. Int J Mol Sci 2024; 25:10835. [PMID: 39409166 PMCID: PMC11477148 DOI: 10.3390/ijms251910835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 09/26/2024] [Accepted: 10/02/2024] [Indexed: 10/20/2024] Open
Abstract
Eukaryotic protein translation has slowly gained the scientific community's attention for its advanced and powerful therapeutic potential. However, recent technical developments in studying ribosomes and global translation have revolutionized our understanding of this complex multistep process. These developments have improved and deepened the current knowledge of mRNA translation, sparking excitement and new possibilities in this field. Translation factors are crucial for maintaining protein synthesis homeostasis. Since actively proliferating cancer cells depend on protein synthesis, dysregulated protein translation is central to tumorigenesis. Translation factors and their abnormal expressions directly affect multiple oncogenes and tumor suppressors. Recently, small molecules have been used to target translation factors, resulting in translation inhibition in a gene-specific manner, opening the door for developing translation inhibitors that can lead to novel chemotherapeutic drugs for treating multiple cancer types caused by dysregulated translation machinery. This review comprehensively summarizes the involvement of translation factors in tumor progression and oncogenesis. Also, it sheds light on the evolution of translation factors as novel drug targets for developing future therapeutic drugs for treating cancer.
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Affiliation(s)
- Urmila Sehrawat
- Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
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Lei J, Aimaier G, Aisha Z, Zhang Y, Ma J. eEF1A1 regulates the expression and alternative splicing of genes associated with Parkinson's disease in U251 cells. Genes Genomics 2024; 46:817-829. [PMID: 38776049 DOI: 10.1007/s13258-024-01516-8] [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: 08/10/2023] [Accepted: 10/12/2023] [Indexed: 06/27/2024]
Abstract
BACKGROUND Eukaryotic elongation factor 1A1 (eEF1A1) is an RNA-binding protein that is associated with PARK2 activity in cells, suggesting a possible role in Parkinson's disease (PD). OBJECTIVE To clear whether eEF1A1 plays a role in PD through transcriptional or posttranscriptional regulation. METHODS The GSE68719 dataset was downloaded from the GEO database, and the RNA-seq data of all brain tissue autopsies were obtained from 29 PD patients and 44 neurologically normal control subjects. To inhibit eEF1A1 from being expressed in U251 cells, siRNA was transfected into those cells, and RNA-seq high-throughput sequencing was used to determine the differentially expressed genes (DEGs) and differentially alternative splicing events (ASEs) resulting from eEF1A1 knockdown. RESULTS eEF1A1 was significantly overexpressed in PD brain tissue in the BA9 area. GO and KEGG enrichment analyses revealed that eEF1A1 knockdown significantly upregulated the expression of the genes CXCL10, NGF, PTX3, IL6, ST6GALNAC3, NUPR1, TNFRSF21, and CXCL2 and upregulated the alternative splicing of the genes ACOT7, DDX10, SHMT2, MYEF2, and NDUFAF5. These genes were enriched in pathways related to PD pathogenesis, such as apoptosis, inflammatory response, and mitochondrial dysfunction. CONCLUSION The results suggesting that eEF1A1 involved in the development of PD by regulating the differential expression and alternative splicing of genes, providing a theoretical basis for subsequent research.
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Affiliation(s)
- Jing Lei
- Department of Neurology, The First Affiliated Hospital of Xinjiang Medical University, No. 137 Liyushan South Road, Xinshi District, Urumqi, Xinjiang, 830054, P.R. China
| | - Guliqiemu Aimaier
- Department of Neurology, The First Affiliated Hospital of Xinjiang Medical University, No. 137 Liyushan South Road, Xinshi District, Urumqi, Xinjiang, 830054, P.R. China
| | - Zaolaguli Aisha
- Department of Neurology, The First Affiliated Hospital of Xinjiang Medical University, No. 137 Liyushan South Road, Xinshi District, Urumqi, Xinjiang, 830054, P.R. China
| | - Yan Zhang
- Department of Neurology, The First Affiliated Hospital of Xinjiang Medical University, No. 137 Liyushan South Road, Xinshi District, Urumqi, Xinjiang, 830054, P.R. China
| | - Jianhua Ma
- Department of Neurology, The First Affiliated Hospital of Xinjiang Medical University, No. 137 Liyushan South Road, Xinshi District, Urumqi, Xinjiang, 830054, P.R. China.
- Xinjiang Medical University, Urumqi, Xinjiang, 830054, China.
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Zhang W, Wang J, Shan C. The eEF1A protein in cancer: Clinical significance, oncogenic mechanisms, and targeted therapeutic strategies. Pharmacol Res 2024; 204:107195. [PMID: 38677532 DOI: 10.1016/j.phrs.2024.107195] [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: 02/28/2024] [Revised: 04/09/2024] [Accepted: 04/22/2024] [Indexed: 04/29/2024]
Abstract
Eukaryotic elongation factor 1A (eEF1A) is among the most abundant proteins in eukaryotic cells. Evolutionarily conserved across species, eEF1A is in charge of translation elongation for protein biosynthesis as well as a plethora of non-translational moonlighting functions for cellular homeostasis. In malignant cells, however, eEF1A becomes a pleiotropic driver of cancer progression via a broad diversity of pathways, which are not limited to hyperactive translational output. In the past decades, mounting studies have demonstrated the causal link between eEF1A and carcinogenesis, gaining deeper insights into its multifaceted mechanisms and corroborating its value as a prognostic marker in various cancers. On the other hand, an increasing number of natural and synthetic compounds were discovered as anticancer eEF1A-targeting inhibitors. Among them, plitidepsin was approved for the treatment of multiple myeloma whereas metarrestin was currently under clinical development. Despite significant achievements in these two interrelated fields, hitherto there lacks a systematic examination of the eEF1A protein in the context of cancer research. Therefore, the present work aims to delineate its clinical implications, molecular oncogenic mechanisms, and targeted therapeutic strategies as reflected in the ever expanding body of literature, so as to deepen mechanistic understanding of eEF1A-involved tumorigenesis and inspire the development of eEF1A-targeted chemotherapeutics and biologics.
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Affiliation(s)
- Weicheng Zhang
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, People's Republic of China.
| | - Jiyan Wang
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, People's Republic of China
| | - Changliang Shan
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, People's Republic of China.
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Kuroshima T, Kawaguchi S, Okada M. Current Perspectives of Mitochondria in Sepsis-Induced Cardiomyopathy. Int J Mol Sci 2024; 25:4710. [PMID: 38731929 PMCID: PMC11083471 DOI: 10.3390/ijms25094710] [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: 03/24/2024] [Revised: 04/19/2024] [Accepted: 04/24/2024] [Indexed: 05/13/2024] Open
Abstract
Sepsis-induced cardiomyopathy (SICM) is one of the leading indicators for poor prognosis associated with sepsis. Despite its reversibility, prognosis varies widely among patients. Mitochondria play a key role in cellular energy production by generating adenosine triphosphate (ATP), which is vital for myocardial energy metabolism. Over recent years, mounting evidence suggests that severe sepsis not only triggers mitochondrial structural abnormalities such as apoptosis, incomplete autophagy, and mitophagy in cardiomyocytes but also compromises their function, leading to ATP depletion. This metabolic disruption is recognized as a significant contributor to SICM, yet effective treatment options remain elusive. Sepsis cannot be effectively treated with inotropic drugs in failing myocardium due to excessive inflammatory factors that blunt β-adrenergic receptors. This review will share the recent knowledge on myocardial cell death in sepsis and its molecular mechanisms, focusing on the role of mitochondria as an important metabolic regulator of SICM, and discuss the potential for developing therapies for sepsis-induced myocardial injury.
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Affiliation(s)
| | | | - Motoi Okada
- Department of Emergency Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan; (T.K.); (S.K.)
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Wilson RB, Kozlov AM, Hatam Tehrani H, Twumasi-Ankrah JS, Chen YJ, Borrelli MJ, Sawyez CG, Maini S, Shepherd TG, Cumming RC, Betts DH, Borradaile NM. Elongation factor 1A1 regulates metabolic substrate preference in mammalian cells. J Biol Chem 2024; 300:105684. [PMID: 38272231 PMCID: PMC10891338 DOI: 10.1016/j.jbc.2024.105684] [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: 08/04/2023] [Revised: 12/28/2023] [Accepted: 01/09/2024] [Indexed: 01/27/2024] Open
Abstract
Eukaryotic elongation factor 1A1 (EEF1A1) is canonically involved in protein synthesis but also has noncanonical functions in diverse cellular processes. Previously, we identified EEF1A1 as a mediator of lipotoxicity and demonstrated that chemical inhibition of EEF1A1 activity reduced mouse liver lipid accumulation. These findings suggested a link between EEF1A1 and metabolism. Therefore, we investigated its role in regulating metabolic substrate preference. EEF1A1-deficient Chinese hamster ovary (2E2) cells displayed reduced media lactate accumulation. These effects were also observed with EEF1A1 knockdown in human hepatocyte-like HepG2 cells and in WT Chinese hamster ovary and HepG2 cells treated with selective EEF1A inhibitors, didemnin B, or plitidepsin. Extracellular flux analyses revealed decreased glycolytic ATP production and increased mitochondrial-to-glycolytic ATP production ratio in 2E2 cells, suggesting a more oxidative metabolic phenotype. Correspondingly, fatty acid oxidation was increased in 2E2 cells. Both 2E2 cells and HepG2 cells treated with didemnin B exhibited increased neutral lipid content, which may be required to support elevated oxidative metabolism. RNA-seq revealed a >90-fold downregulation of a rate-limiting glycolytic enzyme, hexokinase 2, which we confirmed through immunoblotting and enzyme activity assays. Pathway enrichment analysis identified downregulations in TNFA signaling via NFKB and MYC targets. Correspondingly, nuclear abundances of RELB and MYC were reduced in 2E2 cells. Thus, EEF1A1 deficiency may perturb glycolysis by limiting NFKB- and MYC-mediated gene expression, leading to decreased hexokinase expression and activity. This is the first evidence of a role for a translation elongation factor, EEF1A1, in regulating metabolic substrate utilization in mammalian cells.
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Affiliation(s)
- Rachel B Wilson
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | | | - Helia Hatam Tehrani
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Jessica S Twumasi-Ankrah
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Yun Jin Chen
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Matthew J Borrelli
- The Mary & John Knight Translational Ovarian Cancer Research Unit, London Regional Cancer Program, London, Ontario, Canada; Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Cynthia G Sawyez
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Siddhant Maini
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Trevor G Shepherd
- The Mary & John Knight Translational Ovarian Cancer Research Unit, London Regional Cancer Program, London, Ontario, Canada; Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Obstetrics and Gynaecology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Robert C Cumming
- Department of Biology, Western University, London, Ontario, Canada; Genetics and Development Division, The Children's Health Research Institute, Lawson Health Research Institute, London, Ontario, Canada
| | - Dean H Betts
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Biology, Western University, London, Ontario, Canada; Department of Obstetrics and Gynaecology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Genetics and Development Division, The Children's Health Research Institute, Lawson Health Research Institute, London, Ontario, Canada
| | - Nica M Borradaile
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
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Tokarz VL, Mylvaganam S, Klip A. Palmitate-induced insulin resistance causes actin filament stiffness and GLUT4 mis-sorting without altered Akt signalling. J Cell Sci 2023; 136:jcs261300. [PMID: 37815440 DOI: 10.1242/jcs.261300] [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: 05/02/2023] [Accepted: 09/25/2023] [Indexed: 10/11/2023] Open
Abstract
Skeletal muscle insulin resistance, a major contributor to type 2 diabetes, is linked to the consumption of saturated fats. This insulin resistance arises from failure of insulin-induced translocation of glucose transporter type 4 (GLUT4; also known as SLC2A4) to the plasma membrane to facilitate glucose uptake into muscle. The mechanisms of defective GLUT4 translocation are poorly understood, limiting development of insulin-sensitizing therapies targeting muscle glucose uptake. Although many studies have identified early insulin signalling defects and suggest that they are responsible for insulin resistance, their cause-effect has been debated. Here, we find that the saturated fat palmitate (PA) causes insulin resistance owing to failure of GLUT4 translocation in skeletal muscle myoblasts and myotubes without impairing signalling to Akt2 or AS160 (also known as TBC1D4). Instead, PA altered two basal-state events: (1) the intracellular localization of GLUT4 and its sorting towards a perinuclear storage compartment, and (2) actin filament stiffness, which prevents Rac1-dependent actin remodelling. These defects were triggered by distinct mechanisms, respectively protein palmitoylation and endoplasmic reticulum (ER) stress. Our findings highlight that saturated fats elicit muscle cell-autonomous dysregulation of the basal-state machinery required for GLUT4 translocation, which 'primes' cells for insulin resistance.
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Affiliation(s)
- Victoria L Tokarz
- Department of Physiology, University of Toronto, Ontario, M5S 1A8, Canada
- Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada
| | - Sivakami Mylvaganam
- Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada
- Department of Biochemistry, University of Toronto, Ontario, M5S 1A8, Canada
| | - Amira Klip
- Department of Physiology, University of Toronto, Ontario, M5S 1A8, Canada
- Department of Biochemistry, University of Toronto, Ontario, M5S 1A8, Canada
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Zhu L, Li Y, Qiu L, Chen X, Guo B, Li H, Qi P. Screening of genes encoding proteins that interact with Nrf2: Probing a cDNA library from Mytilus coruscus using a yeast two-hybrid system. FISH & SHELLFISH IMMUNOLOGY 2023; 142:109112. [PMID: 37751644 DOI: 10.1016/j.fsi.2023.109112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 07/08/2023] [Accepted: 09/22/2023] [Indexed: 09/28/2023]
Abstract
The Nuclear factor Erythroid 2-related factor 2 (Nrf2) is the most important endogenous antioxidant factor in organisms, and it has been demonstrated that it exerts extensive control over the immune response by interacting with crucial innate immunity components directly or indirectly. Although Nrf2 has been widely confirmed to be involved in stress resistance in mammals and some fish, its contribution to mollusks oxidative stress resistance has not frequently been documented. In this investigation, total RNA was taken from the digestive gland of M. coruscus, and a cDNA library was constructed and screened using the GATEWAY recombination technology. The Nrf2 cDNA sequence of M. coruscus was cloned into the pGBKT7 vector to prepare the bait plasmid. Using yeast two-hybrid system, after auxotrophic medium screening, sequencing, and bioinformatics analysis, 13 binding proteins that interacted with Nrf2 were finally identified. They were QM-like protein, 40S ribosomal protein S4 (RPS4), ribosomal protein S2 (RPS2), ribosomal protein L12 (RPL12), EF1-alpha mRNA for elongation factor 1 alpha (eEF1-alpha), ferritin, alpha-amylase, trypsin, vdg3, period clock protein, cyclophilin A isoform 1 (CYP A), serine protease CFSP2, histone variant H2A.Z (H2A.Z). For a better understanding the physiological function of Nrf2 in animals and as a potential target for future research on protein roles in Nrf2 interactions, it is crucial to clarify these protein interactions.
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Affiliation(s)
- Li Zhu
- National Engineering Research Center of Marine Facilities Aquaculture, Marine Science and Technology College, Zhejiang Ocean University, Zhoushan, Zhejiang, 316004, China
| | - Yaru Li
- National Engineering Research Center of Marine Facilities Aquaculture, Marine Science and Technology College, Zhejiang Ocean University, Zhoushan, Zhejiang, 316004, China
| | - Longmei Qiu
- National Engineering Research Center of Marine Facilities Aquaculture, Marine Science and Technology College, Zhejiang Ocean University, Zhoushan, Zhejiang, 316004, China
| | - Xinglu Chen
- National Engineering Research Center of Marine Facilities Aquaculture, Marine Science and Technology College, Zhejiang Ocean University, Zhoushan, Zhejiang, 316004, China
| | - Baoying Guo
- National Engineering Research Center of Marine Facilities Aquaculture, Marine Science and Technology College, Zhejiang Ocean University, Zhoushan, Zhejiang, 316004, China
| | - Hongfei Li
- National Engineering Research Center of Marine Facilities Aquaculture, Marine Science and Technology College, Zhejiang Ocean University, Zhoushan, Zhejiang, 316004, China; Donghai Laboratory, Zhoushan, Zhejiang, 316021, China.
| | - Pengzhi Qi
- National Engineering Research Center of Marine Facilities Aquaculture, Marine Science and Technology College, Zhejiang Ocean University, Zhoushan, Zhejiang, 316004, China; Donghai Laboratory, Zhoushan, Zhejiang, 316021, China.
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Sécula A, Bluy LE, Chapuis H, Bonnet A, Collin A, Gress L, Cornuez A, Martin X, Bodin L, Bonnefont CMD, Morisson M. Maternal dietary methionine restriction alters hepatic expression of one-carbon metabolism and epigenetic mechanism genes in the ducklings. BMC Genomics 2022; 23:823. [PMID: 36510146 PMCID: PMC9746021 DOI: 10.1186/s12864-022-09066-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 12/05/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Embryonic and fetal development is very susceptible to the availability of nutrients that can interfere with the setting of epigenomes, thus modifying the main metabolic pathways and impacting the health and phenotypes of the future individual. We have previously reported that a 38% reduction of the methyl donor methionine in the diet of 30 female ducks reduced the body weight of their 180 mule ducklings compared to that of 190 ducklings from 30 control females. The maternal methionine-restricted diet also altered plasmatic parameters in 30 of their ducklings when compared to that of 30 ducklings from the control group. Thus, their plasma glucose and triglyceride concentrations were higher while their free fatty acid level and alanine transaminase activity were decreased. Moreover, the hepatic transcript level of 16 genes involved in pathways related to energy metabolism was significantly different between the two groups of ducklings. In the present work, we continued studying the liver of these newly hatched ducklings to explore the impact of the maternal dietary methionine restriction on the hepatic transcript level of 70 genes mostly involved in one-carbon metabolism and epigenetic mechanisms. RESULTS Among the 12 genes (SHMT1, GART, ATIC, FTCD, MSRA, CBS, CTH, AHCYL1, HSBP1, DNMT3, HDAC9 and EZH2) identified as differentially expressed between the two maternal diet groups (p-value < 0.05), 3 of them were involved in epigenetic mechanisms. Ten other studied genes (MTR, GLRX, MTHFR, AHCY, ADK, PRDM2, EEF1A1, ESR1, PLAGL1, and WNT11) tended to be differently expressed (0.05 < p-value < 0.10). Moreover, the maternal dietary methionine restriction altered the number and nature of correlations between expression levels of differential genes for one-carbon metabolism and epigenetic mechanisms, expression levels of differential genes for energy metabolism, and phenotypic traits of ducklings. CONCLUSION This avian model showed that the maternal dietary methionine restriction impacted both the mRNA abundance of 22 genes involved in one-carbon metabolism or epigenetic mechanisms and the mRNA abundance of 16 genes involved in energy metabolism in the liver of the newly hatched offspring, in line with the previously observed changes in their phenotypic traits.
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Affiliation(s)
- Aurélie Sécula
- grid.508721.9GenPhySE, Université de Toulouse, INRAE, ENVT, F-31326 Castanet Tolosan, France
| | - Lisa E. Bluy
- grid.508721.9GenPhySE, Université de Toulouse, INRAE, ENVT, F-31326 Castanet Tolosan, France
| | - Hervé Chapuis
- grid.508721.9GenPhySE, Université de Toulouse, INRAE, ENVT, F-31326 Castanet Tolosan, France
| | - Agnès Bonnet
- grid.508721.9GenPhySE, Université de Toulouse, INRAE, ENVT, F-31326 Castanet Tolosan, France
| | - Anne Collin
- grid.511104.0INRAE, Université de Tours, BOA, 37380 Nouzilly, France
| | - Laure Gress
- grid.508721.9GenPhySE, Université de Toulouse, INRAE, ENVT, F-31326 Castanet Tolosan, France
| | - Alexis Cornuez
- UEPFG INRA Bordeaux-Aquitaine (Unité Expérimentale Palmipèdes à Foie Gras), Domaine d’Artiguères 1076, route de Haut Mauco, F-40280 Benquet, France
| | - Xavier Martin
- UEPFG INRA Bordeaux-Aquitaine (Unité Expérimentale Palmipèdes à Foie Gras), Domaine d’Artiguères 1076, route de Haut Mauco, F-40280 Benquet, France
| | - Loys Bodin
- grid.508721.9GenPhySE, Université de Toulouse, INRAE, ENVT, F-31326 Castanet Tolosan, France
| | - Cécile M. D. Bonnefont
- grid.508721.9GenPhySE, Université de Toulouse, INRAE, ENVT, F-31326 Castanet Tolosan, France
| | - Mireille Morisson
- grid.508721.9GenPhySE, Université de Toulouse, INRAE, ENVT, F-31326 Castanet Tolosan, France
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Liu C, Wang L, Sun Y, Zhao X, Chen T, Su X, Guo H, Wang Q, Xi X, Ding Y, Chen Y. Probe Synthesis Reveals Eukaryotic Translation Elongation Factor 1 Alpha 1 as the Anti‐Pancreatic Cancer Target of BE‐43547A
2. Angew Chem Int Ed Engl 2022; 61:e202206953. [DOI: 10.1002/anie.202206953] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Indexed: 12/17/2022]
Affiliation(s)
- Can Liu
- State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Nankai University 38 Tongyan Road Tianjin 300353 P. R. China
| | - Liang Wang
- State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Nankai University 38 Tongyan Road Tianjin 300353 P. R. China
- College of Chemistry Nankai University 94 Weijin Road Tianjin 300071 P. R. China
| | - Yuanjun Sun
- State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Nankai University 38 Tongyan Road Tianjin 300353 P. R. China
| | - Xiuhe Zhao
- State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Nankai University 38 Tongyan Road Tianjin 300353 P. R. China
| | - Tianyang Chen
- State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Nankai University 38 Tongyan Road Tianjin 300353 P. R. China
| | - Xiuwen Su
- State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Nankai University 38 Tongyan Road Tianjin 300353 P. R. China
| | - Hui Guo
- State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Nankai University 38 Tongyan Road Tianjin 300353 P. R. China
| | - Qin Wang
- State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Nankai University 38 Tongyan Road Tianjin 300353 P. R. China
| | - Xiaonan Xi
- State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Nankai University 38 Tongyan Road Tianjin 300353 P. R. China
| | - Yahui Ding
- State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Nankai University 38 Tongyan Road Tianjin 300353 P. R. China
- College of Chemistry Nankai University 94 Weijin Road Tianjin 300071 P. R. China
| | - Yue Chen
- State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Nankai University 38 Tongyan Road Tianjin 300353 P. R. China
- College of Chemistry Nankai University 94 Weijin Road Tianjin 300071 P. R. China
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Liu C, Wang L, Sun Y, Zhao X, Chen T, Su X, Guo H, Wang Q, Xi X, Ding Y, Chen Y. Probe Synthesis Reveals Eukaryotic Translation Elongation Factor 1 Alpha 1 as the Anti‐Pancreatic Cancer Target of BE‐43547A2. Angew Chem Int Ed Engl 2022. [DOI: 10.1002/ange.202206953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Can Liu
- Nankai University College of Pharmacy CHINA
| | - Liang Wang
- Nankai University College of Chemistry CHINA
| | | | - Xiuhe Zhao
- Nankai University College of Pharmacy CHINA
| | | | - Xiuwen Su
- Nankai University College of Pharmacy CHINA
| | - Hui Guo
- Nankai University College of Pharmacy CHINA
| | - Qin Wang
- Nankai University College of Pharmacy CHINA
| | - Xiaonan Xi
- Nankai University College of Pharmacy CHINA
| | - Yahui Ding
- Nankai University College of Chemistry CHINA
| | - Yue Chen
- Nankai University College of Pharmacy Weijin RoadNankai district 300071 Tianjin CHINA
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11
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DNAJA1 Stabilizes EF1A1 to Promote Cell Proliferation and Metastasis of Liver Cancer Mediated by miR-205-5p. JOURNAL OF ONCOLOGY 2022; 2022:2292481. [PMID: 35586205 PMCID: PMC9110222 DOI: 10.1155/2022/2292481] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 03/05/2022] [Accepted: 03/22/2022] [Indexed: 11/22/2022]
Abstract
Liver cancer is one of the most common and aggressive malignancies worldwide with poor prognosis. Studies on pathogenesis of liver cancer are urgently demanded to develop better treatment strategy. Here, we found that overexpression of DnaJ heat shock protein family (Hsp40) member A1 (DNAJA1) increased cell proliferation, invasion, and angiogenesis in Huh 7 and HepG2 cells, while depletion of DNAJA1 in MHCC-97H and HCC-M3 showed opposite effects. In vivo functional assays indicated that DNAJA1 promoted tumor growth and pulmonary metastasis in mice. Mechanistically, as a direct target of miR-205-5p, DNAJA1 promoted proliferation and metastasis of liver cancer cells by stabilizing eukaryotic elongation factor 1A1 (EF1A1). Moreover, DNAJA was markedly upregulated in liver cancer tissues (P < 0.05) and was significantly associated with poor prognosis. And its expression was correlated with differentiation (P < 0.001), dissemination (P < 0.001), and serum AFP (P = 0.029). The mRNA levels of miR-205-5p and DNAJA1 were negatively correlated in liver cancer. In conclusion, our study reveals that DNAJA1 acts as an oncogene in liver cancer via miR-205-5p/EF1A1 axis and might be a potential biomarker to predict the prognosis for liver cancer patients.
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Ning X, Shi G, Ren S, Liu S, Ding J, Zhang R, Li L, Xie Q, Xu W, Meng F, Ma R. OUP accepted manuscript. Oncologist 2022; 27:e64-e75. [PMID: 35305106 PMCID: PMC8842331 DOI: 10.1093/oncolo/oyab015] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 11/18/2021] [Indexed: 11/17/2022] Open
Abstract
Background The glioblastoma-amplified sequence (GBAS) is a newly identified gene that is amplified in approximately 40% of glioblastomas. This article probes into the expression, prognostic significance, and possible pathways of GBAS in ovarian cancer (OC). Method Immunohistochemical methods were used to evaluate the expression level of GBAS in OC and its relationship with clinicopathological characteristics and prognosis. Glioblastoma-amplified sequence shRNA was designed to transfect into OC cell lines to silence GBAS expression, then detect the proliferation, apoptosis, and migration ability of the cell. Furthermore, an in vitro tumor formation experiment in mice was constructed to prove the effect of GBAS expression on the growth of OC in vivo. To further study the regulation mechanism of GBAS, we performed co-immunoprecipitation (Co-IP) and shotgun LC-MS mass spectrometry identification. Results Immunohistochemistry indicated that GBAS was markedly overexpressed in OC compared with normal ovarian tissue and was associated with lymph node metastasis. Inhibition of GBAS expression can significantly reduce OC cell proliferation, colony formation, promote cell apoptosis, and reduce the ability of cell migration and invasion. In vivo tumor formation experiments showed that the size and weight of tumors in mice after GBAS expression knockdown was significantly smaller. Glioblastoma-amplified sequence may be combined with elongation factor 1 alpha 1 (eEF1A1) to achieve its regulation in OC. Bioinformatics analysis data indicate that GBAS may be a key regulator of mitochondria-associated pathways, therefore controlling cancer progression. MicroRNA-27b, MicroRNA-23a, and MicroRNA-590 may directly targeting GBAS affects the biological behavior of OC cells. Conclusion The glioblastoma-amplified sequence may regulate the proliferation and metastasis of OC cells by combining with eEF1A1.
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Affiliation(s)
- Xin Ning
- Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Guangyue Shi
- Department of Oncology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Sujing Ren
- Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Shuang Liu
- Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Jing Ding
- Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Ruichun Zhang
- Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Lianwei Li
- Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Qin Xie
- Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Wei Xu
- Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Fanling Meng
- Corresponding author: Fanling Meng, Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin 150081, China. Tel: +86 451 85718069;
| | - Rong Ma
- Corresponding author: Rong Ma, Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin 150081, China. Tel: +86 451 85718058;
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Kawaguchi S, Okada M. Cardiac Metabolism in Sepsis. Metabolites 2021; 11:metabo11120846. [PMID: 34940604 PMCID: PMC8707959 DOI: 10.3390/metabo11120846] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/02/2021] [Accepted: 12/02/2021] [Indexed: 12/11/2022] Open
Abstract
The mechanism of sepsis-induced cardiac dysfunction is believed to be different from that of myocardial ischemia. In sepsis, chemical mediators, such as endotoxins, cytokines, and nitric oxide, cause metabolic abnormalities, mitochondrial dysfunction, and downregulation of β-adrenergic receptors. These factors inhibit the production of ATP, essential for myocardial energy metabolism, resulting in cardiac dysfunction. This review focuses on the metabolic changes in sepsis, particularly in the heart. In addition to managing inflammation, interventions focusing on metabolism may be a new therapeutic strategy for cardiac dysfunction due to sepsis.
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Affiliation(s)
- Satoshi Kawaguchi
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Bloomington, IN 46202, USA;
| | - Motoi Okada
- Department of Emergency Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan
- Correspondence: ; Tel.: +81-166-68-2852
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Single-Cell Atlas of Adult Testis in Protogynous Hermaphroditic Orange-Spotted Grouper, Epinephelus coioides. Int J Mol Sci 2021; 22:ijms222212607. [PMID: 34830486 PMCID: PMC8618070 DOI: 10.3390/ijms222212607] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 11/13/2021] [Accepted: 11/19/2021] [Indexed: 01/08/2023] Open
Abstract
Spermatogenesis is a process of self-renewal and differentiation in spermatogonial stem cells. During this process, germ cells and somatic cells interact intricately to ensure long-term fertility and accurate genome propagation. Spermatogenesis has been intensely investigated in mammals but remains poorly understood with regard to teleosts. Here, we performed single-cell RNA sequencing of ~9500 testicular cells from the male, orange-spotted grouper. In the adult testis, we divided the cells into nine clusters and defined ten cell types, as compared with human testis data, including cell populations with characteristics of male germ cells and somatic cells, each of which expressed specific marker genes. We also identified and profiled the expression patterns of four marker genes (calr, eef1a, s100a1, vasa) in both the ovary and adult testis. Our data provide a blueprint of male germ cells and supporting somatic cells. Moreover, the cell markers are candidates that could be used for further cell identification.
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15
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Karwi QG, Sun Q, Lopaschuk GD. The Contribution of Cardiac Fatty Acid Oxidation to Diabetic Cardiomyopathy Severity. Cells 2021; 10:cells10113259. [PMID: 34831481 PMCID: PMC8621814 DOI: 10.3390/cells10113259] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/15/2021] [Accepted: 11/17/2021] [Indexed: 12/17/2022] Open
Abstract
Diabetes is a major risk factor for the development of cardiovascular disease via contributing and/or triggering significant cellular signaling and metabolic and structural alterations at the level of the heart and the whole body. The main cause of mortality and morbidity in diabetic patients is cardiovascular disease including diabetic cardiomyopathy. Therefore, understanding how diabetes increases the incidence of diabetic cardiomyopathy and how it mediates the major perturbations in cell signaling and energy metabolism should help in the development of therapeutics to prevent these perturbations. One of the significant metabolic alterations in diabetes is a marked increase in cardiac fatty acid oxidation rates and the domination of fatty acids as the major energy source in the heart. This increased reliance of the heart on fatty acids in the diabetic has a negative impact on cardiac function and structure through a number of mechanisms. It also has a detrimental effect on cardiac efficiency and worsens the energy status in diabetes, mainly through inhibiting cardiac glucose oxidation. Furthermore, accelerated cardiac fatty acid oxidation rates in diabetes also make the heart more vulnerable to ischemic injury. In this review, we discuss how cardiac energy metabolism is altered in diabetic cardiomyopathy and the impact of cardiac insulin resistance on the contribution of glucose and fatty acid to overall cardiac ATP production and cardiac efficiency. Furthermore, how diabetes influences the susceptibility of the myocardium to ischemia/reperfusion injury and the role of the changes in glucose and fatty acid oxidation in mediating these effects are also discussed.
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Affiliation(s)
- Qutuba G. Karwi
- Cardiovascular Research Centre, Department of Pediatrics, University of Alberta, Edmonton, AB T6G 2S2, Canada; (Q.G.K.); (Q.S.)
| | - Qiuyu Sun
- Cardiovascular Research Centre, Department of Pediatrics, University of Alberta, Edmonton, AB T6G 2S2, Canada; (Q.G.K.); (Q.S.)
| | - Gary D. Lopaschuk
- 423 Heritage Medical Research Centre, University of Alberta, Edmonton, AB T6G 2S2, Canada
- Correspondence: ; Tel.: +1-780-492-2170; Fax: +1-780-492-9753
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16
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Gong T, Shuang Y. Expression and Clinical Value of Eukaryotic Translation Elongation Factor 1A1 (EEF1A1) in Diffuse Large B Cell Lymphoma. Int J Gen Med 2021; 14:7247-7258. [PMID: 34737619 PMCID: PMC8559353 DOI: 10.2147/ijgm.s324645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 07/29/2021] [Indexed: 12/02/2022] Open
Abstract
Background The eukaryotic translation elongation factor 1A1 (EEF1A1) participates in protein translation and has been reported to be involved in tumor progression such as hepatocellular carcinoma. Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults. In the present study, we aimed to detect the expression of EEF1A1 in DLBCL and to analyze its relationship with prognosis. Methods We reviewed medical records of DLBCL patients in our hospital and evaluated their expression level of EEF1A1 in tumor tissues using immunohistochemical (IHC) assay. The Chi-square method was used for correlation analysis. The Kaplan–Meier method with Log rank test was used for univariate analysis. Cox proportional hazards model was used for multivariate analysis. Cellular and mice models were introduced to validate its oncogenic role. Results EEF1A1 expression in tumor cells was higher in certain DLBCL cases. Patients with higher EEF1A1 expression were more likely to have advanced tumor stage and poorer 5-year overall survival (OS) rates. EEF1A1 expression in tumor cells was an independent risk predictor for OS (P < 0.05). Cellular assays demonstrated that EEF1A1-shRNA significantly inhibited lymphoma cell proliferation. The study of xenografts further verified the effect of EEF1A1-shRNA on suppressing tumor growth in vivo. Conclusion EEF1A1 positivity predicts short survival in DLBCL patients. For patients with higher EEF1A1 expression, more strategy such as anti-EEF1A1 antibody treatment should be developed.
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Affiliation(s)
- Tiejun Gong
- Institute of Hematology and Oncology, Harbin the First Hospital, Harbin, 150010, People's Republic of China
| | - Yuerong Shuang
- Department of Lymphatic Hematology and Oncology, Jiangxi Cancer Hospital, Nanchang, 330029, People's Republic of China
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Sletten AC, Davidson JW, Yagabasan B, Moores S, Schwaiger-Haber M, Fujiwara H, Gale S, Jiang X, Sidhu R, Gelman SJ, Zhao S, Patti GJ, Ory DS, Schaffer JE. Loss of SNORA73 reprograms cellular metabolism and protects against steatohepatitis. Nat Commun 2021; 12:5214. [PMID: 34471131 PMCID: PMC8410784 DOI: 10.1038/s41467-021-25457-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 08/06/2021] [Indexed: 02/07/2023] Open
Abstract
Dyslipidemia and resulting lipotoxicity are pathologic signatures of metabolic syndrome and type 2 diabetes. Excess lipid causes cell dysfunction and induces cell death through pleiotropic mechanisms that link to oxidative stress. However, pathways that regulate the response to metabolic stress are not well understood. Herein, we show that disruption of the box H/ACA SNORA73 small nucleolar RNAs encoded within the small nucleolar RNA hosting gene 3 (Snhg3) causes resistance to lipid-induced cell death and general oxidative stress in cultured cells. This protection from metabolic stress is associated with broad reprogramming of oxidative metabolism that is dependent on the mammalian target of rapamycin signaling axis. Furthermore, we show that knockdown of SNORA73 in vivo protects against hepatic steatosis and lipid-induced oxidative stress and inflammation. Our findings demonstrate a role for SNORA73 in the regulation of metabolism and lipotoxicity.
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Affiliation(s)
- Arthur C Sletten
- Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | | | - Busra Yagabasan
- Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
| | - Samantha Moores
- Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
| | | | - Hideji Fujiwara
- Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | - Sarah Gale
- Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | - Xuntian Jiang
- Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | - Rohini Sidhu
- Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | - Susan J Gelman
- Department of Chemistry, Washington University in St. Louis, St. Louis, MO, USA
| | - Shuang Zhao
- Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | - Gary J Patti
- Department of Chemistry, Washington University in St. Louis, St. Louis, MO, USA
| | - Daniel S Ory
- Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | - Jean E Schaffer
- Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
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Niksirat H, Siino V, Steinbach C, Levander F. High-Resolution Proteomic Profiling Shows Sexual Dimorphism in Zebrafish Heart-Associated Proteins. J Proteome Res 2021; 20:4075-4088. [PMID: 34185526 DOI: 10.1021/acs.jproteome.1c00387] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Understanding the molecular basis of sexual dimorphism in the cardiovascular system may contribute to the improvement of the outcome in biological, pharmacological, and toxicological studies as well as on the development of sex-based drugs and therapeutic approaches. Label-free protein quantification using high-resolution mass spectrometry was applied to detect sex-based proteome differences in the heart of zebrafish Danio rerio. Out of almost 3000 unique identified proteins in the heart, 79 showed significant abundance differences between male and female fish. The functional differences were mapped using enrichment analyses. Our results suggest that a large amount of materials needed for reproduction (e.g., sugars, lipids, proteins, etc.) may impose extra pressure on blood, vessels, and heart on their way toward the ovaries. In the present study, the female's heart shows a clear sexual dimorphism by changing abundance levels of numerous proteins, which could be a way to safely overcome material-induced elevated pressures. These proteins belong to the immune system, oxidative stress response, drug metabolization, detoxification, energy, metabolism, and so on. In conclusion, we showed that sex can induce dimorphism at the molecular level in nonsexual organs such as heart and must be considered as an important factor in cardiovascular research. Data are available via ProteomeXchange with identifier PXD023506.
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Affiliation(s)
- Hamid Niksirat
- Faculty of Fisheries and Protection of Waters, CENAKVA, University of South Bohemia in České Budějovice, Vodňany, 370 05 České Budějovice, Czech Republic
| | - Valentina Siino
- Department of Immunotechnology, Lund University, Lund 223 87, Sweden
| | - Christoph Steinbach
- Faculty of Fisheries and Protection of Waters, CENAKVA, University of South Bohemia in České Budějovice, Vodňany, 370 05 České Budějovice, Czech Republic
| | - Fredrik Levander
- Department of Immunotechnology, Lund University, Lund 223 87, Sweden.,National Bioinformatics Infrastructure Sweden (NBIS), Science for Life Laboratory, Lund University, Lund 223 87, Sweden
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Martins M, Ramos LFC, Murillo JR, Torres A, de Carvalho SS, Domont GB, de Oliveira DMP, Mesquita RD, Nogueira FCS, Maciel-de-Freitas R, Junqueira M. Comprehensive Quantitative Proteome Analysis of Aedes aegypti Identifies Proteins and Pathways Involved in Wolbachia pipientis and Zika Virus Interference Phenomenon. Front Physiol 2021; 12:642237. [PMID: 33716790 PMCID: PMC7947915 DOI: 10.3389/fphys.2021.642237] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 02/04/2021] [Indexed: 11/23/2022] Open
Abstract
Zika virus (ZIKV) is a global public health emergency due to its association with microcephaly, Guillain-Barré syndrome, neuropathy, and myelitis in children and adults. A total of 87 countries have had evidence of autochthonous mosquito-borne transmission of ZIKV, distributed across four continents, and no antivirus therapy or vaccines are available. Therefore, several strategies have been developed to target the main mosquito vector, Aedes aegypti, to reduce the burden of different arboviruses. Among such strategies, the use of the maternally-inherited endosymbiont Wolbachia pipientis has been applied successfully to reduce virus susceptibility and decrease transmission. However, the mechanisms by which Wolbachia orchestrate resistance to ZIKV infection remain to be elucidated. In this study, we apply isobaric labeling quantitative mass spectrometry (MS)-based proteomics to quantify proteins and identify pathways altered during ZIKV infection; Wolbachia infection; co-infection with Wolbachia/ZIKV in the A. aegypti heads and salivary glands. We show that Wolbachia regulates proteins involved in reactive oxygen species production, regulates humoral immune response, and antioxidant production. The reduction of ZIKV polyprotein in the presence of Wolbachia in mosquitoes was determined by MS and corroborates the idea that Wolbachia helps to block ZIKV infections in A. aegypti. The present study offers a rich resource of data that may help to elucidate mechanisms by which Wolbachia orchestrate resistance to ZIKV infection in A. aegypti, and represents a step further on the development of new targeted methods to detect and quantify ZIKV and Wolbachia directly in complex tissues.
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Affiliation(s)
- Michele Martins
- Departamento de Bioquímica, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Luis Felipe Costa Ramos
- Departamento de Bioquímica, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Jimmy Rodriguez Murillo
- Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
| | - André Torres
- Carlos Chagas Filho Biophysics Institute, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Gilberto Barbosa Domont
- Departamento de Bioquímica, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Rafael Dias Mesquita
- Departamento de Bioquímica, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fábio César Sousa Nogueira
- Departamento de Bioquímica, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Rafael Maciel-de-Freitas
- Laboratório de Mosquitos Transmissores de Hematozoários, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil
| | - Magno Junqueira
- Departamento de Bioquímica, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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Streidl T, Karkossa I, Segura Muñoz RR, Eberl C, Zaufel A, Plagge J, Schmaltz R, Schubert K, Basic M, Schneider KM, Afify M, Trautwein C, Tolba R, Stecher B, Doden HL, Ridlon JM, Ecker J, Moustafa T, von Bergen M, Ramer-Tait AE, Clavel T. The gut bacterium Extibacter muris produces secondary bile acids and influences liver physiology in gnotobiotic mice. Gut Microbes 2021; 13:1-21. [PMID: 33382950 PMCID: PMC7781625 DOI: 10.1080/19490976.2020.1854008] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 10/09/2020] [Accepted: 11/11/2020] [Indexed: 02/04/2023] Open
Abstract
Extibacter muris is a newly described mouse gut bacterium which metabolizes cholic acid (CA) to deoxycholic acid (DCA) via 7α-dehydroxylation. Although bile acids influence metabolic and inflammatory responses, few in vivo models exist for studying their metabolism and impact on the host. Mice were colonized from birth with the simplified community Oligo-MM12 with or without E. muris. As the metabolism of bile acids is known to affect lipid homeostasis, mice were fed either a low- or high-fat diet for eight weeks before sampling and analyses targeting the gut and liver. Multiple Oligo-MM12 strains were capable of deconjugating primary bile acids in vitro. E. muris produced DCA from CA either as pure compound or in mouse bile. This production was inducible by CA in vitro. Ursodeoxycholic, chenodeoxycholic, and β-muricholic acid were not metabolized under the conditions tested. All gnotobiotic mice were stably colonized with E. muris, which showed higher relative abundances after HF diet feeding. The presence of E. muris had minor, diet-dependent effects on Oligo-MM12 communities. The secondary bile acids DCA and surprisingly LCA and their taurine conjugates were detected exclusively in E. muris-colonized mice. E. muris colonization did not influence body weight, white adipose tissue mass, liver histopathology, hepatic aspartate aminotransferase, or blood levels of cholesterol, insulin, and paralytic peptide (PP). However, proteomics revealed shifts in hepatic pathways involved in amino acid, glucose, lipid, energy, and drug metabolism in E. muris-colonized mice. Liver fatty acid composition was substantially altered by dietary fat but not by E. muris.In summary, E. muris stably colonized the gut of mice harboring a simplified community and produced secondary bile acids, which affected proteomes in the liver. This new gnotobiotic mouse model can now be used to study the pathophysiological role of secondary bile acids in vivo.
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Affiliation(s)
- Theresa Streidl
- Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital of RWTH, Aachen, Germany
| | - Isabel Karkossa
- Department of Molecular Systems Biology, Helmholtz-Centre for Environmental Research, Leipzig, Germany
| | | | - Claudia Eberl
- Max Von Pettenkofer Institute of Hygiene and Medical Microbiology, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Alex Zaufel
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University, Graz, Austria
| | - Johannes Plagge
- Research Group Lipid Metabolism, ZIEL Institute for Food & Health, Technical University, Munich, Germany
| | - Robert Schmaltz
- Department of Food Science & Technology, University of Nebraska-Lincoln, NE, USA
| | - Kristin Schubert
- Department of Molecular Systems Biology, Helmholtz-Centre for Environmental Research, Leipzig, Germany
| | - Marijana Basic
- Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany
| | - Kai Markus Schneider
- Department of Internal Medicine III, University Hospital of RWTH, Aachen, Germany
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Mamdouh Afify
- Institute for Laboratory Animal Science, Faculty of Medicine, University Hospital of RWTH, Aachen, Germany
- Clinic for Cardiology (Internal Medicine I), University Hospital of RWTH, Aachen, Germany
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital of RWTH, Aachen, Germany
| | - René Tolba
- Institute for Laboratory Animal Science, Faculty of Medicine, University Hospital of RWTH, Aachen, Germany
| | - Bärbel Stecher
- Max Von Pettenkofer Institute of Hygiene and Medical Microbiology, Ludwig-Maximilians-University of Munich, Munich, Germany
- German Center for Infection Research (DZIF); Partner Site Munich, Munich, Germany
| | - Heidi L. Doden
- Microbiome Metabolic Engineering Theme, Carl R. Woese Institute for Genomic Biology, Urbana, IL, USA
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
| | - Jason M. Ridlon
- Microbiome Metabolic Engineering Theme, Carl R. Woese Institute for Genomic Biology, Urbana, IL, USA
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
| | - Josef Ecker
- Research Group Lipid Metabolism, ZIEL Institute for Food & Health, Technical University, Munich, Germany
| | - Tarek Moustafa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University, Graz, Austria
| | - Martin von Bergen
- Department of Molecular Systems Biology, Helmholtz-Centre for Environmental Research, Leipzig, Germany
- Institute of Biochemistry, Leipzig University, Leipzig, Germany
| | - Amanda E. Ramer-Tait
- Department of Food Science & Technology, University of Nebraska-Lincoln, NE, USA
- Nebraska Food for Health Center, University of Nebraska-Lincoln, Hannover, NE, USA
| | - Thomas Clavel
- Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital of RWTH, Aachen, Germany
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The marine compound and elongation factor 1A1 inhibitor, didemnin B, provides benefit in western diet-induced non-alcoholic fatty liver disease. Pharmacol Res 2020; 161:105208. [PMID: 32977024 DOI: 10.1016/j.phrs.2020.105208] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 09/08/2020] [Accepted: 09/10/2020] [Indexed: 12/13/2022]
Abstract
Inhibition of eukaryotic elongation factor 1A1 (EEF1A1) with the marine compound didemnin B decreases lipotoxic HepG2 cell death in vitro and improves early stage non-alcoholic fatty liver disease (NAFLD) in young genetically obese mice. However, the effects of didemnin B on NAFLD in a model of long-term diet-induced obesity are not known. We investigated the effects of didemnin B on NAFLD severity and metabolic parameters in western diet-induced obese mice, and on the cell types that contribute to liver inflammation and fibrosis in vitro. Male 129S6 mice were fed either standard chow or western diet for 26 weeks, followed by intervention with didemnin B (50 μg/kg) or vehicle by intraperitoneal (i.p.) injection once every 3 days for 14 days. Didemnin B decreased liver and plasma triglycerides, improved oral glucose tolerance, and decreased NAFLD severity. Moreover, didemnin B moderately increased hepatic expression of genes involved in ER stress response (Perk, Chop), and fatty acid oxidation (Fgf21, Cpt1a). In vitro, didemnin B decreased THP-1 monocyte proliferation, disrupted THP-1 monocyte-macrophage differentiation, decreased THP-1 macrophage IL-1β secretion, and decreased hepatic stellate cell (HSteC) proliferation and collagen secretion under both basal and lipotoxic (high fatty acid) conditions. Thus, didemnin B improves hepatic steatosis, glucose tolerance, and blood lipids in obesity, in association with moderate, possibly hormetic, upregulation of pathways involved in cell stress response and energy balance in the liver. Furthermore, it decreases the activity of the cell types implicated in liver inflammation and fibrosis in vitro. These findings highlight the therapeutic potential of partial protein synthesis inhibition in the treatment of NAFLD.
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Palmitate-induced toxicity is associated with impaired mitochondrial respiration and accelerated oxidative stress in cultured cardiomyocytes: The critical role of coenzyme Q 9/10. Toxicol In Vitro 2020; 68:104948. [PMID: 32683093 DOI: 10.1016/j.tiv.2020.104948] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 06/24/2020] [Accepted: 07/13/2020] [Indexed: 02/09/2023]
Abstract
Impaired mitochondrial function concomitant to enhanced oxidative stress-induced damage are well established mechanisms involved in hyperlipidemia-induced cardiotoxicity. Currently, limited information is available on the direct effect of myocardial lipid overload on endogenous coenzyme Q9/10 (CoQ9/10) levels in association with mitochondrial respiration and oxidative stress status. Here, such effects were explored by exposing H9c2 cardiomyocytes to various doses (0.15 to 1 mM) of palmitate for 24 h. The results demonstrated that palmitate doses ≥0.25 mM are enough to impair mitochondrial respiration and cause oxidative stress. Although endogenous CoQ9/10 levels are enhanced by palmitate doses ≤0.5 mM, this is not enough to counteract oxidative stress, but is sufficient to maintain cell viability of cardiomyocytes. Palmitate doses >0.5 mM caused severe mitochondrial toxicity, including reduction of cell viability. Interestingly, enhancement of CoQ9/10 levels with the lowest dose of palmitate (0.15 mM) was accompanied by a significantly reduction of CoQ9 oxidation status, as well as low cytosolic production of reactive oxygen species. From the overall findings, it appears that CoQ9/10 response may be crucial to improve mitochondrial function in conditions linked to hyperlipidemia-induced insult. Confirmation of such findings in relevant in vivo models remains essential to better understand the cardioprotective effects in association with improving endogenous CoQ9/10 content.
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23
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Abstract
Excess fatty acid accumulation in nonadipose tissues leads to cell dysfunction and cell death that is linked to the pathogenesis of inherited and acquired human diseases. Study of this process, known as lipotoxicity, has provided new insights into the regulation of lipid homeostasis and has revealed new molecular pathways involved in lipid-induced cellular stress. The discovery that disruption of specific small nucleolar RNAs protects against fatty acid-induced cell death and remodels metabolism in vivo opens new opportunities for understanding how nutrient signals influence cellular and systemic metabolic homeostasis through RNA biology.
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Affiliation(s)
- Jean E Schaffer
- Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
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24
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Increase in PKCα Activity during Heart Failure Despite the Stimulation of PKCα Braking Mechanism. Int J Mol Sci 2020; 21:ijms21072561. [PMID: 32272716 PMCID: PMC7177253 DOI: 10.3390/ijms21072561] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 03/31/2020] [Accepted: 04/03/2020] [Indexed: 11/29/2022] Open
Abstract
Rationale: Heart failure (HF) is marked by dampened cardiac contractility. A mild therapeutic target that improves contractile function without desensitizing the β-adrenergic system during HF may improve cardiac contractility and potentially survival. Inhibiting protein kinase C α (PKCα) activity may fit the criteria of a therapeutic target with milder systemic effects that still boosts contractility in HF patients. PKCα activity has been observed to increase during HF. This increase in PKCα activity is perplexing because it is also accompanied by up-regulation of a molecular braking mechanism. Objective: I aim to explore how PKCα activity can be increased and maintained during HF despite the presence of a molecular braking mechanism. Methods and Results: Using a computational approach, I show that the local diacylglycerol (DAG) signaling is regulated through a two-compartment signaling system in cardiomyocytes. These results imply that after massive myocardial infarction (MI), local homeostasis of DAG signaling is disrupted. The loss of this balance leads to prolonged activation of PKCα, a key molecular target linked to LV remodeling and dysfunctional filling and ejection in the mammalian heart. This study also proposes an explanation for how DAG homeostasis is regulated during normal systolic and diastolic cardiac function. Conclusions: I developed a novel two-compartment computational model for regulating DAG homeostasis during Ang II-induced heart failure. This model provides a promising tool with which to study mechanisms of DAG signaling regulation during heart failure. The model can also aid in identification of novel therapeutic targets with the aim of improving the quality of life for heart failure patients.
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25
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Liu L, Xie B, Fan M, Candas-Green D, Jiang JX, Wei R, Wang Y, Chen HW, Hu Y, Li JJ. Low-Level Saturated Fatty Acid Palmitate Benefits Liver Cells by Boosting Mitochondrial Metabolism via CDK1-SIRT3-CPT2 Cascade. Dev Cell 2019; 52:196-209.e9. [PMID: 31866205 DOI: 10.1016/j.devcel.2019.11.012] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 10/10/2019] [Accepted: 11/18/2019] [Indexed: 12/20/2022]
Abstract
Saturated fatty acids (SFAs) (the "bad" fat), especially palmitate (PA), in the human diet are blamed for potential health risks such as obesity and cancer because of SFA-induced lipotoxicity. However, epidemiological results demonstrate a latent benefit of SFAs, and it remains elusive whether a certain low level of SFAs is physiologically essential for maintaining cell metabolic hemostasis. Here, we demonstrate that although high-level PA (HPA) indeed induces lipotoxic effects in liver cells, low-level PA (LPA) increases mitochondrial functions and alleviates the injuries induced by HPA or hepatoxic agent carbon tetrachloride (CCl4). LPA treatment in mice enhanced liver mitochondrial activity and reduced CCl4 hepatotoxicity with improved blood levels of aspartate aminotransferase (AST), alanine transaminase (ALT), and mitochondrial aspartate transaminase (m-AST). LPA-mediated mitochondrial homeostasis is regulated by CDK1-mediated SIRT3 phosphorylation, which in turn deacetylates and dimerizes CPT2 to enhance fatty acid oxidation. Thus, an advantageous effect is suggested by the consumption of LPA that augments mitochondrial metabolic homeostasis via CDK1-SIRT3-CPT2 cascade.
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Affiliation(s)
- Lin Liu
- Department of Radiation Oncology, School of Medicine, University of California, Davis, Sacramento, CA, USA; Institute of Liver Diseases, Shuguan Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Bowen Xie
- Department of Radiation Oncology, School of Medicine, University of California, Davis, Sacramento, CA, USA
| | - Ming Fan
- Department of Radiation Oncology, School of Medicine, University of California, Davis, Sacramento, CA, USA
| | - Demet Candas-Green
- Department of Radiation Oncology, School of Medicine, University of California, Davis, Sacramento, CA, USA
| | - Joy X Jiang
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, School of Medicine, University of California, Davis, Sacramento, CA, USA
| | - Ryan Wei
- Department of Radiation Oncology, School of Medicine, University of California, Davis, Sacramento, CA, USA; Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Yinsheng Wang
- Department of Chemistry, University of California, Riverside, Riverside, CA, USA
| | - Hong-Wu Chen
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA, USA; Comprehensive Cancer Center, University of California, Davis, Sacramento, CA, USA
| | - Yiyang Hu
- Institute of Liver Diseases, Shuguan Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jian Jian Li
- Department of Radiation Oncology, School of Medicine, University of California, Davis, Sacramento, CA, USA; Comprehensive Cancer Center, University of California, Davis, Sacramento, CA, USA.
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26
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Joung EK, Kim J, Yoon N, Maeng LS, Kim JH, Park S, Kang K, Kim JS, Ahn YH, Ko YH, Byun JH, Hong JH. Expression of EEF1A1 Is Associated with Prognosis of Patients with Colon Adenocarcinoma. J Clin Med 2019; 8:jcm8111903. [PMID: 31703307 PMCID: PMC6912729 DOI: 10.3390/jcm8111903] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Revised: 10/31/2019] [Accepted: 11/04/2019] [Indexed: 01/06/2023] Open
Abstract
Background: The prognostic role of the translational factor, elongation factor-1 alpha 1 (EEF1A1), in colon cancer is unclear. Objectives: The present study aimed to investigate the expression of EEF1A in tissues obtained from patients with stage II and III colon cancer and analyze its association with patient prognosis. Methods: A total of 281 patients with colon cancer who underwent curative resection were analyzed according to EEF1A1 expression. Results: The five-year overall survival in the high-EEF1A1 group was 87.7%, whereas it was 65.6% in the low-EEF1A1 expression group (hazard ratio (HR) 2.47, 95% confidence interval (CI) 1.38–4.44, p = 0.002). The five-year disease-free survival of patients with high EEF1A1 expression was 82.5%, which was longer than the rate of 55.4% observed for patients with low EEF1A1 expression (HR 2.94, 95% CI 1.72–5.04, p < 0.001). Univariate Cox regression analysis indicated that age, preoperative carcinoembryonic antigen level, adjuvant treatment, total number of metastatic lymph nodes, and EEF1A1 expression level were significant prognostic factors for death. In multivariate analysis, expression of EEF1A1 was an independent prognostic factor associated with death (HR 3.01, 95% CI 1.636–5.543, p < 0.001). EEF1A1 expression was also an independent prognostic factor for disease-free survival in multivariate analysis (HR 2.54, 95% CI 1.459–4.434, p < 0.001). Conclusions: Our study demonstrated that high expression of EEF1A1 has a favorable prognostic effect on patients with colon adenocarcinoma.
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Affiliation(s)
- Eun kyo Joung
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
| | - Jiyoung Kim
- Department of Pathology, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (J.K.); (N.Y.); (L.-s.M.)
| | - Nara Yoon
- Department of Pathology, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (J.K.); (N.Y.); (L.-s.M.)
| | - Lee-so Maeng
- Department of Pathology, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (J.K.); (N.Y.); (L.-s.M.)
| | - Ji Hoon Kim
- Department of General Surgery, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
| | | | - Keunsoo Kang
- Department of Microbiology, College of Natural Sciences, Dankook University, Cheonan 31116, Korea;
| | - Jeong Seon Kim
- Department of Molecular Medicine and Tissue Injury Defense Research Center, College of Medicine, Ewha Womans University, Seoul 03760, Korea; (J.S.K.); (Y.-H.A.)
| | - Young-Ho Ahn
- Department of Molecular Medicine and Tissue Injury Defense Research Center, College of Medicine, Ewha Womans University, Seoul 03760, Korea; (J.S.K.); (Y.-H.A.)
| | - Yoon Ho Ko
- Division of Oncology, Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, The Catholic University of Korea, Seoul 03312, Korea;
- Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Jae Ho Byun
- Division of Oncology, Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
- Correspondence: (J.H.B.); (J.H.H.)
| | - Ji Hyung Hong
- Division of Oncology, Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, The Catholic University of Korea, Seoul 03312, Korea;
- Correspondence: (J.H.B.); (J.H.H.)
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27
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Wei S, Wang D, Li H, Bi L, Deng J, Zhu G, Zhang J, Li C, Li M, Fang Y, Zhang G, Chen J, Tao S, Zhang XE. Fatty acylCoA synthetase FadD13 regulates proinflammatory cytokine secretion dependent on the NF-κB signalling pathway by binding to eEF1A1. Cell Microbiol 2019; 21:e13090. [PMID: 31364251 PMCID: PMC6899955 DOI: 10.1111/cmi.13090] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 07/26/2019] [Accepted: 07/28/2019] [Indexed: 12/17/2022]
Abstract
Mycobacterium tuberculosis (Mtb) manipulates multiple host defence pathways to survive and persist in host cells. Understanding Mtb–host cell interaction is crucial to develop an efficient means to control the disease. Here, we applied the Mtb proteome chip, through separately interacting with H37Ra and H37Rv stimulated macrophage lysates, screened 283 Mtb differential proteins. Through primary screening, we focused on fatty acylCoA synthetase FadD13. Mtb FadD13 is a potential drug target, but its role in infection remains unclear. Deletion of FadD13 in Mtb reduced the production of proinflammatory cytokines IL‐1β, IL‐18, and IL‐6. Bimolecular fluorescence complementation and colocalization showed that the binding partner of FadD13 in macrophage was eEF1A1 (a translation elongation factor). Knockdown eEF1A1 expression in macrophage abrogated the promotion of proinflammatory cytokines induced by FadD13. In addition, ΔfadD13 mutant decreased the expression of the NF‐κB signalling pathway related proteins p50 and p65, so did the eEF1A1 knockdown macrophage infected with H37Rv. Meanwhile, we found that deletion of FadD13 reduced Mtb survival in macrophages during Mtb infection, and purified FadD13 proteins induced broken of macrophage membrane. Taken together, FadD13 is crucial for Mtb proliferation in macrophages, and it plays a key role in the production of proinflammatory cytokines during Mtb infection.
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Affiliation(s)
- Sha Wei
- State Key Laboratory of Agromicrobiology, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China.,National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Dianbing Wang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Hua Li
- State Key Laboratory of Agromicrobiology, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China.,National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Lijun Bi
- Key Laboratory of Non-Coding RNA and State Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Jiaoyu Deng
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Guofeng Zhu
- Key Laboratory of Non-Coding RNA and State Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Jibin Zhang
- State Key Laboratory of Agromicrobiology, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Chuanyou Li
- Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Min Li
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Yuan Fang
- College of Life Science, Hubei University, Wuhan, China
| | - Guimin Zhang
- College of Life Science, Hubei University, Wuhan, China
| | - Jian Chen
- College of Life Science, Hubei University, Wuhan, China
| | - Shengce Tao
- Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China
| | - Xian-En Zhang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Science, Beijing, China
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28
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Yamamoto T, Endo J, Kataoka M, Matsuhashi T, Katsumata Y, Shirakawa K, Yoshida N, Isobe S, Moriyama H, Goto S, Yamashita K, Nakanishi H, Shimanaka Y, Kono N, Shinmura K, Arai H, Fukuda K, Sano M. Decrease in membrane phospholipids unsaturation correlates with myocardial diastolic dysfunction. PLoS One 2018; 13:e0208396. [PMID: 30533011 PMCID: PMC6289418 DOI: 10.1371/journal.pone.0208396] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Accepted: 11/17/2018] [Indexed: 11/19/2022] Open
Abstract
Increase in saturated fatty acid (SFA) content in membrane phospholipids dramatically affects membrane properties and cellular functioning. We sought to determine whether exogenous SFA from the diet directly affects the degree of membrane phospholipid unsaturation in adult hearts and if these changes correlate with contractile dysfunction. Although both SFA-rich high fat diets (HFDs) and monounsaturated FA (MUFA)-rich HFDs cause the same degree of activation of myocardial FA uptake, triglyceride turnover, and mitochondrial FA oxidation and accumulation of toxic lipid intermediates, the former induced more severe diastolic dysfunction than the latter, which was accompanied with a decrease in membrane phospholipid unsaturation, induction of unfolded protein response (UPR), and a decrease in the expression of Sirt1 and stearoyl-CoA desaturase-1 (SCD1), catalyzing the conversion of SFA to MUFA. When the SFA supply in the heart overwhelms the cellular capacity to use it for energy, excess exogenous SFA channels to membrane phospholipids, leading to UPR induction, and development of diastolic dysfunction.
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Affiliation(s)
- Tsunehisa Yamamoto
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
| | - Jin Endo
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
- Japan Science and Technology Agency, Tokyo, Japan
| | - Masaharu Kataoka
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
| | | | | | - Kohsuke Shirakawa
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
| | - Naohiro Yoshida
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
- Department of Endocrinology and Hypertension, Tokyo Women’s Medical University, Tokyo, Japan
| | - Sarasa Isobe
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
| | - Hidenori Moriyama
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
| | - Shinichi Goto
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
| | - Kaoru Yamashita
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
- Department of Endocrinology and Hypertension, Tokyo Women’s Medical University, Tokyo, Japan
| | | | - Yuta Shimanaka
- Graduate School of Pharmaceutical Sciences, Tokyo University, Tokyo, Japan
| | - Nozomu Kono
- Graduate School of Pharmaceutical Sciences, Tokyo University, Tokyo, Japan
| | - Ken Shinmura
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
- Department of General Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Hiroyuki Arai
- Graduate School of Pharmaceutical Sciences, Tokyo University, Tokyo, Japan
| | - Keiichi Fukuda
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
| | - Motoaki Sano
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
- Japan Science and Technology Agency, Tokyo, Japan
- * E-mail:
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29
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Sletten AC, Peterson LR, Schaffer JE. Manifestations and mechanisms of myocardial lipotoxicity in obesity. J Intern Med 2018; 284:478-491. [PMID: 29331057 PMCID: PMC6045461 DOI: 10.1111/joim.12728] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Environmental and socioeconomic changes over the past thirty years have contributed to a dramatic rise in the worldwide prevalence of obesity. Heart disease is amongst the most serious health risks of obesity, with increases in both atherosclerotic coronary heart disease and heart failure among obese individuals. In this review, we focus on primary myocardial alterations in obesity that include hypertrophic remodelling and diastolic dysfunction. Obesity-associated perturbations in myocardial and systemic lipid metabolism are important contributors to cardiovascular complications of obesity. Accumulation of excess lipid in nonadipose cells of the cardiovascular system can cause cell dysfunction and cell death, a process known as lipotoxicity. Lipotoxicity has been modelled in mice using high-fat diet feeding, inbred lines with mutations in leptin receptor signalling, and in genetically engineered mice with enhanced myocardial fatty acid uptake, altered lipid droplet homoeostasis or decreased cardiac fatty acid oxidation. These studies, along with findings in cell culture model systems, indicate that the molecular pathophysiology of lipid overload involves endoplasmic reticulum stress, alterations in autophagy, de novo ceramide synthesis, oxidative stress, inflammation and changes in gene expression. We highlight recent advances that extend our understanding of the impact of obesity and altered lipid metabolism on cardiac function.
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Affiliation(s)
- A C Sletten
- Department of Medicine, Washington University, St Louis, MO, USA
| | - L R Peterson
- Department of Medicine, Washington University, St Louis, MO, USA
| | - J E Schaffer
- Department of Medicine, Washington University, St Louis, MO, USA
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30
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Angelucci C, D'Alessio A, Iacopino F, Proietti G, Di Leone A, Masetti R, Sica G. Pivotal role of human stearoyl-CoA desaturases (SCD1 and 5) in breast cancer progression: oleic acid-based effect of SCD1 on cell migration and a novel pro-cell survival role for SCD5. Oncotarget 2018; 9:24364-24380. [PMID: 29849946 PMCID: PMC5966257 DOI: 10.18632/oncotarget.25273] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Accepted: 04/05/2018] [Indexed: 01/01/2023] Open
Abstract
The influence of cell membrane fluidity on cancer progression has been established in different solid tumors. We previously reported that “cancer-associated fibroblasts” (CAFs) induced epithelial-mesenchymal transition and increased cell membrane fluidity and migration in poorly (MCF-7) and highly invasive (MDA-MB-231) breast cancer cells. We also found that the membrane fluidity regulating enzyme stearoyl-CoA desaturase 1 (SCD1) was upregulated in tumor cells co-cultured with CAFs and established its essential role for both intrinsic and CAF-driven tumor cell motility. Here, we further explored the mechanisms involved in the SCD1-based modulation of breast cancer cell migration and investigated the role of the other human SCD isoform, SCD5. We showed that the addition of oleic acid, the main SCD1 product, nullified the inhibitory effects produced on MCF-7 and MDA-MB-231 cell migration by SCD1 depletion (pharmacological or siRNA-based). Conversely, SCD5 seemed not involved in the regulation of cancer cell motility. Interestingly, a clear induction of necrosis was observed as a result of the depletion of SCD5 in MCF-7 cells, where the expression of SCD5 was found to be upregulated by CAFs. The necrotic effect was rescued by a 48-h treatment of cells with oleic acid. These results provide further insights in understanding the role of SCD1 in both intrinsic and CAF-stimulated mammary tumor cell migration, unveiling the metabolic basis of this desaturase-triggered effect. Moreover, our data suggest the ability of CAFs to promote the maintenance of tumor cell survival by the induction of SCD5 levels.
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Affiliation(s)
- Cristiana Angelucci
- Istituto di Istologia e Embriologia, Università Cattolica del Sacro Cuore, Roma, Italia
| | - Alessio D'Alessio
- Istituto di Istologia e Embriologia, Università Cattolica del Sacro Cuore, Roma, Italia
| | - Fortunata Iacopino
- Istituto di Istologia e Embriologia, Università Cattolica del Sacro Cuore, Roma, Italia
| | - Gabriella Proietti
- Istituto di Istologia e Embriologia, Università Cattolica del Sacro Cuore, Roma, Italia
| | - Alba Di Leone
- Unità Operativa di Chirurgia Senologica, Università Cattolica Del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli, Roma, Italia
| | - Riccardo Masetti
- Unità Operativa di Chirurgia Senologica, Università Cattolica Del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli, Roma, Italia
| | - Gigliola Sica
- Istituto di Istologia e Embriologia, Università Cattolica del Sacro Cuore, Roma, Italia
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31
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Hassan MK, Kumar D, Naik M, Dixit M. The expression profile and prognostic significance of eukaryotic translation elongation factors in different cancers. PLoS One 2018; 13:e0191377. [PMID: 29342219 PMCID: PMC5771626 DOI: 10.1371/journal.pone.0191377] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Accepted: 01/03/2018] [Indexed: 12/13/2022] Open
Abstract
Eukaryotic translation factors, especially initiation factors have garnered much attention with regards to their role in the onset and progression of different cancers. However, the expression levels and prognostic significance of translation elongation factors remain poorly explored in different cancers. In this study, we have investigated the mRNA transcript levels of seven translation elongation factors in different cancer types using Oncomine and TCGA databases. Furthermore, we have identified the prognostic significance of these factors using Kaplan-Meier Plotter and SurvExpress databases. We observed altered expression levels of all the elongation factors in different cancers. Higher expression of EEF1A2, EEF1B2, EEF1G, EEF1D, EEF1E1 and EEF2 was observed in most of the cancer types, whereas reverse trend was observed for EEF1A1. Overexpression of many factors predicted poor prognosis in breast (EEF1D, EEF1E1, EEF2) and lung cancer (EEF1A2, EEF1B2, EEF1G, EEF1E1). However, we didn’t see any common correlation of expression levels of elongation factors with survival outcomes across cancer types. Cancer subtype stratification showed association of survival outcomes and expression levels of elongation factors in specific sub-types of breast, lung and gastric cancer. Most interestingly, we observed a reciprocal relationship between the expression levels of the two EEF1A isoforms viz. EEF1A1 and EEF1A2, in most of the cancer types. Our results suggest that translation elongation factors can have a role in tumorigenesis and affect survival in cancer specific manner. Elongation factors have potential to serve as biomarkers and therapeutic drug targets, yet further study is required. Reciprocal relationship of differential expression between EEF1A isoforms observed in multiple cancer types indicates opposing roles in cancer and needs further investigation.
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Affiliation(s)
- Md. Khurshidul Hassan
- School of Biological Sciences, National Institute of Science Education and Research, HBNI, Bhimpur- Padanpur, Jatni, Khurda, Odisha, India
| | - Dinesh Kumar
- School of Biological Sciences, National Institute of Science Education and Research, HBNI, Bhimpur- Padanpur, Jatni, Khurda, Odisha, India
| | - Monali Naik
- School of Biological Sciences, National Institute of Science Education and Research, HBNI, Bhimpur- Padanpur, Jatni, Khurda, Odisha, India
| | - Manjusha Dixit
- School of Biological Sciences, National Institute of Science Education and Research, HBNI, Bhimpur- Padanpur, Jatni, Khurda, Odisha, India
- * E-mail:
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32
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Hetherington AM, Sawyez CG, Sutherland BG, Robson DL, Arya R, Kelly K, Jacobs RL, Borradaile NM. Treatment with didemnin B, an elongation factor 1A inhibitor, improves hepatic lipotoxicity in obese mice. Physiol Rep 2017; 4:4/17/e12963. [PMID: 27613825 PMCID: PMC5027364 DOI: 10.14814/phy2.12963] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 08/18/2016] [Indexed: 12/12/2022] Open
Abstract
Eukaryotic elongation factor EEF1A1 is induced by oxidative and ER stress, and contributes to subsequent cell death in many cell types, including hepatocytes. We recently showed that blocking the protein synthesis activity of EEF1A1 with the peptide inhibitor, didemnin B, decreases saturated fatty acid overload-induced cell death in HepG2 cells. In light of this and other recent work suggesting that limiting protein synthesis may be beneficial in treating ER stress-related disease, we hypothesized that acute intervention with didemnin B would decrease hepatic ER stress and lipotoxicity in obese mice with nonalcoholic fatty liver disease (NAFLD). Hyperphagic male ob/ob mice were fed semipurified diet for 4 weeks, and during week 5 received i.p. injections of didemnin B or vehicle on days 1, 4, and 7. Interestingly, we observed that administration of this compound modestly decreased food intake without evidence of illness or distress, and thus included an additional control group matched for food consumption with didemnin B-treated animals. Treatment with didemnin B improved several characteristics of hepatic lipotoxicity to a greater extent than the effects of caloric restriction alone, including hepatic steatosis, and some hepatic markers of ER stress and inflammation (GRP78, Xbp1s, and Mcp1). Plasma lipid and lipoprotein profiles and histopathological measures of NAFLD, including lobular inflammation, and total NAFLD activity score were also improved by didemnin B. These data indicate that acute intervention with the EEF1A inhibitor, didemnin B, improves hepatic lipotoxicity in obese mice with NAFLD through mechanisms not entirely dependent on decreased food intake, suggesting a potential therapeutic strategy for this ER stress-related disease.
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Affiliation(s)
- Alexandra M Hetherington
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry Western University, London, Ontario, Canada
| | - Cynthia G Sawyez
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry Western University, London, Ontario, Canada Robarts Research Institute, Schulich School of Medicine and Dentistry Western University, London, Ontario, Canada Department of Medicine, Schulich School of Medicine and Dentistry Western University, London, Ontario, Canada
| | - Brian G Sutherland
- Robarts Research Institute, Schulich School of Medicine and Dentistry Western University, London, Ontario, Canada
| | - Debra L Robson
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry Western University, London, Ontario, Canada
| | - Rigya Arya
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry Western University, London, Ontario, Canada
| | - Karen Kelly
- Metabolic and Cardiovascular Diseases Laboratory, Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
| | - René L Jacobs
- Metabolic and Cardiovascular Diseases Laboratory, Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
| | - Nica M Borradaile
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry Western University, London, Ontario, Canada
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Iida T, Yi H, Liu S, Ikegami D, Zheng W, Liu Q, Takahashi K, Kashiwagi Y, Goins WF, Glorioso JC, Hao S. MnSOD mediated by HSV vectors in the periaqueductal gray suppresses morphine withdrawal in rats. Gene Ther 2017; 24:314-324. [PMID: 28368370 PMCID: PMC9870211 DOI: 10.1038/gt.2017.22] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 02/11/2017] [Accepted: 03/13/2017] [Indexed: 01/26/2023]
Abstract
Morphine appears to be the most active metabolite of heroin; therefore, the effects of morphine are important in understanding the ramifications of heroin abuse. Opioid physical dependence (withdrawal response) may have very long-lasting effects on the motivation for reward, including the incubation of cue-induced drug-seeking behavior. However, the exact mechanisms of morphine withdrawal (MW) are not clear yet, and its treatment remains elusive. Periaqueductal gray (PAG) is one of the important sites in the pathogenesis of MW. Here, we used recombinant herpes simplex virus (HSV) vectors that encode the sod2 gene expressing manganese superoxide dismutase (MnSOD) to evaluate its therapeutic potential in MW. Microinjection of HSV vectors expressing MnSOD into the PAG reduced the MW syndrome. MnSOD vectors suppressed the upregulated mitochondrial superoxide, and endoplasmic reticulum stress markers (glucose-related protein 78 (GRP78) and activating transcription factor 6 alpha (ATF6α)) in the PAG induced by MW. Immunostaining showed that mitochondrial superoxide, GRP78 and ATF6α were colocalized with neuronal nuclei (a neuronal-specific marker), suggesting that they are located in the neurons in the PAG. These results suggest that overexpression of MnSOD by HSV vectors may relieve opioid dependence. This study may provide a novel therapeutic approach to morphine physical withdrawal response.
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Affiliation(s)
- Takafumi Iida
- Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL33136
| | - Hyun Yi
- Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL33136
| | - Shue Liu
- Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL33136
| | - Daigo Ikegami
- Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL33136
| | - Wenwen Zheng
- Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL33136
| | - Qiaofeng Liu
- Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL33136
| | - Keiya Takahashi
- Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL33136
| | - Yuta Kashiwagi
- Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL33136
| | - William F. Goins
- Department of Microbiology and Molecular Genetics, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15219
| | - Joseph C. Glorioso
- Department of Microbiology and Molecular Genetics, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15219
| | - Shuanglin Hao
- Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL33136
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Abstract
The heart utilizes large amounts of fatty acids as energy providing substrates. The physiological balance of lipid uptake and oxidation prevents accumulation of excess lipids. Several processes that affect cardiac function, including ischemia, obesity, diabetes mellitus, sepsis, and most forms of heart failure lead to altered fatty acid oxidation and often also to the accumulation of lipids. There is now mounting evidence associating certain species of these lipids with cardiac lipotoxicity and subsequent myocardial dysfunction. Experimental and clinical data are discussed and paths to reduction of toxic lipids as a means to improve cardiac function are suggested.
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Affiliation(s)
- P Christian Schulze
- From the Divisions of Cardiology, Friedrich-Schiller-University Jena, Germany, and Columbia University, New York, NY (P.C.S.); Metabolic Biology Laboratory, Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (K.D.); and Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York, NY (I.J.G.).
| | - Konstantinos Drosatos
- From the Divisions of Cardiology, Friedrich-Schiller-University Jena, Germany, and Columbia University, New York, NY (P.C.S.); Metabolic Biology Laboratory, Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (K.D.); and Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York, NY (I.J.G.)
| | - Ira J Goldberg
- From the Divisions of Cardiology, Friedrich-Schiller-University Jena, Germany, and Columbia University, New York, NY (P.C.S.); Metabolic Biology Laboratory, Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (K.D.); and Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York, NY (I.J.G.)
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Liu J, Chen D, Liu X, Liu Z. Cyclosporine A attenuates cardiac dysfunction induced by sepsis via inhibiting calcineurin and activating AMPK signaling. Mol Med Rep 2017; 15:3739-3746. [PMID: 28393192 DOI: 10.3892/mmr.2017.6421] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2015] [Accepted: 01/26/2017] [Indexed: 02/06/2023] Open
Abstract
The aim of the present study was to investigate whether cyclosporine A (CSA) improved cardiac dysfunction at an early stage of sepsis. Male Wistar rats were randomly divided into the following three groups: the sham‑operated control group, the cecal ligation puncture (CLP) procedure‑induced sepsis group and the CSA intervention group. Cecal ligation was performed to generate a sepsis model. At different time points (2, 6, 12, 24 and 72 h) following sepsis induction, blood pressure, cardiac function, and non‑esterified free fatty acid (NEFA) levels in the plasma and myocardia were measured, and the expression levels of components associated with the AMP‑activated protein kinase (AMPK)‑acetyl CoA carboxylase (ACC)‑carnitine palmitoyl transferase 1 (CPT1) signaling pathway were compared among the three groups. Sepsis induced a decrease in blood pressure and cardiac function at 24 h following sepsis induction in the CLP group, and CSA treatment ameliorated these pathophysiological alterations. In addition, rats in the CLP group exhibited significant increases in calcineurin activity and NEFA accumulation in the heart when compared with those in the sham group. These effects were attenuated by CSA treatment. Mechanistically, the activity of the AMPK‑ACC‑CPT1 pathway was enhanced by CSA treatment. The present study revealed that CSA treatment increases cardiac function at an early stage of sepsis in rats. This treatment partially suppresses calcineurin activity while activating the AMPK‑TCC‑CPT1 pathway.
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Affiliation(s)
- Jingmiao Liu
- Department of Emergency Medicine, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Da Chen
- Department of Emergency Medicine, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Xiaowei Liu
- Department of Emergency Medicine, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Zhi Liu
- Department of Emergency Medicine, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
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Li X, Li J, Li F. P21 activated kinase 4 binds translation elongation factor eEF1A1 to promote gastric cancer cell migration and invasion. Oncol Rep 2017; 37:2857-2864. [PMID: 28393218 DOI: 10.3892/or.2017.5543] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2016] [Accepted: 03/03/2017] [Indexed: 11/05/2022] Open
Abstract
P21 activated kinase 4 (PAK4), as an effector of Cdc42, playing important roles in regulating the processes of cytoskeleton organization. PAK4 has been considered to be an oncogenic protein, which has strong relationship with gastric cancer metastasis. However, the mechanism of PAK4 in regulating gastric cancer metastasis is still not fully understood. In this study, using yeast two-hybrid system, we identified that the eukaryotic elongation factor 1 α1 (eEF1A1) is a new binding partner of PAK4. The interaction between PAK4 and eEF1A1 was confirmed by GST pull-down and co-immunoprecipitation. PAK4 co-localized with eEF1A1 in the cytoplasm of gastric cancer cells. Overexpression of PAK4 enhanced the expression level of eEF1A1 and vice versa. PAK4 and eEF1A1 could cooperate to promote gastric cancer cell migration and invasion. Furthermore, the expression of PAK4 and eEF1A1 in clinical gastric cancer samples were examined by western blotting and immunohistochemistry. Statistical analysis indicated that there was positive correlation between the expression of PAK4 and eEF1A1. This study demonstrated for the first time that PAK4 interacted with eEF1A1 to promote migration and invasion of gastric cancer cells, thereby providing new insights into the function of PAK4 and eEF1A1 in the progression of gastric cancer.
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Affiliation(s)
- Xiang Li
- Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, Liaoning, P.R. China
| | - Jiabin Li
- Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, Liaoning, P.R. China
| | - Feng Li
- Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, Liaoning, P.R. China
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Lee GH, Oh KJ, Kim HR, Han HS, Lee HY, Park KG, Nam KH, Koo SH, Chae HJ. Effect of BI-1 on insulin resistance through regulation of CYP2E1. Sci Rep 2016; 6:32229. [PMID: 27576594 PMCID: PMC5006057 DOI: 10.1038/srep32229] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Accepted: 08/04/2016] [Indexed: 12/21/2022] Open
Abstract
Diet-induced obesity is a major contributing factor to the progression of hepatic insulin resistance. Increased free fatty acids in liver enhances endoplasmic reticulum (ER) stress and production of reactive oxygen species (ROS), both are directly responsible for dysregulation of hepatic insulin signaling. BI-1, a recently studied ER stress regulator, was examined to investigate its association with ER stress and ROS in insulin resistance models. To induce obesity and insulin resistance, BI-1 wild type and BI-1 knock-out mice were fed a high-fat diet for 8 weeks. The BI-1 knock-out mice had hyperglycemia, was associated with impaired glucose and insulin tolerance under high-fat diet conditions. Increased activity of NADPH-dependent CYP reductase-associated cytochrome p450 2E1 (CYP2E1) and exacerbation of ER stress in the livers of BI-1 knock-out mice was also observed. Conversely, stable expression of BI-1 in HepG2 hepatocytes was shown to reduce palmitate-induced ER stress and CYP2E1-dependent ROS production, resulting in the preservation of intact insulin signaling. Stable expression of CYP2E1 led to increased ROS production and dysregulation of insulin signaling in hepatic cells, mimicking palmitate-mediated hepatic insulin resistance. We propose that BI-1 protects against obesity-induced hepatic insulin resistance by regulating CYP2E1 activity and ROS production.
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Affiliation(s)
- Geum-Hwa Lee
- Department of Pharmacology and New Drug Development Institute, Medical School, Chonbuk National University, Jeonju, 561-181, Republic of Korea
| | - Kyoung-Jin Oh
- Division of Life Sciences, Korea University, 145 Anam-Ro, Seongbuk-Gu, Seoul, 136-713, Republic of Korea.,Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 305-806, Republic of Korea
| | - Hyung-Ryong Kim
- Department of Dental Pharmacology and Wonkwang Dental Research Institute, School of Dentistry, Wonkwang University, Iksan, 570-749, Republic of Korea
| | - Hye-Sook Han
- Division of Life Sciences, Korea University, 145 Anam-Ro, Seongbuk-Gu, Seoul, 136-713, Republic of Korea
| | - Hwa-Young Lee
- Department of Pharmacology and New Drug Development Institute, Medical School, Chonbuk National University, Jeonju, 561-181, Republic of Korea
| | - Keun-Gyu Park
- Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, 700-721, Republic of Korea
| | - Ki-Hoan Nam
- Laboratory Animal Resource Center, KRIBB, Ochang-eup, 363-883, Republic of Korea
| | - Seung-Hoi Koo
- Division of Life Sciences, Korea University, 145 Anam-Ro, Seongbuk-Gu, Seoul, 136-713, Republic of Korea
| | - Han-Jung Chae
- Department of Pharmacology and New Drug Development Institute, Medical School, Chonbuk National University, Jeonju, 561-181, Republic of Korea
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Ser/Thr kinases and polyamines in the regulation of non-canonical functions of elongation factor 1A. Amino Acids 2016; 48:2339-52. [DOI: 10.1007/s00726-016-2311-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 08/08/2016] [Indexed: 10/21/2022]
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Li S, Zhang L, Ni R, Cao T, Zheng D, Xiong S, Greer PA, Fan GC, Peng T. Disruption of calpain reduces lipotoxicity-induced cardiac injury by preventing endoplasmic reticulum stress. Biochim Biophys Acta Mol Basis Dis 2016; 1862:2023-2033. [PMID: 27523632 DOI: 10.1016/j.bbadis.2016.08.005] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Revised: 07/15/2016] [Accepted: 08/09/2016] [Indexed: 12/16/2022]
Abstract
Diabetes and obesity are prevalent in westernized countries. In both conditions, excessive fatty acid uptake by cardiomyocytes induces cardiac lipotoxicity, an important mechanism contributing to diabetic cardiomyopathy. This study investigated the effect of calpain disruption on cardiac lipotoxicity. Cardiac-specific capns1 knockout mice and their wild-type littermates (male, age of 4weeks) were fed a high fat diet (HFD) or normal diet for 20weeks. HFD increased body weight, altered blood lipid profiles and impaired glucose tolerance comparably in both capns1 knockout mice and their wild-type littermates. Calpain activity, cardiomyocyte cross-sectional areas, collagen deposition and triglyceride were significantly increased in HFD-fed mouse hearts, and these were accompanied by myocardial dysfunction and up-regulation of hypertrophic and fibrotic collagen genes as well as pro-inflammatory cytokines. These effects of HFD were attenuated by disruption of calpain in capns1 knockout mice. Mechanistically, deletion of capns1 in HFD-fed mouse hearts and disruption of calpain with calpain inhibitor-III, silencing of capn1, or deletion of capns1 in palmitate-stimulated cardiomyocytes prevented endoplasmic reticulum stress, apoptosis, cleavage of caspase-12 and junctophilin-2, and pro-inflammatory cytokine expression. Pharmacological inhibition of endoplasmic reticulum stress diminished palmitate-induced apoptosis and pro-inflammatory cytokine expression in cardiomyocytes. In summary, disruption of calpain prevents lipotoxicity-induced apoptosis in cardiomyocytes and cardiac injury in mice fed a HFD. The role of calpain is mediated, at least partially, through endoplasmic reticulum stress. Thus, calpain/endoplasmic reticulum stress may represent a new mechanism and potential therapeutic targets for cardiac lipotoxicity.
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Affiliation(s)
- Shengcun Li
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, China
| | - Lulu Zhang
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, China
| | - Rui Ni
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, China; Critical Illness Research, Lawson Health Research Institute, Western University, London, Ontario N6A 4G5, Canada; Department of Pathology and Laboratory Medicine, Western University, London, Ontario N6A 4G5, Canada
| | - Ting Cao
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, China
| | - Dong Zheng
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, China; Critical Illness Research, Lawson Health Research Institute, Western University, London, Ontario N6A 4G5, Canada; Department of Medicine, Western University, London, Ontario N6A 4G5, Canada
| | - Sidong Xiong
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, China
| | - Peter A Greer
- Division of Cancer Biology and Genetics, Queen's University Cancer Research Institute, Kingston, Ontario K7L 3N6, Canada; Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario K7L 3N6, Canada
| | - Guo-Chang Fan
- Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Tianqing Peng
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, China; Critical Illness Research, Lawson Health Research Institute, Western University, London, Ontario N6A 4G5, Canada; Department of Medicine, Western University, London, Ontario N6A 4G5, Canada; Department of Pathology and Laboratory Medicine, Western University, London, Ontario N6A 4G5, Canada.
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40
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Lockman KA, Htun V, Sinha R, Treskes P, Nelson LJ, Martin SF, Rogers SM, Le Bihan T, Hayes PC, Plevris JN. Proteomic profiling of cellular steatosis with concomitant oxidative stress in vitro. Lipids Health Dis 2016; 15:114. [PMID: 27368608 PMCID: PMC4930558 DOI: 10.1186/s12944-016-0283-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 06/24/2016] [Indexed: 12/14/2022] Open
Abstract
Background Nutrient excess underpins the development of nonalcoholic fatty liver disease (NAFLD). The ensuing metabolic derangement is characterised by increased cellular respiration, oxidative stress and mitochondrial impairment. We have previously recapitulated these events in an in vitro cellular steatosis model. Here, we examined the distinct patterns of protein expression involved using a proteomics approach. Methods Human hepatoblastoma C3A cells were treated with a combination of energy substrates; lactate (L), pyruvate (P), octanoate (O) and ammonia (N). Proteins extracts were trypsinized and analyzed on a capillary HPLC OrbitrapXL mass spectrometer. Proteins were quantified using a label-free intensity based approach. Functional enrichment analysis was performed using ToppCluster via Gene Ontology (GO) database. Results Of the 1327 proteins identified, 104 were differentially expressed between LPON and untreated cells (defined as: ≥2 peptides; fold change ≥1.5; p-value <0.05). Seventy of these were upregulated with LPON. Functional enrichment analysis revealed enhanced protein biosynthesis accompanied by downregulation of histones H2A type 1-A, H1.2, H1.5 and H1.0I in LPON cells. Lipid binding annotations were also enriched as well as proteins involved in cholesterol synthesis, uptake and efflux. Increased expression of aldo-keto reductase family 1, member C1 and C3 suggests enhanced sterol metabolism and increased ROS-mediated lipid peroxidation. Conclusions The surge of energy substrates diverts free fatty acid metabolism towards pathways that can mitigate lipotoxicity. The histones depletion may represent an adaptation to increased protein synthesis. However, this can also expose DNA to oxidative stress thus should be explored further in the context of NAFLD progression.
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Affiliation(s)
- Khalida Ann Lockman
- Hepatology Laboratory, University of Edinburgh, 49 Little France Crescent, Edinburgh, EH16 4SB, Scotland, UK
| | - Varanand Htun
- Hepatology Laboratory, University of Edinburgh, 49 Little France Crescent, Edinburgh, EH16 4SB, Scotland, UK
| | - Rohit Sinha
- Hepatology Laboratory, University of Edinburgh, 49 Little France Crescent, Edinburgh, EH16 4SB, Scotland, UK
| | - Philipp Treskes
- Hepatology Laboratory, University of Edinburgh, 49 Little France Crescent, Edinburgh, EH16 4SB, Scotland, UK
| | - Leonard J Nelson
- Hepatology Laboratory, University of Edinburgh, 49 Little France Crescent, Edinburgh, EH16 4SB, Scotland, UK
| | - Sarah F Martin
- Kinetic Parameter Facility, SynthSys - Centre for Synthetic and Systems Biology, University of Edinburgh, Edinburgh, EH9 3BF, UK
| | - Sophie M Rogers
- Kinetic Parameter Facility, SynthSys - Centre for Synthetic and Systems Biology, University of Edinburgh, Edinburgh, EH9 3BF, UK
| | - Thierry Le Bihan
- Kinetic Parameter Facility, SynthSys - Centre for Synthetic and Systems Biology, University of Edinburgh, Edinburgh, EH9 3BF, UK
| | - Peter C Hayes
- Hepatology Laboratory, University of Edinburgh, 49 Little France Crescent, Edinburgh, EH16 4SB, Scotland, UK
| | - John N Plevris
- Hepatology Laboratory, University of Edinburgh, 49 Little France Crescent, Edinburgh, EH16 4SB, Scotland, UK.
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Liu Y, Jiang S, Yang PY, Zhang YF, Li TJ, Rui YC. EF1A1/HSC70 Cooperatively Suppress Brain Endothelial Cell Apoptosis via Regulating JNK Activity. CNS Neurosci Ther 2016; 22:836-44. [PMID: 27324700 DOI: 10.1111/cns.12581] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Revised: 05/23/2016] [Accepted: 05/25/2016] [Indexed: 12/21/2022] Open
Abstract
AIMS In our previous study, eEF1A1 was identified to be a new target for protecting brain ischemia injury, but the mechanism remains largely unknown. In this study, we screened the downstream cellular protein molecules interacted with eEF1A1 and found mechanism of eEF1A1 in brain ischemia protection. METHODS AND RESULTS Through co-immunoprecipitation and mass spectrometry for searching the interaction of proteins with eEF1A1 in bEnd3 cells, HSC70 was identified to be a binding protein of eEF1A1, which was further validated by Western blot and immunofluorescence. eEF1A1 or HSC70 knockdown, respectively, increased OGD-induced apoptosis of brain vascular endothelial cells, which was detected by Annexin V-FITC/PI staining. HSC70 or eEF1A1 knockdown enhances phosphorylated JNK, phosphorylation of c-JUN (Ser63, Ser73), cleaved caspase-9, and cleaved caspase-3 expression, which could be rescued by JNK inhibitor. CONCLUSION In summary, our data suggest that the presence of chaperone forms of interaction between eEF1A1 and HSC70 in brain vascular endothelial cells, eEF1A1 and HSC70 can play a protective role in the process of ischemic stroke by inhibiting the JNK signaling pathway activation.
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Affiliation(s)
- Ying Liu
- Department of Pharmacology, College of Pharmacy, Second Military Medical University, Shanghai, China
| | - Shu Jiang
- Department of Pharmacology, College of Pharmacy, Second Military Medical University, Shanghai, China
| | - Peng-Yuan Yang
- CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Yue-Fan Zhang
- Department of Pharmacology, College of Pharmacy, Second Military Medical University, Shanghai, China.
| | - Tie-Jun Li
- Department of Pharmacology, College of Pharmacy, Second Military Medical University, Shanghai, China
| | - Yao-Cheng Rui
- Department of Pharmacology, College of Pharmacy, Second Military Medical University, Shanghai, China.
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Wang DD, Zhu HZ, Li SW, Yang JM, Xiao Y, Kang QR, Li CY, Zhao YS, Zeng Y, Li Y, Zhang J, He ZD, Ying Y. Crude Saponins of Panax notoginseng Have Neuroprotective Effects To Inhibit Palmitate-Triggered Endoplasmic Reticulum Stress-Associated Apoptosis and Loss of Postsynaptic Proteins in Staurosporine Differentiated RGC-5 Retinal Ganglion Cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2016; 64:1528-1539. [PMID: 26832452 DOI: 10.1021/acs.jafc.5b05864] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Increased apoptosis of retinal ganglion cells (RGCs) contributes to the gradual loss of retinal neurons at the early phase of diabetic retinopathy (DR). There is an urgent need to search for drugs with neuroprotective effects against apoptosis of RGCs for the early treatment of DR. This study aimed to investigate the neuroprotective effects of saponins extracted from Panax notoginseng, a traditional Chinese medicine, on apoptosis of RGCs stimulated by palmitate, a metabolic factor for the development of diabetes and its complications, and to explore the potential molecular mechanism. We showed that crude saponins of P. notoginseng (CSPN) inhibited the increased apoptosis and loss of postsynaptic protein PSD-95 by palmitate in staurosporine-differentiated RGC-5 cells. Moreover, CSPN suppressed palmitate-induced reactive oxygen species generation and endoplasmic reticulum stress-associated eIF2α/ATF4/CHOP and caspase 12 pathways. Thus, our findings address the potential therapeutic significance of CSPN for the early stage of DR.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Yong Zeng
- The First Affiliated Hospital of Kunming Medical University , Kunming 650000, China
| | - Yan Li
- The First Affiliated Hospital of Kunming Medical University , Kunming 650000, China
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Jia SN, Lin C, Chen DF, Li AQ, Dai L, Zhang L, Zhao LL, Yang JS, Yang F, Yang WJ. The Transcription Factor p8 Regulates Autophagy in Response to Palmitic Acid Stress via a Mammalian Target of Rapamycin (mTOR)-independent Signaling Pathway. J Biol Chem 2016; 291:4462-72. [PMID: 26733200 DOI: 10.1074/jbc.m115.675793] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Indexed: 12/31/2022] Open
Abstract
Autophagy is an evolutionarily conserved degradative process that allows cells to maintain homoeostasis in numerous physiological situations. This process also functions as an essential protective response to endoplasmic reticulum (ER) stress, which promotes the removal and degradation of unfolded proteins. However, little is known regarding the mechanism by which autophagy is initiated and regulated in response to ER stress. In this study, different types of autophagy were identified in human gastric cancer MKN45 cells in response to the stress induced by nutrient starvation or lipotoxicity in which the regulation of these pathways is mammalian target of rapamycin (mTOR)-dependent or -independent, respectively. Interestingly, we found that p8, a stress-inducible transcription factor, was enhanced in MKN45 cells treated with palmitic acid to induce lipotoxicity. Furthermore, an increase in autophagy was observed in MKN45 cells stably overexpressing p8 using a lentivirus system, and autophagy induced by palmitic acid was blocked by p8 RNAi compared with the control. Western blotting analyses showed that autophagy was regulated by p8 or mTOR in response to the protein kinase-like endoplasmic reticulum kinase/activating transcription factor 6-mediated ER stress of lipotoxicity or the parkin-mediated mitochondrial stress of nutrient starvation, respectively. Furthermore, our results indicated that autophagy induced by palmitic acid is mTOR-independent, but this autophagy pathway was regulated by p8 via p53- and PKCα-mediated signaling in MKN45 cells. Our findings provide insights into the role of p8 in regulating autophagy induced by the lipotoxic effects of excess fat accumulation in cells.
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Affiliation(s)
- Sheng-Nan Jia
- From the College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Cheng Lin
- From the College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Dian-Fu Chen
- From the College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - An-Qi Li
- From the College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Li Dai
- From the College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Li Zhang
- From the College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Ling-Ling Zhao
- From the College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Jin-Shu Yang
- From the College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Fan Yang
- From the College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Wei-Jun Yang
- From the College of Life Sciences, Zhejiang University, Hangzhou 310058, China
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Liu T, Yang Y, Wang D, Xiao Y, Du G, Wu L, Ding M, Li L, Wu C. Human eukaryotic elongation factor 1A forms oligomers through specific cysteine residues. Acta Biochim Biophys Sin (Shanghai) 2015; 47:1011-7. [PMID: 26515794 DOI: 10.1093/abbs/gmv113] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2015] [Accepted: 08/15/2015] [Indexed: 12/29/2022] Open
Abstract
Eukaryotic elongation factor 1A (eEF1A) is a multifunctional protein involved in bundling actin, severing microtubule, activating the phosphoinositol-4 kinase, and recruiting aminoacyl-tRNAs to ribosomes during protein biosynthesis. Although evidence has shown the presence of the isoform eEF1A1 oligomers, the substantial mechanism of the self-association remains unclear. Herein, we found that human eEF1A1 could spontaneously form oligomers. Specifically, mutagenesis screen on cysteine residues demonstrated that Cys(234) was essential for eEF1A1 oligomerization. In addition, we also found that hydrogen peroxide treatment could induce the formation of eEF1A oligomers in cells. By cysteine replacement, eEF1A2 isoform displayed the ability to oligomerize in cells under the oxidative environment. In summary, in this study we characterized eEF1A1 oligomerization and demonstrated that specific cysteine residues are required for this oligomerization activity.
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Affiliation(s)
- Tao Liu
- School of Life Sciences and Key Laboratory of Bio-Resources and Eco-Environment, Sichuan University, Ministry of Education, Chengdu 610064, China
| | - Yu Yang
- School of Life Sciences and Key Laboratory of Bio-Resources and Eco-Environment, Sichuan University, Ministry of Education, Chengdu 610064, China
| | - Di Wang
- School of Life Sciences and Key Laboratory of Bio-Resources and Eco-Environment, Sichuan University, Ministry of Education, Chengdu 610064, China
| | - Yan Xiao
- School of Life Sciences and Key Laboratory of Bio-Resources and Eco-Environment, Sichuan University, Ministry of Education, Chengdu 610064, China
| | - Guangshi Du
- School of Life Sciences and Key Laboratory of Bio-Resources and Eco-Environment, Sichuan University, Ministry of Education, Chengdu 610064, China
| | - Lei Wu
- School of Life Sciences and Key Laboratory of Bio-Resources and Eco-Environment, Sichuan University, Ministry of Education, Chengdu 610064, China
| | - Muran Ding
- School of Life Sciences and Key Laboratory of Bio-Resources and Eco-Environment, Sichuan University, Ministry of Education, Chengdu 610064, China
| | - Ling Li
- School of Life Sciences and Key Laboratory of Bio-Resources and Eco-Environment, Sichuan University, Ministry of Education, Chengdu 610064, China
| | - Chuanfang Wu
- School of Life Sciences and Key Laboratory of Bio-Resources and Eco-Environment, Sichuan University, Ministry of Education, Chengdu 610064, China
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45
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Ruiz P, Katsumiti A, Nieto JA, Bori J, Jimeno-Romero A, Reip P, Arostegui I, Orbea A, Cajaraville MP. Short-term effects on antioxidant enzymes and long-term genotoxic and carcinogenic potential of CuO nanoparticles compared to bulk CuO and ionic copper in mussels Mytilus galloprovincialis. MARINE ENVIRONMENTAL RESEARCH 2015; 111:107-20. [PMID: 26297043 DOI: 10.1016/j.marenvres.2015.07.018] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Revised: 07/27/2015] [Accepted: 07/28/2015] [Indexed: 05/21/2023]
Abstract
The aim of this work was to study short-term effects on antioxidant enzyme activities and long-term genotoxic and carcinogenic potential of CuO nanoparticles (NPs) in comparison to bulk CuO and ionic copper in mussels Mytilus galloprovincialis after 21 days exposure to 10 μg Cu L(-1). Then, mussels were kept for up to 122 days in clean water. Cu accumulation depended on the form of the metal and on the exposure time. CuO NPs were localized in lysosomes of digestive cells, as confirmed by TEM and X ray microanalysis. CuO NPs, bulk CuO and ionic copper produced different effects on antioxidant enzyme activities in digestive glands, overall increasing antioxidant activities. CuO NPs significantly induced catalase and superoxide dismutase activities. Fewer effects were observed in gills. Micronuclei frequency increased significantly in mussels exposed to CuO NPs and one organism treated with CuO NPs showed disseminated neoplasia. However, transcription levels of cancer-related genes did not vary significantly. Thus, short-term exposure to CuO NPs provoked oxidative stress and genotoxicity, but further studies are needed to determine whether these early events can lead to cancer development in mussels.
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Affiliation(s)
- Pamela Ruiz
- CBET Research Group, Department of Zoology and Animal Cell Biology, Faculty of Science and Technology and Research Centre for Experimental Marine Biology and Biotechnology PIE, University of the Basque Country UPV/EHU, Basque Country, Spain
| | - Alberto Katsumiti
- CBET Research Group, Department of Zoology and Animal Cell Biology, Faculty of Science and Technology and Research Centre for Experimental Marine Biology and Biotechnology PIE, University of the Basque Country UPV/EHU, Basque Country, Spain
| | - Jose A Nieto
- CBET Research Group, Department of Zoology and Animal Cell Biology, Faculty of Science and Technology and Research Centre for Experimental Marine Biology and Biotechnology PIE, University of the Basque Country UPV/EHU, Basque Country, Spain
| | - Jaume Bori
- CBET Research Group, Department of Zoology and Animal Cell Biology, Faculty of Science and Technology and Research Centre for Experimental Marine Biology and Biotechnology PIE, University of the Basque Country UPV/EHU, Basque Country, Spain
| | - Alba Jimeno-Romero
- CBET Research Group, Department of Zoology and Animal Cell Biology, Faculty of Science and Technology and Research Centre for Experimental Marine Biology and Biotechnology PIE, University of the Basque Country UPV/EHU, Basque Country, Spain
| | - Paul Reip
- Intrinsiq Materials Ltd, Cody Technology Park, Hampshire, UK
| | - Inmaculada Arostegui
- Department of Applied Mathematics, Statistics and Operations Research, Faculty of Science and Technology, University of the Basque Country UPV/EHU, Leioa, Spain
| | - Amaia Orbea
- CBET Research Group, Department of Zoology and Animal Cell Biology, Faculty of Science and Technology and Research Centre for Experimental Marine Biology and Biotechnology PIE, University of the Basque Country UPV/EHU, Basque Country, Spain
| | - Miren P Cajaraville
- CBET Research Group, Department of Zoology and Animal Cell Biology, Faculty of Science and Technology and Research Centre for Experimental Marine Biology and Biotechnology PIE, University of the Basque Country UPV/EHU, Basque Country, Spain.
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46
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Hall ME, Harmancey R, Stec DE. Lean heart: Role of leptin in cardiac hypertrophy and metabolism. World J Cardiol 2015; 7:511-524. [PMID: 26413228 PMCID: PMC4577678 DOI: 10.4330/wjc.v7.i9.511] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 06/16/2015] [Accepted: 07/23/2015] [Indexed: 02/06/2023] Open
Abstract
Leptin is an adipokine that has been linked with the cardiovascular complications resulting from obesity such as hypertension and heart disease. Obese patients have high levels of circulating leptin due to increased fat mass. Clinical and population studies have correlated high levels of circulating leptin with the development of cardiac hypertrophy in obesity. Leptin has also been demonstrated to increase the growth of cultured cardiomyocytes. However, several animal studies of obese leptin deficient mice have not supported a role for leptin in promoting cardiac hypertrophy so the role of leptin in this pathological process remains unclear. Leptin is also an important hormone in the regulation of cardiac metabolism where it supports oxidation of glucose and fatty acids. In addition, leptin plays a critical role in protecting the heart from excess lipid accumulation and the formation of toxic lipids in obesity a condition known as cardiac lipotoxicity. This paper focuses on the data supporting and refuting leptin’s role in promoting cardiac hypertrophy as well as its important role in the regulation of cardiac metabolism and protection against cardiac lipotoxicity.
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47
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Caputa G, Zhao S, Criado AEG, Ory DS, Duncan JG, Schaffer JE. RNASET2 is required for ROS propagation during oxidative stress-mediated cell death. Cell Death Differ 2015. [PMID: 26206090 DOI: 10.1038/cdd.2015.105] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
RNASET2 is a ubiquitously expressed acidic ribonuclease that has been implicated in diverse pathophysiological processes including tumorigeneis, vitiligo, asthenozoospermia, and neurodegeneration. Prior studies indicate that RNASET2 is induced in response to oxidative stress and that overexpression of RNASET2 sensitizes cells to reactive oxygen species (ROS)-induced cell death through a mechanism that is independent of catalytic activity. Herein, we report a loss-of-function genetic screen that identified RNASET2 as an essential gene for lipotoxic cell death. Haploinsufficiency of RNASET2 confers increased antioxidant capacity and generalized resistance to oxidative stress-mediated cell death in cultured cells. This function is critically dependent on catalytic activity. Furthermore, knockdown of RNASET2 in the Drosophila fat body confers increased survival in the setting of oxidative stress inducers. Together, these findings demonstrate that RNASET2 regulates antioxidant tone and is required for physiological ROS responses.
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Affiliation(s)
- G Caputa
- Diabetic Cardiovascular Disease Center, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - S Zhao
- Diabetic Cardiovascular Disease Center, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - A E G Criado
- Diabetic Cardiovascular Disease Center, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - D S Ory
- Diabetic Cardiovascular Disease Center, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - J G Duncan
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
| | - J E Schaffer
- Diabetic Cardiovascular Disease Center, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
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48
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Hafizi Abu Bakar M, Kian Kai C, Wan Hassan WN, Sarmidi MR, Yaakob H, Zaman Huri H. Mitochondrial dysfunction as a central event for mechanisms underlying insulin resistance: the roles of long chain fatty acids. Diabetes Metab Res Rev 2015; 31:453-75. [PMID: 25139820 DOI: 10.1002/dmrr.2601] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2013] [Revised: 04/19/2014] [Accepted: 07/23/2014] [Indexed: 12/25/2022]
Abstract
Insulin resistance is characterized by hyperglycaemia, dyslipidaemia and oxidative stress prior to the development of type 2 diabetes mellitus. To date, a number of mechanisms have been proposed to link these syndromes together, but it remains unclear what the unifying condition that triggered these events in the progression of this metabolic disease. There have been a steady accumulation of data in numerous experimental studies showing the strong correlations between mitochondrial dysfunction, oxidative stress and insulin resistance. In addition, a growing number of studies suggest that the raised plasma free fatty acid level induced insulin resistance with the significant alteration of oxidative metabolism in various target tissues such as skeletal muscle, liver and adipose tissue. In this review, we herein propose the idea of long chain fatty acid-induced mitochondrial dysfunctions as one of the key events in the pathophysiological development of insulin resistance and type 2 diabetes. The accumulation of reactive oxygen species, lipotoxicity, inflammation-induced endoplasmic reticulum stress and alterations of mitochondrial gene subset expressions are the most detrimental that lead to the developments of aberrant intracellular insulin signalling activity in a number of peripheral tissues, thereby leading to insulin resistance and type 2 diabetes.
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Affiliation(s)
- Mohamad Hafizi Abu Bakar
- Department of Bioprocess Engineering, Faculty of Chemical Engineering, Universiti Teknologi Malaysia, Skudai, Johor, Malaysia
| | - Cheng Kian Kai
- Department of Bioprocess Engineering, Faculty of Chemical Engineering, Universiti Teknologi Malaysia, Skudai, Johor, Malaysia
| | - Wan Najihah Wan Hassan
- Department of Bioprocess Engineering, Faculty of Chemical Engineering, Universiti Teknologi Malaysia, Skudai, Johor, Malaysia
| | - Mohamad Roji Sarmidi
- Institute of Bioproduct Development, Universiti Teknologi Malaysia, Skudai, Johor, Malaysia
| | - Harisun Yaakob
- Institute of Bioproduct Development, Universiti Teknologi Malaysia, Skudai, Johor, Malaysia
| | - Hasniza Zaman Huri
- Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
- Clinical Investigation Centre, 13th Floor Main Tower, University Malaya Medical Centre, Lembah Pantai, Kuala Lumpur, Malaysia
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49
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Stoianov AM, Robson DL, Hetherington AM, Sawyez CG, Borradaile NM. Elongation Factor 1A-1 Is a Mediator of Hepatocyte Lipotoxicity Partly through Its Canonical Function in Protein Synthesis. PLoS One 2015; 10:e0131269. [PMID: 26102086 PMCID: PMC4478042 DOI: 10.1371/journal.pone.0131269] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2015] [Accepted: 06/01/2015] [Indexed: 01/22/2023] Open
Abstract
Elongation factor 1A-1 (eEF1A-1) has non-canonical functions in regulation of the actin cytoskeleton and apoptosis. It was previously identified through a promoter-trap screen as a mediator of fatty acid-induced cell death (lipotoxicity), and was found to participate in this process downstream of ER stress. Since ER stress is implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), we investigated the mechanism of action of eEF1A-1 in hepatocyte lipotoxicity. HepG2 cells were exposed to excess fatty acids, followed by assessments of ER stress, subcellular localization of eEF1A-1, and cell death. A specific inhibitor of eEF1A-1 elongation activity, didemnin B, was used to determine whether its function in protein synthesis is involved in lipotoxicity. Within 6 h, eEF1A-1 protein was modestly induced by high palmitate, and partially re-localized from its predominant location at the ER to polymerized actin at the cell periphery. This early induction and subcellular redistribution of eEF1A-1 coincided with the onset of ER stress, and was later followed by cell death. Didemnin B did not prevent the initiation of ER stress by high palmitate, as indicated by eIF2α phosphorylation. However, consistent with sustained inhibition of eEF1A-1-dependent elongation activity, didemnin B prevented the recovery of protein synthesis and increase in GRP78 protein that are normally associated with later phases of the response to ongoing ER stress. This resulted in decreased palmitate-induced cell death. Our data implicate eEF1A-1, and its function in protein synthesis, in hepatocyte lipotoxicity.
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Affiliation(s)
- Alexandra M. Stoianov
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada, N6A 5C1
| | - Debra L. Robson
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada, N6A 5C1
| | - Alexandra M. Hetherington
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada, N6A 5C1
| | - Cynthia G. Sawyez
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada, N6A 5C1
- Department of Medicine, Western University, London, ON, Canada, N6A 5C1
- Robarts Research Institute, Western University, London, ON, Canada, N6A 5C1
| | - Nica M. Borradaile
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada, N6A 5C1
- * E-mail:
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50
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Bosma M, Dapito DH, Drosatos-Tampakaki Z, Huiping-Son N, Huang LS, Kersten S, Drosatos K, Goldberg IJ. Sequestration of fatty acids in triglycerides prevents endoplasmic reticulum stress in an in vitro model of cardiomyocyte lipotoxicity. Biochim Biophys Acta Mol Cell Biol Lipids 2015; 1841:1648-55. [PMID: 25251292 DOI: 10.1016/j.bbalip.2014.09.012] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Revised: 08/31/2014] [Accepted: 09/15/2014] [Indexed: 12/14/2022]
Abstract
We used human cardiomyocyte-derived cells to create an in vitro model to study lipid metabolism and explored the effects of PPARγ; ACSL1 and ATGL on fatty acid-induced ER stress. Compared to oleate, palmitate treatment resulted in less intracellular accumulation of lipid droplets and more ER stress, as measured by upregulation of CHOP, ATF6 and GRP78 gene expression and phosphorylation of eukaryotic initiation factor 2a (EIF2a). Both ACSL1 and PPARγ adenovirus-mediated expression augmented neutral lipid accumulation and reduced palmitate-induced upregulation of ER stress markers to levels similar to those in the oleate and control treatment groups. This suggests that increased channeling of non-esterified free fatty acids (NEFA) towards storage in the form of neutral lipids in lipid droplets protects against palmitate-induced ER stress. Overexpression of ATGL in cells incubated with oleate-containing medium increased NEFA release and stimulated expression of ER stress markers. Thus, inefficient creation of lipid droplets as well greater release of stored lipids induces ER stress.
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