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Inability to switch from ARID1A-BAF to ARID1B-BAF impairs exit from pluripotency and commitment towards neural crest formation in ARID1B-related neurodevelopmental disorders. Nat Commun 2021; 12:6469. [PMID: 34753942 PMCID: PMC8578637 DOI: 10.1038/s41467-021-26810-x] [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: 04/08/2021] [Accepted: 10/21/2021] [Indexed: 01/06/2023] Open
Abstract
Subunit switches in the BAF chromatin remodeler are essential during development. ARID1B and its paralog ARID1A encode for mutually exclusive BAF subunits. De novo ARID1B haploinsufficient mutations cause neurodevelopmental disorders, including Coffin-Siris syndrome, which is characterized by neurological and craniofacial features. Here, we leveraged ARID1B+/− Coffin-Siris patient-derived iPSCs and modeled cranial neural crest cell (CNCC) formation. We discovered that ARID1B is active only during the first stage of this process, coinciding with neuroectoderm specification, where it is part of a lineage-specific BAF configuration (ARID1B-BAF). ARID1B-BAF regulates exit from pluripotency and lineage commitment by attenuating thousands of enhancers and genes of the NANOG and SOX2 networks. In iPSCs, these enhancers are maintained active by ARID1A-containing BAF. At the onset of differentiation, cells transition from ARID1A- to ARID1B-BAF, eliciting attenuation of the NANOG/SOX2 networks and triggering pluripotency exit. Coffin-Siris patient cells fail to perform the ARID1A/ARID1B switch, and maintain ARID1A-BAF at the pluripotency enhancers throughout all stages of CNCC formation. This leads to persistent NANOG/SOX2 activity which impairs CNCC formation. Despite showing the typical neural crest signature (TFAP2A/SOX9-positive), ARID1B-haploinsufficient CNCCs are also aberrantly NANOG-positive. These findings suggest a connection between ARID1B mutations, neuroectoderm specification and a pathogenic mechanism for Coffin-Siris syndrome. Mutations in the ARID1B subunit of the BAF chromatin remodeling complex are associated with the neurodevelopmental Coffin-Siris syndrome. Here the authors reveal that there is a transition from ARID1A-containing complexes to ARID1B during cranial neural crest cell differentiation that is impaired in Coffin-Siris patient-derived cells, which is important for exit from pluripotency.
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2
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Sakae Y, Tanaka M. Metabolism and Sex Differentiation in Animals from a Starvation Perspective. Sex Dev 2021; 15:168-178. [PMID: 34284403 DOI: 10.1159/000515281] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 02/12/2021] [Indexed: 11/19/2022] Open
Abstract
Animals determine their sex genetically (GSD: genetic sex determination) and/or environmentally (ESD: environmental sex determination). Medaka (Oryzias latipes) employ a XX/XY GSD system, however, they display female-to-male sex reversal in response to various environmental changes such as temperature, hypoxia, and green light. Interestingly, we found that 5 days of starvation during sex differentiation caused female-to-male sex reversal. In this situation, the metabolism of pantothenate and fatty acid synthesis plays an important role in sex reversal. Metabolism is associated with other biological factors such as germ cells, HPG axis, lipids, and epigenetics, and supplys substances and acts as signal transducers. In this review, we discuss the importance of metabolism during sex differentiation and how metabolism contributes to sex differentiation.
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Affiliation(s)
- Yuta Sakae
- Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya, Japan
| | - Minoru Tanaka
- Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya, Japan
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3
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Blitek A, Szymanska M. Regulation of expression and role of peroxisome proliferator-activated receptors (PPARs) in luminal epithelial and stromal cells of the porcine endometrium. Theriogenology 2019; 127:88-101. [PMID: 30677596 DOI: 10.1016/j.theriogenology.2019.01.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 12/27/2018] [Accepted: 01/05/2019] [Indexed: 01/11/2023]
Abstract
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family of ligand-dependent transcription factors. PPARs are important regulators of glucose and fatty acid metabolism, apoptosis, angiogenesis, cell proliferation and differentiation, and immune response. Their possible role in the female reproductive tract was demonstrated. In the present study, cultured luminal epithelial (LE) and stromal (ST) cells of the porcine endometrium were used to examine (1) the effect of conceptus exposed medium (CEM) on mRNA and protein expression and DNA binding activity of PPARA, PPARD, and PPARG isoforms, and (2) the effect of PPARA, PPARD, and PPARG agonists on the expression of selected genes, apoptosis, and cell proliferation. The addition of CEM stimulated PPARA expression and DNA binding activity of this isoform in LE and ST cells (P < 0.05). Increased expression of PPARD mRNA in the presence of CEM was detected in ST cells (P < 0.05), while the concentration of PPARG transcripts decreased in response to CEM in both cell types (P < 0.05). LE and ST cells of the pig endometrium possess PPARA, PPARD, and PPARG proteins, with clear nuclear staining visible predominately in ST cells. In LE cells, activation of PPARG with 15-deoxy-Δ12,14-prostaglandin(PG)J2 down-regulated the expression of genes encoding amino acid transporter 1 (SLC38A1), leukemia inhibitory factor (LIF) and enzymes involved in PG synthesis (P < 0.05). In ST cells, activation of PPARD isoform with both agonists used (L-165,041 and cPGI2) and PPARG isoform with 15-deoxy-Δ12,14-PGJ2 increased vascular endothelial growth factor A (VEGFA) mRNA expression (P < 0.05). Moreover, GW9578 (PPARA agonist) and 15-deoxy-Δ12,14-PGJ2 stimulated glucose transporter 1 (SLC2A1) gene expression in ST cells. 15-deoxy-Δ12,14-PGJ2 was also effective in up-regulation of the ratio of BAX/BCL2 mRNA expression and active caspase-3 concentration in ST cells (P < 0.05). Finally, GW9578 stimulated LE and ST cell proliferation, while rosiglitazone (PPARG agonist) increased the number of viable ST but not LE cells. In conclusion, this study demonstrated that conceptus products differentially modulate PPARs expression and activity in the porcine endometrium. Activation of PPARs may in turn affect nutrient transport, PG synthesis, angiogenesis, apoptosis, or cell proliferation in this tissue. Therefore, PPAR isoforms seem to play an important role in development and function of the porcine uterus.
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Affiliation(s)
- Agnieszka Blitek
- Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences, Tuwima 10, 10-748, Olsztyn, Poland.
| | - Magdalena Szymanska
- Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences, Tuwima 10, 10-748, Olsztyn, Poland
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Lee J, Lee J, Cho YS. Peroxisome Proliferator-Activated Receptor α Agonist and Its Target Nanog Cooperate to Induce Pluripotency. J Clin Med 2018; 7:jcm7120488. [PMID: 30486372 PMCID: PMC6306698 DOI: 10.3390/jcm7120488] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 11/22/2018] [Accepted: 11/23/2018] [Indexed: 01/23/2023] Open
Abstract
The pharmaceutical compounds that modulate pluripotent stem cell (PSC) identity and function are increasingly adopted to generate qualified PSCs and their derivatives, which have promising potential in regenerative medicine, in pursuit of more accuracy and safety and less cost. Here, we demonstrate the peroxisome proliferator-activated receptor α (PPARα) agonist as a novel enhancer of pluripotency acquisition and induced pluripotent stem cell (iPSC) generation. We found that PPARα agonist, examined and selected Food and Drug Administration (FDA) -approved compound libraries, increase the expression of pluripotency-associated genes, such as Nanog, Nr5A2, Oct4, and Rex1, during the reprogramming process and facilitate iPSC generation by enhancing their reprogramming efficiency. A reprogramming-promoting effect of PPARα occurred via the upregulation of Nanog, which is essential for the induction and maintenance of pluripotency. Through bioinformatic analysis, we identified putative peroxisome proliferator responsive elements (PPREs) located within the promoter region of the Nanog gene. We also determined that PPARα can activate Nanog transcription by specific binding to putative PPREs. Taken together, our findings suggest that PPARα is an important regulator of PSC pluripotency and reprogramming, and PPARα agonists can be used to improve PSC technology and regenerative medicine.
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Affiliation(s)
- Jungwoon Lee
- Stem Cell Research Laboratory, Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.
| | - Jinhyuk Lee
- Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.
- Department of Biotechnology, KRIBB School, University of Science and Technology (UST), Daejeon 34113, Korea.
| | - Yee Sook Cho
- Stem Cell Research Laboratory, Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.
- Department of Bioscience, KRIBB School, University of Science and Technology (UST), Daejeon 34113, Korea.
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Samanta S, Zhou Z, Rajasingh S, Panda A, Sampath V, Rajasingh J. DNMT and HDAC inhibitors together abrogate endotoxemia mediated macrophage death by STAT3-JMJD3 signaling. Int J Biochem Cell Biol 2018; 102:117-127. [PMID: 30010012 PMCID: PMC6309960 DOI: 10.1016/j.biocel.2018.07.002] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 06/30/2018] [Accepted: 07/11/2018] [Indexed: 12/11/2022]
Abstract
Acute lung injury (ALI) is a common complication of sepsis that often leads to fatal lung disease without effective therapies. It is known that bone marrow derived macrophages are important in resolving the inflammation and maintaining tissue homeostasis. Here, we hypothesize that treatment in combination of DNA methyl transferase inhibitor (DNMTi) 5-Aza 2-deoxycytidine (Aza) and histone deacetylase inhibitor (HDACi) Trichostatin A (TSA) mitigates the inflammation induced pyroptosis and apoptosis during endotoxemia induced ALI. To test this hypothesis, the mice challenged with a sublethal dose of LPS followed by one-hour post-treatment with a single dose of Aza and TSA intraperitoneally showed a substantial attenuation of apoptosis and inflammation. Importantly, we observed significant changes in the mitochondrial membrane structure, and lower levels of DNA fragmentation, reduced expression of apoptotic and pyroptotic genes both transcriptionally and translationally in LPS induced BMDMs treated by a combination of Aza and TSA than in LPS-induced BMDMs treated with either drug alone. The protection was mediated by an inhibition of JNK-ERK and STAT3-JMJD3 activated pathways. Thus, targeting these important signaling pathways with the combination of Aza and TSA would be a good treatment modality for ALI.
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Affiliation(s)
- Saheli Samanta
- Department of Cardiovascular Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Zhigang Zhou
- Department of Cardiovascular Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA; Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, 201620, China
| | - Sheeja Rajasingh
- Department of Cardiovascular Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Arunima Panda
- Department of Cardiovascular Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Venkatesh Sampath
- Department of Pediatrics, Division of Neonatology, Children's Mercy Hospital, Kansas City, MO, USA
| | - Johnson Rajasingh
- Department of Cardiovascular Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA; Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
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Tigistu-Sahle F, Lampinen M, Kilpinen L, Holopainen M, Lehenkari P, Laitinen S, Käkelä R. Metabolism and phospholipid assembly of polyunsaturated fatty acids in human bone marrow mesenchymal stromal cells. J Lipid Res 2016; 58:92-110. [PMID: 27856675 DOI: 10.1194/jlr.m070680] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Revised: 11/08/2016] [Indexed: 01/06/2023] Open
Abstract
High arachidonic acid (20:4n-6) and low n-3 PUFA levels impair the capacity of cultured human bone marrow mesenchymal stromal cells (hBMSCs) to modulate immune functions. The capacity of the hBMSCs to modify PUFA structures was found to be limited. Therefore, different PUFA supplements given to the cells resulted in very different glycerophospholipid (GPL) species profiles and substrate availability for phospholipases, which have preferences for polar head group and acyl chains when liberating PUFA precursors for production of lipid mediators. When supplemented with 20:4n-6, the cells increased prostaglandin E2 secretion. However, they elongated 20:4n-6 to the less active precursor, 22:4n-6, and also incorporated it into triacylglycerols, which may have limited the proinflammatory signaling. The n-3 PUFA precursor, 18:3n-3, had little potency to reduce the GPL 20:4n-6 content, while the eicosapentaenoic (20:5n-3) and docosahexaenoic (22:6n-3) acid supplements efficiently displaced the 20:4n-6 acyls, and created diverse GPL species substrate pools allowing attenuation of inflammatory signaling. The results emphasize the importance of choosing appropriate PUFA supplements for in vitro hBMSC expansion and suggests that for optimal function they require an exogenous fatty acid source providing 20:5n-3 and 22:6n-3 sufficiently, but 20:4n-6 moderately, which calls for specifically designed optimal PUFA supplements for the cultures.
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Affiliation(s)
| | - Milla Lampinen
- Department of Biosciences University of Helsinki, Helsinki, Finland
| | - Lotta Kilpinen
- Department of Biosciences University of Helsinki, Helsinki, Finland.,Advanced Therapies and Product Development, Finnish Red Cross Blood Service, Helsinki, Finland
| | - Minna Holopainen
- Advanced Therapies and Product Development, Finnish Red Cross Blood Service, Helsinki, Finland
| | - Petri Lehenkari
- Institute of Biomedicine, Division of Surgery, University of Oulu and Clinical Research Centre, Department of Surgery and Intensive Care, Oulu, Finland.,Department of Anatomy and Cell Biology, University of Oulu, Finland and Institute of Clinical Medicine, Division of Surgery, University of Oulu and Clinical Research Centre, Department of Surgery and Intensive Care, Oulu, Finland
| | - Saara Laitinen
- Advanced Therapies and Product Development, Finnish Red Cross Blood Service, Helsinki, Finland
| | - Reijo Käkelä
- Department of Biosciences University of Helsinki, Helsinki, Finland
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Rashid MA, Haque M, Akbar M. Role of Polyunsaturated Fatty Acids and Their Metabolites on Stem Cell Proliferation and Differentiation. ADVANCES IN NEUROBIOLOGY 2016; 12:367-80. [PMID: 27651264 DOI: 10.1007/978-3-319-28383-8_20] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The nervous system is highly enriched with long-chain polyunsaturated fatty acids (PUFAs). Essential fatty acids, namely, ω-6 (n - 6) and ω-3 (n - 3) PUFA, and their metabolites are critical components of cell structure and function and could therefore influence stem cell fate. The available supporting experimental data reveal that n - 6 and n - 3 PUFA and their metabolites can act through multiple mechanisms to promote the proliferation and differentiation of various stem cell types. PUFAs and their mediators regulate several processes within the brain, such as neurotransmission, cell survival and neuroinflammation, and thereby mood and cognition. PUFA levels and the signaling pathways that they regulate are altered in various neurological disorders, including Alzheimer's disease and major depression. Therefore, elucidating the role of PUFAs and their metabolites in stem cell fate regulation is important for stem cell biology as well as stem cell therapy. PUFA-based interventions to generate a positive environment for stem cell proliferation or differentiation might be a promising and practical approach to controlling stem cell fate for clinical applications.
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Affiliation(s)
- Mohammad Abdur Rashid
- Laboratory of Molecular Signaling, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD, 20852, USA.
| | - Mahmuda Haque
- Department of Pharmacy, Southeast University, Dhaka, 1213, Bangladesh
| | - Mohammed Akbar
- Laboratory of Molecular Pharmacology and Toxicology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD, 20852, USA
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Kang JX, Wan JB, He C. Concise review: Regulation of stem cell proliferation and differentiation by essential fatty acids and their metabolites. Stem Cells 2014; 32:1092-8. [PMID: 24356924 DOI: 10.1002/stem.1620] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Revised: 11/08/2013] [Accepted: 11/26/2013] [Indexed: 12/17/2022]
Abstract
Stem cell therapy holds great promise for regenerative medicine and the treatment of numerous diseases. A key issue of stem cell therapy is the control of stem cell fate, but safe and practical methods are limited. Essential fatty acids, namely ω-6 (n-6) and ω-3 (n-3) polyunsaturated fatty acids (PUFA), and their metabolites are critical components of cell structure and function, and could therefore influence stem cell fate. The available evidence demonstrates that n-6 and n-3 PUFA and their metabolites can act through multiple mechanisms to promote the proliferation and differentiation of various stem cell types. Therefore, elucidating the role of PUFA and their metabolites in stem cell fate regulation is both a challenge and an opportunity for stem cell biology as well as stem cell therapy. PUFA-based interventions to create a favorable environment for stem cell proliferation or differentiation may thus be a promising and practical approach to controlling stem cell fate for clinical applications.
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Affiliation(s)
- Jing X Kang
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Meli L, Barbosa HSC, Hickey AM, Gasimli L, Nierode G, Diogo MM, Linhardt RJ, Cabral JMS, Dordick JS. Three dimensional cellular microarray platform for human neural stem cell differentiation and toxicology. Stem Cell Res 2014; 13:36-47. [PMID: 24816401 DOI: 10.1016/j.scr.2014.04.004] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2013] [Revised: 03/18/2014] [Accepted: 04/08/2014] [Indexed: 01/10/2023] Open
Abstract
We developed a three-dimensional (3D) cellular microarray platform for the high-throughput (HT) analysis of human neural stem cell (hNSC) growth and differentiation. The growth of an immortalized hNSC line, ReNcell VM, was evaluated on a miniaturized cell culture chip consisting of 60nl spots of cells encapsulated in alginate, and compared to standard 2D well plate culture conditions. Using a live/dead cell viability assay, we demonstrated that the hNSCs are able to expand on-chip, albeit with lower proliferation rates and viabilities than in conventional 2D culture platforms. Using an in-cell, on-chip immunofluorescence assay, which provides quantitative information on cellular levels of proteins involved in neural fate, we demonstrated that ReNcell VM can preserve its multipotent state during on-chip expansion. Moreover, differentiation of the hNSCs into glial progeny was achieved both off- and on-chip six days after growth factor removal, accompanied by a decrease in the neural progenitor markers. The versatility of the platform was further demonstrated by complementing the cell culture chip with a chamber system that allowed us to screen for differential toxicity of small molecules to hNSCs. Using this approach, we showed differential toxicity when evaluating three neurotoxic compounds and one antiproliferative compound, and the null effect of a non-toxic compound at relevant concentrations. Thus, our 3D high-throughput microarray platform may help predict, in vitro, which compounds pose an increased threat to neural development and should therefore be prioritized for further screening and evaluation.
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Affiliation(s)
- Luciana Meli
- Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY, USA
| | - Hélder S C Barbosa
- Institute for Biotechnology and Bioengineering, Instituto Superior Técnico, University of Lisbon, Portugal; Department of Bioengineering, Instituto Superior Técnico, University of Lisbon, Portugal
| | - Anne Marie Hickey
- Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY, USA
| | - Leyla Gasimli
- Department of Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA
| | - Gregory Nierode
- Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY, USA
| | - Maria Margarida Diogo
- Institute for Biotechnology and Bioengineering, Instituto Superior Técnico, University of Lisbon, Portugal; Department of Bioengineering, Instituto Superior Técnico, University of Lisbon, Portugal
| | - Robert J Linhardt
- Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY, USA; Department of Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA; Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA; Department of Biomedical Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA
| | - Joaquim M S Cabral
- Institute for Biotechnology and Bioengineering, Instituto Superior Técnico, University of Lisbon, Portugal; Department of Bioengineering, Instituto Superior Técnico, University of Lisbon, Portugal
| | - Jonathan S Dordick
- Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY, USA; Department of Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA; Department of Biomedical Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA; Department of Materials Science and Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA.
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Farshbaf MJ, Ghaedi K, Shirani M, Nasr-Esfahani MH. Peroxisome proliferator activated receptor gamma (PPARγ) as a therapeutic target for improvement of cognitive performance in Fragile-X. Med Hypotheses 2013; 82:291-4. [PMID: 24456944 DOI: 10.1016/j.mehy.2013.12.012] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2013] [Revised: 12/03/2013] [Accepted: 12/18/2013] [Indexed: 02/07/2023]
Abstract
Rare disorders leading to intellectual disability, such as Fragile X syndrome (FXS) alter synaptic plasticity. Ligand identification of orphan nuclear receptors has led to the discovery of many signaling pathways and has revealed a direct link of nuclear receptors with human conditions such as mental retardation and neurodegenerative diseases. PPARγ agonists can act as neuroprotective agents, promoting synaptic plasticity and neurite outgrowth. Therefore, selective PPARγ agonists are good candidates for therapeutic evaluation in intellectual disabilities. Preliminary results suggest that PPARγ agonists such as Pioglitazone, Rosiglitazone and synthetic agonist, GW1929, are used as the therapeutic agent in neurological disorders. These components interact with intracellular transduction signals (e.g. GSK3β, PI3K/Akt, Wnt/β-Catenin, Rac1 and MMP-9). It seems that interaction with these pathways can improve memory recognition in FXS animal models. The present hypothesis consists of enhancing synaptic plasticity that may then rescue the learning and memory in FXS. This will open many new therapeutic avenues for a variety of human diseases.
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Affiliation(s)
- Mohammad Jodeiri Farshbaf
- Department of Biology, School of Sciences, University of Isfahan, Isfahan, Iran; Department of Cellular Biotechnology at Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Kamran Ghaedi
- Department of Biology, School of Sciences, University of Isfahan, Isfahan, Iran; Department of Cellular Biotechnology at Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.
| | - Mahsa Shirani
- Department of Biology, School of Sciences, University of Isfahan, Isfahan, Iran
| | - Mohammad Hossein Nasr-Esfahani
- Department of Cellular Biotechnology at Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.
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Dutta D, Ghosh S, Pandit K, Mukhopadhyay P, Chowdhury S. Leptin and cancer: Pathogenesis and modulation. Indian J Endocrinol Metab 2012; 16:S596-S600. [PMID: 23565495 PMCID: PMC3602989 DOI: 10.4103/2230-8210.105577] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Leptin, a product of Ob gene from adipocytes regulates appetite, energy expenditure and body mass composition by decreasing orexigenic and increasing anorexigenic neuropeptide release from hypothalamus. Research over the past few years have suggested leptin/leptin receptor dysregulation to have a role in the development of a large variety of malignancies like breast ca, thyroid ca, endometrial ca and gastrointestinal malignancies, predominantly through JAK/STAT pathway which modulates PI3K/AKT3 signaling, ERK1/2 signaling, expression of antiapoptotic proteins (like XIAP), systemic inflammation (TNF-α, IL6), angiogenic factors (VEGF) and hypoxia inducible factor-1a (HIF-1a) expression. In this review, the current understanding of leptin's role in carcinogenesis has been elaborated. Also a few agents modulating leptin signaling to inhibit cancer cell growth has been described.
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Affiliation(s)
- Deep Dutta
- Department of Endocrinology and Metabolism, Institute of Post Graduate Medical Education and Research Kolkata, Kolkata, India
| | - Sujoy Ghosh
- Department of Endocrinology and Metabolism, Institute of Post Graduate Medical Education and Research Kolkata, Kolkata, India
| | - Kaushik Pandit
- Department of Endocrinology and Metabolism, Institute of Post Graduate Medical Education and Research Kolkata, Kolkata, India
| | - Pradip Mukhopadhyay
- Department of Endocrinology and Metabolism, Institute of Post Graduate Medical Education and Research Kolkata, Kolkata, India
| | - Subhankar Chowdhury
- Department of Endocrinology and Metabolism, Institute of Post Graduate Medical Education and Research Kolkata, Kolkata, India
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12
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Kanakasabai S, Pestereva E, Chearwae W, Gupta SK, Ansari S, Bright JJ. PPARγ agonists promote oligodendrocyte differentiation of neural stem cells by modulating stemness and differentiation genes. PLoS One 2012. [PMID: 23185633 PMCID: PMC3503969 DOI: 10.1371/journal.pone.0050500] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Neural stem cells (NSCs) are a small population of resident cells that can grow, migrate and differentiate into neuro-glial cells in the central nervous system (CNS). Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor transcription factor that regulates cell growth and differentiation. In this study we analyzed the influence of PPARγ agonists on neural stem cell growth and differentiation in culture. We found that in vitro culture of mouse NSCs in neurobasal medium with B27 in the presence of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) induced their growth and expansion as neurospheres. Addition of all-trans retinoic acid (ATRA) and PPARγ agonist ciglitazone or 15-Deoxy-Δ12,14-Prostaglandin J2 (15d-PGJ2) resulted in a dose-dependent inhibition of cell viability and proliferation of NSCs in culture. Interestingly, NSCs cultured with PPARγ agonists, but not ATRA, showed significant increase in oligodendrocyte precursor-specific O4 and NG2 reactivity with a reduction in NSC marker nestin, in 3–7 days. In vitro treatment with PPARγ agonists and ATRA also induced modest increase in the expression of neuronal β-III tubulin and astrocyte-specific GFAP in NSCs in 3–7 days. Further analyses showed that PPARγ agonists and ATRA induced significant alterations in the expression of many stemness and differentiation genes associated with neuro-glial differentiation in NSCs. These findings highlight the influence of PPARγ agonists in promoting neuro-glial differentiation of NSCs and its significance in the treatment of neurodegenerative diseases.
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Affiliation(s)
- Saravanan Kanakasabai
- Neuroscience Research Laboratory, Methodist Research Institute, Indiana University Health, Indianapolis, Indiana, United States of America
| | - Ecaterina Pestereva
- Neuroscience Research Laboratory, Methodist Research Institute, Indiana University Health, Indianapolis, Indiana, United States of America
| | - Wanida Chearwae
- Neuroscience Research Laboratory, Methodist Research Institute, Indiana University Health, Indianapolis, Indiana, United States of America
| | - Sushil K. Gupta
- Neuroscience Research Laboratory, Methodist Research Institute, Indiana University Health, Indianapolis, Indiana, United States of America
| | - Saif Ansari
- Neuroscience Research Laboratory, Methodist Research Institute, Indiana University Health, Indianapolis, Indiana, United States of America
| | - John J. Bright
- Neuroscience Research Laboratory, Methodist Research Institute, Indiana University Health, Indianapolis, Indiana, United States of America
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
- * E-mail:
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Kurdi M, Sivakumaran V, Duhé RJ, Aon MA, Paolocci N, Booz GW. Depletion of cellular glutathione modulates LIF-induced JAK1-STAT3 signaling in cardiac myocytes. Int J Biochem Cell Biol 2012; 44:2106-15. [PMID: 22939972 DOI: 10.1016/j.biocel.2012.08.016] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2012] [Revised: 08/10/2012] [Accepted: 08/15/2012] [Indexed: 12/30/2022]
Abstract
Previously we reported that the sesquiterpene lactone parthenolide induces oxidative stress in cardiac myocytes, which blocks Janus kinase (JAK) activation by the interleukin 6 (IL-6)-type cytokines. One implication suggested by this finding is that IL-6 signaling is dependent upon cellular anti-oxidant defenses or redox status. Therefore, the present study was undertaken to directly test the hypothesis that JAK1 signaling by the IL-6-type cytokines in cardiac myocytes is impaired by glutathione (GSH) depletion, since this tripeptide is one of the major anti-oxidant molecules and redox-buffers in cells. Cardiac myocytes were pretreated for 6h with l-buthionine-sulfoximine (BSO) to inhibit GSH synthesis. After 24h, cells were dosed with the IL-6-like cytokine, leukemia inhibitory factor (LIF). BSO treatment decreased GSH levels and dose-dependently attenuated activation of JAK1, Signal Transducer and Activator of Transcription 3 (STAT3), and extracellular signal regulated kinases 1 and 2 (ERK1/2). Addition of glutathione monoethyl ester, which is cleaved intracellularly to GSH, prevented attenuation of LIF-induced JAK1 and STAT3 activation, as did the reductant N-acetyl-cysteine. Unexpectedly, LIF-induced STAT1 activation was unaffected by GSH depletion. Evidence was found that STAT3 is more resistant than STAT1 to intermolecular disulfide bond formation under oxidizing conditions and more likely to retain the monomeric form, suggesting that conformational differences explain the differential effect of GSH depletion on STAT1 and STAT3. Overall, our findings indicate that activation of both JAK1 and STAT3 is redox-sensitive and the character of IL-6 type cytokine signaling in cardiac myocytes is sensitive to changes in the cellular redox status. In cardiac myocytes, activation of STAT1 may be favored over STAT3 under oxidizing conditions due to GSH depletion and/or augmented reactive oxygen species production, such as in ischemia-reperfusion and heart failure.
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Affiliation(s)
- Mazen Kurdi
- Department of Chemistry and Biochemistry, Lebanese University, Rafic Hariri Educational Campus, Hadath, Lebanon.
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Zgheib C, Kurdi M, Zouein FA, Gunter BW, Stanley BA, Zgheib J, Romero DG, King SB, Paolocci N, Booz GW. Acyloxy nitroso compounds inhibit LIF signaling in endothelial cells and cardiac myocytes: evidence that STAT3 signaling is redox-sensitive. PLoS One 2012; 7:e43313. [PMID: 22905257 PMCID: PMC3419695 DOI: 10.1371/journal.pone.0043313] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2012] [Accepted: 07/19/2012] [Indexed: 12/31/2022] Open
Abstract
We previously showed that oxidative stress inhibits leukemia inhibitory factor (LIF) signaling by targeting JAK1, and the catalytic domains of JAK 1 and 2 have a cysteine-based redox switch. Thus, we postulated that the NO sibling and thiophylic compound, nitroxyl (HNO), would inhibit LIF-induced JAK-STAT3 activation. Pretreatment of human microvascular endothelial cells (HMEC-1) or neonatal rat cardiomyocytes with the HNO donors Angeli’s salt or nitrosocyclohexyl acetate (NCA) inhibited LIF-induced STAT3 activation. NCA pretreatment also blocked the induction of downstream inflammatory genes (e.g. intercellular adhesion molecule 1, CCAAT/enhancer binding protein delta). The related 1-nitrosocyclohexyl pivalate (NCP; not a nitroxyl donor) was equally effective in inhibiting STAT3 activation, suggesting that these compounds act as thiolate targeting electrophiles. The JAK1 redox switch is likely not a target of acyloxy nitroso compounds, as NCA had no effect on JAK1 catalytic activity and only modestly affected JAK1-induced phosphorylation of the LIF receptor. However, pretreatment of recombinant human STAT3 with NCA or NCP reduced labeling of free sulfhydryl residues. We show that NCP in the presence of diamide enhanced STAT3 glutathionylation and dimerization in adult mouse cardiac myocytes and altered STAT3 under non-reducing conditions. Finally, we show that monomeric STAT3 levels are decreased in the Gαq model of heart failure in a redox-sensitive manner. Altogether, our evidence indicates that STAT3 has redox-sensitive cysteines that regulate its activation and are targeted by HNO donors and acyloxy nitroso compounds. These findings raise the possibility of new therapeutic strategies to target STAT3 signaling via a redox-dependent manner, particularly in the context of cardiac and non-cardiac diseases with prominent pro-inflammatory signaling.
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Affiliation(s)
- Carlos Zgheib
- Departments of Pharmacology and Toxicology, School of Medicine, and Center for Excellence in Cardiovascular-Renal Research, The University of Mississippi Medical Center, Jackson, Mississippi, United States of America
| | - Mazen Kurdi
- Department of Chemistry and Biochemistry, Faculty of Sciences, Lebanese University, Rafic Hariri Educational Campus, Hadath, Lebanon
| | - Fouad A. Zouein
- Departments of Pharmacology and Toxicology, School of Medicine, and Center for Excellence in Cardiovascular-Renal Research, The University of Mississippi Medical Center, Jackson, Mississippi, United States of America
| | - Barak W. Gunter
- Departments of Pharmacology and Toxicology, School of Medicine, and Center for Excellence in Cardiovascular-Renal Research, The University of Mississippi Medical Center, Jackson, Mississippi, United States of America
| | - Brian A. Stanley
- Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America
| | - Joe Zgheib
- Department of Medicine, Division of Cardiology, Centre Hospitalier Universitaire de Nancy, Brabois, France
| | - Damian G. Romero
- Department of Biochemistry, School of Medicine, and Center for Excellence in Cardiovascular-Renal Research, The University of Mississippi Medical Center, Jackson, Mississippi, United States of America
| | - S. Bruce King
- Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina, United States of America
| | - Nazareno Paolocci
- Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America
- Clinical Medicine Department, Section of General Pathology, University of Perugia, Perugia, Italy
| | - George W. Booz
- Departments of Pharmacology and Toxicology, School of Medicine, and Center for Excellence in Cardiovascular-Renal Research, The University of Mississippi Medical Center, Jackson, Mississippi, United States of America
- * E-mail:
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15
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Kim HH, Kim YS, Kang YK, Moon JS. Leptin and peroxisome proliferator-activated receptor γ expression in colorectal adenoma. World J Gastroenterol 2012; 18:557-62. [PMID: 22363123 PMCID: PMC3280402 DOI: 10.3748/wjg.v18.i6.557] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2011] [Revised: 09/07/2011] [Accepted: 09/14/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expressions of leptin and peroxisome proliferator-activated receptor γ (PPARG) in relation to body mass index (BMI).
METHODS: We evaluated leptin and PPARG expression in 30 adenomas over 1 cm in size by immunohistochemical staining. In addition, clinicopathologic features including BMI were assessed.
RESULTS: PPARG and leptin expression showed a strong positive correlation (P = 0.035). The average BMI of the leptin-positive group was higher than that of the leptin-negative group (25.4 ± 3.4 kg/m2vs 22.6 ± 2.4 kg/m2, P = 0.018), and leptin expression was significantly correlated with high BMI (P = 0.024). Leptin expression was more frequently observed in intermediate/high grade dysplasia than in low grade dysplasia (P = 0.030). However, PPARG expression was not correlated with BMI and grade of dysplasia.
CONCLUSION: BMI has influenced on the leptin expression of colorectal adenoma. The exact mechanism underlies the strong correlation between leptin and PPARG expression needs further study.
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Demyanets S, Huber K, Wojta J. Vascular effects of glycoprotein130 ligands--part II: biomarkers and therapeutic targets. Vascul Pharmacol 2012; 57:29-40. [PMID: 22245786 DOI: 10.1016/j.vph.2011.12.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2011] [Revised: 12/15/2011] [Accepted: 12/25/2011] [Indexed: 12/13/2022]
Abstract
Glycoprotein130 (gp130) ligands are defined by the use of the common receptor subunit gp130 and comprise interleukin (IL)-6, oncostatin M (OSM), IL-11, leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine (CLC), ciliary neurotrophic factor (CNTF), IL-27 and neuropoietin (NP). In part I of this review we addressed the pathophysiological functions of gp130 ligands with respect to the vascular wall. In part II of this review on the vascular effects of gp130 ligands we will discuss data about possible use of these molecules as biomarkers to predict development or progression of cardiovascular diseases. Furthermore, the possibility to modulate circulating levels of gp130 ligands or their tissue expression by specific antibodies, soluble gp130 protein, renin-angiotensin-aldosterone system (RASS) inhibitors, statins, agonists of peroxisome proliferator-activated receptors (PPAR), hormone replacement therapy, nonsteroidal anti-inflammatory drugs (NSAID) or lifestyle modulating strategies are presented. Recent knowledge about the application of recombinant cytokines from the gp130 cytokine family as therapeutic agents in obesity or atherosclerosis is also summarized. Thus the purpose of this review is to cover a possible usefulness of gp130 ligands as biomarkers and targets for therapy in cardiovascular pathologies.
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Affiliation(s)
- Svitlana Demyanets
- Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
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Abstract
In this article we review the evolution of cancer research involving PPARgamma, including mechanisms, target genes, and clinical applications. For the last thirteen years, the effects of PPARgamma activity on tumor biology have been studied intensely. Most of this research has focused upon the potential for employing agonists of this nuclear receptor in cancer treatment. As a monotherapy such agonists have shown little success in clinical trials, while they have shown promise as components of combination treatments both in culture and in animal models. Other investigations have explored a possible role for PPARgamma as a tumor suppressor, and as an inducer of differentiation of cancer stem cells. Whereas early studies have yielded variable conclusions regarding the prevalence of PPARgamma mutations in cancer, the protein level of this receptor has been more recently identified as a significant prognostic marker. We predict that indicators of PPARgamma activity may also serve as predictive markers for tailoring treatments.
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Affiliation(s)
- Gregory T Robbins
- Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine
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18
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Vitale G, Zappavigna S, Marra M, Dicitore A, Meschini S, Condello M, Arancia G, Castiglioni S, Maroni P, Bendinelli P, Piccoletti R, van Koetsveld PM, Cavagnini F, Budillon A, Abbruzzese A, Hofland LJ, Caraglia M. The PPAR-γ agonist troglitazone antagonizes survival pathways induced by STAT-3 in recombinant interferon-β treated pancreatic cancer cells. Biotechnol Adv 2012; 30:169-84. [DOI: 10.1016/j.biotechadv.2011.08.001] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2011] [Revised: 07/22/2011] [Accepted: 08/02/2011] [Indexed: 12/30/2022]
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The influence of peroxisome proliferator-activated receptor γ1 during differentiation of mouse embryonic stem cells to neural cells. Differentiation 2012; 83:60-7. [DOI: 10.1016/j.diff.2011.08.009] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2011] [Revised: 08/12/2011] [Accepted: 08/22/2011] [Indexed: 11/23/2022]
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20
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Surh YJ, Na HK, Park JM, Lee HN, Kim W, Yoon IS, Kim DD. 15-Deoxy-Δ¹²,¹⁴-prostaglandin J₂, an electrophilic lipid mediator of anti-inflammatory and pro-resolving signaling. Biochem Pharmacol 2011; 82:1335-51. [PMID: 21843512 DOI: 10.1016/j.bcp.2011.07.100] [Citation(s) in RCA: 103] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2011] [Revised: 07/28/2011] [Accepted: 07/29/2011] [Indexed: 01/22/2023]
Abstract
15-deoxy-Δ(12,14)-prostagandin J(2) (15d-PGJ2) is produced in the inflamed cells and tissues as a consequence of upregulation of cyclooxygenase-2 (COX-2). 15d-PGJ2 is known to be the endogenous ligand of peroxisome proliferator-activated receptor gamma (PPARγ) with multiple physiological properties. Though one of the terminal products of the COX-2-catalyzed reactions, this cyclopentenone prostaglandin exerts potent anti-inflammatory actions, in part, by antagonizing the activities of pro-inflammatory transcription factors, such as NF-κB, STAT3, and AP-1, while stimulating the anti-inflammatory transcription factor Nrf2. These effects are not necessarily dependent on its activation of PPARγ, but often involves direct interaction with the above signaling molecules and their regulators. The locally produced 15d-PGJ2 is also involved in the resolution of inflammatory responses. Thus, 15d-PGJ2, especially formed during the late phase of inflammation, might inhibit cytokine secretion and other events by antigen-presenting cells like dendritic cells or macrophages. 15d-PGJ2 can also affect the priming and effector functions of T lymphocytes and induce their apoptotic cell death. These represent a negative feedback explaining how once-initiated immunologic and inflammatory responses are switched off and terminated. In this context, 15d-PGJ2 and its synthetic derivatives have therapeutic potential for the treatment of inflammatory disorders.
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Affiliation(s)
- Young-Joon Surh
- WCU Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul 151-742, South Korea.
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21
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Nuclear Receptors in Regulation of Mouse ES Cell Pluripotency and Differentiation. PPAR Res 2011; 2007:61563. [PMID: 18274628 PMCID: PMC2233893 DOI: 10.1155/2007/61563] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2007] [Accepted: 06/11/2007] [Indexed: 12/25/2022] Open
Abstract
Embryonic stem (ES) cells have great therapeutic potential because they are capable of indefinite self-renewal and have the potential to differentiate into over 200 different cell types that compose the human body. The switch from the pluripotent phenotype to a differentiated cell involves many complex signaling pathways including those involving LIF/Stat3 and the transcription factors Sox2, Nanog and Oct-4. Many nuclear receptors play an important role in the maintenance of pluripotence (ERRβ, SF-1, LRH-1, DAX-1) repression of the ES cell phenotype (RAR, RXR, GCNF) and also the differentiation of ES cells (PPARγ). Here we review the roles of the nuclear receptors involved in regulating these important processes in ES cells.
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Constitutive androstane receptor agonist CITCO inhibits growth and expansion of brain tumour stem cells. Br J Cancer 2011; 104:448-59. [PMID: 21224854 PMCID: PMC3049563 DOI: 10.1038/sj.bjc.6606064] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Background: Brain tumours present unique challenges to conventional therapies and pose major health problems around the world. Brain tumour stem cells (BTSCs) represent a small fraction of tumour cells that maintain growth, drug resistance and recurrence properties. Constitutive androstane receptor (CAR) is a nuclear receptor transcription factor that regulates drug metabolism and homoeostasis. In this study, we examined the effect of CAR agonist, 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehydeO-(3,4-dichlorobenzyl)oxime (CITCO) on BTSCs. Methods: The expression of CAR in BTSCs was detected by quantitative RT–PCR and western blot. The antiproliferative effect of CITCO on BTSCs was determined by WST-1 and 3H thymidine uptake assays. The effect of CITCO on CD133 expression, cell cycle progression and apoptosis in BTSCs was analysed by immunostaining and flow cytometry. The in vivo effect of CITCO was studied using subcutaneous (s.c.) BTSC xenograft in nude mice. Results: We show for the first time that BTSCs express altered levels of nuclear receptors compared with glioma cells. The expression of CAR mRNA and protein was low in BTSCs and that increased following treatment with CITCO in culture. CITCO induced a dose-dependent decrease in growth and expansion of CD133+ BTSCs as gliospheres in culture. Cell cycle arrest and apoptosis in BTSCs were induced by CITCO, but not in normal astrocytes. Growth of s.c BTSC xenograft in nude mice was also inhibited by CITCO. Conclusion: These findings indicate that CITCO inhibits the growth and expansion of BTSCs, suggesting the use of CAR agonists for the treatment of brain tumour.
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Mo C, Chearwae W, Bright JJ. PPARγ regulates LIF-induced growth and self-renewal of mouse ES cells through Tyk2-Stat3 pathway. Cell Signal 2010; 22:495-500. [DOI: 10.1016/j.cellsig.2009.11.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2009] [Accepted: 11/09/2009] [Indexed: 10/20/2022]
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Abstract
Brain tumour stem cells (BTSCs) are a small population of cells that has self-renewal, transplantation, multidrug resistance and recurrence properties, thus remain novel therapeutic target for brain tumour. Recent studies have shown that peroxisome proliferator-activated receptor gamma (PPARgamma) agonists induce growth arrest and apoptosis in glioblastoma cells, but their effects on BTSCs are largely unknown. In this study, we generated gliospheres with more than 50% CD133+ BTSC by culturing U87MG and T98G human glioblastoma cells with epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). In vitro treatment with PPARgamma agonist, 15-Deoxy-Delta(12,14)-Prostaglandin J(2) (15d-PGJ2) or all-trans retinoic acid resulted in a reversible inhibition of gliosphere formation in culture. Peroxisome proliferator-activated receptor gamma agonists inhibited the proliferation and expansion of glioma and gliosphere cells in a dose-dependent manner. Peroxisome proliferator-activated receptor gamma agonists also induced cell cycle arrest and apoptosis in association with the inhibition of EGF/bFGF signalling through Tyk2-Stat3 pathway and expression of PPARgamma in gliosphere cells. These findings demonstrate that PPARgamma agonists regulate growth and expansion of BTSCs and extend their use to target BTSCs in the treatment of brain tumour.
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25
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Ideguchi M, Shinoyama M, Gomi M, Hayashi H, Hashimoto N, Takahashi J. Immune or inflammatory response by the host brain suppresses neuronal differentiation of transplanted ES cell-derived neural precursor cells. J Neurosci Res 2008; 86:1936-43. [PMID: 18335525 DOI: 10.1002/jnr.21652] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Embryonic stem (ES) cells are a promising donor source for transplantation therapy, but several problems must be solved before they can be clinically useful. One of these is the host immune reaction to allogeneic grafts. In this article, we examine the effect of the host immune reaction on survival and differentiation of grafted ES cell-derived neural precursor cells (NPCs). We induced NPCs from mouse ES cells by stromal cell-derived inducing activity and then transplanted them into mouse brains with or without administering the immunosuppressant cyclosporine A (CsA). Two and 8 weeks following transplantation, the accumulation of host-derived microglia/macrophages and lymphocytes was observed around the graft. This effect was reduced by CsA treatment, although no significant difference in graft volume was observed. These data suggest that an immune response occurs in allografts of ES cell-derived NPCs. Intriguingly, however, the ratio of neurons to astrocytes in the graft was higher in immunosuppressed mice. Because inflammatory or immune cells produce various cytokines, we examined the effect of IL-1beta, IL-6, IFN-gamma, and TNF-alpha on the differentiation of NPCs in vitro. Only IL-6 promoted glial cell fate, and this effect could be reversed by the addition of an IL-6 neutralizing antibody. These results suggest that allogeneic ES cell-derived NPCs can cause an immune response by the host brain, but it is not strong enough to reject the graft. More important, activated microglia and lymphocytes can suppress neuronal differentiation of grafted NPCs in vivo by producing cytokines such as IL-6.
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Affiliation(s)
- Makoto Ideguchi
- Department of Neurosurgery, Clinical Neuroscience, Kyoto University Graduate School of Medicine, Kyoto, Japan
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26
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Breier JM, Radio NM, Mundy WR, Shafer TJ. Development of a high-throughput screening assay for chemical effects on proliferation and viability of immortalized human neural progenitor cells. Toxicol Sci 2008; 105:119-33. [PMID: 18550602 DOI: 10.1093/toxsci/kfn115] [Citation(s) in RCA: 109] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
There is considerable public concern that the majority of commercial chemicals have not been evaluated for their potential to cause developmental neurotoxicity. Although several chemicals are assessed annually under the current developmental neurotoxicity guidelines, time, resource, and animal constraints prevent testing of large numbers of chemicals using this approach. Thus, incentive is mounting to develop in vitro methods to screen chemicals for their potential to harm the developing human nervous system. As an initial step toward this end, the present studies evaluated an automated, high-throughput method for screening chemical effects on proliferation and viability using ReNcell CX cells, a human neural progenitor cell (hNPC) line. ReNcell CX cells doubled in approximately 36 h and expressed the neural progenitor markers nestin and SOX2. High-throughput assays for cell proliferation (5-bromo-2'-deoxyuridine incorporation) and viability (propidium iodide exclusion) were optimized and tested using known antiproliferative compounds. The utility of this in vitro screen was evaluated further using a set of compounds containing eight known to cause developmental neurotoxicity and eight presumably nontoxic compounds. Six out of eight developmental neurotoxicants significantly inhibited ReNcell CX cell proliferation and/or viability, whereas two out of eight nontoxic chemicals caused only minimal effects. These results demonstrate that chemical effects on cell proliferation and viability can be assessed via high-throughput methods using hNPCs. Further development of this approach as part of a strategy to screen compounds for potential effects on nervous system development is warranted.
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Affiliation(s)
- Joseph M Breier
- The Curriculum in Toxicology, UNC School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
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Kuniyasu H. The Roles of Dietary PPARgamma Ligands for Metastasis in Colorectal Cancer. PPAR Res 2008; 2008:529720. [PMID: 18551182 PMCID: PMC2422868 DOI: 10.1155/2008/529720] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2008] [Accepted: 05/14/2008] [Indexed: 12/15/2022] Open
Abstract
Dietary peroxisome proliferator-activated receptor (PPAR)gamma ligands, linoleic acid (LA) and conjugated linoleic acid (CLA), showed anticancer effects in colorectal carcinoma cells. LA is metabolized by two pathways. Cyclooxygenase (COX)-2 produces procarcinogenic prostaglandin E2, whereas 15-lipoxygenase (LOX)-1 produces PPARgamma ligands. The 15LOX-1 pathway, which is dominant in colorectal adenomas, was downregulated and inversely COX-2 was upregulated in colorectal cancer. LA and CLA inhibited peritoneal metastasis of colorectal cancer cells in nude mice. The inhibitory effect was abrogated by PPARgamma antisense treatment. A continuous LA treatment provided cancer cells quiescence. These quiescent cells formed dormant nests in nude mice administrated LA. The quiescent and dormant cells showed downregulated PPARgamma and upregulated nucleostemin. Thus, short-term exposure to dietary PPARgamma ligands inhibits cancer metastasis, whereas consistent exposure to LA provides quiescent/dormant status with possible induction of cancer stem and/or progenitor phenotype. The complicated roles of dietary PPARgamma ligands are needed to examine further.
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Affiliation(s)
- Hiroki Kuniyasu
- Department of Molecular Pathology, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan
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28
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Hagland H, Nikolaisen J, Hodneland LI, Gjertsen BT, Bruserud Ø, Tronstad KJ. Targeting mitochondria in the treatment of human cancer: a coordinated attack against cancer cell energy metabolism and signalling. Expert Opin Ther Targets 2007; 11:1055-69. [PMID: 17665978 DOI: 10.1517/14728222.11.8.1055] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Mitochondria have major roles in bioenergetics and vital signalling of the mammalian cell. Consequently, these organelles have been implicated in the process of carcinogenesis, which includes alterations of cellular metabolism and cell death pathways. Multiple molecular routes of malignant transformation appear to result in the common ability of many tumours to take up large amounts of glucose. This metabolic twist has been explained by phenomena such as aerobic glycolysis and impaired mitochondrial function, and is linked to tumour growth potential via major cellular signalling pathways. This paper reviews the literature on central mechanisms through which energy metabolism merges with growth, proliferation and death signalling, which tend to include mitochondria at some level. These processes can potentially be targeted by pharmacological agents for therapeutic and chemosensitising purposes.
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Affiliation(s)
- Hanne Hagland
- University of Bergen, Department of Biomedicine, Bergen, Norway.
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Rajasingh J, Bord E, Hamada H, Lambers E, Qin G, Losordo DW, Kishore R. STAT3-dependent mouse embryonic stem cell differentiation into cardiomyocytes: analysis of molecular signaling and therapeutic efficacy of cardiomyocyte precommitted mES transplantation in a mouse model of myocardial infarction. Circ Res 2007; 101:910-8. [PMID: 17823373 DOI: 10.1161/circresaha.107.156786] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Pluripotent embryonic stem (ES) cell therapy may be an attractive source for postinfarction myocardial repair and regeneration. However, the specific stimuli and signal pathways that may control ES cell-mediated cardiomyogenesis remains to be completely defined. The aim of the present study was to investigate (1) the effect and underlying signal transduction pathways of leukemia inhibitory factor (LIF) and bone-morphogenic protein-2 (BMP-2)-induced mouse ES cell (mES-D3 line) differentiation into cardiomyocytes (CMC) and (2) the efficacy of CMC precommitted mES cells for functional and anatomical cardiac repair in surgically-induced mouse acute myocardial infarction (AMI) model. Various doses of LIF and BMP-2 and their inhibitors or blocking antibodies were tested for mES differentiation to CMC in vitro. CMC differentiation was assessed by mRNA and protein expression of CMC-specific markers, Connexin-43, CTI, CTT, Mef2c, Tbx5, Nkx2.5, GATA-4, and alphaMHC. LIF and BMP-2 synergistically induced the expression of CMC markers as early as 2 to 4 days in culture. Signaling studies identified STAT3 and MAP kinase (ERK1/2) as specific signaling components of LIF+BMP-2-mediated CMC differentiation. Inhibition of either STAT3 or MAPK activation by specific inhibitors drastically suppressed LIF+BMP-2-mediated CMC differentiation. Moreover, in mouse AMI, transplantation of lentivirus-GFP-transduced, LIF+BMP-2 precommitted mES cells, improved post-MI left ventricular functions, and enhanced capillary density. Transplanted cells engrafted in myocardium and differentiated into CMC and endothelial cells. Our data suggest that LIF and BMP-2 may synergistically enhance CMC differentiation of transplanted stem cells. Thus augmentation of LIF/BMP-2 downstream signaling components or cell type specific precommitment may facilitate the effects of ES cell-based therapies for post-MI myocardial repair and regeneration.
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Affiliation(s)
- Johnson Rajasingh
- Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, 303 E Chicago Ave, Chicago, IL 60611, USA
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