Publications by authors named "Anh Thu Nguyen-Lefebvre"

7 Publications

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The hippo pathway: A master regulator of liver metabolism, regeneration, and disease.

FASEB J 2021 May;35(5):e21570

Department of Medicine, Multi-Organ Transplant Program, Toronto General Hospital, Toronto, ON, Canada.

The liver is the only visceral organ in the body with a tremendous capacity to regenerate in response to insults that induce inflammation, cell death, and injury. Liver regeneration is a complicated process involving a well-orchestrated activation of non-parenchymal cells in the injured area and proliferation of undamaged hepatocytes. Furthermore, the liver has a Hepatostat, defined as adjustment of its volume to that required for homeostasis. Understanding the mechanisms that control different steps of liver regeneration is critical to informing therapies for liver repair, to help patients with liver disease. The Hippo signaling pathway is well known for playing an essential role in the control and regulation of liver size, regeneration, stem cell self-renewal, and liver cancer. Thus, the Hippo pathway regulates dynamic cell fates in liver, and in absence of its downstream effectors YAP and TAZ, liver regeneration is severely impaired, and the proliferative expansion of liver cells blocked. We will mainly review upstream mechanisms activating the Hippo signaling pathway following partial hepatectomy in mouse model and patients, its roles during different steps of liver regeneration, metabolism, and cancer. We will also discuss how targeting the Hippo signaling cascade might improve liver regeneration and suppress liver tumorigenesis.
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http://dx.doi.org/10.1096/fj.202002284RRDOI Listing
May 2021

HLA-G dimer targets Granzyme B pathway to prolong human renal allograft survival.

FASEB J 2019 04 8;33(4):5220-5236. Epub 2019 Jan 8.

Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.

Human leukocyte antigen G (HLA-G), a nonclassic HLA class Ib molecule involved in the maintenance of maternal tolerance to semiallogeneic fetal tissues during pregnancy, has emerged as a potential therapeutic target to control allograft rejection. We demonstrate here that the level of soluble HLA-G dimer was higher in a group of 90 patients with a functioning renal allograft compared with 40 patients who rejected (RJ) their transplants. The HLA-G dimer level was not affected by demographic status. One of the potential mechanisms in tissue-organ allograft rejection involves the induction of granzymes and perforin, which are the main effector molecules expressed by CD8 cytotoxic T lymphocytes and function to destroy allogeneic transplants. Using genomics and molecular and cellular analyses of cells from T-cell-mediated RJ and nonrejected kidney transplant patients, cells from leukocyte Ig-like receptor B1 (LILRB1) transgenic mice, humanized mice, and genetically engineered HLA-G dimer, we demonstrated a novel mechanism by which HLA-G dimer inhibits activation and cytotoxic capabilities of human CD8 T cells. This mechanism implicated the down-regulation of Granzyme B expression and the essential involvement of LILRB1. Thus, HLA-G dimer has the potential to be a specific and effective therapy for prevention of allograft rejection and prolongation of graft survival.-Ajith, A., Portik-Dobos, V., Nguyen-Lefebvre, A. T., Callaway, C., Horuzsko, D. D., Kapoor, R., Zayas, C., Maenaka, K., Mulloy, L. L., Horuzsko, A. HLA-G dimer targets Granzyme B pathway to prolong human renal allograft survival.
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http://dx.doi.org/10.1096/fj.201802017RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436663PMC
April 2019

The innate immune receptor TREM-1 promotes liver injury and fibrosis.

J Clin Invest 2018 11 2;128(11):4870-4883. Epub 2018 Oct 2.

Molecular Oncology and Biomarkers Program, Georgia Cancer Center, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.

Inflammation occurs in all tissues in response to injury or stress and is the key process underlying hepatic fibrogenesis. Targeting chronic and uncontrolled inflammation is one strategy to prevent liver injury and fibrosis progression. Here, we demonstrate that triggering receptor expressed on myeloid cells 1 (TREM-1), an amplifier of inflammation, promotes liver disease by intensifying hepatic inflammation and fibrosis. In the liver, TREM-1 expression was limited to liver macrophages and monocytes and was highly upregulated on Kupffer cells, circulating monocytes, and monocyte-derived macrophages in a mouse model of chronic liver injury and fibrosis induced by carbon tetrachloride (CCl4) administration. TREM-1 signaling promoted proinflammatory cytokine production and mobilization of inflammatory cells to the site of injury. Deletion of Trem1 reduced liver injury, inflammatory cell infiltration, and fibrogenesis. Reconstitution of Trem1-deficient mice with Trem1-sufficient Kupffer cells restored the recruitment of inflammatory monocytes and the severity of liver injury. Markedly increased infiltration of liver fibrotic areas with TREM-1-positive Kupffer cells and monocytes/macrophages was found in patients with hepatic fibrosis. Our data support a role of TREM-1 in liver injury and hepatic fibrogenesis and suggest that TREM-1 is a master regulator of Kupffer cell activation, which escalates chronic liver inflammatory responses, activates hepatic stellate cells, and reveals a mechanism of promotion of liver fibrosis.
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http://dx.doi.org/10.1172/JCI98156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205377PMC
November 2018

expression in acute myeloid leukemia.

Oncotarget 2018 Jan 15;9(7):7442-7452. Epub 2017 Dec 15.

Present address: Stony Brook University Cancer Center, Stony Brook, NY, USA.

Similar signaling pathways could operate in both normal hematopoietic stem and progenitor cells (HSPCs) and leukemia stem cells (LSCs). Thus, targeting LSCs signaling without substantial toxicities to normal HSPCs remains challenging. SALL1, is a member of the transcriptional network that regulates stem cell pluripotency, and lacks significant expression in most adult tissues, including normal bone marrow (NBM). We examined the expression and functional characterization of SALL1 in NBM and in acute myeloid leukemia (AML) using and assays. We showed that SALL1 is expressed preferentially in LSCs- enriched CD34+CD38- cell subpopulation but not in NBM. SALL1 inhibition resulted in decreased cellular proliferation and in inferior AML engraftment in NSG mice and it was also associated with upregulation of PTEN and downregulation of m-TOR, β-catenin, and NF-қB expression. These findings suggest that SALL1 inhibition interrupts leukemogenesis. Further studies to validate SALL1 as a potential biomarker for minimal residual disease (MRD) and to determine SALL1's role in prognostication are ongoing. Additionally, pre-clinical evaluation of SALL1 as a therapeutic target in AML is warranted.
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http://dx.doi.org/10.18632/oncotarget.23448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800914PMC
January 2018

Mouse models for studies of HLA-G functions in basic science and pre-clinical research.

Hum Immunol 2016 Sep 13;77(9):711-9. Epub 2016 Apr 13.

Molecular Oncology and Biomarkers Program, Georgia Regents University Cancer Center, 1140 Laney Walker Blvd, Augusta, GA 30912, USA; Department of Medicine, Georgia Regents University, 1120 15th Street, Augusta, GA 30912, USA. Electronic address:

HLA-G was described originally as a tolerogenic molecule that allows the semiallogeneic fetus to escape from recognition by the maternal immune response. This review will discuss different steps in the study of HLA-G expression and functions in vivo, starting with analyses of expression of the HLA-G gene and its receptors in transgenic mice, and continuing with applications of HLA-G and its receptors in prevention of allograft rejection, transplantation tolerance, and controlling the development of infection. Humanized mouse models have been discussed for developing in vivo studies of HLA-G in physiological and pathological conditions. Collectively, animal models provide an opportunity to evaluate the importance of the interaction between HLA-G and its receptors in terms of its ability to regulate immune responses during maternal-fetal tolerance, survival of allografts, tumor-escape mechanisms, and development of infections when both HLA-G and its receptors are expressed. In addition, in vivo studies on HLA-G also offer novel approaches to achieve a reproducible transplantation tolerance and to develop personalized medicine to prevent allograft rejection.
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http://dx.doi.org/10.1016/j.humimm.2016.02.012DOI Listing
September 2016

Kupffer Cell Metabolism and Function.

J Enzymol Metab 2015;1(1). Epub 2015 Aug 14.

Cancer Center, Molecular Oncology Program, Georgia Regents University, Augusta, GA, 30912, USA; Cancer Center, Molecular Oncology Program, Department of Medicine, Georgia Regents University, 1410 Laney Walker Blvd., Augusta, GA, 30912, USA.

Kupffer cells are resident liver macrophages and play a critical role in maintaining liver functions. Under physiological conditions, they are the first innate immune cells and protect the liver from bacterial infections. Under pathological conditions, they are activated by different components and can differentiate into M1-like (classical) or M2-like (alternative) macrophages. The metabolism of classical or alternative activated Kupffer cells will determine their functions in liver damage. Special functions and metabolism of Kupffer cells suggest that they are an attractive target for therapy of liver inflammation and related diseases, including cancer and infectious diseases. Here we review the different types of Kupffer cells and their metabolism and functions in physiological and pathological conditions.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4771376PMC
August 2015

Identification of human, rat and chicken ribosomal proteins by a combination of two-dimensional polyacrylamide gel electrophoresis and mass spectrometry.

J Proteomics 2011 Feb 3;74(2):167-85. Epub 2010 Nov 3.

Université de Lyon, F-69622, Lyon, France.

To identify the exact spot position of human, rat and chicken ribosomal proteins (RP) separated by two-dimensional polyacrylamide gel electrophoresis (2-DE), a 2-DE system was designed to separate RP with a pI>8.6 according to their charge in the first dimension and to their molecular mass in the second dimension. Individual proteins were excised from the gels and identified by mass spectrometry after digestion by trypsin. In addition, a mixture of purified RP from these three species was also analyzed by tandem mass tag spectrometry. By combining those two methods 74 RP from human, 76 from rat and 67 from chicken were identified according to the nomenclature initially defined for rat liver RP and by using the Swiss-Prot/trEMBL databases. Whereas human and rat RP were well described, most of RP from chicken were not characterized in databases, since 35 out of 67 chicken RP identified in this study were not listed yet. We propose here the first comprehensive description of chicken RP and their comparison to those from human and rat.
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http://dx.doi.org/10.1016/j.jprot.2010.10.007DOI Listing
February 2011