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Buishand FO, Chan PYK, Xia D, Davison LJ. Single-cell transcriptome conservation in a multispecies comparative analysis of fresh and cryopreserved insulinoma cell lines. VETERINARY ONCOLOGY (LONDON, ENGLAND) 2025; 2:14. [PMID: 40438246 PMCID: PMC12106491 DOI: 10.1186/s44356-025-00025-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 04/07/2025] [Indexed: 06/01/2025]
Abstract
Background Insulinoma is the most common pancreatic neuroendocrine tumour in dogs and humans. The understanding of driving factors and critical survival genes in insulinomas is limited and overall survival is poor for canine and human malignant insulinoma. This study aimed to use single-cell RNA-sequencing to conduct a multispecies analysis of insulinoma cell lines to understand their single-cell transcriptomic landscape. Secondly, the impact of freeze-thawing on the pancreatic beta single-cell transcriptome was investigated, to determine whether cryoarchiving of primary insulinoma samples may be feasible in future studies. Methods Single-cell transcriptomic analysis was performed using fresh and cryopreserved multispecies insulinoma cell lines (canINS, CM, INS-1 and MIN6). R and Seurat were used to perform cell clustering and specific cluster marker genes were identified by the FindMarkers function. Metascape was used to identify statistically enriched pathways for specific cell clusters. Differentially expressed genes between fresh and cryopreserved single-cell transcriptome profiles, were defined as genes with a log2 fold change > 0.25 and a Bonferroni-adjusted P < 0.05, based on the Wilcoxon rank sum test. Results Based on the specific cell line single-cell transcriptome profiles, five or six cell clusters were constructed per cell line. All cell lines expressed neuroendocrine markers and additionally INS-1 and MIN6 displayed a gene signature indicative of mature/functional pancreatic islet/beta-cells. DEPTOR, BICC1, GHR, CCNB2, CENPA, LMO4, VANGL1, and L1CAM were identified as cross-species conserved insulinoma cluster marker genes. Little effect was found of cryopreservation and thawing on overall gene expression at the single-cell level in insulinoma cell lines: only 6 and 29 genes had a log2 fold change > 1 in cryopreserved versus fresh canINS and CM, respectively. Conclusions canINS, CM, INS-1 and MIN6 are all principally relevant as insulinoma models and the demonstrated differences in their single-cell transcriptomic profiles could aid researchers in selecting the appropriate cell lines for specific study objectives. Cross-species conserved insulinoma cluster marker genes were identified that harbour oncogenes and their involvement in insulinoma tumourigenesis should be investigated in future studies. The good comparability between cryopreserved and fresh insulinoma cells allows for inclusion of cryopreserved insulinoma patient samples in future studies, which allows for reduced assay-based variability. Supplementary Information The online version contains supplementary material available at 10.1186/s44356-025-00025-4.
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Affiliation(s)
- Floryne O. Buishand
- Department of Clinical Science and Services, Royal Veterinary College, Hatfield, AL9 7TA UK
| | - Phoebe Y. K. Chan
- Department of Clinical Science and Services, Royal Veterinary College, Hatfield, AL9 7TA UK
| | - Dong Xia
- Department of Pathobiology and Population Sciences, Royal Veterinary College, Hatfield, AL9 7TA UK
| | - Lucy J. Davison
- Department of Clinical Science and Services, Royal Veterinary College, Hatfield, AL9 7TA UK
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Reddy T, Puri A, Guzman-Rojas L, Thomas C, Qian W, Zhou J, Zhao H, Mahboubi B, Oo A, Cho YJ, Kim B, Thaiparambil J, Rosato R, Martinez KO, Chervo MF, Ayerbe C, Giese N, Wink D, Lockett S, Wong S, Chang J, Krishnamurthy S, Yam C, Moulder S, Piwnica-Worms H, Meric-Bernstam F, Chang J. NOS inhibition sensitizes metaplastic breast cancer to PI3K inhibition and taxane therapy via c-JUN repression. Nat Commun 2024; 15:10737. [PMID: 39737957 PMCID: PMC11685991 DOI: 10.1038/s41467-024-54651-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 11/19/2024] [Indexed: 01/01/2025] Open
Abstract
Metaplastic breast cancer (MpBC) is a highly chemoresistant subtype of breast cancer with no standardized therapy options. A clinical study in anthracycline-refractory MpBC patients suggested that nitric oxide synthase (NOS) inhibitor NG-monomethyl-l-arginine (L-NMMA) may augment anti-tumor efficacy of taxane. We report that NOS blockade potentiated response of human MpBC cell lines and tumors to phosphoinositide 3-kinase (PI3K) inhibitor alpelisib and taxane. Mechanistically, NOS blockade leads to a decrease in the S-nitrosylation of c-Jun NH2-terminal kinase (JNK)/c-Jun complex to repress its transcriptional output, leading to enhanced tumor differentiation and associated chemosensitivity. As a result, combined NOS and PI3K inhibition with taxane targets MpBC stem cells and improves survival in patient-derived xenograft models relative to single-/dual-agent therapy. Similarly, biopsies from MpBC tumors that responded to L-NMMA+taxane therapy showed a post-treatment reversal of epithelial-to-mesenchymal transition and decreased stemness. Our findings suggest that combined inhibition of iNOS and PI3K is a unique strategy to decrease chemoresistance and improve clinical outcomes in MpBC.
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Affiliation(s)
- Tejaswini Reddy
- Department of Internal Medicine, Baylor College of Medicine, Houston, TX, USA
- Houston Methodist Research Institute, Houston, TX, USA
- Houston Methodist Neal Cancer Center, Houston, TX, USA
| | - Akshjot Puri
- Houston Methodist Research Institute, Houston, TX, USA
- Houston Methodist Neal Cancer Center, Houston, TX, USA
| | | | - Christoforos Thomas
- Houston Methodist Research Institute, Houston, TX, USA
- Houston Methodist Neal Cancer Center, Houston, TX, USA
| | - Wei Qian
- Houston Methodist Research Institute, Houston, TX, USA
| | - Jianying Zhou
- Houston Methodist Research Institute, Houston, TX, USA
| | - Hong Zhao
- Houston Methodist Research Institute, Houston, TX, USA
- Houston Methodist Neal Cancer Center, Houston, TX, USA
| | - Bijan Mahboubi
- Adams School of Dentistry, University of North Carolina, Chapel Hill, USA
| | - Adrian Oo
- Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA, USA
| | - Young-Jae Cho
- Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA, USA
| | - Baek Kim
- Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA, USA
| | | | | | | | | | - Camila Ayerbe
- McGovern Medical School, The University of Texas Health Science Center, Houston, TX, USA
| | - Noah Giese
- Houston Methodist Research Institute, Houston, TX, USA
- Houston Methodist Neal Cancer Center, Houston, TX, USA
| | - David Wink
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institute of Health, Frederick, MD, USA
| | - Stephen Lockett
- Optical Microscopy and Analysis Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA
| | - Stephen Wong
- Houston Methodist Research Institute, Houston, TX, USA
- Houston Methodist Neal Cancer Center, Houston, TX, USA
| | - Jeffrey Chang
- McGovern Medical School, The University of Texas Health Science Center, Houston, TX, USA
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Clinton Yam
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | | | | | - Jenny Chang
- Houston Methodist Research Institute, Houston, TX, USA.
- Houston Methodist Neal Cancer Center, Houston, TX, USA.
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3
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Talarico G, Franceschini A, Raveane A, Falvo P, Mazzara S, Melle F, Motta G, Orecchioni S, Tenore A, Gregato G, Poletti C, Chiarle R, Pileri S, Mancuso P, Bertolini F. HSP and CD279 gene expression as candidate biomarkers in symptomatic LGLL patients. Discov Oncol 2024; 15:764. [PMID: 39692827 DOI: 10.1007/s12672-024-01657-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 12/02/2024] [Indexed: 12/19/2024] Open
Abstract
The clinical presentation of T-cell large granular lymphocytic leukemia (T-LGLL) is extremely variable: 30% of patients have neutropenia with no associated symptoms, others present with bacterial infections and sepsis may occur. Tools to predict patient outcome are lacking. Stemming from preliminary results obtained by single cell-RNAseq we investigated by qPCR HSP and IFIT gene families in 27 LGLL patients (23T-LGLL and 4 NK-LGLL), including 11 with neutropenia and/or thrombocytopenia and 16 asymptomatic for the disease. HSP90AA1 and HSPA1B, among HSP family and CD279 exhibited a significantly higher expression in CD3 + CD57 + sorted cells of symptomatic LGLL patients compared to asymptomatic patients and healthy controls. Also, monocytes derived from symptomatic LGLL patients expressed high levels of CCL3, CCL4 and CCL5 mRNA and of IL-1β, IL-6, TNF, and PD-L1 mRNA, thus confirming a pro-inflammatory cytokine profile reminiscent of a non-classical phenotype. Overall, these data provide a rationale for considering HSP and CD279 genes as potential biomarkers for distinguishing symptomatic LGLL patients from asymptomatic ones, emphasizing the importance of further research to explore their implications for targeted therapy development.
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Affiliation(s)
- Giovanna Talarico
- Laboratory of Hematology-Oncology, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141, Milan, MI, Italy
- Onco-Tech Lab, European Institute of Oncology IRCCS and Politecnico di Milano, Milan, Italy
| | - Andrea Franceschini
- Laboratory of Hematology-Oncology, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141, Milan, MI, Italy
- Onco-Tech Lab, European Institute of Oncology IRCCS and Politecnico di Milano, Milan, Italy
| | - Alessandro Raveane
- Laboratory of Hematology-Oncology, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141, Milan, MI, Italy
- Onco-Tech Lab, European Institute of Oncology IRCCS and Politecnico di Milano, Milan, Italy
- Human Technopole, 20157, Milan, Italy
| | - Paolo Falvo
- Laboratory of Hematology-Oncology, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141, Milan, MI, Italy
- Onco-Tech Lab, European Institute of Oncology IRCCS and Politecnico di Milano, Milan, Italy
| | - Saveria Mazzara
- Haematopathology Division, IRCCS, Istituto Europeo Di Oncologia, IEO, Milan, Italy
| | - Federica Melle
- Haematopathology Division, IRCCS, Istituto Europeo Di Oncologia, IEO, Milan, Italy
| | - Giovanna Motta
- Haematopathology Division, IRCCS, Istituto Europeo Di Oncologia, IEO, Milan, Italy
| | - Stefania Orecchioni
- Laboratory of Hematology-Oncology, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141, Milan, MI, Italy
- Onco-Tech Lab, European Institute of Oncology IRCCS and Politecnico di Milano, Milan, Italy
| | - Annamaria Tenore
- Laboratory of Hematology-Oncology, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141, Milan, MI, Italy
- Onco-Tech Lab, European Institute of Oncology IRCCS and Politecnico di Milano, Milan, Italy
| | - Giuliana Gregato
- Laboratory of Hematology-Oncology, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141, Milan, MI, Italy
- Onco-Tech Lab, European Institute of Oncology IRCCS and Politecnico di Milano, Milan, Italy
| | - Claudia Poletti
- Laboratory of Hematology-Oncology, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141, Milan, MI, Italy
- Onco-Tech Lab, European Institute of Oncology IRCCS and Politecnico di Milano, Milan, Italy
| | - Roberto Chiarle
- Haematopathology Division, IRCCS, Istituto Europeo Di Oncologia, IEO, Milan, Italy
| | - Stefano Pileri
- Haematopathology Division, IRCCS, Istituto Europeo Di Oncologia, IEO, Milan, Italy
| | - Patrizia Mancuso
- Laboratory of Hematology-Oncology, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141, Milan, MI, Italy
- Onco-Tech Lab, European Institute of Oncology IRCCS and Politecnico di Milano, Milan, Italy
| | - Francesco Bertolini
- Laboratory of Hematology-Oncology, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141, Milan, MI, Italy.
- Onco-Tech Lab, European Institute of Oncology IRCCS and Politecnico di Milano, Milan, Italy.
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Profantová B, Římal V, Profant V, Socha O, Barvík I, Štěpánková H, Štěpánek J. Polymorphic potential of SRF binding site of c-Fos gene promoter: in vitro study. RSC Adv 2024; 14:38253-38267. [PMID: 39628460 PMCID: PMC11613138 DOI: 10.1039/d4ra05897f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 11/25/2024] [Indexed: 12/06/2024] Open
Abstract
Recently published in vivo observations have highlighted the presence of cruciform structures within the genome, suggesting their potential significance in the rapid recognition of the target sequence for transcription factor binding. In this in vitro study, we investigate the organization and stability of the sense (coding) strand within the Serum Response Element of the c-Fos gene promoter (c-Fos SRE), specifically focusing on segments spanning 12 to 36 nucleotides, centered around the CArG-box. Through a thorough examination of UV absorption patterns with varying temperatures, we identified the emergence of a remarkably stable structure, which we conclusively characterized as a hairpin using complementary 1H NMR experiments. Our research decisively ruled out the formation of homoduplexes, as confirmed by supplementary fluorescence experiments. Utilizing molecular dynamics simulations with atomic distance constraints derived from NMR data, we explored the structural intricacies of the compact hairpin. Notably, the loop consisting of the six-membered A/T sequence demonstrated substantial stabilization through extensive stacking, non-canonical inter-base hydrogen bonding, and hydrophobic clustering of thymine methyl groups. These findings suggest the potential of the c-Fos SRE to adopt a cruciform structure (consisting of two opposing hairpins), potentially providing a topological recognition site for the SRF transcription factor under cellular conditions. Our results should inspire further biochemical and in vivo studies to explore the functional implications of these non-canonical DNA structures.
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Affiliation(s)
- Barbora Profantová
- Institute of Physics, Faculty of Mathematics and Physics, Charles University Ke Karlovu 5, 121 16 Prague 2 Czech Republic +420 95155 1471
| | - Václav Římal
- Department of Low-Temperature Physics, Faculty of Mathematics and Physics, Charles University V Holešovičkách 2, 180 00 Prague 8 Czech Republic
| | - Václav Profant
- Institute of Physics, Faculty of Mathematics and Physics, Charles University Ke Karlovu 5, 121 16 Prague 2 Czech Republic +420 95155 1471
| | - Ondřej Socha
- Department of Low-Temperature Physics, Faculty of Mathematics and Physics, Charles University V Holešovičkách 2, 180 00 Prague 8 Czech Republic
| | - Ivan Barvík
- Institute of Physics, Faculty of Mathematics and Physics, Charles University Ke Karlovu 5, 121 16 Prague 2 Czech Republic +420 95155 1471
| | - Helena Štěpánková
- Department of Low-Temperature Physics, Faculty of Mathematics and Physics, Charles University V Holešovičkách 2, 180 00 Prague 8 Czech Republic
| | - Josef Štěpánek
- Institute of Physics, Faculty of Mathematics and Physics, Charles University Ke Karlovu 5, 121 16 Prague 2 Czech Republic +420 95155 1471
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Hu Z, Li G, Luo X, Peng W, Liu J, Zhu X, Wu J. Identification of Cancer Driver Genes based on Dynamic Incentive Model. IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2024; 21:2371-2381. [PMID: 39316497 DOI: 10.1109/tcbb.2024.3467119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2024]
Abstract
Cancer is a complex genomic mutation disease, and identifying cancer driver genes promotes the development of targeted drugs and personalized therapies. The current computational method takes less consideration of the relationship among features and the effect of noise in protein-protein interaction(PPI) data, resulting in a low recognition rate. In this paper, we propose a cancer driver genes identification method based on dynamic incentive model, DIM. This method firstly constructs a hypergraph to reduce the impact of false positive data in PPI. Then, the importance of genes in each hyperedge in hypergraph is considered from three perspectives, network and functional score(NFS) is proposed. By analyzing the relation among features, the dynamic incentive model is proposed to fuse NFS, the differential expression score of mRNA and the differential expression score of miRNA. DIM is compared with some classical methods on breast cancer, lung cancer, prostate cancer, and pan-cancer datasets. The results show that DIM has the best performance on statistical evaluation indicators, functional consistency and the partial area under the ROC curve, and has good cross-cancer capability.
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Guo M, Wang T, Ge W, Ren C, Ko BCB, Zeng X, Cao D. Role of AKR1B10 in inflammatory diseases. Scand J Immunol 2024; 100:e13390. [PMID: 38769661 DOI: 10.1111/sji.13390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 05/01/2024] [Accepted: 05/05/2024] [Indexed: 05/22/2024]
Abstract
Inflammation is an important pathophysiological process in many diseases; it has beneficial and harmful effects. When exposed to various stimuli, the body triggers an inflammatory response to eliminate invaded pathogens and damaged tissues to maintain homeostasis. However, uncontrollable persistent or excessive inflammatory responses may damage tissues and induce various diseases, such as metabolic diseases (e.g. diabetes), autoimmune diseases, nervous system-related diseases, digestive system-related diseases, and even tumours. Aldo-keto reductase 1B10 (AKR1B10) is an important player in the development and progression of multiple diseases, such as tumours and inflammatory diseases. AKR1B10 is upregulated in solid tumours, such as hepatocellular carcinoma (HCC), non-small cell lung carcinoma, and breast cancer, and is a reliable serum marker. However, information on the role of AKR1B10 in inflammation is limited. In this study, we summarized the role of AKR1B10 in inflammatory diseases, including its expression, functional contribution to inflammatory responses, and regulation of signalling pathways related to inflammation. We also discussed the role of AKR1B10 in glucose and lipid metabolism and oxidative stress. This study provides novel information and increases the understanding of clinical inflammatory diseases.
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Affiliation(s)
- Min Guo
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Tao Wang
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Wenjun Ge
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Chenran Ren
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Ben Chi-Bun Ko
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
| | - Xi Zeng
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Deliang Cao
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, China
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7
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Thiel G, Rössler OG. Signal Transduction of Transient Receptor Potential TRPM8 Channels: Role of PIP5K, Gq-Proteins, and c-Jun. Molecules 2024; 29:2602. [PMID: 38893478 PMCID: PMC11174004 DOI: 10.3390/molecules29112602] [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: 04/30/2024] [Revised: 05/24/2024] [Accepted: 05/26/2024] [Indexed: 06/21/2024] Open
Abstract
Transient receptor potential melastatin-8 (TRPM8) is a cation channel that is activated by cold and "cooling agents" such as menthol and icilin, which induce a cold sensation. The stimulation of TRPM8 activates an intracellular signaling cascade that ultimately leads to a change in the gene expression pattern of the cells. Here, we investigate the TRPM8-induced signaling pathway that links TRPM8 channel activation to gene transcription. Using a pharmacological approach, we show that the inhibition of phosphatidylinositol 4-phosphate 5 kinase α (PIP5K), an enzyme essential for the biosynthesis of phosphatidylinositol 4,5-bisphosphate, attenuates TRPM8-induced gene transcription. Analyzing the link between TRPM8 and Gq proteins, we show that the pharmacological inhibition of the βγ subunits impairs TRPM8 signaling. In addition, genetic studies show that TRPM8 requires an activated Gα subunit for signaling. In the nucleus, the TRPM8-induced signaling cascade triggers the activation of the transcription factor AP-1, a complex consisting of a dimer of basic region leucine zipper (bZIP) transcription factors. Here, we identify the bZIP protein c-Jun as an essential component of AP-1 within the TRPM8-induced signaling cascade. In summary, with PIP5K, Gq subunits, and c-Jun, we identified key molecules in TRPM8-induced signaling from the plasma membrane to the nucleus.
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Affiliation(s)
- Gerald Thiel
- Department of Medical Biochemistry and Molecular Biology, Medical Faculty, Saarland University, 66421 Homburg, Germany;
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Perrone MC, Lerner MG, Dunworth M, Ewald AJ, Bader JS. Prioritizing drug targets by perturbing biological network response functions. PLoS Comput Biol 2024; 20:e1012195. [PMID: 38935814 PMCID: PMC11236158 DOI: 10.1371/journal.pcbi.1012195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 07/10/2024] [Accepted: 05/24/2024] [Indexed: 06/29/2024] Open
Abstract
Therapeutic interventions are designed to perturb the function of a biological system. However, there are many types of proteins that cannot be targeted with conventional small molecule drugs. Accordingly, many identified gene-regulatory drivers and downstream effectors are currently undruggable. Drivers and effectors are often connected by druggable signaling and regulatory intermediates. Methods to identify druggable intermediates therefore have general value in expanding the set of targets available for hypothesis-driven validation. Here we identify and prioritize potential druggable intermediates by developing a network perturbation theory, termed NetPert, for response functions of biological networks. Dynamics are defined by a network structure in which vertices represent genes and proteins, and edges represent gene-regulatory interactions and protein-protein interactions. Perturbation theory for network dynamics prioritizes targets that interfere with signaling from driver to response genes. Applications to organoid models for metastatic breast cancer demonstrate the ability of this mathematical framework to identify and prioritize druggable intermediates. While the short-time limit of the perturbation theory resembles betweenness centrality, NetPert is superior in generating target rankings that correlate with previous wet-lab assays and are more robust to incomplete or noisy network data. NetPert also performs better than a related graph diffusion approach. Wet-lab assays demonstrate that drugs for targets identified by NetPert, including targets that are not themselves differentially expressed, are active in suppressing additional metastatic phenotypes.
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Affiliation(s)
- Matthew C. Perrone
- Institute for Computational Medicine and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Michael G. Lerner
- Department of Physics, Engineering and Astronomy, Earlham College, Richmond, Indiana, United States of America
| | - Matthew Dunworth
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Andrew J. Ewald
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, United States of America
- Giovanis Institute for Translational Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Joel S. Bader
- Institute for Computational Medicine and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, United States of America
- Giovanis Institute for Translational Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
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Kazanietz MG, Cooke M. Protein kinase C signaling "in" and "to" the nucleus: Master kinases in transcriptional regulation. J Biol Chem 2024; 300:105692. [PMID: 38301892 PMCID: PMC10907189 DOI: 10.1016/j.jbc.2024.105692] [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: 10/23/2023] [Revised: 01/08/2024] [Accepted: 01/09/2024] [Indexed: 02/03/2024] Open
Abstract
PKC is a multifunctional family of Ser-Thr kinases widely implicated in the regulation of fundamental cellular functions, including proliferation, polarity, motility, and differentiation. Notwithstanding their primary cytoplasmic localization and stringent activation by cell surface receptors, PKC isozymes impel prominent nuclear signaling ultimately impacting gene expression. While transcriptional regulation may be wielded by nuclear PKCs, it most often relies on cytoplasmic phosphorylation events that result in nuclear shuttling of PKC downstream effectors, including transcription factors. As expected from the unique coupling of PKC isozymes to signaling effector pathways, glaring disparities in gene activation/repression are observed upon targeting individual PKC family members. Notably, specific PKCs control the expression and activation of transcription factors implicated in cell cycle/mitogenesis, epithelial-to-mesenchymal transition and immune function. Additionally, PKCs isozymes tightly regulate transcription factors involved in stepwise differentiation of pluripotent stem cells toward specific epithelial, mesenchymal, and hematopoietic cell lineages. Aberrant PKC expression and/or activation in pathological conditions, such as in cancer, leads to profound alterations in gene expression, leading to an extensive rewiring of transcriptional networks associated with mitogenesis, invasiveness, stemness, and tumor microenvironment dysregulation. In this review, we outline the current understanding of PKC signaling "in" and "to" the nucleus, with significant focus on established paradigms of PKC-mediated transcriptional control. Dissecting these complexities would allow the identification of relevant molecular targets implicated in a wide spectrum of diseases.
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Affiliation(s)
- Marcelo G Kazanietz
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
| | - Mariana Cooke
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
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Magnard R, Fouyssac M, Vachez YM, Cheng Y, Dufourd T, Carcenac C, Boulet S, Janak PH, Savasta M, Belin D, Carnicella S. Pramipexole restores behavioral inhibition in highly impulsive rats through a paradoxical modulation of frontostriatal networks. Transl Psychiatry 2024; 14:86. [PMID: 38336862 PMCID: PMC10858232 DOI: 10.1038/s41398-024-02804-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 01/18/2024] [Accepted: 01/23/2024] [Indexed: 02/12/2024] Open
Abstract
Impulse control disorders (ICDs), a wide spectrum of maladaptive behaviors which includes pathological gambling, hypersexuality and compulsive buying, have been recently suggested to be triggered or aggravated by treatments with dopamine D2/3 receptor agonists, such as pramipexole (PPX). Despite evidence showing that impulsivity is associated with functional alterations in corticostriatal networks, the neural basis of the exacerbation of impulsivity by PPX has not been elucidated. Here we used a hotspot analysis to assess the functional recruitment of several corticostriatal structures by PPX in male rats identified as highly (HI), moderately impulsive (MI) or with low levels of impulsivity (LI) in the 5-choice serial reaction time task (5-CSRTT). PPX dramatically reduced impulsivity in HI rats. Assessment of the expression pattern of the two immediate early genes C-fos and Zif268 by in situ hybridization subsequently revealed that PPX resulted in a decrease in Zif268 mRNA levels in different striatal regions of both LI and HI rats accompanied by a high impulsivity specific reduction of Zif268 mRNA levels in prelimbic and cingulate cortices. PPX also decreased C-fos mRNA levels in all striatal regions of LI rats, but only in the dorsolateral striatum and nucleus accumbens core (NAc Core) of HI rats. Structural equation modeling further suggested that the anti-impulsive effect of PPX was mainly attributable to the specific downregulation of Zif268 mRNA in the NAc Core. Altogether, our results show that PPX restores impulse control in highly impulsive rats by modulation of limbic frontostriatal circuits.
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Affiliation(s)
- Robin Magnard
- Univ. Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, 38000, Grenoble, France.
| | - Maxime Fouyssac
- Department of Psychology, University of Cambridge, Downing Street, CB2 3EB, Cambridge, United Kingdom
| | - Yvan M Vachez
- Univ. Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, 38000, Grenoble, France
| | - Yifeng Cheng
- Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, MD, 21218, USA
| | - Thibault Dufourd
- Univ. Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, 38000, Grenoble, France
| | - Carole Carcenac
- Univ. Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, 38000, Grenoble, France
| | - Sabrina Boulet
- Univ. Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, 38000, Grenoble, France
| | - Patricia H Janak
- Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, MD, 21218, USA
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Marc Savasta
- Univ. Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, 38000, Grenoble, France
| | - David Belin
- Department of Psychology, University of Cambridge, Downing Street, CB2 3EB, Cambridge, United Kingdom
| | - Sebastien Carnicella
- Univ. Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, 38000, Grenoble, France
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11
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Gui Y, Qian X, Ding Y, Chen Q, Fangyu Ye, Ye Y, Hou Y, Yu J, Zhao L. c-Fos regulated by TMPO/ERK axis promotes 5-FU resistance via inducing NANOG transcription in colon cancer. Cell Death Dis 2024; 15:61. [PMID: 38233377 PMCID: PMC10794174 DOI: 10.1038/s41419-024-06451-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 01/05/2024] [Accepted: 01/08/2024] [Indexed: 01/19/2024]
Abstract
Acquired drug resistance is one of the most common limitations for the clinical response of colon cancer to 5-Fluorouracil (5-FU)-based chemotherapy. The relevant molecular mechanisms might be diversity, but still not be elucidated clearly. In this study, we aimed to investigate the potential mechanisms of c-Fos, a subfamily of activator protein-1, in 5-FU chemoresistance. We determined that phosphorylated c-Fos promoted colon cancer cells resistance to 5-FU by facilitating the cancer stemness. Mechanically, 5-FU treatment induced autolysosome-dependent degradation of TMPO, which subsequently triggered ERK-mediated phosphorylation of c-Fos. Additionally, c-Fos was found to bind to the promoter of NANOG and phosphorylation of c-Fos at Ser 374 was required for its regulation of NANOG expression. NANOG ablation impaired c-Fos/p-c-Fos induced 5-FU resistance and stemness. Taken together, these findings revealed that TMPO-mediated phosphorylation of c-Fos conferred 5-FU resistance by regulating NANOG expression and promoting cell stemness in colon cancer cells. c-Fos could be as a therapeutic target for colon cancer.
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Affiliation(s)
- Yanping Gui
- Public Experimental Platform, China Pharmaceutical University, Nanjing, 211198, China
| | - Xiaoping Qian
- Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, 215153, China
| | - Youxiang Ding
- Department of Pathology, Nanjing Drum Tower Hospital, Affiliated to Medical College of Nanjing University, Nanjing, 210008, China
| | - Qianqian Chen
- Public Experimental Platform, China Pharmaceutical University, Nanjing, 211198, China
| | - Fangyu Ye
- Public Experimental Platform, China Pharmaceutical University, Nanjing, 211198, China
| | - Yuting Ye
- Public Experimental Platform, China Pharmaceutical University, Nanjing, 211198, China
| | - Yingjian Hou
- Public Experimental Platform, China Pharmaceutical University, Nanjing, 211198, China
| | - Jun Yu
- Jiangsu Cancer Hospital, Nanjing, 210009, China
| | - Li Zhao
- Public Experimental Platform, China Pharmaceutical University, Nanjing, 211198, China.
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12
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Lu K, Wang HC, Tu YC, Chang CC, Lou PJ, Chang TC, Lin JJ. Suppressing c-FOS expression by G-quadruplex ligands inhibits osimertinib-resistant non-small cell lung cancer. J Natl Cancer Inst 2023; 115:1383-1391. [PMID: 37481710 DOI: 10.1093/jnci/djad142] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 05/01/2023] [Accepted: 07/19/2023] [Indexed: 07/24/2023] Open
Abstract
BACKGROUND Osimertinib is the first-line therapy for patients with non-small cell lung cancer harboring epidermal growth factor receptor-activating alterations. Although osimertinib has been shown to elicit profound patient responses, cancer cells frequently develop additional alterations that sustain their proliferation capacity. This acquired resistance represents a substantial hurdle in precision medicine for patients with lung cancer. METHODS The biological and cellular properties of the G-quadruplex ligand BMVC-8C3O and its anticancer activities were evaluated in non-small cell lung carcinomas. In addition, combined treatment with BMVC-8C3O and osimertinib was evaluated for its effects on the growth of osimertinib-resistant tumors in vivo. RESULTS We demonstrate that BMVC-8C3O effectively suppresses c-FOS expression by stabilizing G-rich sequences located at the c-FOS promoter. The suppression c-FOS expression by BMVC-8C3O increases the sensitivity of acquired resistant cancer cells to osimertinib. Combining BMVC-8C3O and osimertinib has a synergistic effect in inhibiting the growth of acquired resistant cancers both in vitro and in mouse models. The combined inhibitory effect is not limited to BMVC-8C3O, either: several G-quadruplex ligands show varying levels of inhibition activity. We also show that simultaneous inhibition of both the c-FOS and PI3K/AKT pathways by BMVC-8C3O and osimertinib synergistically inhibits the growth of acquired resistant cancer cells. CONCLUSION These findings unveil a synthetic lethal strategy to prevent and inhibit epidermal growth factor receptor-altered lung cancers with acquired osimertinib resistance. G-quadruplex ligands have the potential to be integrated into current osimertinib-based treatment regimens.
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Affiliation(s)
- Kai Lu
- Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Hsin-Chiao Wang
- Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yi-Chen Tu
- Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Cheng-Chung Chang
- Graduate Institute of Biomedical Engineering, National Chung Hsing University, Taichung, Taiwan
| | - Pei-Jen Lou
- Department of Otolaryngology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ta-Chau Chang
- Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, Taiwan
| | - Jing-Jer Lin
- Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei, Taiwan
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13
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Li X, Sun T, Liu J, Wei S, Yang Y, Liu J, Zhang B, Li W. Phloretin alleviates doxorubicin-induced cardiotoxicity through regulating Hif3a transcription via targeting transcription factor Fos. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 120:155046. [PMID: 37659297 DOI: 10.1016/j.phymed.2023.155046] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 08/15/2023] [Accepted: 08/24/2023] [Indexed: 09/04/2023]
Abstract
BACKGROUND Doxorubicin (Dox), a chemotherapeutic agent known for its efficacy, has been associated with the development of severe cardiotoxicity, commonly referred to as doxorubicin-induced cardiotoxicity (DIC). The role and mechanism of action of phloretin (Phl) in cardiovascular diseases are well-established; however, its specific function and underlying mechanism in the context of DIC have yet to be fully elucidated. OBJECTIVE This research aimed to uncover the protective effect of Phl against DIC in vivo and in vitro, while also providing a comprehensive understanding of the underlying mechanisms involved. METHODS DIC cell and murine models were established. The action targets and mechanism of Phl against DIC were comprehensively examined by systematic network pharmacology, molecular docking, transcriptomics technologies, transcription factor (TF) prediction, and experimental validation. RESULTS Phl relieved Dox-induced cell apoptosis in vitro and in vivo. Through network pharmacology analysis, a total of 554 co-targeted genes of Phl and Dox were identified. Enrichment analysis revealed several key pathways including the PI3K-Akt signaling pathway, Apoptosis, and the IL-17 signaling pathway. Protein-protein interaction (PPI) analysis identified 24 core co-targeted genes, such as Fos, Jun, Hif1a, which were predicted to bind well to Phl based on molecular docking. Transcriptomics analysis was performed to identify the top 20 differentially expressed genes (DEGs), and 202 transcription factors (TFs) were predicted for these DEGs. Among these TFs, 10 TFs (Fos, Jun, Hif1a, etc.) are also the co-targeted genes, and 3 TFs (Fos, Jun, Hif1a) are also the core co-targeted genes. Further experiments validated the finding that Phl reduced the elevated levels of Hif3a (one of the top 20 DEGs) and Fos (one of Hif3a's predicted TFs) induced by Dox. Moreover, the interaction between Fos protein and the Hif3a promoter was confirmed through luciferase reporter assays. CONCLUSION Phl actively targeted and down-regulated the Fos protein to inhibit its binding to the promoter region of Hif3a, thereby providing protection against DIC.
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Affiliation(s)
- Xiangyun Li
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China; School of Pharmacy, Central South University, Changsha, Hunan 410078, China
| | - Taoli Sun
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
| | - Jiaqin Liu
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China
| | - Shanshan Wei
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China
| | - Yuanying Yang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China
| | - Jian Liu
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China
| | - Bikui Zhang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China; School of Pharmacy, Central South University, Changsha, Hunan 410078, China.
| | - Wenqun Li
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China.
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14
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Ribeiro E. Silva A, Diallo MA, Sausset A, Robert T, Bach S, Bussière FI, Laurent F, Lacroix-Lamandé S, Silvestre A. Overexpression of Eimeria tenella Rhoptry Kinase 2 Induces Early Production of Schizonts. Microbiol Spectr 2023; 11:e0013723. [PMID: 37260371 PMCID: PMC10434272 DOI: 10.1128/spectrum.00137-23] [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: 01/10/2023] [Accepted: 05/04/2023] [Indexed: 06/02/2023] Open
Abstract
Eimeria tenella is an obligate intracellular parasite responsible for avian coccidiosis. Like other apicomplexan parasites, such as Toxoplasma gondii, cell invasion and intracellular development rely on apical organelle content discharge, named micronemes and rhoptries. Some rhoptry (ROP) kinases (ROPK) are key virulence factors in T. gondii. To date, among the 28 ropk genes carried by E. tenella, only two to four were confirmed by proteomic analysis or immunostaining to be expressed at the sporozoite stage. We have previously shown that EtROP1 is implicated in the inhibition of host cell apoptosis by interacting with the cellular p53. This work functionally described the second ROP kinase expressed at the sporozoite stage in E. tenella. EtROP2 is an active kinase that phosphorylates cell substrates of approximately 50 kDa. Its overexpression leads to the shortening of the prepatent period and to the early development of first-generation schizonts. Conduction of RNA sequencing analysis and reverse transcriptase quantitative PCR (RT-qPCR) on the host cell allowed us to identify the mitogen-activated protein kinase (MAPK) pathway and the transcription factor cFos to be upregulated by EtROP2. We also showed by immunofluorescence assay that the active kinase EtROP2 is implicated in the p38 MAPK pathway activation. We established here that EtROP2 activates the p38 MAPK pathway through a direct or indirect phosphorylation, leading to the overexpression of the master transcription factor cFos known to be implicated in E. tenella development. IMPORTANCE Rhoptries are specialized secretory organelles found in zoite stages of apicomplexan parasites. In addition to well-conserved rhoptry neck proteins, their protein consists mostly of kinase proteins, highly divergent from eukaryotic kinases. Some of those kinases are described as major virulence factors in Toxoplasma gondii, secreted into the host cell to hijack signaling pathways. Most of those kinases remain to be characterized in Eimeria tenella. Deciphering their cellular function is a prerequisite to supporting their relevance as a druggable target in development of new means of Eimeria tenella control. Secreted divergent kinases that interact with host cell partners to modulate pathways are good candidates, as they coevolve with their host targets to ensure their function within the host and are less prone to mutations that would lead to drug resistance. The absence of any orthologous kinase in host cells makes these parasite kinases a promising drug target candidate.
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Affiliation(s)
| | | | - Alix Sausset
- ISP, INRAE, Université de Tours, Nouzilly, France
| | - Thomas Robert
- Sorbonne Université, CNRS, UMR 8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, Roscoff, France
- Sorbonne Université, CNRS, FR 2424, Plateforme de Criblage KISSf (Kinase Inhibitor Specialized Screening Facility), Station Biologique de Roscoff, Roscoff, France
| | - Stéphane Bach
- Sorbonne Université, CNRS, UMR 8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, Roscoff, France
- Sorbonne Université, CNRS, FR 2424, Plateforme de Criblage KISSf (Kinase Inhibitor Specialized Screening Facility), Station Biologique de Roscoff, Roscoff, France
- Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa
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15
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Agrawal R, Natarajan KN. Oncogenic signaling pathways in pancreatic ductal adenocarcinoma. Adv Cancer Res 2023; 159:251-283. [PMID: 37268398 DOI: 10.1016/bs.acr.2023.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common (∼90% cases) pancreatic neoplasm and one of the most lethal cancer among all malignances. PDAC harbor aberrant oncogenic signaling that may result from the multiple genetic and epigenetic alterations such as the mutation in driver genes (KRAS, CDKN2A, p53), genomic amplification of regulatory genes (MYC, IGF2BP2, ROIK3), deregulation of chromatin-modifying proteins (HDAC, WDR5) among others. A key event is the formation of Pancreatic Intraepithelial Neoplasia (PanIN) that often results from the activating mutation in KRAS. Mutated KRAS can direct a variety of signaling pathways and modulate downstream targets including MYC, which play an important role in cancer progression. In this review, we discuss recent literature shedding light on the origins of PDAC from the perspective of major oncogenic signaling pathways. We highlight how MYC directly and indirectly, with cooperation with KRAS, affect epigenetic reprogramming and metastasis. Additionally, we summarize the recent findings from single cell genomic approaches that highlight heterogeneity in PDAC and tumor microenvironment, and provide molecular avenues for PDAC treatment in the future.
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Affiliation(s)
- Rahul Agrawal
- DTU Bioengineering, Technical University of Denmark, Kongens Lyngby, Denmark
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16
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Yoshimura Y, Nakamura K, Seno M, Mochizuki M, Kawai K, Koba S, Watanabe T. Generation of c-Fos knockout rats, and observation of their phenotype. Exp Anim 2023; 72:95-102. [PMID: 36216550 PMCID: PMC9978135 DOI: 10.1538/expanim.22-0077] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
c-Fos is a useful marker gene of neuron activation for neuroscience and physiology research. The mechanism and function of neural networks have been elucidated using c-Fos reporter knock-in (KI) mice, but the small size of the mice makes it difficult to perform surgical procedures on specific brain regions. On the other hand, there is a large amount of accumulated data on behavioral studies using rats. Thus, the generation of c-Fos reporter rat is expected, but it is difficult to generate gene-modified rats. Furthermore, c-Fos gene abnormality is expected to be severe in rats, as shown in homozygous of c-Fos knockout (KO) mouse, but such analysis has rarely been performed and is not certain. This study generated c-Fos-deficient rats using CRISPR/Cas, with 1067 bp deletion including exon 1 of the c-Fos gene. Homozygous c-Fos KO rats had growth latency and the same tooth and bone abnormality as homozygous c-Fos KO mice but not heterozygous c-Fos KO rats. Therefore, the c-Fos gene in rats is expected to have the same function as that in mice, and the generation of c-Fos reporter KI rats is further anticipated.
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Affiliation(s)
- Yuki Yoshimura
- Division of Integrative Physiology, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan
| | - Kazuomi Nakamura
- Advanced Medicine Innovation and Clinical Research Center, Tottori University Hospital, 36-1 Nishi-cho, Yonago, Tottori 683-8504, Japan,Advanced Medicine & Translational Research Center, Organization for Research Initiative and Promotion, Tottori University, 86 Nishi-cho, Yonago, Tottori
683-8503, Japan
| | - Misako Seno
- Advanced Medicine & Translational Research Center, Organization for Research Initiative and Promotion, Tottori University, 86 Nishi-cho, Yonago, Tottori
683-8503, Japan
| | - Misa Mochizuki
- Pathology Center, Central Institute for Experimental Animals, 3-25-12 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210-0821, Japan
| | - Kenji Kawai
- Pathology Center, Central Institute for Experimental Animals, 3-25-12 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210-0821, Japan
| | - Satoshi Koba
- Division of Integrative Physiology, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan
| | - Tatsuo Watanabe
- Division of Integrative Physiology, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan
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17
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Henn M, Martin-Gorgojo V, Martin-Moreno JM. Vitamin D in Cancer Prevention: Gaps in Current Knowledge and Room for Hope. Nutrients 2022; 14:4512. [PMID: 36364774 PMCID: PMC9657468 DOI: 10.3390/nu14214512] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/20/2022] [Accepted: 10/21/2022] [Indexed: 08/03/2023] Open
Abstract
Intensive epigenome and transcriptome analyses have unveiled numerous biological mechanisms, including the regulation of cell differentiation, proliferation, and induced apoptosis in neoplastic cells, as well as the modulation of the antineoplastic action of the immune system, which plausibly explains the observed population-based relationship between low vitamin D status and increased cancer risk. However, large randomized clinical trials involving cholecalciferol supplementation have so far failed to show the potential of such interventions in cancer prevention. In this article, we attempt to reconcile the supposed contradiction of these findings by undertaking a thorough review of the literature, including an assessment of the limitations in the design, conduct, and analysis of the studies conducted thus far. We examine the long-standing dilemma of whether the beneficial effects of vitamin D levels increase significantly above a critical threshold or if the conjecture is valid that an increase in available cholecalciferol translates directly into an increase in calcitriol activity. In addition, we try to shed light on the high interindividual epigenetic and transcriptomic variability in response to cholecalciferol supplementation. Moreover, we critically review the standards of interpretation of the available study results and propose criteria that could allow us to reach sound conclusions in this field. Finally, we advocate for options tailored to individual vitamin D needs, combined with a comprehensive intervention that favors prevention through a healthy environment and responsible health behaviors.
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Affiliation(s)
- Matthias Henn
- Department of Preventive Medicine and Public Health, University of Navarra-IdiSNA (Instituto de Investigación Sanitaria de Navarra), 31008 Pamplona, Spain
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Victor Martin-Gorgojo
- Biomedical Research Institute INCLIVA, Hospital Clínico Universitario de Valencia, 46010 Valencia, Spain
- Orthopedic Surgery and Traumatology Department, Hospital Clínico Universitario de Valencia, 46010 Valencia, Spain
| | - Jose M. Martin-Moreno
- Biomedical Research Institute INCLIVA, Hospital Clínico Universitario de Valencia, 46010 Valencia, Spain
- Department of Preventive Medicine and Public Health, Universitat de Valencia, 46010 Valencia, Spain
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18
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Transcriptomic Analysis in Marine Medaka Gill Reveals That the Hypo-Osmotic Stress Could Alter the Immune Response via the IL17 Signaling Pathway. Int J Mol Sci 2022; 23:ijms232012417. [PMID: 36293271 PMCID: PMC9604416 DOI: 10.3390/ijms232012417] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 10/03/2022] [Accepted: 10/12/2022] [Indexed: 11/17/2022] Open
Abstract
Fish gills are the major osmoregulatory tissue that contact the external water environment and have developed an effective osmoregulatory mechanism to maintain cellular function. Marine medaka (Oryzias melastigma) has the ability to live in both seawater and fresh water environments. The present study performed a seawater (SW) to 50% seawater (SFW) transfer, and the gill samples were used for comparative transcriptomic analysis to study the alteration of hypo-osmotic stress on immune responsive genes in this model organism. The result identified 518 differentiated expressed genes (DEGs) after the SW to SFW transfer. Various pathways such as p53 signaling, forkhead box O signaling, and the cell cycle were enriched. Moreover, the immune system was highlighted as one of the top altered biological processes in the enrichment analysis. Various cytokines, chemokines, and inflammatory genes that participate in the IL-17 signaling pathway were suppressed after the SW to SFW transfer. On the other hand, some immunoglobulin-related genes were up-regulated. The results were further validated by real-time qPCR. Taken together, our study provides additional gill transcriptome information in marine medaka; it also supports the notion that osmotic stress could influence the immune responses in fish gills.
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19
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Weber Boutros S, Unni VK, Raber J. An Adaptive Role for DNA Double-Strand Breaks in Hippocampus-Dependent Learning and Memory. Int J Mol Sci 2022; 23:8352. [PMID: 35955487 PMCID: PMC9368779 DOI: 10.3390/ijms23158352] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 07/22/2022] [Accepted: 07/25/2022] [Indexed: 12/10/2022] Open
Abstract
DNA double-strand breaks (DSBs), classified as the most harmful type of DNA damage based on the complexity of repair, lead to apoptosis or tumorigenesis. In aging, DNA damage increases and DNA repair decreases. This is exacerbated in disease, as post-mortem tissue from patients diagnosed with mild cognitive impairment (MCI) or Alzheimer's disease (AD) show increased DSBs. A novel role for DSBs in immediate early gene (IEG) expression, learning, and memory has been suggested. Inducing neuronal activity leads to increases in DSBs and upregulation of IEGs, while increasing DSBs and inhibiting DSB repair impairs long-term memory and alters IEG expression. Consistent with this pattern, mice carrying dominant AD mutations have increased baseline DSBs, and impaired DSB repair is observed. These data suggest an adaptive role for DSBs in the central nervous system and dysregulation of DSBs and/or repair might drive age-related cognitive decline (ACD), MCI, and AD. In this review, we discuss the adaptive role of DSBs in hippocampus-dependent learning, memory, and IEG expression. We summarize IEGs, the history of DSBs, and DSBs in synaptic plasticity, aging, and AD. DSBs likely have adaptive functions in the brain, and even subtle alterations in their formation and repair could alter IEGs, learning, and memory.
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Affiliation(s)
- Sydney Weber Boutros
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA;
| | - Vivek K. Unni
- Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA;
- Jungers Center for Neurosciences Research, Oregon Health & Science University, Portland, OR 97239, USA
- Oregon Health & Science University Parkinson Center, Portland, OR 97239, USA
| | - Jacob Raber
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA;
- Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA;
- Department of Radiation Medicine, Oregon Health & Science University, Portland, OR 97239, USA
- Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR 97006, USA
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20
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Takeuchi H, Kato Y, Sasaki N, Tanigaki K, Yamaga S, Mita E, Kuboniwa M, Matsusaki M, Amano A. Surface pre-reacted glass-ionomer eluate protects gingival epithelium from penetration by lipopolysaccharides and peptidoglycans via transcription factor EB pathway. PLoS One 2022; 17:e0271192. [PMID: 35895663 PMCID: PMC9328573 DOI: 10.1371/journal.pone.0271192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 06/24/2022] [Indexed: 11/25/2022] Open
Abstract
Surface pre-reacted glass-ionomer (S-PRG) filler, produced by PRG technology for use with various dental materials, is bioactive and known to release ions from a glass-ionomer phase. We previously reported that coxsackievirus and adenovirus receptor (CXADR), a tight junction associated protein, was located in the epithelial barrier of gingival epithelium. In the present study, the tissue protective effects of an S-PRG eluate prepared with S-PRG filler were investigated using a three-dimensional human gingival epithelial tissue model. The results showed that the S-PRG eluate specifically induced CXADR expression at the transcriptional level of messenger RNA as well as the protein level, and also nuclear translocation of transcription factor EB (TFEB) in gingival epithelial cells. Furthermore, shigyakusan, a TFEB inhibitor, canceled induction of the CXADR protein by the S-PRG eluate. Additionally, gingival epithelial permeation by 40-kDa dextran, lipopolysaccharide, and peptidoglycan in the 3D-tissue models was prevented by the eluate, with those effects abrogated by knockdown of CXADR. These findings suggest that S-PRG eluate increases CXADR expression via the TFEB pathway, thus inhibiting penetration of bacterial virulence factors into subepithelial tissues.
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Affiliation(s)
- Hiroki Takeuchi
- Department of Preventive Dentistry, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan
- * E-mail:
| | - Yuta Kato
- Department of Preventive Dentistry, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan
| | - Naoko Sasaki
- Joint Research Laboratory (TOPPAN) for Advanced Cell Regulatory Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka, Japan
| | - Keita Tanigaki
- Department of Preventive Dentistry, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan
| | - Shunsuke Yamaga
- Department of Preventive Dentistry, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan
| | - Ena Mita
- Department of Preventive Dentistry, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan
| | - Masae Kuboniwa
- Department of Preventive Dentistry, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan
| | - Michiya Matsusaki
- Joint Research Laboratory (TOPPAN) for Advanced Cell Regulatory Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka, Japan
- Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka, Japan
| | - Atsuo Amano
- Department of Preventive Dentistry, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan
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21
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Quantitative phosphoproteomics reveals ectopic ATP synthase on mesenchymal stem cells to promote tumor progression via ERK/c-Fos pathway activation. Mol Cell Proteomics 2022; 21:100237. [PMID: 35439648 PMCID: PMC9117939 DOI: 10.1016/j.mcpro.2022.100237] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 04/01/2022] [Accepted: 04/13/2022] [Indexed: 11/22/2022] Open
Abstract
The tumor microenvironment (TME), which comprises cellular and noncellular components, is involved in the complex process of cancer development. Emerging evidence suggests that mesenchymal stem cells (MSCs), one of the vital regulators of the TME, foster tumor progression through paracrine secretion. However, the comprehensive phosphosignaling pathways that are mediated by MSC-secreting factors have not yet been fully established. In this study, we attempt to dissect the MSC-triggered mechanism in lung cancer using quantitative phosphoproteomics. A total of 1958 phosphorylation sites are identified in lung cancer cells stimulated with MSC-conditioned medium. Integrative analysis of the identified phosphoproteins and predicted kinases demonstrates that MSC-conditioned medium functionally promotes the proliferation and migration of lung cancer via the ERK/phospho-c-Fos-S374 pathway. Recent studies have reported that extracellular ATP accumulates in the TME and stimulates the P2X7R on the cancer cell membrane via purinergic signaling. We observe that ectopic ATP synthase is located on the surface of MSCs and excreted extracellular ATP into the lung cancer microenvironment to trigger the ERK/phospho-c-Fos-S374 pathway, which is consistent with these previous findings. Our results suggest that ectopic ATP synthase on the surface of MSCs releases extracellular ATP into the TME, which promotes cancer progression via activation of the ERK/phospho-c-Fos-S374 pathway.
Mesenchymal stem cells (MSCs) enhance lung cancer development through extracellular factor secretion. Phosphoproteomics discover MSCs-regulated phosphosignaling in the lung cancer. Ectopic ATP synthase on MSCs surface produces ATP into the tumor microenvironment. MSC-secreted extracellular ATP mediates the phosphorylation of the ERK/c-Fos axis.
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22
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Gonzalez Abreu JA, Rosenberg AE, Fricker BA, Wallace KJ, Seifert AW, Kelly AM. Species-typical group size differentially influences social reward neural circuitry during nonreproductive social interactions. iScience 2022; 25:104230. [PMID: 35521530 PMCID: PMC9062245 DOI: 10.1016/j.isci.2022.104230] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/24/2022] [Accepted: 04/06/2022] [Indexed: 11/22/2022] Open
Abstract
We investigated whether nonreproductive social interactions may be rewarding for colonial but not non-colonial species. We found that the colonial spiny mouse (Acomys cahirinus) is significantly more gregarious, more prosocial, and less aggressive than its non-colonial relative, the Mongolian gerbil (Meriones unguiculatus). In an immediate-early gene study, we examined oxytocin (OT) and tyrosine hydroxylase (TH) neural responses to interactions with a novel, same-sex conspecific or a novel object. The paraventricular nucleus of the hypothalamus (PVN) OT cell group was more responsive to interactions with a conspecific compared to a novel object in both species. However, the ventral tegmental area (VTA) TH cell group showed differential responses only in spiny mice. Further, PVN OT and VTA TH neural responses positively correlated in spiny mice, suggesting functional connectivity. These results suggest that colonial species may have evolved neural mechanisms associated with reward in novel, nonreproductive social contexts to promote large group-living.
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Affiliation(s)
| | - Ashley E. Rosenberg
- Department of Psychology, Emory University, 36 Eagle Row, Atlanta, GA 30322, USA
| | - Brandon A. Fricker
- Department of Psychology, Emory University, 36 Eagle Row, Atlanta, GA 30322, USA
| | - Kelly J. Wallace
- Department of Psychology, Emory University, 36 Eagle Row, Atlanta, GA 30322, USA
| | - Ashley W. Seifert
- Department of Biology, University of Kentucky, 675 Rose Street, Lexington, KY 40506, USA
| | - Aubrey M. Kelly
- Department of Psychology, Emory University, 36 Eagle Row, Atlanta, GA 30322, USA
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23
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Anti-Inflammatory Activities of an Anti-Histamine Drug, Loratadine, by Suppressing TAK1 in AP-1 Pathway. Int J Mol Sci 2022; 23:ijms23073986. [PMID: 35409346 PMCID: PMC8999734 DOI: 10.3390/ijms23073986] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 04/01/2022] [Accepted: 04/01/2022] [Indexed: 02/05/2023] Open
Abstract
Loratadine is an anti-histamine routinely used for treating allergies. However, recent findings have shown that Loratadine may also have anti-inflammatory functions, while their exact mechanisms have not yet been fully uncovered. In this paper, we investigated whether Loratadine can be utilized as an anti-inflammatory drug through a series of in vitro and in vivo experiments using a murine macrophage cell line and an acute gastritis mouse model. Loratadine was found to dramatically reduce the expression of pro-inflammatory genes, including MMP1, MMP3, and MMP9, and inhibit AP-1 transcriptional activation, as demonstrated by the luciferase assay. Therefore, we decided to further explore its role in the AP-1 signaling pathway. The expression of c-Jun and c-Fos, AP-1 subunits, was repressed by Loratadine and, correspondingly, the expression of p-JNK, p-MKK7, and p-TAK1 was also inhibited. In addition, Loratadine was able to reduce gastric bleeding in acute gastritis-induced mice; Western blotting using the stomach samples showed reduced p-c-Fos protein levels. Loratadine was shown to effectively suppress inflammation by specifically targeting TAK1 and suppressing consequent AP-1 signaling pathway activation and inflammatory cytokine production.
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24
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Attwaters M, Hughes SM. Cellular and molecular pathways controlling muscle size in response to exercise. FEBS J 2022; 289:1428-1456. [PMID: 33755332 DOI: 10.1111/febs.15820] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 02/27/2021] [Accepted: 03/12/2021] [Indexed: 12/14/2022]
Abstract
From the discovery of ATP and motor proteins to synaptic neurotransmitters and growth factor control of cell differentiation, skeletal muscle has provided an extreme model system in which to understand aspects of tissue function. Muscle is one of the few tissues that can undergo both increase and decrease in size during everyday life. Muscle size depends on its contractile activity, but the precise cellular and molecular pathway(s) by which the activity stimulus influences muscle size and strength remain unclear. Four correlates of muscle contraction could, in theory, regulate muscle growth: nerve-derived signals, cytoplasmic calcium dynamics, the rate of ATP consumption and physical force. Here, we summarise the evidence for and against each stimulus and what is known or remains unclear concerning their molecular signal transduction pathways and cellular effects. Skeletal muscle can grow in three ways, by generation of new syncytial fibres, addition of nuclei from muscle stem cells to existing fibres or increase in cytoplasmic volume/nucleus. Evidence suggests the latter two processes contribute to exercise-induced growth. Fibre growth requires increase in sarcolemmal surface area and cytoplasmic volume at different rates. It has long been known that high-force exercise is a particularly effective growth stimulus, but how this stimulus is sensed and drives coordinated growth that is appropriately scaled across organelles remains a mystery.
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Affiliation(s)
- Michael Attwaters
- Randall Centre for Cell and Molecular Biophysics, School of Basic and Medical Biosciences, King's College London, UK
| | - Simon M Hughes
- Randall Centre for Cell and Molecular Biophysics, School of Basic and Medical Biosciences, King's College London, UK
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25
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Lee C, Kim Y, Kaang BK. The primary motor cortex: the hub of motor learning in rodents. Neuroscience 2022; 485:163-170. [PMID: 35051529 DOI: 10.1016/j.neuroscience.2022.01.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Revised: 01/07/2022] [Accepted: 01/10/2022] [Indexed: 12/31/2022]
Abstract
The primary motor cortex, a dynamic center for overall motion control and decision making, undergoes significant alterations upon neural stimulation. Over the last few decades, data from numerous studies using rodent models have improved our understanding of the morphological and functional plasticity of the primary motor cortex. In particular, spatially specific formation of dendritic spines and their maintenance during distinct behaviors is considered crucial for motor learning. However, whether the modifications of specific synapses are associated with motor learning should be studied further. In this review, we summarized the findings of prior studies on the features and dynamics of the primary motor cortex in rodents.
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Affiliation(s)
- Chaery Lee
- School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Yeonjun Kim
- Interdisciplinary Program in Neuroscience, Seoul National University, Seoul 08826, Republic of Korea
| | - Bong-Kiun Kaang
- School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Republic of Korea.
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26
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Nguyen HT, Najih M, Martin LJ. The AP-1 family of transcription factors are important regulators of gene expression within Leydig cells. Endocrine 2021; 74:498-507. [PMID: 34599696 DOI: 10.1007/s12020-021-02888-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 09/16/2021] [Indexed: 10/20/2022]
Abstract
PURPOSE Members of the AP-1 family of transcription factors are immediate early genes being modulated by different extracellular signals. The aim of this review is to highlight the important roles of AP-1 members in transcriptional regulation of genes important for testicular Leydig cell function and male testosterone production. METHODS A search of the relevant literature was performed in Google Scholar and NCBI Pubmed for AP-1 members and Leydig cells. Additional information was accessed from references of relevant articles. Only primary data from original peer-reviewed articles was considered for this review. RESULTS Different signaling pathways important for Leydig cells' functions are involved in the regulation of the activity of AP-1 members. These transcription factors participate in the regulation of genes related to different biological processes important for Leydig cells. CONCLUSIONS We conclude that members of the AP-1 family of transcription factors play critical roles in the regulation of Leydig cell proliferation, steroidogenesis, and cell-to-cell communication.
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Affiliation(s)
- Ha Tuyen Nguyen
- Biology Department, Université de Moncton, Moncton, NB, E1A 3E9, Canada
| | - Mustapha Najih
- Biology Department, Université de Moncton, Moncton, NB, E1A 3E9, Canada
| | - Luc J Martin
- Biology Department, Université de Moncton, Moncton, NB, E1A 3E9, Canada.
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Zavvarian MM, Zhou C, Kahnemuyipour S, Hong J, Fehlings MG. The MAPK Signaling Pathway Presents Novel Molecular Targets for Therapeutic Intervention after Traumatic Spinal Cord Injury: A Comparative Cross-Species Transcriptional Analysis. Int J Mol Sci 2021; 22:12934. [PMID: 34884738 PMCID: PMC8657729 DOI: 10.3390/ijms222312934] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 11/26/2021] [Accepted: 11/26/2021] [Indexed: 11/29/2022] Open
Abstract
Despite the debilitating consequences following traumatic spinal cord injury (SCI), there is a lack of safe and effective therapeutics in the clinic. The species-specific responses to SCI present major challenges and opportunities for the clinical translation of biomolecular and pharmacological interventions. Recent transcriptional analyses in preclinical SCI studies have provided a snapshot of the local SCI-induced molecular responses in different animal models. However, the variation in the pathogenesis of traumatic SCI across species is yet to be explored. This study aims to identify and characterize the common and inconsistent SCI-induced differentially expressed genes across species to identify potential therapeutic targets of translational relevance. A comprehensive search of open-source transcriptome datasets identified four cross-compatible microarray experiments in rats, mice, and salamanders. We observed consistent expressional changes in extracellular matrix components across the species. Conversely, salamanders showed downregulation of intracellular MAPK signaling compared to rodents. Additionally, sequence conservation and interactome analyses highlighted the well-preserved sequences of Fn1 and Jun with extensive protein-protein interaction networks. Lastly, in vivo immunohistochemical staining for fibronectin was used to validate the observed expressional pattern. These transcriptional changes in extracellular and MAPK pathways present potential therapeutic targets for traumatic SCI with promising translational relevance.
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Affiliation(s)
- Mohammad-Masoud Zavvarian
- Division of Genetics and Development, Krembil Brain Institute, University Health Network, Toronto, ON M5T 2S8, Canada; (M.-M.Z.); (C.Z.); (J.H.)
- Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Cindy Zhou
- Division of Genetics and Development, Krembil Brain Institute, University Health Network, Toronto, ON M5T 2S8, Canada; (M.-M.Z.); (C.Z.); (J.H.)
- Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Sabah Kahnemuyipour
- Human Biology Department, University of Toronto, Toronto, ON M5S 3J6, Canada;
| | - James Hong
- Division of Genetics and Development, Krembil Brain Institute, University Health Network, Toronto, ON M5T 2S8, Canada; (M.-M.Z.); (C.Z.); (J.H.)
- Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Michael G. Fehlings
- Division of Genetics and Development, Krembil Brain Institute, University Health Network, Toronto, ON M5T 2S8, Canada; (M.-M.Z.); (C.Z.); (J.H.)
- Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, ON M5T 1P5, Canada
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Fukutin Protein Participates in Cell Proliferation by Enhancing Cyclin D1 Expression through Binding to the Transcription Factor Activator Protein-1: An In Vitro Study. Int J Mol Sci 2021; 22:ijms222212153. [PMID: 34830034 PMCID: PMC8622492 DOI: 10.3390/ijms222212153] [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: 10/08/2021] [Revised: 10/30/2021] [Accepted: 11/08/2021] [Indexed: 11/16/2022] Open
Abstract
The causative gene of Fukuyama congenital muscular dystrophy (fukutin) is involved in formation of the basement membrane through glycosylation of alpha-dystroglycan. However, there are other proposed functions that have not been fully understood. Using cultured astrocytes (1321N1), we found nuclear localization of fukutin and a positive relationship between fukutin expression and cell proliferation. Among potential proteins regulating cell proliferation, we focused on cyclin D1, by reverse-transcription polymerase chain reaction, Western blotting, immunocytochemistry, enzyme-linked immunosorbent assay (ELISA), and sandwich ELISA. Expression of cyclin D1 was significantly downregulated by fukutin knockdown and significantly upregulated by fukutin overexpression. Moreover, fukutin was proven to bind to the activator protein-1 (AP-1) binding site of cyclin D1 promoter, as well as the AP-1 component c-Jun. The c-Jun phosphorylation status was not significantly influenced by knockdown or overexpression of fukutin. The present results provide in vitro evidence for a novel function of fukutin, which participates in cell proliferation by enhancing cyclin D1 expression through forming a complex with AP-1. It is likely that fukutin is a potential cofactor of AP-1.
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Engineering digitizer circuits for chemical and genetic screens in human cells. Nat Commun 2021; 12:6150. [PMID: 34686672 PMCID: PMC8536748 DOI: 10.1038/s41467-021-26359-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 09/30/2021] [Indexed: 12/26/2022] Open
Abstract
Cell-based transcriptional reporters are invaluable in high-throughput compound and CRISPR screens for identifying compounds or genes that can impact a pathway of interest. However, many transcriptional reporters have weak activities and transient responses. This can result in overlooking therapeutic targets and compounds that are difficult to detect, necessitating the resource-consuming process of running multiple screens at various timepoints. Here, we present RADAR, a digitizer circuit for amplifying reporter activity and retaining memory of pathway activation. Reporting on the AP-1 pathway, our circuit identifies compounds with known activity against PKC-related pathways and shows an enhanced dynamic range with improved sensitivity compared to a classical reporter in compound screens. In the first genome-wide pooled CRISPR screen for the AP-1 pathway, RADAR identifies canonical genes from the MAPK and PKC pathways, as well as non-canonical regulators. Thus, our scalable system highlights the benefit and versatility of using genetic circuits in large-scale cell-based screening.
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miRNA-27a Transcription Activated by c-Fos Regulates Myocardial Ischemia-Reperfusion Injury by Targeting ATAD3a. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:2514947. [PMID: 34413925 PMCID: PMC8369174 DOI: 10.1155/2021/2514947] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 07/27/2021] [Indexed: 11/29/2022]
Abstract
MicroRNA-27a (miR-27a) has been implicated in myocardial ischemia-reperfusion injury (MIRI), but the underlying mechanism is not well understood. This study is aimed at determining the role of miR-27a in MIRI and at investigating upstream molecules that regulate miR-27a expression and its downstream target genes. miR-27a expression was significantly upregulated in myocardia exposed to ischemia/reperfusion (I/R) and cardiomyocytes exposed to hypoxia/reoxygenation (H/R). c-Fos could regulate miR-27a expression by binding to its promoter region. Moreover, overexpression of miR-27a led to a decrease in cell viability, an increase in LDH and CK-MB secretion, and an increase in apoptosis rates. In contrast, suppression of miR-27a expression resulted in the opposite effects. ATPase family AAA-domain-containing protein 3A (ATAD3a) was identified as a target of miR-27a. miR-27a regulated the translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus and H/R-induced apoptosis via the regulation of ATAD3a. It was found that inhibiting miR-27a in vivo by injecting a miR-27a sponge could ameliorate MIRI in an isolated rat heart model. In conclusion, our study demonstrated that c-Fos functions as an upstream regulator of miR-27a and that miR-27a regulates the translocation of AIF from the mitochondria to the nucleus by targeting ATAD3a, thereby contributing to MIRI. These findings provide new insight into the role of the c-Fos/miR-27a/ATAD3a axis in MIRI.
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Bryan de la Peña J, Kunder N, Lou TF, Chase R, Stanowick A, Barragan-Iglesias P, Pancrazio JJ, Campbell ZT. A Role for Translational Regulation by S6 Kinase and a Downstream Target in Inflammatory Pain. Br J Pharmacol 2021; 178:4675-4690. [PMID: 34355805 DOI: 10.1111/bph.15646] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 07/23/2021] [Accepted: 07/26/2021] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND AND PURPOSE Translational controls pervade neurobiology. Nociceptors play an integral role in the detection and propagation of pain signals. Nociceptors can undergo persistent changes in their intrinsic excitability. Pharmacologic disruption of nascent protein synthesis diminishes acute and chronic forms of pain-associated behaviors. Yet, the targets of translational controls that facilitate plasticity in nociceptors are unclear. EXPERIMENTAL APPROACH We used ribosome profiling to probe the translational landscape in DRG neurons after treatment of the inflammatory mediators NGF and IL-6. We validated the expression dynamics of c-Fos using immunoblotting and immunohistochemistry. Given that inflammation is known to stimulate mTOR signaling, we reasoned that downstream factors (e.g., ribosomal protein S6 kinase 1, S6K1) might control c-Fos levels. We utilized small-molecule inhibitors of S6K1 (DG2) or c-Fos (T-5224) to probe their effects on nociceptor activity in vitro using multi-electrode arrays (MEAs) and pain behavior in vivo using a hyperalgesic priming model. KEY RESULTS We demonstrate that c-Fos is expressed in sensory neurons. Inflammatory mediators that promote pain in both humans and rodents promote c-Fos translation. We demonstrate that the mTOR effector S6K1 is essential for c-Fos biosynthesis. Inhibition of S6K1 or c-Fos with small molecules diminish mechanical and thermal hypersensitivity in response to inflammatory cues. Additionally, both inhibitors reduce evoked nociceptor activity. CONCLUSION Our data reveal a novel role of S6K1 in modulating rapid response to inflammatory mediators, with c-Fos being one key downstream target. Targeting the S6 kinase pathway or c-Fos is an exciting new avenue for pain-modulating compounds.
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Affiliation(s)
- June Bryan de la Peña
- Department of Biological Sciences, University of Texas at Dallas, Richardson, TX, USA
| | - Nikesh Kunder
- Department of Biological Sciences, University of Texas at Dallas, Richardson, TX, USA
| | - Tzu-Fang Lou
- Department of Biological Sciences, University of Texas at Dallas, Richardson, TX, USA
| | - Rebecca Chase
- Department of Biological Sciences, University of Texas at Dallas, Richardson, TX, USA
| | - Alexander Stanowick
- Department of Biological Sciences, University of Texas at Dallas, Richardson, TX, USA
| | - Paulino Barragan-Iglesias
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA.,Department of Physiology and Pharmacology, Center for Basic Sciences, Autonomous University of Aguascalientes, Aguascalientes, Mexico
| | - Joseph J Pancrazio
- Department of Bioengineering, University of Texas at Dallas, Richardson, TX, USA.,Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX, USA
| | - Zachary T Campbell
- Department of Biological Sciences, University of Texas at Dallas, Richardson, TX, USA.,Department of Bioengineering, University of Texas at Dallas, Richardson, TX, USA.,Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX, USA
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Basatinya AM, Sajedianfard J, Nazifi S, Hosseinzadeh S, Kamrani Mehni M, Farahi A, Rahimi K, Derakhshanfar A, Salavati S. Effects of ethanolic extracts of Quercus, Cirsium vulgare, and Falcaria vulgaris on gastric ulcer, antioxidant and inflammatory indices, and gene expression in rats. Physiol Rep 2021; 9:e14954. [PMID: 34405561 PMCID: PMC8371353 DOI: 10.14814/phy2.14954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 06/14/2021] [Accepted: 06/15/2021] [Indexed: 11/24/2022] Open
Abstract
INTRODUCTION Gastric ulcer is a multifaceted process and is usually caused by mucosal damage. Herbal medicines have received much attention considering the side effects of chemical drugs. Nowadays, the use of herbal medicines has received much attention considering the side effects of chemical drugs. Quercus brantii Lindl, Cirsium vulgare (Savi) Ten, and Falcaria vulgaris Bernh are plants used as traditional phytomedicine for gastric ulcer diseases. AIM OF THE STUDY This study was aimed to investigate the protective effects of hydroalcoholic extracts of these herbs on ethanol-induced gastric ulceration, in addition, to investigate the antioxidant, anti-inflammatory, and gene expression. MATERIALS AND METHODS Thirty Sprague Dawley rats, (200-250 g), were divided into six groups: Control: intact animals; sham: gavaged with distilled water (14 days); negative control: gavaged with 20 mg/kg of omeprazole (14 days); experimental groups I, II, and III: gavaged with 500 mg/kg of the extract of Falcaria vulgaris, Quercus brantii, and Cirsium vulgare, respectively, (14 days). The number of ulcers and pathological parameters were assessed. The serum superoxide dismutase, catalase, glutathione peroxidase, malondialdehyde, total antioxidant capacity, albumin, total protein, haptoglobin, alpha-1-acid glycoprotein, total globulin, alpha-2-macroglobulin, C-fos, C-myc, and Caspase-9 were measured by ELISA and RT-PCR. RESULTS The extracts significantly reduced gastric ulcer (52.33%). The results showed that the Quercus brantii extract was more effective. There were significant differences between the serum levels of alpha-1-acid glycoprotein and those of alpha-2-macroglobulin. Also, there was a significant difference in the serum level of antioxidant parameters. Changes in the expression of the genes also confirmed the results suggested by other parameters. The expression levels of C-fos, C-myc, and caspase-9 were decreased, but the Bcl-2 expression increased. CONCLUSION The hydro-alcoholic extracts revealed various protection and noticeable change in the expression of caspase-9, C-myc, C-fos, and Bcl-2 genes in rats.
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Affiliation(s)
| | - Javad Sajedianfard
- Department of Basic SciencesSchool of Veterinary ScienceShiraz UniversityShirazIran
| | - Saeed Nazifi
- Department of Clinical ScienceSchool of Veterinary ScienceShiraz UniversityShirazIran
| | - Saied Hosseinzadeh
- Department of Hygiene and Food Quality ControlSchool of Veterinary ScienceShiraz UniversityShirazIran
| | | | - Abolfazl Farahi
- Department of Basic SciencesSchool of Veterinary ScienceShiraz UniversityShirazIran
| | - Kaveh Rahimi
- Department of Basic SciencesSchool of Veterinary ScienceShiraz UniversityShirazIran
| | - Amin Derakhshanfar
- Diagnostic Laboratory Sciences and Technology Research CenterSchool of Paramedical SciencesShiraz University of Medical SciencesShirazIran
| | - Sina Salavati
- Department of Basic SciencesSchool of Veterinary ScienceShiraz UniversityShirazIran
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Kato Y, Tonomura Y, Hanafusa H, Nishimura K, Fukushima T, Ueno M. Adult Zebrafish Model for Screening Drug-Induced Kidney Injury. Toxicol Sci 2021; 174:241-253. [PMID: 32040193 DOI: 10.1093/toxsci/kfaa009] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Drug-induced kidney injury is a serious safety issue in drug development. In this study, we evaluated the usefulness of adult zebrafish as a small in vivo system for detecting drug-induced kidney injury. We first investigated the effects of typical nephrotoxicants, gentamicin and doxorubicin, on adult zebrafish. We found that gentamicin induced renal tubular necrosis with increased lysosome and myeloid bodies, and doxorubicin caused foot process fusion of glomerular podocytes. These findings were similar to those seen in mammals, suggesting a common pathogenesis. Second, to further evaluate the performance of the model in detecting drug-induced kidney injury, adult zebrafish were treated with 28 nephrotoxicants or 14 nonnephrotoxicants for up to 4 days, euthanized 24 h after the final treatment, and examined histopathologically. Sixteen of the 28 nephrotoxicants and none of the 14 nonnephrotoxicants caused drug-induced kidney injury in zebrafish (sensitivity, 57%; specificity, 100%; positive predictive value, 100%; negative predictive value, 54%). Finally, we explored genomic biomarker candidates using kidneys isolated from gentamicin- and cisplatin-treated zebrafish using microarray analysis and identified 3 candidate genes, egr1, atf3, and fos based on increased expression levels and biological implications. The expression of these genes was upregulated dose dependently in cisplatin-treated groups and was > 25-fold higher in gentamicin-treated than in the control group. In conclusion, these results suggest that the adult zebrafish has (1) similar nephrotoxic response to those of mammals, (2) considerable feasibility as an experimental model for toxicity studies, and (3) applicability to pathological examination and genomic biomarker evaluation in drug-induced kidney injury.
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Affiliation(s)
- Yuki Kato
- Drug Safety Evaluation, Research Laboratory for Development, Shionogi and Co., Ltd., Toyonaka, Osaka 561-0825, Japan
| | - Yutaka Tonomura
- Drug Safety Evaluation, Research Laboratory for Development, Shionogi and Co., Ltd., Toyonaka, Osaka 561-0825, Japan
| | - Hiroyuki Hanafusa
- Drug Safety Evaluation, Research Laboratory for Development, Shionogi and Co., Ltd., Toyonaka, Osaka 561-0825, Japan
| | - Kyohei Nishimura
- Drug Safety Evaluation, Research Laboratory for Development, Shionogi and Co., Ltd., Toyonaka, Osaka 561-0825, Japan
| | - Tamio Fukushima
- Drug Safety Evaluation, Research Laboratory for Development, Shionogi and Co., Ltd., Toyonaka, Osaka 561-0825, Japan
| | - Motonobu Ueno
- Drug Safety Evaluation, Research Laboratory for Development, Shionogi and Co., Ltd., Toyonaka, Osaka 561-0825, Japan
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Chen G, Li PH, He JY, Su YL, Chen HJ, Dong JD, Huang YH, Huang XH, Jiang YF, Qin QW, Sun HY. Molecular cloning, inducible expression with SGIV and Vibrio alginolyticus challenge, and function analysis of Epinephelus coioides PDCD4. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2021; 119:104013. [PMID: 33465381 DOI: 10.1016/j.dci.2021.104013] [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: 07/30/2020] [Revised: 01/11/2021] [Accepted: 01/11/2021] [Indexed: 06/12/2023]
Abstract
Programmed cell death 4 (PDCD4) in mammals, a gene closely associated with apoptosis, is involved in many biological processes, such as cell aging, differentiation, regulation of cell cycle, and inflammatory response. In this study, grouper Epinephelus coioides PDCD4, EcPDCD4-1 and EcPDCD4-2, were obtained. The open reading frame (ORF) of EcPDCD4-1 is 1413 bp encoding 470 amino acids with a molecular mass of 52.39 kDa and a theoretical pI of 5.33. The ORF of EcPDCD4-2 is 1410 bp encoding 469 amino acids with a molecular mass of 52.29 kDa and a theoretical pI of 5.29. Both EcPDCD4-1 and EcPDCD4-2 proteins contain two conserved MA3 domains, and their mRNA were detected in all eight tissues of E. coioides by quantitative real-time PCR (qRT-PCR) with the highest expression in liver. The expressions of two EcPDCD4s were significantly up-regulated after Singapore grouper iridovirus (SGIV) or Vibrio alginolyticus infection. In addition, over-expression of EcPDCD4-1 or EcPDCD4-2 can inhibit the activity of the nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), and regulate SGIV-induced apoptosis. The results demonstrated that EcPDCD4s might play important roles in E. coioides tissues during pathogen-caused inflammation.
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Affiliation(s)
- Guo Chen
- Joint Laboratory of Guangdong Province and Hong Kong Regions on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China; Hainan Key Laboratory of Tropical Marine Biotechnology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, 510301, PR China; Department of Laboratory, Jining No.1 People's Hospital; Postdoctoral Mobile Station of Shandong University of Traditional Chinese Medicine, Shandong, 272111, PR China; Life Sciences Institute, Zhejiang University, Zhejiang Province, 310058, PR China
| | - Pin-Hong Li
- Joint Laboratory of Guangdong Province and Hong Kong Regions on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China
| | - Jia-Yang He
- Joint Laboratory of Guangdong Province and Hong Kong Regions on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China
| | - Yu-Ling Su
- Joint Laboratory of Guangdong Province and Hong Kong Regions on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China
| | - He-Jia Chen
- Joint Laboratory of Guangdong Province and Hong Kong Regions on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China
| | - Jun-De Dong
- Hainan Key Laboratory of Tropical Marine Biotechnology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, 510301, PR China
| | - You-Hua Huang
- Joint Laboratory of Guangdong Province and Hong Kong Regions on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China
| | - Xiao-Hong Huang
- Joint Laboratory of Guangdong Province and Hong Kong Regions on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China
| | - Yu-Feng Jiang
- Department of Laboratory, Jining No.1 People's Hospital; Postdoctoral Mobile Station of Shandong University of Traditional Chinese Medicine, Shandong, 272111, PR China.
| | - Qi-Wei Qin
- Joint Laboratory of Guangdong Province and Hong Kong Regions on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China.
| | - Hong-Yan Sun
- Joint Laboratory of Guangdong Province and Hong Kong Regions on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China.
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Endo S, Matsunaga T, Nishinaka T. The Role of AKR1B10 in Physiology and Pathophysiology. Metabolites 2021; 11:332. [PMID: 34063865 PMCID: PMC8224097 DOI: 10.3390/metabo11060332] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/17/2021] [Accepted: 05/19/2021] [Indexed: 12/16/2022] Open
Abstract
AKR1B10 is a human nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reductase belonging to the aldo-keto reductase (AKR) 1B subfamily. It catalyzes the reduction of aldehydes, some ketones and quinones, and interacts with acetyl-CoA carboxylase and heat shock protein 90α. The enzyme is highly expressed in epithelial cells of the stomach and intestine, but down-regulated in gastrointestinal cancers and inflammatory bowel diseases. In contrast, AKR1B10 expression is low in other tissues, where the enzyme is upregulated in cancers, as well as in non-alcoholic fatty liver disease and several skin diseases. In addition, the enzyme's expression is elevated in cancer cells resistant to clinical anti-cancer drugs. Thus, growing evidence supports AKR1B10 as a potential target for diagnosing and treating these diseases. Herein, we reviewed the literature on the roles of AKR1B10 in a healthy gastrointestinal tract, the development and progression of cancers and acquired chemoresistance, in addition to its gene regulation, functions, and inhibitors.
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Affiliation(s)
- Satoshi Endo
- Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan
| | - Toshiyuki Matsunaga
- Education Center of Green Pharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 502-8585, Japan;
| | - Toru Nishinaka
- Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi 584-8540, Osaka, Japan;
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Mehta SL, Chokkalla AK, Kim T, Bathula S, Chelluboina B, Morris-Blanco KC, Holmes A, Banerjee A, Chauhan A, Lee J, Venna VR, McCullough LD, Vemuganti R. Long Noncoding RNA Fos Downstream Transcript Is Developmentally Dispensable but Vital for Shaping the Poststroke Functional Outcome. Stroke 2021; 52:2381-2392. [PMID: 33940958 DOI: 10.1161/strokeaha.120.033547] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Suresh L Mehta
- Department of Neurological Surgery (S.L.M., A.K.C., T.K., S.B., B.C., K.C.M.-B., R.V.), University of Wisconsin-Madison
| | - Anil K Chokkalla
- Department of Neurological Surgery (S.L.M., A.K.C., T.K., S.B., B.C., K.C.M.-B., R.V.), University of Wisconsin-Madison.,Cellular & Molecular Pathology Graduate Program (A.K.C., R.V.), University of Wisconsin-Madison
| | - TaeHee Kim
- Department of Neurological Surgery (S.L.M., A.K.C., T.K., S.B., B.C., K.C.M.-B., R.V.), University of Wisconsin-Madison
| | - Saivenkateshkomal Bathula
- Department of Neurological Surgery (S.L.M., A.K.C., T.K., S.B., B.C., K.C.M.-B., R.V.), University of Wisconsin-Madison
| | - Bharath Chelluboina
- Department of Neurological Surgery (S.L.M., A.K.C., T.K., S.B., B.C., K.C.M.-B., R.V.), University of Wisconsin-Madison
| | - Kahlilia C Morris-Blanco
- Department of Neurological Surgery (S.L.M., A.K.C., T.K., S.B., B.C., K.C.M.-B., R.V.), University of Wisconsin-Madison
| | - Aleah Holmes
- Department of Neurology, University of Texas-Houston (A.H., A.B., A.C., J.L., V.R.V., L.D.M.)
| | - Anik Banerjee
- Department of Neurology, University of Texas-Houston (A.H., A.B., A.C., J.L., V.R.V., L.D.M.)
| | - Anjali Chauhan
- Department of Neurology, University of Texas-Houston (A.H., A.B., A.C., J.L., V.R.V., L.D.M.)
| | - Juneyoung Lee
- Department of Neurology, University of Texas-Houston (A.H., A.B., A.C., J.L., V.R.V., L.D.M.)
| | - Venugopal R Venna
- Department of Neurology, University of Texas-Houston (A.H., A.B., A.C., J.L., V.R.V., L.D.M.)
| | - Louise D McCullough
- Department of Neurology, University of Texas-Houston (A.H., A.B., A.C., J.L., V.R.V., L.D.M.)
| | - Raghu Vemuganti
- Department of Neurological Surgery (S.L.M., A.K.C., T.K., S.B., B.C., K.C.M.-B., R.V.), University of Wisconsin-Madison.,Cellular & Molecular Pathology Graduate Program (A.K.C., R.V.), University of Wisconsin-Madison.,William S. Middleton Veterans Hospital, Madison (R.V.)
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Thiel G, Backes TM, Guethlein LA, Rössler OG. Chromatin-embedded reporter genes: Quantification of stimulus-induced gene transcription. Gene 2021; 787:145645. [PMID: 33848575 DOI: 10.1016/j.gene.2021.145645] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 04/07/2021] [Indexed: 02/07/2023]
Abstract
Receptors and ion channels expressed on the cell surface ensure proper communication between the cells and the environment. In multicellular organism, stimulus-regulated gene transcription is the basis for communication with the environment allowing individual cells to respond to stimuli such as nutrients, chemical stressors and signaling molecules released by other cells of the organism. Hormones, cytokines, and mitogens bind to receptors and ion channels and induce intracellular signaling cascades involving second messengers, kinases, phosphatases, and changes in the concentration of particular ions. Ultimately, the signaling cascades reach the nucleus. Transcription factors are activated that respond to cellular stimulation and induce changes in gene transcription. Investigating stimulus-transcription coupling combines cell biology with genetics. In this review, we discuss the molecular biology of stimulus-induced transcriptional activators and their responsiveness to extracellular and intracellular signaling molecules and to epigenetic regulators. Stimulus-induced gene expression is measured by several methods, including detection of nuclear translocation of transcription factors, phosphorylation or DNA binding. In this article, we emphasize that the most reliable method to directly measure transcriptional activation involves the use of chromatin-embedded reporter genes.
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Affiliation(s)
- Gerald Thiel
- Department of Medical Biochemistry and Molecular Biology, Saarland University Medical Faculty, D-66421 Homburg, Germany.
| | - Tobias M Backes
- Department of Medical Biochemistry and Molecular Biology, Saarland University Medical Faculty, D-66421 Homburg, Germany
| | - Lisbeth A Guethlein
- Department of Structural Biology and Department of Microbiology & Immunology, School of Medicine, Stanford University, Stanford, CA 94305, USA
| | - Oliver G Rössler
- Department of Medical Biochemistry and Molecular Biology, Saarland University Medical Faculty, D-66421 Homburg, Germany
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38
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Schlabitz S, Monni L, Ragot A, Dipper-Wawra M, Onken J, Holtkamp M, Fidzinski P. Spatiotemporal Correlation of Epileptiform Activity and Gene Expression in vitro. Front Mol Neurosci 2021; 14:643763. [PMID: 33859552 PMCID: PMC8042243 DOI: 10.3389/fnmol.2021.643763] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 03/03/2021] [Indexed: 11/14/2022] Open
Abstract
Epileptiform activity alters gene expression in the central nervous system, a phenomenon that has been studied extensively in animal models. Here, we asked whether also in vitro models of seizures are in principle suitable to investigate changes in gene expression due to epileptiform activity and tested this hypothesis mainly in rodent and additionally in some human brain slices. We focused on three genes relevant for seizures and epilepsy: FOS proto-oncogene (c-Fos), inducible cAMP early repressor (Icer) and mammalian target of rapamycin (mTor). Seizure-like events (SLEs) were induced by 4-aminopyridine (4-AP) in rat entorhinal-hippocampal slices and by 4-AP/8 mM potassium in human temporal lobe slices obtained from surgical treatment of epilepsy. SLEs were monitored simultaneously by extracellular field potentials and intrinsic optical signals (IOS) for 1–4 h, mRNA expression was quantified by real time PCR. In rat slices, both duration of SLE exposure and SLE onset region were associated with increased expression of c-Fos and Icer while no such association was shown for mTor expression. Similar to rat slices, c-FOS induction in human tissue was increased in slices with epileptiform activity. Our results indicate that irrespective of limitations imposed by ex vivo conditions, in vitro models represent a suitable tool to investigate gene expression. Our finding is of relevance for the investigation of human tissue that can only be performed ex vivo. Specifically, it presents an important prerequisite for future studies on transcriptome-wide and cell-specific changes in human tissue with the goal to reveal novel candidates involved in the pathophysiology of epilepsy and possibly other CNS pathologies.
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Affiliation(s)
- Sophie Schlabitz
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neurology with Experimental Neurology, Clinical and Experimental Epileptology, Berlin, Germany
| | - Laura Monni
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neurology with Experimental Neurology, Clinical and Experimental Epileptology, Berlin, Germany
| | - Alienor Ragot
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neurology with Experimental Neurology, Clinical and Experimental Epileptology, Berlin, Germany
| | - Matthias Dipper-Wawra
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neurology with Experimental Neurology, Clinical and Experimental Epileptology, Berlin, Germany
| | - Julia Onken
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neurosurgery, Berlin, Germany
| | - Martin Holtkamp
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neurology with Experimental Neurology, Clinical and Experimental Epileptology, Berlin, Germany.,Epilepsy-Center Berlin-Brandenburg, Institute for Diagnostics of Epilepsy, Berlin, Germany
| | - Pawel Fidzinski
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neurology with Experimental Neurology, Clinical and Experimental Epileptology, Berlin, Germany.,Epilepsy-Center Berlin-Brandenburg, Institute for Diagnostics of Epilepsy, Berlin, Germany.,Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, NeuroCure Cluster of Excellence, Neuroscience Research Center, Berlin, Germany
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Zhao X, Xing J, Li J, Hou R, Niu X, Liu R, Jiao J, Yang X, Li J, Liang J, Zhou L, Wang Q, Chang W, Yin G, Li X, Zhang K. Dysregulated Dermal Mesenchymal Stem Cell Proliferation and Differentiation Interfered by Glucose Metabolism in Psoriasis. Int J Stem Cells 2021; 14:85-93. [PMID: 33632981 PMCID: PMC7904530 DOI: 10.15283/ijsc20073] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 09/30/2020] [Accepted: 10/12/2020] [Indexed: 12/18/2022] Open
Abstract
Background and Objectives Psoriasis is a chronic inflammatory skin disease, which the mechanisms behind its initiation and development are related to many factors. DMSCs (dermal mesenchymal stem cells) represent an important member of the skin microenvironment and play an important role in the surrounding environment and in neighbouring cells, but they are also affected by the microenvironment. We studied the glucose metabolism of DMSCs in psoriasis patients and a control group to reveal the relationship among glucose metabolism, cell proliferation activity，and VEC (vascular endothelial cell) differentiation in vitro, we demonstrated the biological activity and molecular mechanisms of DMSCs in psoriasis. Methods and Results We found that the OCR of DMSCs in psoriatic lesions was higher than that in the control group, and mRNA of GLUT1 and HK2 were up-regulated compared with the control group. The proliferative activity of DMSCs in psoriasis was reduced at an early stage, and mRNA involved in proliferation, JUNB and FOS were expressed at lower levels than those in the control group. The number of blood vessels in psoriatic lesions was significantly higher than that in the control group (p<0.05), which the mRNA of VEC differentiation, CXCL12, CXCR7, HEYL and RGS5 tended to be increased in psoriatic lesions compared to the control group, in addition to Notch3. Conclusions We speculated that DMSCs affected local psoriatic blood vessels through glucose metabolism, and the differentiation of VECs, which resulted in the pathophysiological process of psoriasis.
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Affiliation(s)
- Xincheng Zhao
- Shanxi Key Laboratory of Stem Cell for Immunological Dermatosis, Institute of Dermatology, Taiyuan City Centre Hospital of Shanxi Medical University, Taiyuan, China
| | - Jianxiao Xing
- Shanxi Key Laboratory of Stem Cell for Immunological Dermatosis, Institute of Dermatology, Taiyuan City Centre Hospital of Shanxi Medical University, Taiyuan, China
| | - Junqin Li
- Shanxi Key Laboratory of Stem Cell for Immunological Dermatosis, Institute of Dermatology, Taiyuan City Centre Hospital of Shanxi Medical University, Taiyuan, China
| | - Ruixia Hou
- Shanxi Key Laboratory of Stem Cell for Immunological Dermatosis, Institute of Dermatology, Taiyuan City Centre Hospital of Shanxi Medical University, Taiyuan, China
| | - Xuping Niu
- Shanxi Key Laboratory of Stem Cell for Immunological Dermatosis, Institute of Dermatology, Taiyuan City Centre Hospital of Shanxi Medical University, Taiyuan, China
| | - Ruifeng Liu
- Shanxi Key Laboratory of Stem Cell for Immunological Dermatosis, Institute of Dermatology, Taiyuan City Centre Hospital of Shanxi Medical University, Taiyuan, China
| | - Juanjuan Jiao
- Shanxi Key Laboratory of Stem Cell for Immunological Dermatosis, Institute of Dermatology, Taiyuan City Centre Hospital of Shanxi Medical University, Taiyuan, China
| | - Xiaohong Yang
- Shanxi Key Laboratory of Stem Cell for Immunological Dermatosis, Institute of Dermatology, Taiyuan City Centre Hospital of Shanxi Medical University, Taiyuan, China
| | - Juan Li
- Shanxi Key Laboratory of Stem Cell for Immunological Dermatosis, Institute of Dermatology, Taiyuan City Centre Hospital of Shanxi Medical University, Taiyuan, China
| | - Jiannan Liang
- Shanxi Key Laboratory of Stem Cell for Immunological Dermatosis, Institute of Dermatology, Taiyuan City Centre Hospital of Shanxi Medical University, Taiyuan, China
| | - Ling Zhou
- Shanxi Key Laboratory of Stem Cell for Immunological Dermatosis, Institute of Dermatology, Taiyuan City Centre Hospital of Shanxi Medical University, Taiyuan, China
| | - Qiang Wang
- Shanxi Key Laboratory of Stem Cell for Immunological Dermatosis, Institute of Dermatology, Taiyuan City Centre Hospital of Shanxi Medical University, Taiyuan, China
| | - Wenjuan Chang
- Shanxi Key Laboratory of Stem Cell for Immunological Dermatosis, Institute of Dermatology, Taiyuan City Centre Hospital of Shanxi Medical University, Taiyuan, China
| | - Guohua Yin
- Shanxi Key Laboratory of Stem Cell for Immunological Dermatosis, Institute of Dermatology, Taiyuan City Centre Hospital of Shanxi Medical University, Taiyuan, China
| | - Xinhua Li
- Shanxi Key Laboratory of Stem Cell for Immunological Dermatosis, Institute of Dermatology, Taiyuan City Centre Hospital of Shanxi Medical University, Taiyuan, China
| | - Kaiming Zhang
- Shanxi Key Laboratory of Stem Cell for Immunological Dermatosis, Institute of Dermatology, Taiyuan City Centre Hospital of Shanxi Medical University, Taiyuan, China
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40
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Bongartz H, Seiß EA, Bock J, Schaper F. Glucocorticoids attenuate interleukin-6-induced c-Fos and Egr1 expression and impair neuritogenesis in PC12 cells. J Neurochem 2021; 157:532-549. [PMID: 33454999 DOI: 10.1111/jnc.15305] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 01/07/2021] [Accepted: 01/10/2021] [Indexed: 01/15/2023]
Abstract
Interleukin-6 (IL-6) is a cytokine primarily known for immune regulation. There is also growing evidence that IL-6 triggers neurogenesis and impacts neural development, both life-long occurring processes that can be impaired by early-life and adult stress. Stress induces the release of glucocorticoids by activation of the hypothalamic-pituitary-adrenal (HPA) axis. On the cellular level, glucocorticoids act via the ubiquitously expressed glucocorticoid receptor. Thus, we aimed to elucidate whether glucocorticoids affect IL-6-induced neural development. Here, we show that IL-6 signalling induces neurite outgrowth in adrenal pheochromocytoma PC12 cells in a mitogen-activated protein kinase (MAPK) pathway-dependent manner, since neurite outgrowth was diminished upon Mek-inhibitor treatment. Using quantitative biochemical approaches, such as qRT-PCR analysis of Hyper-IL-6 treated PC12 cells, we show that neurite outgrowth induced by IL-6 signalling is accompanied by early and transient MAPK-dependent mRNA expression of immediate early genes coding for proteins such as early growth response protein 1 (Egr1) and c-Fos. This correlates with reduced proliferation and prolonged G0/G1 cell cycle arrest as determined by monitoring the cellular DNA content using flow cytometry. These results indicate for IL-6 signalling-induced neural differentiation. Interestingly, the glucocorticoid Dexamethasone impairs early IL-6 signalling-induced mRNA expression of c-Fos and Egr1 and restrains neurite outgrowth. Impaired Egr1 and c-Fos expression in neural development is implicated in the aetiology of neuropathologies. Thus, it appears likely that stress-induced release of glucocorticoids, as well as therapeutically administered glucocorticoids, contribute to the development of neuropathologies by reducing the expression of Egr1 and c-Fos, and by restraining IL-6-dependent neural differentiation.
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Affiliation(s)
- Hannes Bongartz
- Institute of Biology, Department of Systems Biology, Otto-von-Guericke University, Magdeburg, Germany
| | - Elena Anne Seiß
- Institute of Biology, Department of Systems Biology, Otto-von-Guericke University, Magdeburg, Germany
| | - Jörg Bock
- Institute of Biology, PG "Epigenetics and Structural Plasticity", Otto-von-Guericke University, Magdeburg, Germany.,Center for Behavioral Brain Sciences (CBBS), Otto-von-Guericke University, Magdeburg, Germany
| | - Fred Schaper
- Institute of Biology, Department of Systems Biology, Otto-von-Guericke University, Magdeburg, Germany.,Center for Dynamic Systems: Systems Engineering (CDS), Otto-von-Guericke University, Magdeburg, Germany.,Magdeburg Center for Systems Biology (MACS), Otto-von-Guericke University, Magdeburg, Germany
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41
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Uebbing S, Gockley J, Reilly SK, Kocher AA, Geller E, Gandotra N, Scharfe C, Cotney J, Noonan JP. Massively parallel discovery of human-specific substitutions that alter enhancer activity. Proc Natl Acad Sci U S A 2021; 118:e2007049118. [PMID: 33372131 PMCID: PMC7812811 DOI: 10.1073/pnas.2007049118] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Genetic changes that altered the function of gene regulatory elements have been implicated in the evolution of human traits such as the expansion of the cerebral cortex. However, identifying the particular changes that modified regulatory activity during human evolution remain challenging. Here we used massively parallel enhancer assays in neural stem cells to quantify the functional impact of >32,000 human-specific substitutions in >4,300 human accelerated regions (HARs) and human gain enhancers (HGEs), which include enhancers with novel activities in humans. We found that >30% of active HARs and HGEs exhibited differential activity between human and chimpanzee. We isolated the effects of human-specific substitutions from background genetic variation to identify the effects of genetic changes most relevant to human evolution. We found that substitutions interacted in both additive and nonadditive ways to modify enhancer function. Substitutions within HARs, which are highly constrained compared to HGEs, showed smaller effects on enhancer activity, suggesting that the impact of human-specific substitutions is buffered in enhancers with constrained ancestral functions. Our findings yield insight into how human-specific genetic changes altered enhancer function and provide a rich set of candidates for studies of regulatory evolution in humans.
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Affiliation(s)
- Severin Uebbing
- Department of Genetics, Yale School of Medicine, New Haven, CT 06510
| | - Jake Gockley
- Department of Genetics, Yale School of Medicine, New Haven, CT 06510
| | - Steven K Reilly
- Department of Genetics, Yale School of Medicine, New Haven, CT 06510
| | - Acadia A Kocher
- Department of Genetics, Yale School of Medicine, New Haven, CT 06510
| | - Evan Geller
- Department of Genetics, Yale School of Medicine, New Haven, CT 06510
| | - Neeru Gandotra
- Department of Genetics, Yale School of Medicine, New Haven, CT 06510
| | - Curt Scharfe
- Department of Genetics, Yale School of Medicine, New Haven, CT 06510
| | - Justin Cotney
- Department of Genetics, Yale School of Medicine, New Haven, CT 06510
| | - James P Noonan
- Department of Genetics, Yale School of Medicine, New Haven, CT 06510;
- Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT 06520
- Department of Neuroscience, Yale School of Medicine, New Haven, CT 06510
- Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510
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Ren B, Schmid M, Scheiner M, Mollenkopf HJ, Lucius R, Heitlinger E, Gupta N. Toxoplasma and Eimeria co-opt the host cFos expression for intracellular development in mammalian cells. Comput Struct Biotechnol J 2021; 19:719-731. [PMID: 33510872 PMCID: PMC7817532 DOI: 10.1016/j.csbj.2020.12.045] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 12/30/2020] [Accepted: 12/31/2020] [Indexed: 12/05/2022] Open
Abstract
Gene expression profiles differ significantly between Toxoplasma and Eimeria-infected host cells. Several distinct and shared host-signaling cascades are regulated by coccidian parasites. cFos is one of the few host transcripts mutually regulated during infection by both pathogens. Host cFos is required for optimal in vitro development of E. falciformis and T. gondii. Transcriptomics of parasitized wild-type and cFos-/- host cells reveals a perturbation of cFos network. Successful asexual reproduction of intracellular pathogens depends on their potential to exploit host resources and subvert antimicrobial defense. In this work, we deployed two prevalent apicomplexan parasites of mammalian cells, namely Toxoplasma gondii and Eimeria falciformis, to identify potential host determinants of infection. Expression analyses of the young adult mouse colonic (YAMC) epithelial cells upon infection by either parasite showed regulation of several distinct transcripts, indicating that these two pathogens program their intracellular niches in a tailored manner. Conversely, parasitized mouse embryonic fibroblasts (MEFs) displayed a divergent transcriptome compared to corresponding YAMC epithelial cells, suggesting that individual host cells mount a fairly discrete response when encountering a particular pathogen. Among several host transcripts similarly altered by T. gondii and E. falciformis, we identified cFos, a master transcription factor, that was consistently induced throughout the infection. Indeed, asexual growth of both parasites was strongly impaired in MEF host cells lacking cFos expression. Last but not the least, our differential transcriptomics of the infected MEFs (parental and cFos-/- mutant) and YAMC epithelial cells disclosed a cFos-centered network, underlying signal cascades, as well as a repertoire of nucleotides- and ion-binding proteins, which presumably act in consort to acclimatize the mammalian cell and thereby facilitate the parasite development.
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Affiliation(s)
- Bingjian Ren
- Department of Molecular Parasitology, Institute of Biology, Humboldt University, Berlin, Germany
| | - Manuela Schmid
- Department of Molecular Parasitology, Institute of Biology, Humboldt University, Berlin, Germany
| | - Mattea Scheiner
- Department of Molecular Parasitology, Institute of Biology, Humboldt University, Berlin, Germany
| | - Hans-Joachim Mollenkopf
- Microarray and Genomics Core Facility, Max-Planck Institute for Infection Biology, Berlin, Germany
| | - Richard Lucius
- Department of Molecular Parasitology, Institute of Biology, Humboldt University, Berlin, Germany
| | - Emanuel Heitlinger
- Department of Molecular Parasitology, Institute of Biology, Humboldt University, Berlin, Germany.,Research Group Ecology and Evolution of Parasite Host Interactions, Leibniz Institute for Zoo and Wildlife Research, Berlin, Germany
| | - Nishith Gupta
- Department of Molecular Parasitology, Institute of Biology, Humboldt University, Berlin, Germany.,Department of Biological Sciences, Birla Institute of Technology and Science Pilani (BITS-P), Hyderabad, India
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43
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Guan Y, Yang YJ, Nagarajan P, Ge Y. Transcriptional and signalling regulation of skin epithelial stem cells in homeostasis, wounds and cancer. Exp Dermatol 2020; 30:529-545. [PMID: 33249665 DOI: 10.1111/exd.14247] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 10/10/2020] [Accepted: 11/13/2020] [Indexed: 02/06/2023]
Abstract
The epidermis and skin appendages are maintained by their resident epithelial stem cells, which undergo long-term self-renewal and multilineage differentiation. Upon injury, stem cells are activated to mediate re-epithelialization and restore tissue function. During this process, they often mount lineage plasticity and expand their fates in response to damage signals. Stem cell function is tightly controlled by transcription machineries and signalling transductions, many of which derail in degenerative, inflammatory and malignant dermatologic diseases. Here, by describing both well-characterized and newly emerged pathways, we discuss the transcriptional and signalling mechanisms governing skin epithelial homeostasis, wound repair and squamous cancer. Throughout, we highlight common themes underscoring epithelial stem cell plasticity and tissue-level crosstalk in the context of skin physiology and pathology.
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Affiliation(s)
- Yinglu Guan
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Youn Joo Yang
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Priyadharsini Nagarajan
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yejing Ge
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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44
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Song C, Jeong D, Hong YH, Li WY, Lee SW, Hossain MA, Taamalli A, Kim JH, Kim JH, Cho JY. Anti-Inflammatory and Photoaging-Protective Effects of Olea europaea through Inhibition of AP-1 and NF-
κ
B Pathways. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2020; 48:1895-1913. [PMID: 33308098 DOI: 10.1142/s0192415x20500950] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Olea europaea is a beneficial edible plant with a number of biological activities like anti-inflammatory, anti-oxidant, antithrombic, antihyperglycemic, and anti-ischemic activities. The mechanisms behind the antiphotoaging and anti-inflammatory effects of Olea europaea are not fully understood. To investigate how an ethanol extract of Olea europaea (Oe-EE) exerts these effects, we explored its activities in human keratinocytes and dermal fibroblasts. We assessed the anti-oxidant effects of Oe-EE via 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′ -azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) assays and measured the expression levels of matrix metalloproteinases (MMPs), cyclooxygenase-2, interleukin (IL)-6, tumor necrosis factor (TNF)-α , and moisturizing factors. Antiphotoaging and anti-inflammatory mechanisms of Oe-EE were explored by assessing signaling molecule activation via immunoblotting. Oe-EE treatment decreased the mRNA expression level of MMPs, cyclooxygenase-2, IL-6, and TNF-α and restored type I collagen, filaggrin, and sirtuin 1 expression in UVB-irradiated cells. Furthermore, Oe-EE inhibited the activities of several activator protein 1 regulatory enzymes, including extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK), and inhibited nuclear factor (NF)-κ B pathway signaling proteins. Therefore, our results indicate that Oe-EE has photoaging-protective and anti-inflammatory effects.
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Affiliation(s)
- Chaoran Song
- Department of Integrative Biotechnology and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Deok Jeong
- Department of Integrative Biotechnology and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Yo Han Hong
- Department of Integrative Biotechnology and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Wan Yi Li
- Institute of Medicinal Plants, Yunnan Academy of Agricultural Sciences, Yunnan 650205, P. R. China
| | - Sang Woo Lee
- International Biological Material Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141 Republic of Korea
| | - Mohammad Amjad Hossain
- College of Veterinary Medicine, Chonbuk National University, Iksan 54596, Republic of Korea
| | - Amani Taamalli
- Laboratory of Olive Biotechnology, Center of Biotechnology-Technopole of Borj-Cedria, BP 901, Hammam-Lif 2050, Tunisia
- Department of Chemistry, University of Hafr Al Batin, Hafr Al Batin 31991, Kingdom of Saudi Arabia
| | - Ji Hye Kim
- Department of Integrative Biotechnology and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Jong-Hoon Kim
- International Biological Material Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141 Republic of Korea
| | - Jae Youl Cho
- Department of Integrative Biotechnology and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, Republic of Korea
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45
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Papavassiliou AG, Musti AM. The Multifaceted Output of c-Jun Biological Activity: Focus at the Junction of CD8 T Cell Activation and Exhaustion. Cells 2020; 9:2470. [PMID: 33202877 PMCID: PMC7697663 DOI: 10.3390/cells9112470] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 11/07/2020] [Accepted: 11/11/2020] [Indexed: 12/19/2022] Open
Abstract
c-Jun is a major component of the dimeric transcription factor activator protein-1 (AP-1), a paradigm for transcriptional response to extracellular signaling, whose components are basic-Leucine Zipper (bZIP) transcription factors of the Jun, Fos, activating transcription factor (ATF), ATF-like (BATF) and Jun dimerization protein 2 (JDP2) gene families. Extracellular signals regulate c-Jun/AP-1 activity at multiple levels, including transcriptional and posttranscriptional regulation of c-Jun expression and transactivity, in turn, establishing the magnitude and the duration of c-Jun/AP-1 activation. Another important level of c-Jun/AP-1 regulation is due to the capability of Jun family members to bind DNA as a heterodimer with every other member of the AP-1 family, and to interact with other classes of transcription factors, thereby acquiring the potential to integrate diverse extrinsic and intrinsic signals into combinatorial regulation of gene expression. Here, we review how these features of c-Jun/AP-1 regulation underlie the multifaceted output of c-Jun biological activity, eliciting quite distinct cellular responses, such as neoplastic transformation, differentiation and apoptosis, in different cell types. In particular, we focus on the current understanding of the role of c-Jun/AP-1 in the response of CD8 T cells to acute infection and cancer. We highlight the transcriptional and epigenetic regulatory mechanisms through which c-Jun/AP-1 participates in the productive immune response of CD8 T cells, and how its downregulation may contribute to the dysfunctional state of tumor infiltrating CD8 T cells. Additionally, we discuss recent insights pointing at c-Jun as a suitable target for immunotherapy-based combination approaches to reinvigorate anti-tumor immune functions.
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Affiliation(s)
- Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Anna Maria Musti
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
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46
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Sinha NK, Ordureau A, Best K, Saba JA, Zinshteyn B, Sundaramoorthy E, Fulzele A, Garshott DM, Denk T, Thoms M, Paulo JA, Harper JW, Bennett EJ, Beckmann R, Green R. EDF1 coordinates cellular responses to ribosome collisions. eLife 2020; 9:e58828. [PMID: 32744497 PMCID: PMC7486125 DOI: 10.7554/elife.58828] [Citation(s) in RCA: 114] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 08/02/2020] [Indexed: 12/11/2022] Open
Abstract
Translation of aberrant mRNAs induces ribosomal collisions, thereby triggering pathways for mRNA and nascent peptide degradation and ribosomal rescue. Here we use sucrose gradient fractionation combined with quantitative proteomics to systematically identify proteins associated with collided ribosomes. This approach identified Endothelial differentiation-related factor 1 (EDF1) as a novel protein recruited to collided ribosomes during translational distress. Cryo-electron microscopic analyses of EDF1 and its yeast homolog Mbf1 revealed a conserved 40S ribosomal subunit binding site at the mRNA entry channel near the collision interface. EDF1 recruits the translational repressors GIGYF2 and EIF4E2 to collided ribosomes to initiate a negative-feedback loop that prevents new ribosomes from translating defective mRNAs. Further, EDF1 regulates an immediate-early transcriptional response to ribosomal collisions. Our results uncover mechanisms through which EDF1 coordinates multiple responses of the ribosome-mediated quality control pathway and provide novel insights into the intersection of ribosome-mediated quality control with global transcriptional regulation.
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Affiliation(s)
- Niladri K Sinha
- Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Alban Ordureau
- Department of Cell Biology, Blavatnik Institute of Harvard Medical SchoolBostonUnited States
| | - Katharina Best
- Gene Center, Department of Biochemistry, Ludwig-Maximilians-Universität MünchenMunichGermany
| | - James A Saba
- Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Boris Zinshteyn
- Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Elayanambi Sundaramoorthy
- Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San DiegoSan DiegoUnited States
| | - Amit Fulzele
- Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San DiegoSan DiegoUnited States
| | - Danielle M Garshott
- Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San DiegoSan DiegoUnited States
| | - Timo Denk
- Gene Center, Department of Biochemistry, Ludwig-Maximilians-Universität MünchenMunichGermany
| | - Matthias Thoms
- Gene Center, Department of Biochemistry, Ludwig-Maximilians-Universität MünchenMunichGermany
| | - Joao A Paulo
- Department of Cell Biology, Blavatnik Institute of Harvard Medical SchoolBostonUnited States
| | - J Wade Harper
- Department of Cell Biology, Blavatnik Institute of Harvard Medical SchoolBostonUnited States
| | - Eric J Bennett
- Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San DiegoSan DiegoUnited States
| | - Roland Beckmann
- Gene Center, Department of Biochemistry, Ludwig-Maximilians-Universität MünchenMunichGermany
| | - Rachel Green
- Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of MedicineBaltimoreUnited States
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47
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Tian S, Jing R, Zhang W. Network-Based Approach to Identify the Antiproliferative Mechanisms of Bruceine D in Breast Cancer From the Cancer Genome Atlas. Front Oncol 2020; 10:1001. [PMID: 32714860 PMCID: PMC7343963 DOI: 10.3389/fonc.2020.01001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Accepted: 05/20/2020] [Indexed: 12/18/2022] Open
Abstract
Bruceine D (BD) is a natural compound extracted from a Chinese herb Brucea javanica that has been used for anti-inflammatory and anti-cancer treatment. However, little is reported about BD's effects in breast cancer tumorigenesis. In this paper, we aimed to investigate the effect of BD in breast cancer and elucidate the potential mechanism of BD by integrated multiple databases. Our data suggested BD inhibited MCF-7 and MDA-MB-231 cells proliferation and promoted cells apoptosis. We integrated multiple bioinformatics analysis strategies to identify genes, hub modules and pathways associated with BD treatment. Three key pathways, including AMIT_SERUM_RESPONSE_40_MCF10A, BILD_HRAS_ONCOGENIC_SIGNATURE, and NAGASHIMA_NRG1_SIGNALING_UP were identified to be associated with therapeutic effects of BD in breast cancer. Additionally, we validated the key genes by using quantitative real-time PCR and western blot. In conclusion, these findings revealed potential molecular mechanisms of BD to treat breast cancer by affecting AMIT_SERUM_RESPONSE_40_MCF10A, BILD_HRAS_ONCOGENIC_SIGNATURE, and NAGASHIMA_NRG1_SIGNALING_UP pathways and regulating expression of ZFP36, EGR1, and FOS.
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Affiliation(s)
- Saisai Tian
- School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Rui Jing
- School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Weidong Zhang
- School of Pharmacy, Second Military Medical University, Shanghai, China.,Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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48
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Neves LMG, Parizotto NA, Tim CR, Floriano EM, Lopez RFV, Venâncio T, Fernandes JB, Cominetti MR. Polysaccharide-rich hydrogel formulation combined with photobiomodulation repairs UV-induced photodamage in mice skin. Wound Repair Regen 2020; 28:645-655. [PMID: 32590890 DOI: 10.1111/wrr.12826] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 04/15/2020] [Accepted: 04/28/2020] [Indexed: 12/26/2022]
Abstract
Prolonged skin exposure to ultraviolet radiation (UVR) induces premature aging in both the epidermis and the dermis. Chronic exposure to UVR induces the activation of mitogen-activated protein kinase (MAPK) signaling pathway, activating c-Jun, c-Fos expression, and transcription factor of AP-1 activating protein. AP-1 activation results in the positive induction of matrix metalloproteinase (MMP) synthesis, which degrade skin collagen fibers. Polysaccharides from the fruit of Lycium barbarum (LBP fraction) have a range of activities and have been demonstrate to repair the photodamage. In different approaches, laser application aims to recover the aged skin without destroying the epidermis, promoting a modulation, called photobiomodulation (PBM), which leads to protein synthesis and cell proliferation, favoring tissue repair. Here we developed a topical hydrogel formulation from a polysaccharide-rich fraction of Lycium barbarum fruits (LBP). This formulation was associated with PBM (red laser) to evaluate whether the isolated and combined treatments would reduce the UVR-mediated photodamage in mice skin. Hairless mice were photoaged for 6 weeks and then treated singly or in combination with LBP and PBM. Histological, immunohistochemistry, and immunofluorescence analyses were used to investigate the levels of c-Fos, c-Jun, MMP-1, -2, and -9, collagen I, III, and FGF2. The combined regimen inhibited UVR-induced skin thickening, decreased the expression of c-Fos and c-Jun, as well as MMP-1, -2, and -9 and concomitantly increased the levels of collagen I, III, and FGF2. The PBM in combination with LBP treatment is a promising strategy for the repair of photodamaged skin, presenting potential clinical application in skin rejuvenation.
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Affiliation(s)
- Lia Mara Grosso Neves
- Laboratory of Biology of Aging (LABEN), Department of Gerontology, Federal University of São Carlos, São Carlos, São Paulo, Brazil
| | - Nivaldo Antonio Parizotto
- Joint Graduate Program in Physical Therapy, Federal University of São Carlos, São Carlos, São Paulo, Brazil.,Postgraduate Program in Biotechnology in Regenerative Medicine and Medical Chemistry, University of Araraquara, Araraquara, São Paulo, Brazil.,Postgraduate Program in Biomedical Engineering, University Brazil, São Paulo, São Paulo, Brazil
| | - Carla Roberta Tim
- Joint Graduate Program in Physical Therapy, Federal University of São Carlos, São Carlos, São Paulo, Brazil.,Postgraduate Program in Biotechnology in Regenerative Medicine and Medical Chemistry, University of Araraquara, Araraquara, São Paulo, Brazil
| | - Elaine Medeiros Floriano
- Department of Pathology and Legal Medicine, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Renata F Vianna Lopez
- Ribeirão Preto School of Pharmaceutical Sciences (FCFRP), University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Tiago Venâncio
- Department of Chemistry, Federal University of São Carlos, São Carlos, São Paulo, Brazil
| | - João Batista Fernandes
- Department of Chemistry, Federal University of São Carlos, São Carlos, São Paulo, Brazil
| | - Marcia Regina Cominetti
- Laboratory of Biology of Aging (LABEN), Department of Gerontology, Federal University of São Carlos, São Carlos, São Paulo, Brazil
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49
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Duliban M, Gurgul A, Szmatola T, Pawlicki P, Milon A, Arent ZJ, Grzmil P, Kotula-Balak M, Bilinska B. Mouse testicular transcriptome after modulation of non-canonical oestrogen receptor activity. Reprod Fertil Dev 2020; 32:903-913. [PMID: 32586420 DOI: 10.1071/rd20025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Accepted: 05/08/2020] [Indexed: 12/30/2022] Open
Abstract
The aims of this study were to shed light on the role of G-protein-coupled membrane oestrogen receptor (GPER) and oestrogen-related receptor (ERR) in mouse testis function at the gene expression level, as well as the involvement of GPER and ERR in cellular and molecular processes. Male mice were injected (50µg kg-1,s.c.) with the GPER antagonist G-15, the ERRα inverse agonist XCT790 or the ERRβ/ERRγ agonist DY131. Next-generation sequencing (RNA-Seq) was used to evaluate gene expression. Bioinformatic analysis of read abundance revealed that 50, 86 and 171 transcripts were differentially expressed in the G-15-, XCT790- and DY131-treated groups respectively compared with the control group. Annotated genes and their protein products were categorised regarding their associated biological processes and molecular functions. In the XCT790-treated group, genes involved in immunological processes were upregulated. In the DY131-treated group, genes with increased expression were primarily engaged in protein modification (protein folding and small protein conjugation). In addition, the expression of genes recognised as oncogenes, such as BMI1 proto-oncogene, polycomb ring finger (Bmi1) and nucleophosphin 1 (Npm1), was significantly increased in all experimental groups. This study provides detailed information regarding the genetic changes in the testicular transcriptome of the mouse in response to modulation of non-canonical oestrogen receptor activity.
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Affiliation(s)
- M Duliban
- Department of Endocrinology, Institute of Zoology, Jagiellonian University in Krakow, Gronostajowa 9, 30-387 Krakow, Poland; and Corresponding author.
| | - A Gurgul
- University Centre of Veterinary Medicine, University of Agriculture in Krakow, Mickiewicza 24/28, 30-059, Krakow, Poland
| | - T Szmatola
- University Centre of Veterinary Medicine, University of Agriculture in Krakow, Mickiewicza 24/28, 30-059, Krakow, Poland
| | - P Pawlicki
- Department of Endocrinology, Institute of Zoology, Jagiellonian University in Krakow, Gronostajowa 9, 30-387 Krakow, Poland
| | - A Milon
- Department of Endocrinology, Institute of Zoology, Jagiellonian University in Krakow, Gronostajowa 9, 30-387 Krakow, Poland
| | - Z J Arent
- University Centre of Veterinary Medicine, University of Agriculture in Krakow, Mickiewicza 24/28, 30-059, Krakow, Poland
| | - P Grzmil
- Department of Genetics and Evolution Institute of Zoology, Jagiellonian University in Krakow, Gronostajowa 9, 30-387 Krakow, Poland
| | - M Kotula-Balak
- University Centre of Veterinary Medicine, University of Agriculture in Krakow, Mickiewicza 24/28, 30-059, Krakow, Poland
| | - B Bilinska
- Department of Endocrinology, Institute of Zoology, Jagiellonian University in Krakow, Gronostajowa 9, 30-387 Krakow, Poland
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50
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Wang W, Xiong L, Wang P, Wang F, Ma Q. Major vault protein plays important roles in viral infection. IUBMB Life 2020; 72:624-631. [PMID: 31769934 PMCID: PMC7165711 DOI: 10.1002/iub.2200] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 10/30/2019] [Indexed: 12/12/2022]
Abstract
Viral replication and related protein expression inside the host cells, and host antiviral immune responses can lead to the occurrence of diverse diseases. With the outbreak of viral infection, a large number of newly diagnosed and died patients infected with various viruses are still reported every year. Viral infection has already been one of the major global public health issues and lead to huge economic and social burdens. Studying of viral pathogenesis is a very important way to find methods for prevention, diagnosis, and cure of viral infection; more evidence has confirmed that major vault protein (MVP) is closely associated with viral infection and pathogenesis, and this review is intended to provide a broad relationship between viruses and MVP to stimulate the interest of related researchers.
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Affiliation(s)
- Wei Wang
- Department of Clinical Laboratory, Puai Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Liang Xiong
- Department of Clinical Laboratory, Liyuan Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Pengyun Wang
- Department of Clinical Laboratory, Liyuan Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Fubing Wang
- Department of Laboratory MedicineZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Qingfeng Ma
- Department of Clinical Laboratory, Liyuan Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
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