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Liu X, Zhang X, He Q, Sun X, Wang W, Li S. Effects of increasing n3:n6 ratio by replacing extruded soybeans with extruded flaxseed on dry matter intake, rumen fluid bacteria, and liver lipid metabolism in transition cows. BMC Microbiol 2025; 25:138. [PMID: 40087566 PMCID: PMC11907948 DOI: 10.1186/s12866-024-03733-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 12/23/2024] [Indexed: 03/17/2025] Open
Abstract
BACKGROUND The drop of dry matter intake (DMI) and rise of milk production in transitional dairy cows would mobilize reserved fat and disrupt lipid metabolism, eventually attributed to negative energy balance (NEB) and immune injury. The positive effect of n-3 polyunsaturated fatty acids (PUFA) on regulating energy metabolism and inflammation has been elucidated, however, the lack of regulatory mechanism of dairy cows deserves further investigation. In this study, 30 Holstein transition cows were divided into the control (CON) and HN3 groups based on the n-3: n-6 PUFA ratio in the diet. RESULTS The results showed that compared to the CON group, high n-3: n-6 PUFA ratio-supplemented cows in the prepartum phase reduced the relative abundance of gram-negative bacteria in the rumen, the concentration of lipopolysaccharide in the plasma and liver also significantly decreased (P < 0.05). Transcriptomic analysis of the liver showed that the NF-κB signaling pathway significantly down-regulated and the taste transduction pathway up-regulated (P < 0.05) in the HN3 group. In the postpartum phase, a high n-3/n-6 PUFA ratio in the diet increased the relative abundance of Prevotella, Succinimonas and Treponema in the rumen, at the same time, orexins in plasma were also changed (P < 0.05). Further, the insulin resistance pathway significantly down-regulated and the taste transduction pathway up-regulated (P < 0.05) in the liver. CONCLUSIONS Overall, these results showed that a high n-3: n-6 PUFA ratio in the diet attenuates inflammatory responses in the prepartum phase and increases milk protein in the postpartum phase of transitional dairy cows. Appropriate increase in the proportion of n-3: n-6 PUFA ratio in the diet may be an effective measure to alleviate postpartum metabolic disease in dairy cows.
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Affiliation(s)
- Xiaojing Liu
- State Key Laboratory of Animal Nutrition, Beijing Engineering Technology Research Center of Raw Milk Quality and Safety Control, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Xinyue Zhang
- State Key Laboratory of Animal Nutrition, Beijing Engineering Technology Research Center of Raw Milk Quality and Safety Control, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Qiongyu He
- Animal Genomics, ETH Zurich, Universitatstrasse 2, Zurich, 8092, Switzerland
| | - Xiaoge Sun
- State Key Laboratory of Animal Nutrition, Beijing Engineering Technology Research Center of Raw Milk Quality and Safety Control, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China.
- Department of the neurosurgery, Penn State College of Medicine, 700 HMC Cres Rd, Hummelstown, PA, 17036, USA.
| | - Wei Wang
- State Key Laboratory of Animal Nutrition, Beijing Engineering Technology Research Center of Raw Milk Quality and Safety Control, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China.
| | - Shengli Li
- State Key Laboratory of Animal Nutrition, Beijing Engineering Technology Research Center of Raw Milk Quality and Safety Control, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China.
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2
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Pan Z, Ye YS, Liu C, Li W. Role of liver-resident NK cells in liver immunity. Hepatol Int 2025:10.1007/s12072-025-10778-7. [PMID: 39893278 DOI: 10.1007/s12072-025-10778-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 01/10/2025] [Indexed: 02/04/2025]
Abstract
The tolerogenic immune microenvironment of the liver (the immune system avoids attacking harmless antigens, such as antigens derived from food and gut microbiota) has garnered significant attention in recent years. Inherent immune cells in the liver play a unique role in regulating this microenvironment. Liver-resident natural killer (LrNK) cells, also known as liver type 1 innate lymphoid cells (ILC1s), are a recently discovered subset of immune cells that possess properties distinct from those of conventional NK (cNK) cells. Accumulating evidence suggests that there are significant differences between LrNK and cNK cells, with LrNK cells potentially exhibiting immunosuppressive functions in the liver. This review summarizes the latest findings on LrNK cells, focusing on their phenotype, heterogeneity, plasticity, origin, development, and the required transcription factors. In addition, immune functions of LrNK cells in various liver diseases, including liver cancer, viral infections, liver injury, and cirrhosis, were analyzed. By elucidating the role of LrNK cells in liver immunity, this review aims to enhance our understanding of the mechanisms underlying liver immunity and contribute to the improvement of liver disease treatment.
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Affiliation(s)
- Zheng Pan
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, 130033, China
| | - Yan-Shuo Ye
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, 130033, China
| | - Chang Liu
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, 130033, China
| | - Wei Li
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, 130033, China.
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Valdez CN, Sánchez-Zuno GA, Bucala R, Tran TT. Macrophage Migration Inhibitory Factor (MIF) and D-Dopachrome Tautomerase (DDT): Pathways to Tumorigenesis and Therapeutic Opportunities. Int J Mol Sci 2024; 25:4849. [PMID: 38732068 PMCID: PMC11084905 DOI: 10.3390/ijms25094849] [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: 03/28/2024] [Revised: 04/24/2024] [Accepted: 04/25/2024] [Indexed: 05/13/2024] Open
Abstract
Discovered as inflammatory cytokines, MIF and DDT exhibit widespread expression and have emerged as critical mediators in the response to infection, inflammation, and more recently, in cancer. In this comprehensive review, we provide details on their structures, binding partners, regulatory mechanisms, and roles in cancer. We also elaborate on their significant impact in driving tumorigenesis across various cancer types, supported by extensive in vitro, in vivo, bioinformatic, and clinical studies. To date, only a limited number of clinical trials have explored MIF as a therapeutic target in cancer patients, and DDT has not been evaluated. The ongoing pursuit of optimal strategies for targeting MIF and DDT highlights their potential as promising antitumor candidates. Dual inhibition of MIF and DDT may allow for the most effective suppression of canonical and non-canonical signaling pathways, warranting further investigations and clinical exploration.
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Affiliation(s)
- Caroline Naomi Valdez
- School of Medicine, Yale University, 333 Cedar St., New Haven, CT 06510, USA; (C.N.V.); (R.B.)
| | - Gabriela Athziri Sánchez-Zuno
- Section of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Yale University, 333 Cedar St., New Haven, CT 06510, USA;
| | - Richard Bucala
- School of Medicine, Yale University, 333 Cedar St., New Haven, CT 06510, USA; (C.N.V.); (R.B.)
- Section of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Yale University, 333 Cedar St., New Haven, CT 06510, USA;
- Yale Cancer Center, Yale University, 333 Cedar St., New Haven, CT 06510, USA
| | - Thuy T. Tran
- School of Medicine, Yale University, 333 Cedar St., New Haven, CT 06510, USA; (C.N.V.); (R.B.)
- Yale Cancer Center, Yale University, 333 Cedar St., New Haven, CT 06510, USA
- Section of Medical Oncology, Department of Internal Medicine, Yale University, 333 Cedar St., New Haven, CT 06510, USA
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4
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Yu H, Yan X, Wang N, Liu X, Xue T, Li C, Zhang X. Characterization of caspase gene family in Sebastes schlegelii and their expression profiles under Aeromonas salmonicida and Vibrio anguillarum infection. Comp Biochem Physiol B Biochem Mol Biol 2024; 270:110913. [PMID: 37913865 DOI: 10.1016/j.cbpb.2023.110913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 10/27/2023] [Accepted: 10/27/2023] [Indexed: 11/03/2023]
Abstract
The caspase, functioning as a proteinase, plays a crucial role in eukaryotic cell apoptosis, regulation of apoptosis, cellular growth, differentiation, and immunity. The identification of caspase gene family in Sebastes schlegelii is of great help to understand its antimicrobial research. In S. schlegelii, we totally identified nine caspase genes, including four apoptosis initiator caspases (caspase 2, caspase 8, caspase 9 and caspase 10), four apoptosis executioners (caspase 3a, caspase 3b, caspase 6, and caspase 7) and one inflammatory executioner (caspase 1). The duplication of caspase 3 genes on chr3 and chr8 may have been facilitated by whole genome duplication (WGD) events or other complex evolutionary processes. In general, the number of caspase genes relatively conserved in high vertebrates, while exhibiting variation in teleosts. Furthermore, syntenic analysis and phylogenetic relationships analysis supported the correct classification of these caspase gene family in S. schlegelii, especially for genes with duplicated copies. Additionally, the expression patterns of these caspase genes in different tissues of S. schlegelii under healthy conditions were assessed. The results revealed that the expression levels of most caspase genes were significantly elevated in the intestine, spleen, and liver. To further investigate the potential immune functions of these caspase genes in S. schlegelii, we challenged individuals with A. salmonicida and V. anguillarum, respectively. After infection with A. salmonicida, the expression levels of caspase 1 in the liver and spleen of S. schlegelii remained consistently elevated throughout the infection time points. The expression levels of most caspase family members in the intestine exhibited significant divergence following V. anguillarum infection. This study provides a comprehensive understanding of the caspase gene families in S. schlegelii, thereby establishing a solid foundation for further investigations into the functional roles of these caspase genes.
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Affiliation(s)
- Haohui Yu
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China
| | - Xu Yan
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao, 266071, China, Qingdao 266011, China; College of Life Sciences, Qingdao University, Qingdao 266071, China
| | - Ningning Wang
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China
| | - Xiantong Liu
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China
| | - Ting Xue
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China
| | - Chao Li
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China.
| | - Xiaoyan Zhang
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China.
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Synoradzki KJ, Paduszyńska N, Solnik M, Toro MD, Bilmin K, Bylina E, Rutkowski P, Yousef YA, Bucolo C, Zweifel SA, Reibaldi M, Fiedorowicz M, Czarnecka AM. From Molecular Biology to Novel Immunotherapies and Nanomedicine in Uveal Melanoma. Curr Oncol 2024; 31:778-800. [PMID: 38392052 PMCID: PMC10887618 DOI: 10.3390/curroncol31020058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 12/09/2023] [Accepted: 12/19/2023] [Indexed: 02/24/2024] Open
Abstract
Molecular biology studies of uveal melanoma have resulted in the development of novel immunotherapy approaches including tebentafusp-a T cell-redirecting bispecific fusion protein. More biomarkers are currently being studied. As a result, combined immunotherapy is being developed as well as immunotherapy with bifunctional checkpoint inhibitory T cell engagers and natural killer cells. Current trials cover tumor-infiltrating lymphocytes (TIL), vaccination with IKKb-matured dendritic cells, or autologous dendritic cells loaded with autologous tumor RNA. Another potential approach to treat UM could be based on T cell receptor engineering rather than antibody modification. Immune-mobilizing monoclonal T cell receptors (TCR) against cancer, called ImmTAC TM molecules, represent such an approach. Moreover, nanomedicine, especially miRNA approaches, are promising for future trials. Finally, theranostic radiopharmaceuticals enabling diagnosis and therapy with the same molecule bring hope to this research.
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Affiliation(s)
- Kamil J. Synoradzki
- Environmental Laboratory of Pharmacological and Toxicological Research, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawinskiego Str., 02-106 Warsaw, Poland;
| | - Natalia Paduszyńska
- Faculty of Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland; (N.P.); (M.S.)
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 5 Roentgen Str., 02-781 Warsaw, Poland; (E.B.); (P.R.)
| | - Malgorzata Solnik
- Faculty of Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland; (N.P.); (M.S.)
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 5 Roentgen Str., 02-781 Warsaw, Poland; (E.B.); (P.R.)
| | - Mario Damiano Toro
- Chair and Department of General and Pediatric Ophthalmology, Medical University of Lublin, 1 Chmielna Str., 20-079 Lublin, Poland;
- Eye Clinic, Public Health Department, Federico II University, Via Pansini 5, 80131 Naples, Italy
| | - Krzysztof Bilmin
- Research and Development Centre Novasome Sp. z o.o., 51-423 Wrocław, Poland;
| | - Elżbieta Bylina
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 5 Roentgen Str., 02-781 Warsaw, Poland; (E.B.); (P.R.)
- Department of Clinical Trials, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland
| | - Piotr Rutkowski
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 5 Roentgen Str., 02-781 Warsaw, Poland; (E.B.); (P.R.)
| | - Yacoub A. Yousef
- Department of Surgery (Ophthalmology), King Hussein Cancer Centre, Amman 11941, Jordan;
| | - Claudio Bucolo
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 97, 95123 Catania, Italy;
| | - Sandrine Anne Zweifel
- Department of Ophthalmology, University Hospital Zurich, 8091 Zurich, Switzerland;
- Faculty of Human Medicine, University of Zurich, 8032 Zurich, Switzerland
| | - Michele Reibaldi
- Department of Surgical Sciences, Eye Clinic Section, Citta della Salute e della Scienza, Turin University, 10122 Turin, Italy;
| | - Michal Fiedorowicz
- Small Animal Magnetic Resonance Imaging Laboratory, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawinskiego Str., 02-106 Warsaw, Poland
| | - Anna M. Czarnecka
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 5 Roentgen Str., 02-781 Warsaw, Poland; (E.B.); (P.R.)
- Department of Experimental Pharmacology, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawinskiego Str., 02-106 Warsaw, Poland
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Zhao W, Li M, Song S, Zhi Y, Huan C, Lv G. The role of natural killer T cells in liver transplantation. Front Cell Dev Biol 2024; 11:1274361. [PMID: 38250325 PMCID: PMC10796773 DOI: 10.3389/fcell.2023.1274361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 12/15/2023] [Indexed: 01/23/2024] Open
Abstract
Natural killer T cells (NKTs) are innate-like lymphocytes that are abundant in the liver and participate in liver immunity. NKT cells express both NK cell and T cell markers, modulate innate and adaptive immune responses. Type I and Type II NKT cells are classified according to the TCR usage, while they recognize lipid antigen in a non-classical major histocompatibility (MHC) molecule CD1d-restricted manner. Once activated, NKT cells can quickly produce cytokines and chemokines to negatively or positively regulate the immune responses, depending on the different NKT subsets. In liver transplantation (LTx), the immune reactions in a series of processes determine the recipients' long-term survival, including ischemia-reperfusion injury, alloresponse, and post-transplant infection. This review provides insight into the research on NKT cells subpopulations in LTx immunity during different processes, and discusses the shortcomings of the current research on NKT cells. Additionally, the CD56-expressing T cells are recognized as a NK-like T cell population, they were also discussed during these processes.
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Affiliation(s)
- Wenchao Zhao
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Mingqian Li
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Shifei Song
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yao Zhi
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Chen Huan
- Center of Infectious Diseases and Pathogen Biology, Institute of Virology and AIDS Research, Key Laboratory of Organ Regeneration and Transplantation of The Ministry of Education, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Guoyue Lv
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
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Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:1-95. [DOI: 10.1016/b978-0-7020-8228-3.00001-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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8
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Lafuente-Gómez N, de Lázaro I, Dhanjani M, García-Soriano D, Sobral MC, Salas G, Mooney DJ, Somoza Á. Multifunctional magnetic nanoparticles elicit anti-tumor immunity in a mouse melanoma model. Mater Today Bio 2023; 23:100817. [PMID: 37822453 PMCID: PMC10562177 DOI: 10.1016/j.mtbio.2023.100817] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 09/19/2023] [Accepted: 09/22/2023] [Indexed: 10/13/2023] Open
Abstract
Immunotherapy has emerged as a promising strategy to eradicate cancer cells. Particularly, the development of cancer vaccines to induce a potent and sustained antigen-specific T cell response has become a center of attention. Herein, we describe a novel immunotherapy based on magnetic nanoparticles (MNP) covalently modified with the OVA254-267 antigen and a CpG oligonucleotide via disulfide bonds. The MNP-CpG-COVA significantly enhances dendritic cell activation and CD8+ T cell antitumoral response against B16-OVA melanoma cells in vitro. Notably, the immune response induced by the covalently modified MNP is more potent and sustained over time than that triggered by the free components, highlighting the advantage of nanoformulations in immunotherapies. What is more, the nanoparticles are stable in the blood after in vivo administration and induce potent levels of systemic tumor-specific effector CD8 + T cells. Overall, our findings highlight the potential of covalently functionalized MNP to induce robust immune responses against mouse melanoma.
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Affiliation(s)
- Nuria Lafuente-Gómez
- Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA Nanociencia), Madrid, 28049, Spain
- Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, 02138, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA
- Immunology Service, Hospital Universitario de la Princesa, Instituto Investigación Sanitaria Princesa, Madrid, 28006, Spain
| | - Irene de Lázaro
- Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, 02138, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA
- Department of Biomedical Engineering, NYU Tandon School of Engineering, New York University, New York, NY, 10010, USA
- NYU Cardiovascular Research Center, Division of Cardiology, Department of Medicine, NYU Grossman School of Medicine, New York University, New York, NY, 10010, USA
| | - Mónica Dhanjani
- Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA Nanociencia), Madrid, 28049, Spain
| | - David García-Soriano
- Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA Nanociencia), Madrid, 28049, Spain
| | - Miguel C. Sobral
- Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, 02138, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA
| | - Gorka Salas
- Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA Nanociencia), Madrid, 28049, Spain
- Unidad de Nanobiotecnología Asociada al Centro Nacional de Biotecnología (CNB-CSIC), Madrid, 28049, Spain
| | - David J. Mooney
- Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, 02138, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA
| | - Álvaro Somoza
- Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA Nanociencia), Madrid, 28049, Spain
- Unidad de Nanobiotecnología Asociada al Centro Nacional de Biotecnología (CNB-CSIC), Madrid, 28049, Spain
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Liu J, Ding H, Yan C, He Z, Zhu H, Ma KY. Effect of tea catechins on gut microbiota in high fat diet-induced obese mice. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2023; 103:2436-2445. [PMID: 36715435 DOI: 10.1002/jsfa.12476] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 01/06/2023] [Accepted: 01/30/2023] [Indexed: 06/18/2023]
Abstract
BACKGROUND Tea catechins have been shown to have beneficial effects on the alleviation of obesity, the prevention of diabetes, and the amelioration of metabolic syndrome. The purpose of the present work is to explore the underlying mechanisms linking the intestinal microbiota and anti-obesity benefits of green tea, oolong tea, and black tea catechins in C57BL/6J mice fed with a high-fat diet (HFD). RESULTS The results indicated that, after the dietary intake of three tea catechins, obesity and low-grade inflammation were significantly alleviated. Hepatic steatosis was prevented, and this was accompanied by the upregulation of the mRNA and protein expressions of hepatic peroxisome proliferator-activated receptor α (PPARα). Metagenomic analysis of fecal samples suggested that the three tea catechins similarly changed the microbiota in terms of overall structure, composition, and protein functions by regulating the metabolites, facilitating the generation of short-chain fatty acids (SCFAs), and repressing lipopolysaccharides. CONCLUSION The anti-obese properties of three tea catechins were partially mediated by their positive effect on gut microbiota, hepatic steatosis alleviation, and anti-inflammatory activity. © 2023 Society of Chemical Industry.
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Affiliation(s)
- Jianhui Liu
- College of Food Science and Engineering, Nanjing University of Finance and Economics/Collaborative Innovation Center for Modern Grain Circulation and Safety, Nanjing, China
- School of Life Sciences, The Chinese University of Hong Kong, Shatin, China
| | - Huafang Ding
- School of Life Sciences, The Chinese University of Hong Kong, Shatin, China
| | - Chi Yan
- School of Life Sciences, The Chinese University of Hong Kong, Shatin, China
| | - Zouyan He
- School of Life Sciences, The Chinese University of Hong Kong, Shatin, China
- School of Public Health, Guangxi Medical University, Nanning, China
| | - Hanyue Zhu
- School of Life Sciences, The Chinese University of Hong Kong, Shatin, China
- School of Food Science and Engineering / South China Food Safety Research Center, Foshan University, Foshan, China
| | - Ka Ying Ma
- School of Life Sciences, The Chinese University of Hong Kong, Shatin, China
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10
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Yuan P, Xu H, Ma Y, Niu J, Liu Y, Huang L, Jiang S, Jiao N, Yuan X, Yang W, Li Y. Effects of dietary Galla Chinensis tannin supplementation on immune function and liver health in broiler chickens challenged with lipopolysaccharide. Front Vet Sci 2023; 10:1126911. [PMID: 36865438 PMCID: PMC9974168 DOI: 10.3389/fvets.2023.1126911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Accepted: 01/30/2023] [Indexed: 02/16/2023] Open
Abstract
Herein, Galla Chinensis tannin (GCT) was examined for its influence on preventing lipopolysaccharide (LPS)-induced liver damage in broiler chickens. Approximately 486 one-day-old healthy broilers were randomly allocated to 3 treatment groups (control, LPS, and LPS + GCT). The control and LPS groups were fed a basal diet and the LPS+GCT group was fed the basal diet supplemented with 300 mg/kg GCT. LPS was intraperitoneally injected (1 mg/kg body weight BW) in broilers in the LPS and LPS+GCT groups at 17, 19, and 21 days of age. The results manifested that dietary GCT addition attenuated LPS-induced deleterious effects on serum parameters and significantly increased serum immunoglobulin and complement C3 concentrations relative to the control and LPS groups. Dietary supplementation of GCT inhibited LPS-induced increase in broiler hepatic inflammatory cytokines, caspases activities, and TLR4/NF-κB pathway-related gene mRNA expression. Therefore, 300 mg/kg GCT addition to the diet improved the immune function of broilers and inhibit liver inflammation by blocking the TLR4/NF-κB pathway. Our findings provide support for the application of GCT in poultry production.
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Affiliation(s)
- Peng Yuan
- Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an, China
| | - Haitao Xu
- Animal Husbandry Development Center of Changyi City, Weifang, China
| | - Yuanfei Ma
- Agricultural and Rural Comprehensive Service Center of Bincheng District, Binzhou, China
| | - Jiaxing Niu
- Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an, China
| | - Yang Liu
- Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an, China
| | - Libo Huang
- Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an, China
| | - Shuzhen Jiang
- Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an, China
| | - Ning Jiao
- Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an, China
| | - Xuejun Yuan
- College of Life Sciences, Shandong Agricultural University, Tai'an, China
| | - Weiren Yang
- Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an, China,*Correspondence: Weiren Yang ✉
| | - Yang Li
- Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an, China,Yang Li ✉
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11
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Babu G, Mohanty B. Neurotensin modulation of lipopolysaccharide induced inflammation of gut-liver axis: Evaluation using neurotensin receptor agonist and antagonist. Neuropeptides 2023; 97:102297. [PMID: 36368076 DOI: 10.1016/j.npep.2022.102297] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 10/13/2022] [Accepted: 10/16/2022] [Indexed: 11/07/2022]
Abstract
Lipopolysaccharide (LPS), a toxic component of the cell wall of Gram-negative bacteria, is a potent immune stressor. LPS-induced inflammation of the gut-liver axis is well demonstrated. Neurotensin (NTS), a tri-decapeptide present in the gastrointestinal tract, has anti-inflammatory, anti-oxidative, and growth-promoting properties. This study elucidated the efficacy of PD149163, the type I NTS receptor agonist (NTS1) in the modulation of LPS-induced inflammation of the gut-liver axis of mice. Young-adult female mice (Age: 8 weeks; BW: 25 ± 2.5 g) were maintained in six groups (6/group); Group I as control and Group II, III & IV were exposed to LPS (1 mg/kg BW/Day; i.p.) for five days. LPS pre-exposed Group III and Group IV mice were treated with NTS1 agonist PD149163 (100 μg/kg BW i.p.) and antagonist SR48692 (0.5 mg/kg BW i.p.) respectively for 28 days. Group V and Group VI mice were exposed to only PD149163 and only SR48692 respectively with the doses as mentioned above for 28 days. Group I and LPS-exposed Group II mice were also maintained four weeks without further treatment. Histopathology revealed LPS-induced inflammation of the gut and liver. Significant elevation of plasma TNF-α and IL-6 and serum ALT and AST reflected as biomarkers of inflammation. Oxidative stress on both organs was distinct from decreased glutathione reductase and increased lipid peroxidation. PD149163 but not SR48692 ameliorated LPS-induced inflammation in both gut and liver counteracting inflammatory responses and oxidative stress. The use of NTS agonists including PD149163 could be exploited for therapeutic intervention of inflammatory diseases including that of the gut-liver axis.
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Affiliation(s)
- Gyan Babu
- Department of Zoology, University of Allahabad, Prayagraj, Uttar Pradesh 211002, India
| | - Banalata Mohanty
- Department of Zoology, University of Allahabad, Prayagraj, Uttar Pradesh 211002, India.
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12
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Gou H, Liu S, Liu L, Luo M, Qin S, He K, Yang X. Obeticholic acid and 5β-cholanic acid 3 exhibit anti-tumor effects on liver cancer through CXCL16/CXCR6 pathway. Front Immunol 2022; 13:1095915. [PMID: 36605219 PMCID: PMC9807878 DOI: 10.3389/fimmu.2022.1095915] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 12/06/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver malignancy with a high incidence and mortality rate. Previous in vitro and in vivo studies have confirmed that liver sinusoidal endothelial cells (LSEC) secrete CXCL16, which acts as a messenger to increase the hepatic accumulation of CXCR6+ natural killer T (NKT) cells and exert potent antitumor effects. However, evidence for this process in humans is lacking and its clinical significance is still unclear. In this study, by dissecting the human HCC single-cell RNA-seq data, we verified this process through cellphoneDB. NKT cells in patients with high expression of CXCL16 exhibited a higher activation state and produced more interferon-γ (IFN-γ) compared with those with low expression. We next investigated the signaling pathways between activated (CD69 high) and unactivated NKT cells (CD69 low) using NKT cell-developmental trajectories and functional enrichment analyses. In vivo experiments, we found that farnesoid X receptor agonist (obeticholic acid) combined with the takeda G protein coupled receptor 5 antagonist (5β-cholanic acid 3) exhibited significant tumor suppressive effects in the orthotopic liver tumor model and this result may be related to the CXCL16/CXCR6 axis. In conclusion, our study provides the basis and potential strategies for HCC immunotherapy based on NKT cells.
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Affiliation(s)
- Haoxian Gou
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China,Academician Workstation of Sichuan Province, Luzhou, China
| | - Shenglu Liu
- Academician Workstation of Sichuan Province, Luzhou, China
| | - Linxin Liu
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Ming Luo
- Academician Workstation of Sichuan Province, Luzhou, China
| | - Shu Qin
- Academician Workstation of Sichuan Province, Luzhou, China
| | - Kai He
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China,Academician Workstation of Sichuan Province, Luzhou, China,*Correspondence: Xiaoli Yang, ; Kai He,
| | - Xiaoli Yang
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China,Academician Workstation of Sichuan Province, Luzhou, China,*Correspondence: Xiaoli Yang, ; Kai He,
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13
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Liu N, Bauer M, Press AT. The immunological function of CXCR2 in the liver during sepsis. J Inflamm (Lond) 2022; 19:23. [DOI: 10.1186/s12950-022-00321-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 11/15/2022] [Indexed: 12/02/2022] Open
Abstract
Abstract
Background
The chemokine receptor CXCR2 and its ligands, especially CXCL8, are crucial mediators for the progression of liver inflammation and liver failure in sepsis. Neutrophils have the highest CXCR2 expression in mice and humans, and their activation via CXCL8 facilitates their migration to the inflamed liver for the clearance of the pathogens and, in turn, the inflammation.
Main body
In sepsis, the inflammatory insult causes extensive neutrophil migration to the liver that overwhelms the immune response. To compensate for the strong receptor activation, CXCR2 desensitizes, incapacitating the immune cells to efficiently clear pathogens, causing further life-threatening liver damage and uncontrolled pathogen spread.
Conclusion
CXCR2 function during infection strongly depends on the expressing cell type. It signals pro- and anti-inflammatory effects that may prompt novel cell-type-specific CXCR2-directed therapeutics.
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14
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Niu J, Wang Q, Jing C, Liu Y, Liu H, Jiao N, Huang L, Jiang S, Guan Q, Li Y, Yang W. Dietary Galla Chinensis tannic acid supplementation in the diets improves growth performance, immune function and liver health status of broiler chicken. Front Vet Sci 2022; 9:1024430. [PMID: 36311675 PMCID: PMC9614106 DOI: 10.3389/fvets.2022.1024430] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Accepted: 09/26/2022] [Indexed: 11/04/2022] Open
Abstract
This experiment was conducted to investigate the effects of Galla Chinensis tannic acid (TA) on growth performance, immune function, and liver health status in broilers. A total of 288 1-day-old Arbor Acres broiler chickens were randomly divided into two groups in a 42-days study. The two groups were a basal diet (CON group) and a basal diet supplemented with 300 mg/kg Galla Chinensis tannic acid (TA group). The results showed that the TA group had significantly decreased feed-to-gain ratio (F/G) throughout the experiment (P < 0.05). The levels of total protein, albumin, low density lipoprotein, high density lipoprotein, urea, total cholesterol, and glucose in the TA group were significantly higher than in the CON group (P < 0.05). In addition, the serum immunoglobulin G, immunoglobulin M, and complements (C3, C4) levels in the TA group were significantly higher than those in the CON group (P < 0.05). Compared with the CON group, the hepatic interleukin-6, interleukin-18, NLRs family pyrin domain containing 3 (NLRP3), caspase-1, and caspase-3 in the TA group were significantly decreased (P < 0.05). Besides, TA group had significantly lower mRNA expression levels of toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), nuclear factor-kappa B (NF-κB), and NLRP3 in liver (P < 0.05). The TA group had significantly higher the mRNA expression levels of Bcl-2 than CON group in liver (P < 0.05). Moreover, TA group tended to decrease Bax/Bcl-2 ratio in liver (P < 0.10). To sum up, dietary supplemented with microencapsulated TA from Galla Chinensis had beneficial effects on growth performance, immune function, and liver health status in broilers. The protective role of TA from Galla Chinensis in liver health of broilers might be related to the inhibition of hepatic apoptosis and pyroptosis via inactivation of TLR4/MyD88/NF-κB signaling pathway.
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Affiliation(s)
- Jiaxing Niu
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Qinjin Wang
- Shandong Wonong Agro-tech Group Co., Ltd., Weifang, China
| | - Changwei Jing
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Yang Liu
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Hua Liu
- College of Animal Science and Technology, Hunan Agriculture University, Changsha, China
| | - Ning Jiao
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Libo Huang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Shuzhen Jiang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Qinglin Guan
- Shandong Landoff Biotechnology Co., Ltd., Taian, China
| | - Yang Li
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China,*Correspondence: Yang Li
| | - Weiren Yang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China,Weiren Yang
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15
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Sharafi F, Hasani SA, Alesaeidi S, Kahrizi MS, Adili A, Ghoreishizadeh S, Shomali N, Tamjidifar R, Aslaminabad R, Akbari M. A comprehensive review about the utilization of immune checkpoint inhibitors and combination therapy in hepatocellular carcinoma: an updated review. Cancer Cell Int 2022; 22:269. [PMID: 35999569 PMCID: PMC9400240 DOI: 10.1186/s12935-022-02682-z] [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: 02/09/2022] [Accepted: 08/15/2022] [Indexed: 11/10/2022] Open
Abstract
A pharmacological class known as immune checkpoint inhibitors (ICIs) has been developed as a potential treatment option for various malignancies, including HCC. In HCC, ICIs have demonstrated clinically significant advantages as monotherapy or combination therapy. ICIs that target programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1), as well as cytotoxic T lymphocyte antigen 4 (CTLA-4), have made significant advances in cancer treatment. In hepatocellular carcinoma (HCC), several ICIs are being tested in clinical trials, and the area is quickly developing. As immunotherapy-related adverse events (irAEs) linked with ICI therapy expands and gain worldwide access, up-to-date management guidelines become crucial to the safety profile of ICIs. This review aims to describe the evidence for ICIs in treating HCC, emphasizing the use of combination ICIs.
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Affiliation(s)
- Faezeh Sharafi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sadegh Abaei Hasani
- Cancer Research Center, Department of General Surgery, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Samira Alesaeidi
- Department of Internal Medicine and Rheumatology, Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Ali Adili
- Senior Adult Oncology Department, Moffitt Cancer Center, University of South Florida, Tampa, Florida, USA
- Department of Oncology, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Navid Shomali
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Rozita Tamjidifar
- Department of Medical Biochemistry, Faculty of Medicine, Ege University, Izmir, 35100, Turkey
- Department of Stem Cell, Institute of Health Sciences, Ege University, Izmir, 35100, Turkey
| | - Ramin Aslaminabad
- Department of Medical Biochemistry, Faculty of Medicine, Ege University, Izmir, 35100, Turkey
| | - Morteza Akbari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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16
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Jameson G, Harmon C, Santiago RM, Houlihan DD, Gallagher TK, Lynch L, Robinson MW, O’Farrelly C. Human Hepatic CD56bright NK Cells Display a Tissue-Resident Transcriptional Profile and Enhanced Ability to Kill Allogenic CD8+ T Cells. Front Immunol 2022; 13:921212. [PMID: 35865550 PMCID: PMC9295839 DOI: 10.3389/fimmu.2022.921212] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 05/30/2022] [Indexed: 12/20/2022] Open
Abstract
Liver-resident CD56brightCD16- natural killer (NK) cells are enriched in the human liver and are phenotypically distinct from their blood counterparts. Although these cells are capable of rapid cytotoxic effector activity, their functional role remains unclear. We hypothesise that they may contribute to immune tolerance in the liver during transplantation. RNA sequencing was carried out on FACS sorted NK cell subpopulations from liver perfusates (n=5) and healthy blood controls (n=5). Liver-resident CD56brightCD16+/- NK cells upregulate genes associated with tissue residency. They also upregulate expression of CD160 and LY9, both of which encode immune receptors capable of activating NK cells. Co-expression of CD160 and Ly9 on liver-resident NK cells was validated using flow cytometry. Hepatic NK cell cytotoxicity against allogenic T cells was tested using an in vitro co-culture system of liver perfusate-derived NK cells and blood T cells (n=10-13). In co-culture experiments, hepatic NK cells but not blood NK cells induced significant allogenic T cell death (p=0.0306). Allogenic CD8+ T cells were more susceptible to hepatic NK cytotoxicity than CD4+ T cells (p<0.0001). Stimulation of hepatic CD56bright NK cells with an anti-CD160 agonist mAb enhanced this cytotoxic response (p=0.0382). Our results highlight a role for donor liver NK cells in regulating allogenic CD8+ T cell activation, which may be important in controlling recipient CD8+ T cell-mediated rejection post liver-transplant.
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Affiliation(s)
- Gráinne Jameson
- School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Cathal Harmon
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Rhyla Mae Santiago
- Department of Biology, Kathleen Lonsdale Institute of Human Health Research, Maynooth University, Maynooth, Ireland
| | | | - Tom K. Gallagher
- Hepatopancreaticobiliary Group, St. Vincent’s University Hospital, Dublin, Ireland
| | - Lydia Lynch
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Mark W. Robinson
- Department of Biology, Kathleen Lonsdale Institute of Human Health Research, Maynooth University, Maynooth, Ireland
- *Correspondence: Mark W. Robinson,
| | - Cliona O’Farrelly
- School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
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17
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Feige-Diller J, Herrera-Rivero M, Witten A, Stoll M, Kaiser S, Richter SH, Sachser N. The Impact of Varying Food Availability on Gene Expression in the Liver: Testing the Match-Mismatch Hypothesis. Front Nutr 2022; 9:910762. [PMID: 35859757 PMCID: PMC9289739 DOI: 10.3389/fnut.2022.910762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 06/02/2022] [Indexed: 11/29/2022] Open
Abstract
Background During early phases of life, such as prenatal or early postnatal development and adolescence, an organism's phenotype can be shaped by the environmental conditions it experiences. According to the Match-Mismatch hypothesis (MMH), changes to this environment during later life stages can result in a mismatch between the individual's adaptations and the prevailing environmental conditions. Thus, negative consequences in welfare and health can occur. We aimed to test the MMH in the context of food availability, assuming adolescence as a sensitive period of adaptation. Methods We have previously reported a study of the physiological and behavioral effects of match and mismatch conditions of high (ad libitum) and low (90% of ad libitum intake) food availability from adolescence to early adulthood in female C57BL/6J mice (n = 62). Here, we performed RNA-sequencing of the livers of a subset of these animals (n = 16) to test the effects of match and mismatch feeding conditions on the liver transcriptome. Results In general, we found no effect of the match-mismatch situations. Contrarily, the amount of food available during early adulthood (low vs. high) drove the differences we observed in final body weight and gene expression in the liver, regardless of the amount of food available to the animals during adolescence. Many of the differentially expressed genes and the corresponding biological processes found to be overrepresented overlapped, implicating common changes in various domains. These included metabolism, homeostasis, cellular responses to diverse stimuli, transport of bile acids and other molecules, cell differentiation, major urinary proteins, and immunity and inflammation. Conclusions Our previous and present observations found no support for the MMH in the context of low vs high food availability from adolescence to early adulthood in female C57BL/6J mice. However, even small differences of approximately 10% in food availability during early adulthood resulted in physiological and molecular changes with potential beneficial implications for metabolic diseases.
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Affiliation(s)
- Janina Feige-Diller
- Department of Behavioral Biology, University of Münster, Münster, Germany
- DFG RTG EvoPAD, WWU Münster, Münster, Germany
- Janina Feige-Diller
| | - Marisol Herrera-Rivero
- Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany
- *Correspondence: Marisol Herrera-Rivero ;
| | - Anika Witten
- Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany
- Core Facility Genomics, Medical Faculty, University of Münster, Münster, Germany
| | - Monika Stoll
- DFG RTG EvoPAD, WWU Münster, Münster, Germany
- Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany
| | - Sylvia Kaiser
- Department of Behavioral Biology, University of Münster, Münster, Germany
| | - S. Helene Richter
- Department of Behavioral Biology, University of Münster, Münster, Germany
- DFG RTG EvoPAD, WWU Münster, Münster, Germany
| | - Norbert Sachser
- Department of Behavioral Biology, University of Münster, Münster, Germany
- DFG RTG EvoPAD, WWU Münster, Münster, Germany
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18
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Li D, Chen S, Liu C, Wei B, Li X. Liver transcriptome analysis reveals biological pathways and transcription factors in response to high ammonia exposure. Inhal Toxicol 2022; 34:219-229. [PMID: 35648801 DOI: 10.1080/08958378.2022.2083275] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Aim: Ammonia is a toxic gas that not only causes environmental pollution, but also is harmful to human health after inhalation. Liver is an important detoxification organ that can convert external or metabolized toxic substances into nontoxic substances. However, the toxic effects of ammonia exposure on livers have not been well studied.Method: In this study, pigs were used as an animal model and were exposed to 80 ppm ammonia (8 h during 12 days), and then, RNA-seq were conducted to explore the key genes in response to high ammonia exposure in livers.Result: Gene set enrichment analysis (GSEA) showed that the genes associated with hypoxia, inflammatory response, and apoptosis were up-regulated in the ammonia group, but the genes associated with DNA replication, linoleic acid metabolism, and glycolysis were down-regulated. Totally, 556 differentially expressed genes (DEGs) including 54 genes that encode the transcription factors (TFs) were identified between the exposure and control groups. GO and KEGG pathway analysis suggested that these DEGs were involved in inflammatory response, oxidative stress, apoptosis, immune, and cell cycle. Furthermore, the TF-target interaction analysis showed that FOS, HIF-1α, JUNB, ATF3, REL, and KLF4 were important TFs in regulating the hepatic gene expression in response to high ammonia exposure.Conclusion: Altogether, our findings not only presented a comprehensive mRNA transcriptome profile of liver after high ammonia exposure, but also found some key genes and TFs that could be used to investigate the toxicity mechanism of high ammonia on livers.
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Affiliation(s)
- Daojie Li
- Key Laboratory of Smart Animal Farming Technology, Ministry of Agriculture, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Shuangzhao Chen
- Key Laboratory of Smart Animal Farming Technology, Ministry of Agriculture, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Chun Liu
- Key Laboratory of Smart Animal Farming Technology, Ministry of Agriculture, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Baoxing Wei
- Key Laboratory of Smart Animal Farming Technology, Ministry of Agriculture, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Xiaoping Li
- Key Laboratory of Smart Animal Farming Technology, Ministry of Agriculture, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
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19
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Mooli RGR, Mukhi D, Ramakrishnan SK. Oxidative Stress and Redox Signaling in the Pathophysiology of Liver Diseases. Compr Physiol 2022; 12:3167-3192. [PMID: 35578969 PMCID: PMC10074426 DOI: 10.1002/cphy.c200021] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The increased production of derivatives of molecular oxygen and nitrogen in the form of reactive oxygen species (ROS) and reactive nitrogen species (RNS) lead to molecular damage called oxidative stress. Under normal physiological conditions, the ROS generation is tightly regulated in different cells and cellular compartments. Any disturbance in the balance between the cellular generation of ROS and antioxidant balance leads to oxidative stress. In this article, we discuss the sources of ROS (endogenous and exogenous) and antioxidant mechanisms. We also focus on the pathophysiological significance of oxidative stress in various cell types of the liver. Oxidative stress is implicated in the development and progression of various liver diseases. We narrate the master regulators of ROS-mediated signaling and their contribution to liver diseases. Nonalcoholic fatty liver diseases (NAFLD) are influenced by a "multiple parallel-hit model" in which oxidative stress plays a central role. We highlight the recent findings on the role of oxidative stress in the spectrum of NAFLD, including fibrosis and liver cancer. Finally, we provide a brief overview of oxidative stress biomarkers and their therapeutic applications in various liver-related disorders. Overall, the article sheds light on the significance of oxidative stress in the pathophysiology of the liver. © 2022 American Physiological Society. Compr Physiol 12:3167-3192, 2022.
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Affiliation(s)
- Raja Gopal Reddy Mooli
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Dhanunjay Mukhi
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Sadeesh K Ramakrishnan
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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20
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Zhao H, Lu J, He F, Wang M, Yan Y, Chen B, Xie D, Xu C, Wang Q, Liu W, Yu W, Xi Y, Yu L, Yamamoto T, Koyama H, Wang W, Zhang C, Cheng J. Hyperuricemia contributes to glucose intolerance of hepatic inflammatory macrophages and impairs the insulin signaling pathway via IRS2-proteasome degradation. Front Immunol 2022; 13:931087. [PMID: 36177037 PMCID: PMC9513153 DOI: 10.3389/fimmu.2022.931087] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 08/24/2022] [Indexed: 02/05/2023] Open
Abstract
AIM Numerous reports have demonstrated the key importance of macrophage-elicited metabolic inflammation in insulin resistance (IR). Our previous studies confirmed that hyperuricemia or high uric acid (HUA) treatment induced an IR state in several peripheral tissues to promote the development of type 2 diabetes mellitus (T2DM). However, the effect of HUA on glucose uptake and the insulin sensitivity of macrophages and its mechanism is unclear. METHODS To assess systemic IR, we generated hyperuricemic mice by urate oxidase knockout (UOX-KO). Then, glucose/insulin tolerance, the tissue uptake of 18F-fluorodeoxyglucose, body composition, and energy balance were assessed. Glucose uptake of circulating infiltrated macrophages in the liver was evaluated by glucose transporter type 4 (GLUT-4) staining. Insulin sensitivity and the insulin signaling pathway of macrophages were demonstrated using the 2-NBDG kit, immunoblotting, and immunofluorescence assays. The immunoprecipitation assay and LC-MS analysis were used to determine insulin receptor substrate 2 (IRS2) levels and its interacting protein enrichment under HUA conditions. RESULTS Compared to WT mice (10 weeks old), serum uric acid levels were higher in UOX-KO mice (WT, 182.3 ± 5.091 μM versus KO, 421.9 ± 45.47 μM). Hyperuricemic mice with metabolic disorders and systemic IR showed inflammatory macrophage recruitment and increased levels of circulating proinflammatory cytokines. HUA inhibited the nuclear translocation of GLUT-4 in hepatic macrophages, restrained insulin-induced glucose uptake and glucose tolerance, and blocked insulin IRS2/PI3K/AKT signaling. Meanwhile, HUA mediated the IRS2 protein degradation pathway and activated AMPK/mTOR in macrophages. LC-MS analysis showed that ubiquitination degradation could be involved in IRS2 and its interacting proteins to contribute to IR under HUA conditions. CONCLUSION The data suggest that HUA-induced glucose intolerance in hepatic macrophages contributed to insulin resistance and impaired the insulin signaling pathway via IRS2-proteasome degradation.
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Affiliation(s)
- Hairong Zhao
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, Xiamen University, Xiamen, China
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical Research and Development (R&D), College of Pharmacy, Dali University, Dali, China
| | - Jiaming Lu
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, Xiamen University, Xiamen, China
| | - Furong He
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, Xiamen University, Xiamen, China
| | - Mei Wang
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical Research and Development (R&D), College of Pharmacy, Dali University, Dali, China
| | - Yunbo Yan
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, Xiamen University, Xiamen, China
| | - Binyang Chen
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, Xiamen University, Xiamen, China
| | - De Xie
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, Xiamen University, Xiamen, China
| | - Chenxi Xu
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, Xiamen University, Xiamen, China
| | - Qiang Wang
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, Xiamen University, Xiamen, China
| | - Weidong Liu
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, Xiamen University, Xiamen, China
| | - Wei Yu
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, Xiamen University, Xiamen, China
| | - Yuemei Xi
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, Xiamen University, Xiamen, China
| | - Linqian Yu
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, Xiamen University, Xiamen, China
| | - Tetsuya Yamamoto
- Department of Diabetes, Endocrinology and Clinical Immunology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hidenori Koyama
- Department of Diabetes, Endocrinology and Clinical Immunology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Wei Wang
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, Xiamen University, Xiamen, China
| | - Chenggui Zhang
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical Research and Development (R&D), College of Pharmacy, Dali University, Dali, China
- *Correspondence: Chenggui Zhang, ; Jidong Cheng,
| | - Jidong Cheng
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, Xiamen University, Xiamen, China
- Department of Diabetes, Endocrinology and Clinical Immunology, Hyogo College of Medicine, Nishinomiya, Japan
- *Correspondence: Chenggui Zhang, ; Jidong Cheng,
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21
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Argemi J, Ponz-Sarvise M, Sangro B. Immunotherapies for hepatocellular carcinoma and intrahepatic cholangiocarcinoma: Current and developing strategies. Adv Cancer Res 2022; 156:367-413. [PMID: 35961706 DOI: 10.1016/bs.acr.2022.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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22
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Liu W, Zeng X, Liu Y, Liu J, Li C, Chen L, Chen H, Ouyang D. The Immunological Mechanisms and Immune-Based Biomarkers of Drug-Induced Liver Injury. Front Pharmacol 2021; 12:723940. [PMID: 34721020 PMCID: PMC8554067 DOI: 10.3389/fphar.2021.723940] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 09/06/2021] [Indexed: 12/12/2022] Open
Abstract
Drug-induced liver injury (DILI) has become one of the major challenges of drug safety all over the word. So far, about 1,100 commonly used drugs including the medications used regularly, herbal and/or dietary supplements, have been reported to induce liver injury. Moreover, DILI is the main cause of the interruption of new drugs development and drugs withdrawn from the pharmaceutical market. Acute DILI may evolve into chronic DILI or even worse, commonly lead to life-threatening acute liver failure in Western countries. It is generally considered to have a close relationship to genetic factors, environmental risk factors, and host immunity, through the drug itself or its metabolites, leading to a series of cellular events, such as haptenization and immune response activation. Despite many researches on DILI, the specific biomarkers about it are not applicable to clinical diagnosis, which still relies on the exclusion of other causes of liver disease in clinical practice as before. Additionally, circumstantial evidence has suggested that DILI is mediated by the immune system. Here, we review the underlying mechanisms of the immune response to DILI and provide guidance for the future development of biomarkers for the early detection, prediction, and diagnosis of DILI.
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Affiliation(s)
- Wenhui Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China
| | - Xiangchang Zeng
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China
| | - Yating Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China
| | - Jinfeng Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China
| | - Chaopeng Li
- Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd., Changsha, China
| | - Lulu Chen
- Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd., Changsha, China
| | - Hongying Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China
| | - Dongsheng Ouyang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China.,Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd., Changsha, China
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23
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Radtanakatikanon A, Moore PF, Keller SM, Vernau W. Novel clonality assays for T cell lymphoma in cats targeting the T cell receptor beta, T cell receptor delta, and T cell receptor gamma loci. J Vet Intern Med 2021; 35:2865-2875. [PMID: 34929760 PMCID: PMC8692208 DOI: 10.1111/jvim.16288] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 10/11/2021] [Accepted: 10/13/2021] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND T cell clonality assays in veterinary medicine currently target only the T cell receptor gamma (TRG) locus. Existing assays have suboptimal sensitivity because of insufficient primer coverage of all possible rearrangements. OBJECTIVE Develop higher sensitivity clonality assays targeting the TRG, delta (TRD), and beta (TRB) loci in cats. ANIMALS Cats with histopathologically confirmed lymphoma (n = 89), non-lymphoma (n = 35), and possible hepatic small cell lymphoma (n = 31). METHODS Molecular clonality assay development utilizing our recently reported topology and expressed repertoire data of the T cell receptor loci in cats. Determination of clonality status of lymphoma, non lymphoma, and possible hepatic small cell lymphoma samples, and calculation of assay sensitivity and specificity. RESULTS The new multiplex TRG assay yielded the highest sensitivity (95.5%). All assays yielded 100% specificity except for the new multiplex TRG assay (97.3%). The combination of the new TRG and TRB assays yielded sensitivity of 98.9% and specificity of 97.0%. The new TRG assay detected clonality in 17/31 possible small cell lymphoma livers, whereas an existing TRG assay detected clonality in 6/31 livers. CONCLUSIONS AND CLINICAL IMPORTANCE The assessment of multiple T cell loci compensates for the potential shortcomings of individual assays. Using a combination of molecular clonality assays will increase the overall sensitivity for the diagnosis of T-cell lymphoma in cats, especially intestinal, and hepatic small cell lymphoma. Hepatic small cell lymphomas detected by the new TRG assay utilized rarely expressed V and J genes not recognized by previous assays, likely indicating unique biology of hepatic small cell lymphoma in cats.
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Affiliation(s)
- Araya Radtanakatikanon
- Department of Pathology, Microbiology and ImmunologySchool of Veterinary Medicine, University of CaliforniaDavisCaliforniaUSA
- Department of Pathology, Faculty of Veterinary ScienceChulalongkorn UniversityBangkokThailand
| | - Peter F. Moore
- Department of Pathology, Microbiology and ImmunologySchool of Veterinary Medicine, University of CaliforniaDavisCaliforniaUSA
| | - Stefan M. Keller
- Department of Pathology, Microbiology and ImmunologySchool of Veterinary Medicine, University of CaliforniaDavisCaliforniaUSA
| | - William Vernau
- Department of Pathology, Microbiology and ImmunologySchool of Veterinary Medicine, University of CaliforniaDavisCaliforniaUSA
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24
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Del Piccolo N, Shirure VS, Bi Y, Goedegebuure SP, Gholami S, Hughes CC, Fields RC, George SC. Tumor-on-chip modeling of organ-specific cancer and metastasis. Adv Drug Deliv Rev 2021; 175:113798. [PMID: 34015419 DOI: 10.1016/j.addr.2021.05.008] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 05/04/2021] [Accepted: 05/11/2021] [Indexed: 02/08/2023]
Abstract
Every year, cancer claims millions of lives around the globe. Unfortunately, model systems that accurately mimic human oncology - a requirement for the development of more effective therapies for these patients - remain elusive. Tumor development is an organ-specific process that involves modification of existing tissue features, recruitment of other cell types, and eventual metastasis to distant organs. Recently, tissue engineered microfluidic devices have emerged as a powerful in vitro tool to model human physiology and pathology with organ-specificity. These organ-on-chip platforms consist of cells cultured in 3D hydrogels and offer precise control over geometry, biological components, and physiochemical properties. Here, we review progress towards organ-specific microfluidic models of the primary and metastatic tumor microenvironments. Despite the field's infancy, these tumor-on-chip models have enabled discoveries about cancer immunobiology and response to therapy. Future work should focus on the development of autologous or multi-organ systems and inclusion of the immune system.
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25
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Pan M, Liu J, Huang D, Guo Y, Luo K, Yang M, Gao W, Xu Q, Zhang W, Mai K. FoxO3 Modulates LPS-Activated Hepatic Inflammation in Turbot ( Scophthalmus maximus L.). Front Immunol 2021; 12:679704. [PMID: 34276667 PMCID: PMC8281027 DOI: 10.3389/fimmu.2021.679704] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 06/17/2021] [Indexed: 12/19/2022] Open
Abstract
In mammals, forkhead box O3 (foxo3) plays important roles in liver immune system. The foxo3 can regulate cell cycle, DNA repair, hypoxia, apoptosis and so on. However, as such an important transcription factor, few studies on foxo3 in fish have been reported. The present study characterized the foxo3 in turbot (Scophthalmus maximus L.). Lipopolysaccharide (LPS) incubated in vitro (hepatocytes) and injected in vivo (turbot liver) were used to construct inflammatory models. The foxo3 was interfered and overexpressed to investigate its functions in liver inflammation. The open reading frame (ORF) of foxo3 was 1998 bp (base pair), encoding 665 amino acids. Sequence analysis showed that foxo3 of turbot was highly homologous to other fishes. Tissue distribution analysis revealed that the highest expression of foxo3 was in muscle. Immunofluorescence result showed that foxo3 was expressed in cytoplasm and nucleus. Knockdown of foxo3 significantly increased mRNA levels of tumor necrosis factor-α (tnf-α), interleukin-1β (il-1β), interleukin-6 (il-6), myeloid-differentiation factor 88 (myd88), cd83, toll-like receptor 2 (tlr-2) and protein level of c-Jun N-terminal kinase (JNK) in sifoxo3 + LPS (siRNA of foxo3+ LPS) group compared with NC + LPS (negative control + LPS) group in turbot hepatocytes. Overexpressed foxo3 significantly decreased mRNA levels of tnf-α, il-6, nuclear transcription factor-kappa B (nf-κb), cd83, tlr-2 and the protein level of JNK in vitro. In vivo analysis, foxo3 knockdown significantly increased levels of GOT in serum after LPS injection compared with NC+LPS group. Overexpressed foxo3 significantly decreased levels of GPT and GOT in pcDNA3.1-foxo3+LPS group compared with pcDNA3.1+LPS group in vivo. Foxo3 knockdown significantly increased mRNA levels of tnf-α, il-1β, il-6, nf-κb, myd88 and protein level of JNK in vivo in sifoxo3+LPS group compared with NC+LPS group in turbot liver. Overexpressed foxo3 significantly decreased mRNA levels of il-1β, il-6, myd88, cd83, jnk and protein level of JNK in pcDNA3.1-foxo3+LPS group compared with pcDNA3.1+LPS group in turbot liver. The results indicated that foxo3 might modulate LPS-activated hepatic inflammation in turbot by decreasing the proinflammatory cytokines, the levels of GOT and GPT as well as activating JNK/caspase-3 and tlr-2/myd88/nf-κb pathways. Taken together, these findings indicated that FoxO3 may play important roles in liver immune responses to LPS in turbot and the research of FoxO3 in liver immunity enriches the studies on immune regulation, and provides theoretical basis and molecular targets for solving liver inflammation and liver injury in fish.
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Affiliation(s)
- Mingzhu Pan
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture and Rural Affairs), Fisheries College, Ocean University of China, Qingdao, China
| | - Jiahuan Liu
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture and Rural Affairs), Fisheries College, Ocean University of China, Qingdao, China
| | - Dong Huang
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture and Rural Affairs), Fisheries College, Ocean University of China, Qingdao, China
| | - Yanlin Guo
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture and Rural Affairs), Fisheries College, Ocean University of China, Qingdao, China
| | - Kai Luo
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture and Rural Affairs), Fisheries College, Ocean University of China, Qingdao, China
| | - Mengxi Yang
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture and Rural Affairs), Fisheries College, Ocean University of China, Qingdao, China
| | - Weihua Gao
- Department of Fisheries, College of Animal Science, Yangtze University, Jingzhou, China
| | - Qiaoqing Xu
- Department of Fisheries, College of Animal Science, Yangtze University, Jingzhou, China
| | - Wenbing Zhang
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture and Rural Affairs), Fisheries College, Ocean University of China, Qingdao, China
- Department of Fisheries, College of Animal Science, Yangtze University, Jingzhou, China
| | - Kangsen Mai
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture and Rural Affairs), Fisheries College, Ocean University of China, Qingdao, China
- Department of Fisheries, College of Animal Science, Yangtze University, Jingzhou, China
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26
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Liu WB, Wang MM, Dai LY, Dong SH, Yuan XD, Yuan SL, Tang Y, Liu JH, Peng LY, Xiao YM. Enhanced Immune Response Improves Resistance to Cadmium Stress in Triploid Crucian Carp. Front Physiol 2021; 12:666363. [PMID: 34149447 PMCID: PMC8213368 DOI: 10.3389/fphys.2021.666363] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 04/22/2021] [Indexed: 01/16/2023] Open
Abstract
Previous research has indicated that triploid crucian carp (3n fish) have preferential resistance to cadmium (Cd) compared to Carassius auratas red var. (2n fish). In this article, comparative research is further conducted between the 2n and 3n fish in terms of the immune response to Cd-induced stress. Exposure to 9 mg/L Cd for 96 h changed the hepatic function indexes remarkably in the 2n fish, but not in the 3n fish. In the serum of Cd-treated 2n fish, the levels of alanine amino transferase, aspartate aminotransferase, adenosine deaminase, and total bilirubin significantly increased, while the levels of total protein, albumin, lysozyme, and anti-superoxide anion radicals decreased demonstrating hepatotoxicity. By analysis of transcriptome profiles, many immune-related pathways were found to be involved in the response of 3n fish to the Cd-induced stress. Expression levels of the immune genes, including the interleukin genes, tumor necrosis factor super family member genes, chemokine gene, toll-like receptor gene, and inflammatory marker cyclooxygenase 2 gene were significantly enhanced in the hepatopancreas of the Cd-treated 3n fish. In contrast, the expression levels of these genes decreased in the 2n fish. This research provides a theoretical basis for polyploid fish breeding and is helpful for the ecological restoration of water due to pollution.
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Affiliation(s)
- Wen-Bin Liu
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha, China.,College of Life Sciences, Hunan Normal University, Changsha, China
| | - Min-Meng Wang
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha, China.,College of Life Sciences, Hunan Normal University, Changsha, China
| | - Liu-Ye Dai
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha, China.,College of Life Sciences, Hunan Normal University, Changsha, China
| | - Sheng-Hua Dong
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha, China.,College of Life Sciences, Hunan Normal University, Changsha, China
| | - Xiu-Dan Yuan
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha, China.,College of Life Sciences, Hunan Normal University, Changsha, China
| | - Shu-Li Yuan
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha, China.,College of Life Sciences, Hunan Normal University, Changsha, China
| | - Yi Tang
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha, China.,College of Life Sciences, Hunan Normal University, Changsha, China
| | - Jin-Hui Liu
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha, China.,College of Life Sciences, Hunan Normal University, Changsha, China
| | - Liang-Yue Peng
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha, China.,College of Life Sciences, Hunan Normal University, Changsha, China
| | - Ya-Mei Xiao
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha, China.,College of Life Sciences, Hunan Normal University, Changsha, China
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27
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Ahmed O, Robinson MW, O'Farrelly C. Inflammatory processes in the liver: divergent roles in homeostasis and pathology. Cell Mol Immunol 2021; 18:1375-1386. [PMID: 33864004 PMCID: PMC8166849 DOI: 10.1038/s41423-021-00639-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 01/10/2021] [Indexed: 02/07/2023] Open
Abstract
The hepatic immune system is designed to tolerate diverse harmless foreign moieties to maintain homeostasis in the healthy liver. Constant priming and regulation ensure that appropriate immune activation occurs when challenged by pathogens and tissue damage. Failure to accurately discriminate, regulate, or effectively resolve inflammation offsets this balance, jeopardizing overall tissue health resulting from an either overly tolerant or an overactive inflammatory response. Compelling scientific and clinical evidence links dysregulated hepatic immune and inflammatory responses upon sterile injury to several pathological conditions in the liver, particularly nonalcoholic steatohepatitis and ischemia-reperfusion injury. Murine and human studies have described interactions between diverse immune repertoires and nonhematopoietic cell populations in both physiological and pathological activities in the liver, although the molecular mechanisms driving these associations are not clearly understood. Here, we review the dynamic roles of inflammatory mediators in responses to sterile injury in the context of homeostasis and disease, the clinical implications of dysregulated hepatic immune activity and therapeutic developments to regulate liver-specific immunity.
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Affiliation(s)
- Ola Ahmed
- School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Mark W Robinson
- Department of Biology, Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Ireland
| | - Cliona O'Farrelly
- School of Medicine, Trinity College Dublin, Dublin, Ireland.
- School of Biochemistry & Immunology, Trinity College Dublin, Dublin 2, Ireland.
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28
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Ni X, Wang Q, Gu J, Lu L. Clinical and Basic Research Progress on Treg-Induced Immune Tolerance in Liver Transplantation. Front Immunol 2021; 12:535012. [PMID: 34093514 PMCID: PMC8173171 DOI: 10.3389/fimmu.2021.535012] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 04/26/2021] [Indexed: 12/29/2022] Open
Abstract
Rejection after organ transplantation is a cause of graft failure. Effectively reducing rejection and inducing tolerance is a challenge in the field of transplantation immunology. The liver, as an immunologically privileged organ, has high rates of spontaneous and operational tolerance after transplantation, allowing it to maintain its normal function for long periods. Although modern immunosuppression regimens have serious toxicity and side effects, it is very risky to discontinue immunosuppression regimens blindly. A more effective treatment to induce immune tolerance is the most sought-after goal in transplant medicine. Tregs have been shown to play a pivotal role in the regulation of immune balance, and infusion of Tregs can also effectively prevent rejection and cure autoimmune diseases without significant side effects. Given the immune characteristics of the liver, the correct use of Tregs can more effectively induce the occurrence of operational tolerance for liver transplants than for other organ transplants. This review mainly summarizes the latest research advances regarding the characteristics of the hepatic immune microenvironment, operational tolerance, Treg generation in vitro, and the application of Tregs in liver transplantation. It is hoped that this review will provide a deeper understanding of Tregs as the most effective treatment to induce and maintain operational tolerance after liver transplantation.
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Affiliation(s)
- Xuhao Ni
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Qi Wang
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Jian Gu
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Ling Lu
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
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29
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MicroRNA Interference in Hepatic Host-Pathogen Interactions. Int J Mol Sci 2021; 22:ijms22073554. [PMID: 33808062 PMCID: PMC8036276 DOI: 10.3390/ijms22073554] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 03/24/2021] [Accepted: 03/27/2021] [Indexed: 12/14/2022] Open
Abstract
The liver is well recognized as a non-immunological visceral organ that is involved in various metabolic activities, nutrient storage, and detoxification. Recently, many studies have demonstrated that resident immune cells in the liver drive various immunological reactions by means of several molecular modulators. Understanding the mechanistic details of interactions between hepatic host immune cells, including Kupffer cells and lymphocytes, and various hepatic pathogens, especially viruses, bacteria, and parasites, is necessary. MicroRNAs (miRNAs), over 2600 of which have been discovered, are small, endogenous, interfering, noncoding RNAs that are predicted to regulate more than 15,000 genes by degrading specific messenger RNAs. Several recent studies have demonstrated that some miRNAs are associated with the immune response to pathogens in the liver. However, the details of the underlying mechanisms of miRNA interference in hepatic host-pathogen interactions still remain elusive. In this review, we summarize the relationship between the immunological interactions of various pathogens and hepatic resident immune cells, as well as the role of miRNAs in the maintenance of liver immunity against pathogens.
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30
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Jiménez-Torres C, El-Kehdy H, Hernández-Kelly LC, Sokal E, Ortega A, Najimi M. Acute Liver Toxicity Modifies Protein Expression of Glutamate Transporters in Liver and Cerebellar Tissue. Front Neurosci 2021; 14:613225. [PMID: 33488353 PMCID: PMC7815688 DOI: 10.3389/fnins.2020.613225] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 11/27/2020] [Indexed: 12/24/2022] Open
Abstract
Glutamate is the main excitatory amino acid acting at the level of pre and postsynaptic neurons, as well as in glial cells. It is involved in the coordinated modulation of energy metabolism, glutamine synthesis, and ammonia detoxification. The relationship between the functional status of liver and brain has been known for many years. The most widely recognized aspect of this relation is the brain dysfunction caused by acute liver injury that manifests a wide spectrum of neurologic and psychiatric abnormalities. Inflammation, circulating neurotoxins, and impaired neurotransmission have been reported in this pathophysiology. In the present contribution, we report the effect of a hepatotoxic compound like CCl4 on the expression of key proteins involved in glutamate uptake and metabolism as glutamate transporters and glutamine synthetase in mice liver, brain, and cerebellum. Our findings highlight a differential expression pattern of glutamate transporters in cerebellum. A significant Purkinje cells loss, in parallel to an up-regulation of glutamine synthetase, and astrogliosis in the brain have also been noticed. In the intoxicated liver, glutamate transporter 1 expression is up-regulated, in contrast to glutamine synthetase which is reduced in a time-dependent manner. Taken together our results demonstrate that the exposure to an acute CCl4 insult, leads to the disruption of glutamate transporters expression in the liver-brain axis and therefore a severe alteration in glutamate-mediated neurotransmission might be present in the central nervous system.
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Affiliation(s)
- Catya Jiménez-Torres
- Laboratorio de Neurotoxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (Cinvestav-IPN), Departamento de Toxicología, Mexico City, Mexico
| | - Hoda El-Kehdy
- Laboratory of Pediatric Hepatology and Cell Therapy, UCLouvain, Institut de Recherche Expérimentale et Clinique (IREC), Brussels, Belgium
| | - Luisa C Hernández-Kelly
- Laboratorio de Neurotoxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (Cinvestav-IPN), Departamento de Toxicología, Mexico City, Mexico
| | - Etienne Sokal
- Laboratory of Pediatric Hepatology and Cell Therapy, UCLouvain, Institut de Recherche Expérimentale et Clinique (IREC), Brussels, Belgium
| | - Arturo Ortega
- Laboratorio de Neurotoxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (Cinvestav-IPN), Departamento de Toxicología, Mexico City, Mexico
| | - Mustapha Najimi
- Laboratory of Pediatric Hepatology and Cell Therapy, UCLouvain, Institut de Recherche Expérimentale et Clinique (IREC), Brussels, Belgium
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31
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Molecular profiling and functional delineation of peroxiredoxin 3 (HaPrx3) from the big-belly seahorses (Hippocampus abdominalis) and understanding their immunological responses. Gene 2020; 771:145350. [PMID: 33333216 DOI: 10.1016/j.gene.2020.145350] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 10/13/2020] [Accepted: 12/01/2020] [Indexed: 12/14/2022]
Abstract
Peroxiredoxins (Prxs) are ubiquitously expressed antioxidant proteins that can protect aerobic organisms from oxidative stress. Here, we characterized the HaPrx3 homolog at the molecular level from big-belly seahorse (Hippocampus abdominalis) and analyzed its functional activities. The coding sequence of HaPrx3 consists of 726 bp, which encodes 241 amino acids. The predicted molecular weight and theoretical isoelectric point (pI) of HaPrx3 was 26.20 kDa and 7.04, respectively. Multiple sequence alignments revealed that the arrangements of domains, catalytic triads, dimers, and decamer interfaces of HaPrx3 were conserved among Prx sequences of other organisms. According to the phylogenetic analysis, HaPrx3 is clustered with the teleost Prx3 subclade. The highest transcript level of HaPrx3 was detected in the ovary tissue among fourteen healthy fish tissues. The mRNA levels of HaPrx3 in blood and liver tissues were significantly (P < 0.05) upregulated in response to lipopolysaccharide (LPS), polyinosinic-polycytidylic (poly I:C), Edwardsiella tarda, and Streptococcus iniae, suggesting its involvement in immune responses. Under functional properties, insulin disulfide reduction assay confirmed the oxidoreductase activity of recombinant HaPrx3. A cell viability assay and Hoechst staining indicated cell survival ability and reduction of apoptotic activity, respectively. Moreover, a peroxidase activity assay verified peroxidase activity, while a metal-catalyzed oxidation (MCO) assay indicated the DNA protection ability of HaPrx3. Collectively, it is concluded that HaPrx3 may play a significant role in oxidative stress and immune responses against pathogenic infections in big-belly seahorses.
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Yang A, Chen J, Zhao XM. nMAGMA: a network-enhanced method for inferring risk genes from GWAS summary statistics and its application to schizophrenia. Brief Bioinform 2020; 22:5998843. [PMID: 33230537 DOI: 10.1093/bib/bbaa298] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/21/2020] [Accepted: 10/07/2020] [Indexed: 12/21/2022] Open
Abstract
MOTIVATION Annotating genetic variants from summary statistics of genome-wide association studies (GWAS) is crucial for predicting risk genes of various disorders. The multimarker analysis of genomic annotation (MAGMA) is one of the most popular tools for this purpose, where MAGMA aggregates signals of single nucleotide polymorphisms (SNPs) to their nearby genes. In biology, SNPs may also affect genes that are far away in the genome, thus missed by MAGMA. Although different upgrades of MAGMA have been proposed to extend gene-wise variant annotations with more information (e.g. Hi-C or eQTL), the regulatory relationships among genes and the tissue specificity of signals have not been taken into account. RESULTS We propose a new approach, namely network-enhanced MAGMA (nMAGMA), for gene-wise annotation of variants from GWAS summary statistics. Compared with MAGMA and H-MAGMA, nMAGMA significantly extends the lists of genes that can be annotated to SNPs by integrating local signals, long-range regulation signals (i.e. interactions between distal DNA elements), and tissue-specific gene networks. When applied to schizophrenia (SCZ), nMAGMA is able to detect more risk genes (217% more than MAGMA and 57% more than H-MAGMA) that are involved in SCZ compared with MAGMA and H-MAGMA, and more of nMAGMA results can be validated with known SCZ risk genes. Some disease-related functions (e.g. the ATPase pathway in Cortex) are also uncovered in nMAGMA but not in MAGMA or H-MAGMA. Moreover, nMAGMA provides tissue-specific risk signals, which are useful for understanding disorders with multitissue origins.
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Affiliation(s)
- Anyi Yang
- Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, China
| | - Jingqi Chen
- Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, China
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Yuan JM, Wang Y, Wang R, Luu HN, Adams-Haduch J, Koh WP, Gao YT, Behari J, Lotze MT. Serum IL27 in Relation to Risk of Hepatocellular Carcinoma in Two Nested Case-Control Studies. Cancer Epidemiol Biomarkers Prev 2020; 30:388-395. [PMID: 33203693 DOI: 10.1158/1055-9965.epi-20-1081] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 09/24/2020] [Accepted: 11/12/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND IL27 mRNA is highly enriched in the tissue of hepatocellular carcinoma. Overexpression of IL27 gene has been found to increase T-cell expression of inhibitory receptors, an immunosuppressive feature in tumor microenvironment, that promotes the development of hepatocellular carcinoma. METHODS Two parallel case-control studies of hepatocellular carcinoma, each with 100 case-control pairs were conducted in the Singapore Chinese Health Study and the Shanghai Cohort Study to examine the association between serum IL27 levels and risk of developing hepatocellular carcinoma. RESULTS The IL27 concentrations were significantly elevated in sera collected from study participants 4 to 5 years prior to the diagnosis of hepatocellular carcinoma in both cohort studies. Compared with the lowest tertile of IL27, odds ratios (OR) of hepatocellular carcinoma for the highest tertile of IL27 was 46.08 [95% confidence interval (CI), 4.68-453.86] in the Singapore Chinese Health Study and 19.09 (95% CI, 3.81-95.57) in the Shanghai Cohort Study (both P trend <0.001). The corresponding ORs in both cohort studies were 42.47 (95% CI, 8.30-217.40) among individuals negative for hepatitis B surface antigen (HBsAg) and 242.46 (95% CI, 38.42-1,529.01) among those positive for HBsAg compared with the lowest tertile of interleukin-27 and negative HBsAg. CONCLUSIONS Levels of IL27 in prediagnostic sera were significantly associated with increased risk of hepatocellular carcinoma development. IMPACT IL27, through its immunosuppressive property, may play a significant role in the development of hepatocellular carcinoma. Serum levels of IL27 may be used as a biomarker for prediction of hepatocellular carcinoma development.
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Affiliation(s)
- Jian-Min Yuan
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania. .,Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania
| | - Yue Wang
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania
| | - Renwei Wang
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania
| | - Hung N Luu
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.,Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania
| | | | - Woon-Puay Koh
- Health Service and Systems Research, Duke-NUS Medical School, Singapore.,Saw Swee Hock School of Public Health, National University of Singapore, Singapore
| | - Yu-Tang Gao
- Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jaideep Behari
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Michael T Lotze
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.,Departments of Surgery, Immunology and Bioengineering, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Patel K, Lamm R, Altshuler P, Dang H, Shah AP. Hepatocellular Carcinoma-The Influence of Immunoanatomy and the Role of Immunotherapy. Int J Mol Sci 2020; 21:ijms21186757. [PMID: 32942580 PMCID: PMC7555667 DOI: 10.3390/ijms21186757] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/09/2020] [Accepted: 09/14/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related morbidity and mortality worldwide. Most patients are diagnosed with advanced disease, limiting their options for treatment. While current treatments are adequate for lower staged disease, available systemic treatments are limited, with marginal benefit at best. Chimeric antigen receptor (CAR) T cell therapy, effective in treating liquid tumors such as B-cell lymphoma, presents a potentially promising treatment option for advanced HCC. However, new challenges specific to solid tumors, such as tumor immunoanatomy or the immune cell presence and position anatomically and the tumor microenvironment, need to be defined and overcome. Immunotherapy currently in use must be re-engineered and re-envisioned to treat HCC with the hopes of ushering in an answer to advanced stage solid tumor disease processes. Future therapy options must address the uniqueness of the tumors under the umbrella of HCC. This review strives to summarize HCC, its staging system, current therapy and immunotherapy medications currently being utilized or studied in the treatment of HCC with the hopes of highlighting what is being done and suggesting what needs to be done in the future to champion this therapy as an effective option.
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Affiliation(s)
- Keyur Patel
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19144, USA; (K.P.); (R.L.); (P.A.)
| | - Ryan Lamm
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19144, USA; (K.P.); (R.L.); (P.A.)
| | - Peter Altshuler
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19144, USA; (K.P.); (R.L.); (P.A.)
| | - Hien Dang
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19144, USA; (K.P.); (R.L.); (P.A.)
- Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA
- Correspondence: (H.D.); (A.P.S.)
| | - Ashesh P. Shah
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19144, USA; (K.P.); (R.L.); (P.A.)
- Correspondence: (H.D.); (A.P.S.)
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Onuma AE, Zhang H, Huang H, Williams TM, Noonan A, Tsung A. Immune Checkpoint Inhibitors in Hepatocellular Cancer: Current Understanding on Mechanisms of Resistance and Biomarkers of Response to Treatment. Gene Expr 2020; 20:53-65. [PMID: 32340652 PMCID: PMC7284108 DOI: 10.3727/105221620x15880179864121] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy worldwide and a leading cause of death worldwide. Its incidence continues to increase in the US due to hepatitis C infection and nonalcoholic steatohepatitis. Liver transplantation and resection remain the best therapeutic options for cure, but these are limited by the shortage of available organs for transplantation, diagnosis at advanced stage, and underlying chronic liver disease found in most patients with HCC. Immune checkpoint inhibitors (ICIs) have been shown to be an evolving novel treatment option in certain advanced solid tumors and have been recently approved for inoperable, advanced, and metastatic HCC. Unfortunately, a large cohort of patients with HCC fail to respond to immunotherapy. In this review, we discuss the ICIs currently approved for HCC treatment and their various mechanisms of action. We will highlight current understanding of mechanism of resistance and limitations to ICIs. Finally, we will describe emerging biomarkers of response to ICIs and address future direction on overcoming resistance to immune checkpoint therapy.
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Affiliation(s)
- Amblessed E. Onuma
- *Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Hongji Zhang
- *Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
- †Department of Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Hai Huang
- *Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Terence M. Williams
- ‡Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Anne Noonan
- §Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Allan Tsung
- *Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
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Abstract
The human liver is an organ with a diverse array of immunologic functions. Its unique anatomic position that leads to it receiving all the mesenteric venous blood, combined with its unique micro anatomy, allows it to serve as a sentinel for the body's immune system. Hepatocytes, biliary epithelial cells, Kupffer cells, stellate cells, and liver sinusoidal endothelial cells express key molecules that recruit and activate innate and adaptive immunity. Additionally, a diverse array of lymphoid and myeloid immune cells resides within and traffics to the liver in specific circumstances. Derangement of these trafficking mechanisms underlies the pathophysiology of autoimmune liver diseases, nonalcoholic steatohepatitis, and liver transplantation. Here, we review these pathways and interactions along with potential targets that have been identified to be exploited for therapeutic purposes.
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Ponce M, Zuasti E, Anguís V, Fernández-Díaz C. Effects of the sulfated polysaccharide ulvan from Ulva ohnoi on the modulation of the immune response in Senegalese sole (Solea senegalensis). FISH & SHELLFISH IMMUNOLOGY 2020; 100:27-40. [PMID: 32113938 DOI: 10.1016/j.fsi.2020.02.054] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 02/20/2020] [Accepted: 02/24/2020] [Indexed: 06/10/2023]
Abstract
Sulfated polysaccharides derived from green seaweeds exhibit many beneficial biological activities and have great potential to be used as nutraceutical in aquaculture. In this work, we evaluated the effects of the sulfated polysaccharide ulvan from Ulva ohnoi on Senegalese sole (Solea senegalensis) juveniles at the transcriptomic level. Cytotoxicity assay performed in liver primary cell cultures from sole determined that the different ulvan concentrations assayed did not impair cell viability. Juveniles were intraperitoneally (IP) injected with ulvan (0.5 mg/fish) followed by a challenge with Photobacterium damselae subsp. piscicida (Phdp) at 7 days. RNASeq analyses at 2 days post injection (dpi) revealed that 402 transcripts were differentially expressed in liver between ulvan IP injected and control groups before the challenge. Genes related to bacterial and antiviral defence, complement system, chemokines, proteasomes and antigen presentation were upregulated in ulvan treated groups. A detailed expression analysis of sixteen genes related to innate and adaptive immune system was performed in two systemic tissues: liver and spleen. Ulvan injection provoked the upregulation of tlr22 and a transient inflammatory response was initiated in both liver and spleen at 2 dpi. As consequence, expression of acute phase proteins, antimicrobial peptides and complement genes was induced. Moreover, expression of mhcI, mhcII, psmb10 and bcl6 was also induced 2 dpi. At 2 dpi with Phdp, inflammatory cytokines and genes related to bacterial and antiviral defense, iron metabolism, complement system and antigen presentation were differentially modulated in survival juveniles previously IP injected with ulvan. Moreover, mortality was retarded in ulvan treated juveniles. These results provide new evidence about the role of ulvan as a bioactive compound with immunomodulatory activity in Senegalese sole as well as its possible use as vaccine adjuvant against Phdp. This is the first published study that evaluates the transcriptomic response of Senegalese sole IP injected with ulvan.
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Affiliation(s)
- Marian Ponce
- IFAPA Centro El Toruño, Camino Tiro Pichón s/n, 11500, El Puerto de Santa María, Cádiz, Spain.
| | - Eugenia Zuasti
- IFAPA Centro El Toruño, Camino Tiro Pichón s/n, 11500, El Puerto de Santa María, Cádiz, Spain
| | - Victoria Anguís
- IFAPA Centro El Toruño, Camino Tiro Pichón s/n, 11500, El Puerto de Santa María, Cádiz, Spain
| | - Catalina Fernández-Díaz
- IFAPA Centro El Toruño, Camino Tiro Pichón s/n, 11500, El Puerto de Santa María, Cádiz, Spain.
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Martini DJ, Liu Y, Shabto JM, Carthon BC, Hitron EE, Russler GA, Caulfield S, Kissick HT, Harris WB, Kucuk O, Master VA, Bilen MA. Novel Risk Scoring System for Patients with Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors. Oncologist 2020; 25:e484-e491. [PMID: 32162798 PMCID: PMC7066702 DOI: 10.1634/theoncologist.2019-0578] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Accepted: 11/05/2019] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria are the gold standard for risk-stratifying patients with metastatic renal cell cancer (mRCC). We developed a novel risk scoring system for patients with mRCC treated with immune checkpoint inhibitors (ICIs). METHODS We performed a retrospective analysis of 100 ICI-treated patients with mRCC at Winship Cancer Institute from 2015 to 2018. Several baseline variables were collected, including markers of inflammation, body mass index (BMI), and sites of metastatic disease, and all were considered for inclusion in our risk scoring system. Upon variable selection in multivariable model, monocyte-to-lymphocyte ratio (MLR), BMI, and number and sites of metastases at baseline were used for risk score calculation. Patients were categorized using four-level risk groups as good (risk score = 0), intermediate (risk score = 1), poor (risk score = 2), or very poor (risk score = 3-4). Cox's proportional hazard model and the Kaplan-Meier method were implemented for survival outcomes. RESULTS Most patients were male (66%) with clear cell renal cell carcinoma (72%). The majority (71%) received anti-programmed cell death protein-1 monotherapy. Our risk scoring criteria had higher Uno's concordance statistics than IMDC in predicting overall survival (OS; 0.71 vs. 0.57) and progression-free survival (0.61 vs. 0.58). Setting good risk (MLR <0.93, BMI ≥24, and D_Met = 0) as the reference, the OS hazard ratios were 29.5 (95% confidence interval [CI], 3.64-238.9), 6.58 (95% CI, 0.84-51.68), and 3.75 (95% CI, 0.49-28.57) for very poor, poor, and intermediate risk groups, respectively. CONCLUSION Risk scoring using MLR, BMI, and number and sites of metastases may be an effective way to predict survival in patients with mRCC receiving ICI. These results should be validated in a larger, prospective study. IMPLICATIONS FOR PRACTICE A risk scoring system was created for patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors. The results of this study have significant implications for practicing oncologists in the community and academic setting. Importantly, these results identify readily available risk factors that can be used clinically to risk-stratify patients with metastatic renal cell carcinoma who are treated with immune checkpoint inhibitors.
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Affiliation(s)
- Dylan J. Martini
- Department of Hematology and Medical Oncology, Emory University School of MedicineAtlantaGeorgiaUSA
- Winship Cancer Institute of Emory UniversityAtlantaGeorgiaUSA
| | - Yuan Liu
- Departments of Biostatistics and Bioinformatics, Emory UniversityAtlantaGeorgiaUSA
| | - Julie M. Shabto
- Department of Hematology and Medical Oncology, Emory University School of MedicineAtlantaGeorgiaUSA
- Winship Cancer Institute of Emory UniversityAtlantaGeorgiaUSA
| | - Bradley C. Carthon
- Department of Hematology and Medical Oncology, Emory University School of MedicineAtlantaGeorgiaUSA
- Winship Cancer Institute of Emory UniversityAtlantaGeorgiaUSA
| | - Emilie Elise Hitron
- Department of Hematology and Medical Oncology, Emory University School of MedicineAtlantaGeorgiaUSA
- Winship Cancer Institute of Emory UniversityAtlantaGeorgiaUSA
| | - Greta Anne Russler
- Department of Hematology and Medical Oncology, Emory University School of MedicineAtlantaGeorgiaUSA
- Winship Cancer Institute of Emory UniversityAtlantaGeorgiaUSA
| | - Sarah Caulfield
- Winship Cancer Institute of Emory UniversityAtlantaGeorgiaUSA
- Department of Pharmaceutical Services, Emory University School of MedicineAtlantaGeorgiaUSA
| | - Haydn T. Kissick
- Department of Urology, Emory University School of MedicineAtlantaGeorgiaUSA
- Winship Cancer Institute of Emory UniversityAtlantaGeorgiaUSA
| | - Wayne B. Harris
- Department of Hematology and Medical Oncology, Emory University School of MedicineAtlantaGeorgiaUSA
- Winship Cancer Institute of Emory UniversityAtlantaGeorgiaUSA
| | - Omer Kucuk
- Department of Hematology and Medical Oncology, Emory University School of MedicineAtlantaGeorgiaUSA
- Winship Cancer Institute of Emory UniversityAtlantaGeorgiaUSA
| | - Viraj A. Master
- Department of Urology, Emory University School of MedicineAtlantaGeorgiaUSA
| | - Mehmet Asim Bilen
- Department of Hematology and Medical Oncology, Emory University School of MedicineAtlantaGeorgiaUSA
- Winship Cancer Institute of Emory UniversityAtlantaGeorgiaUSA
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Ovary removal modifies liver message RNA profiles in single Comb White Leghorn chickens. Poult Sci 2020; 99:1813-1821. [PMID: 32241461 PMCID: PMC7587799 DOI: 10.1016/j.psj.2019.12.036] [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: 10/21/2018] [Revised: 11/29/2019] [Accepted: 12/02/2019] [Indexed: 12/12/2022] Open
Abstract
Ovaries produce sex hormones, and ovariectomized animals are often used as models for ovarian dysfunction. The liver is a vital organ involved in metabolism and immunity. In the present study, we conducted experiments to investigate the effects of ovariectomy on transcription and metabolic processes in the liver in chicken. Eight Single Comb White Leghorn (SCWL) female chickens were ovariectomized at 17 wk of age, and 8 intact SCWL females served as controls. At 100 wk of age, all chickens were euthanized. High-throughput transcriptome sequencing was performed on liver RNA obtained from ovariectomized and intact females. A total of 267 differentially expressed genes (DEG) were identified in our study. After analysis using DAVID functional annotation tool, one significant Kyoto Encyclopedia of Genes and Genomes pathway, the phosphatidylinositol signaling pathway, was clustered. Gene Ontology enrichment analysis yielded 46 significant Gene Ontology terms. Among terms describing biological processes, the glycerolipid metabolic and lipid localization processes were dominant. The anabolic genes, PEPCK and GK5, and the catabolic genes, VTG1; VTG2; PLD5; DGKQ; DGKE; and FABP3, were detected in ovariectomized chickens. Differentially expressed genes such as ENSGALG00000000162, IL-1Β, SVOPL, and CA12 implied that livers in ovariectomized chickens were subjected to strong inflammatory reactions, whereas defenses against endogenous materials were compromised. A comprehensive view of gene expression in the liver of ovariectomized chickens would advance our understanding of lipid metabolism, glycometabolism, and their relationships to pathologies induced by absence of the ovary. The identified DEG indicated that ovariectomy disturbed lipid metabolism in the liver and was accompanied by an increase in hepatic gluconeogenesis and reductions in phosphatidic acid synthesis and lipid carrier capacity.
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Wessely A, Steeb T, Erdmann M, Heinzerling L, Vera J, Schlaak M, Berking C, Heppt MV. The Role of Immune Checkpoint Blockade in Uveal Melanoma. Int J Mol Sci 2020; 21:ijms21030879. [PMID: 32013269 PMCID: PMC7037664 DOI: 10.3390/ijms21030879] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/27/2020] [Accepted: 01/27/2020] [Indexed: 12/25/2022] Open
Abstract
Uveal melanoma (UM) represents the most common intraocular malignancy in adults and accounts for about 5% of all melanomas. Primary disease can be effectively controlled by several local therapy options, but UM has a high potential for metastatic spread, especially to the liver. Despite its clinical and genetic heterogeneity, therapy of metastatic UM has largely been adopted from cutaneous melanoma (CM) with discouraging results until now. The introduction of antibodies targeting CTLA-4 and PD-1 for immune checkpoint blockade (ICB) has revolutionized the field of cancer therapy and has achieved pioneering results in metastatic CM. Thus, expectations were high that patients with metastatic UM would also benefit from these new therapy options. This review provides a comprehensive and up-to-date overview on the role of ICB in UM. We give a summary of UM biology, its clinical features, and how it differs from CM. The results of several studies that have been investigating ICB in metastatic UM are presented. We discuss possible reasons for the lack of efficacy of ICB in UM compared to CM, highlight the pitfalls of ICB in this cancer entity, and explain why other immune-modulating therapies could still be an option for future UM therapies.
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Affiliation(s)
- Anja Wessely
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich Alexander University, Ulmenweg 18, 91054 Erlangen, Germany; (A.W.); (T.S.); (M.E.); (L.H.); (J.V.); (C.B.)
| | - Theresa Steeb
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich Alexander University, Ulmenweg 18, 91054 Erlangen, Germany; (A.W.); (T.S.); (M.E.); (L.H.); (J.V.); (C.B.)
| | - Michael Erdmann
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich Alexander University, Ulmenweg 18, 91054 Erlangen, Germany; (A.W.); (T.S.); (M.E.); (L.H.); (J.V.); (C.B.)
| | - Lucie Heinzerling
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich Alexander University, Ulmenweg 18, 91054 Erlangen, Germany; (A.W.); (T.S.); (M.E.); (L.H.); (J.V.); (C.B.)
| | - Julio Vera
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich Alexander University, Ulmenweg 18, 91054 Erlangen, Germany; (A.W.); (T.S.); (M.E.); (L.H.); (J.V.); (C.B.)
| | - Max Schlaak
- Department of Dermatology and Allergy, University Hospital, LMU Munich, Frauenlobstr. 9-11, 80337 Munich, Germany;
| | - Carola Berking
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich Alexander University, Ulmenweg 18, 91054 Erlangen, Germany; (A.W.); (T.S.); (M.E.); (L.H.); (J.V.); (C.B.)
| | - Markus Vincent Heppt
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich Alexander University, Ulmenweg 18, 91054 Erlangen, Germany; (A.W.); (T.S.); (M.E.); (L.H.); (J.V.); (C.B.)
- Correspondence: ; Tel.: +49-9131-85-35747
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Giambartolomei GH, Delpino MV. Immunopathogenesis of Hepatic Brucellosis. Front Cell Infect Microbiol 2019; 9:423. [PMID: 31956605 PMCID: PMC6951397 DOI: 10.3389/fcimb.2019.00423] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 11/28/2019] [Indexed: 01/18/2023] Open
Abstract
The hepatic immune system can induce rapid and controlled responses to pathogenic microorganisms and tumor cells. Accordingly, most of the microorganisms that reach the liver through the blood are eliminated. However, some of them, including Brucella spp., take advantage of the immunotolerant capacity of the liver to persist in the host. Brucella has a predilection for surviving in the reticuloendothelial system, with the liver being the largest organ of this system in the human body. Therefore, its involvement in brucellosis is practically invariable. In patients with active brucellosis, the liver is commonly affected, and the most frequent clinical manifestation is hepatosplenomegaly. The molecular mechanisms implicated in liver damage have been recently elucidated. It has been demonstrated how Brucella interacts with hepatocytes inducing its death by apoptosis. The inflammatory microenvironment and the direct effect of Brucella on hepatic stellate cells (HSC) induce their activation and turn these cells from its quiescent form to their fibrogenic phenotype. This HSC activation induced by Brucella infection relies on the presence of a functional type IV secretion system and the effector protein BPE005 through a mechanism involved in the activation of the autophagic pathway. Finally, the molecular mechanisms of liver brucellosis observed so far are shedding light on how the interaction of Brucella with liver cells may play an important role in the discovery of new targets to control the infection. In this review, we report the current understanding of the interaction between liver structural cells and immune system cells during Brucella infection.
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Affiliation(s)
- Guillermo Hernán Giambartolomei
- Instituto de Inmunología, Genética y Metabolismo (INIGEM), Universidad de Buenos Aires, Buenos Aires (UBA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - María Victoria Delpino
- Instituto de Inmunología, Genética y Metabolismo (INIGEM), Universidad de Buenos Aires, Buenos Aires (UBA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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PM2.5 Exposure in the Respiratory System Induces Distinct Inflammatory Signaling in the Lung and the Liver of Mice. J Immunol Res 2019; 2019:3486841. [PMID: 31871955 PMCID: PMC6913334 DOI: 10.1155/2019/3486841] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 10/09/2019] [Accepted: 10/10/2019] [Indexed: 02/05/2023] Open
Abstract
Fine particulate matter 2.5 (PM2.5) is a harmful air pollutant currently threatening public health. Although many studies have been performed on the general negative effects of PM2.5 in mice and humans, the migration patterns of various immune cells in response to PM2.5 exposure remain unclear. In this study, we aimed to investigate the immune cell migratory response in the lung and the liver of intratracheally PM2.5-inoculated mice. To investigate the migration trajectory of immune cells in the lung and the liver tissues of mice, we employed microscopic tools including two-photon intravital imaging, histological analysis, and transmission electron microscopy. Our data from two-photon intravital imaging showed that there was no significant difference in the number of infiltrated neutrophils in the lung and the liver of PM2.5-treated mice, compared to the nontreated condition. However, from the histological analysis and the transmission electron microscopy after vascular perfusion to remove intravascular leukocytes, we observed that some leukocytes were frequently observed in the lung and the liver of PM2.5-treated mice. Interestingly, quantification of leukocyte population using flow cytometry showed significant increase of neutrophils and macrophages in the lung, but not much in the liver, 24 h post-PM2.5 treatment. These data imply that two-photon intravital imaging of the lung and the liver actually visualized neutrophils, which were adherent to the luminal side of the vasculature. We then conducted mRNA microarray analysis to further observe how PM2.5 affects gene expression patterns in the lung and the liver. PM2.5 treatment changed the mRNA expression associated with the IL-17 signaling pathway in the lung and changed the mRNA expression associated with metabolic pathways in the liver. In summary, these results suggest that the immune response in the lung is distinctly regulated from that in the liver under acute PM2.5-induced inflammation and that these organs consequently are regulated via distinct signaling pathways.
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Rossetto A, De Re V, Steffan A, Ravaioli M, Miolo G, Leone P, Racanelli V, Uzzau A, Baccarani U, Cescon M. Carcinogenesis and Metastasis in Liver: Cell Physiological Basis. Cancers (Basel) 2019; 11:E1731. [PMID: 31694274 PMCID: PMC6895858 DOI: 10.3390/cancers11111731] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 10/29/2019] [Accepted: 11/01/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) incidence is rising. This paper summarises the current state of knowledge and recent discoveries in the cellular and physiological mechanisms leading to the development of liver cancer, especially HCC, and liver metastases. After reviewing normal hepatic cytoarchitecture and immunological characteristics, the paper addresses the pathophysiological factors that cause liver damage and predispose to neoplasia. Particular attention is given to chronic liver diseases, metabolic syndrome and the impact of altered gut microbiota, disrupted circadian rhythm and psychological stress. Improved knowledge of the multifactorial aetiology of HCC has important implications for the prevention and treatment of this cancer and of liver metastases in general.
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Affiliation(s)
- Anna Rossetto
- Department of Organ Insufficiency and Transplantation, General Surgery and Transplantation, University Hospital of Bologna, Policlinico S. Orsola-Malpighi, 40138 Bologna, Italy; (M.R.); (M.C.)
| | - Valli De Re
- Immunopatologia e Biomarcatori Oncologici/Bio-proteomics Facility, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy;
| | - Agostino Steffan
- Immunopatologia e Biomarcatori Oncologici/Bio-proteomics Facility, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy;
| | - Matteo Ravaioli
- Department of Organ Insufficiency and Transplantation, General Surgery and Transplantation, University Hospital of Bologna, Policlinico S. Orsola-Malpighi, 40138 Bologna, Italy; (M.R.); (M.C.)
| | - Gianmaria Miolo
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy;
| | - Patrizia Leone
- Department of Biomedical Sciences and Human Oncology, G. Baccelli Section of Internal Medicine, University of Bari Medical School, 70124 Bari, Italy; (P.L.); (V.R.)
| | - Vito Racanelli
- Department of Biomedical Sciences and Human Oncology, G. Baccelli Section of Internal Medicine, University of Bari Medical School, 70124 Bari, Italy; (P.L.); (V.R.)
| | - Alessandro Uzzau
- Program of Oncology Surgery, Dipartimento di Area Medica, University of Udine, 33100 Udine, Italy;
| | - Umberto Baccarani
- Surgery and Transplantation, Dipartimento di Area Medica, University of Udine, 33100 Udine, Italy;
| | - Matteo Cescon
- Department of Organ Insufficiency and Transplantation, General Surgery and Transplantation, University Hospital of Bologna, Policlinico S. Orsola-Malpighi, 40138 Bologna, Italy; (M.R.); (M.C.)
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Ke XL, Zhang DF, Li QY, Liu ZG, Gao FY, Lu MX, Yang H. Digital gene expression analysis in the liver of ScpB-vaccinated and Streptococcus agalactiae-challenged Nile tilapia. FISH & SHELLFISH IMMUNOLOGY 2019; 94:249-257. [PMID: 31470139 DOI: 10.1016/j.fsi.2019.08.072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 08/09/2019] [Accepted: 08/27/2019] [Indexed: 06/10/2023]
Abstract
In recent years, streptococcal diseases have severely threatened the development of tilapia aquaculture, but effective prevention and control methods have not yet been established. To understand the immune responses of vaccinated Nile tilapia (Oreochromis niloticus), digital gene expression (DGE) technology was applied in this study to detect the gene expression profile of the Nile tilapia (O. niloticus) liver in response to ScpB (Streptococcal C5a peptidase from group B Streptococcus, ScpB) vaccination and a Streptococcus agalactiae-challenge. The control and the ScpB-vaccinated Nile tilapia yielded a total of 25,788,734 and 27,088,598 clean reads, respectively. A total of 1234 significant differentially expressed unigenes were detected (P < 0.05), of which 236 were significantly up-regulated, and 269 were significantly down-regulated (P < 0.05, |fold|>2, FDR<0.05). Of the differentially expressed gene, the identified genes which were enriched using databases of GO and KEGG could be categorized into a total of 67 functional groups and were mapped to 153 signaling pathways including 15 immune-related pathways. The differentially expressed genes (TLR1, TLR2, TLR3, TLR5, TLR9, MyD88, C3, IL-1β, IL-10) were detected in the expression profiles, and this was subsequently verified via quantitative real-time PCR (qPCR). The results of this study can serve as a basis for future research not only on the molecular mechanism of S. agalactiae invasion, but also on the anti-S. agalactiae mechanism in targeted tissues of Nile tilapia.
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Affiliation(s)
- Xiao-Li Ke
- Key Laboratory of Tropical & Subtropical Fishery Resource Application & Cultivation, Ministry of Agriculture, Key Laboratory of Aquatic Animal Immune Technology of Guangdong Province, Pearl River Fisheries Research Institute, Chinese Academy of Fisheries Science, Guangzhou, 510380, China
| | - De-Feng Zhang
- Key Laboratory of Tropical & Subtropical Fishery Resource Application & Cultivation, Ministry of Agriculture, Key Laboratory of Aquatic Animal Immune Technology of Guangdong Province, Pearl River Fisheries Research Institute, Chinese Academy of Fisheries Science, Guangzhou, 510380, China
| | - Qing-Yong Li
- Fisheries Research & Extension Center of Huizhou, Huizhou, 516002, China
| | - Zhi-Gang Liu
- Key Laboratory of Tropical & Subtropical Fishery Resource Application & Cultivation, Ministry of Agriculture, Key Laboratory of Aquatic Animal Immune Technology of Guangdong Province, Pearl River Fisheries Research Institute, Chinese Academy of Fisheries Science, Guangzhou, 510380, China
| | - Feng-Ying Gao
- Key Laboratory of Tropical & Subtropical Fishery Resource Application & Cultivation, Ministry of Agriculture, Key Laboratory of Aquatic Animal Immune Technology of Guangdong Province, Pearl River Fisheries Research Institute, Chinese Academy of Fisheries Science, Guangzhou, 510380, China
| | - Mai-Xin Lu
- Key Laboratory of Tropical & Subtropical Fishery Resource Application & Cultivation, Ministry of Agriculture, Key Laboratory of Aquatic Animal Immune Technology of Guangdong Province, Pearl River Fisheries Research Institute, Chinese Academy of Fisheries Science, Guangzhou, 510380, China.
| | - Hong Yang
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fisheries Science, Wuxi, 214081, China.
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Marnis H, Kania PW, Syahputra K, Zuo S, Dirks RP, Buchmann K. Transcriptomic analysis of Baltic cod (Gadus morhua) liver infected with Contracaecum osculatum third stage larvae indicates parasitic effects on growth and immune response. FISH & SHELLFISH IMMUNOLOGY 2019; 93:965-976. [PMID: 31419536 DOI: 10.1016/j.fsi.2019.08.034] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Revised: 08/09/2019] [Accepted: 08/13/2019] [Indexed: 06/10/2023]
Abstract
High infection levels due to third-stage larvae of the anisakid nematode Contracaecum osculatum have been documented in cod from the eastern part of the Baltic sea during the latest decades. The nematode larvae mainly infect the liver of Baltic cod and prevalence of infection has reached 100% with a mean intensity up to 80 parasites per host in certain areas and size classes. Low condition factors of the cod have been observed concomitant with the rise in parasite abundance suggesting a parasitic effect on growth parameters. To investigate any association between parasite infection and physiological status of the host we performed a comparative transcriptomic analysis of liver obtained from C. osculatum infected and non-infected cod. A total of 47,025 predicted gene models showed expression in cod liver and sequences corresponding to 2084 (4.43%) unigenes were differentially expressed in infected liver when compared to non-infected liver. Of the differentially expressed unigenes (DEGs) 1240 unigenes were up-regulated while 844 unigenes were down-regulated. The Gene Ontology (GO) enrichment analysis showed that 1304 DEGs were represented in cellular process and single-organism process, cell and cell part, binding and catalytic activity. As determined by the Kyoto Encyclopedia of Gene and Genomes (KEGG) Pathways analysis, 454 DEGs were involved in 138 pathways. Ninety-seven genes were related to metabolic pathways including carbohydrate, lipid, and amino acid metabolism. Thirteen regulated genes were playing a role in immune response such as Toll-like receptor signaling, NOD-like receptor signaling, RIG-I-like receptor signalling and thirty-six genes were associated with growth processes. This indicates that the nematode infection in Baltic cod may affect on molecular mechanisms involving metabolism, immune function and growth.
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Affiliation(s)
- Huria Marnis
- Department of Veterinary and Animal Science, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark.
| | - Per W Kania
- Department of Veterinary and Animal Science, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Khairul Syahputra
- Department of Veterinary and Animal Science, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Shaozhi Zuo
- Department of Veterinary and Animal Science, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Ron P Dirks
- Future Genomics Technologies B.V, Leiden, the Netherlands
| | - Kurt Buchmann
- Department of Veterinary and Animal Science, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
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Duan X, Liu J, Cui J, Ma B, Zhou Q, Yang X, Lu Z, Du Y, Su C. Expression of TIGIT/CD155 and correlations with clinical pathological features in human hepatocellular carcinoma. Mol Med Rep 2019; 20:3773-3781. [PMID: 31485637 PMCID: PMC6755146 DOI: 10.3892/mmr.2019.10641] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 06/25/2019] [Indexed: 12/16/2022] Open
Abstract
T cell immunoglobulin and ITIM domain (TIGIT) is a recently identified T cell coinhibitory receptor. Studies have shown that TIGIT is expressed in colon adenocarcinoma, uterine corpus endometrioid carcinoma, breast carcinoma and kidney renal clear cell carcinoma. However, the role of the TIGIT/human poliovirus receptor (CD155) pathway in the pathogenesis of hepatocellular carcinoma (HCC) remains to be elucidated. In the present study, the expression of TIGIT and CD155 in HCC tissues and peripheral blood were determined, and correlations among TIGIT, CD155, TIGIT+ CD4+ T cells, TIGIT+ regulatory T (Treg) cells and α-fetoprotein (AFP) were investigated in order to identify a potential target for diagnosing and treating HCC. Immunohistochemistry, reverse transcription-quantitative PCR analysis and western blotting were used to examine the expression of TIGIT and CD155 in cancerous tissues and peripheral blood collected from patients with HCC. The frequency of TIGIT+ CD4+ T cells and TIGIT+ Treg cells and the concentration of inflammatory cytokines secreted by T cell subsets were analyzed by flow cytometry and a Merck Milliplex assay. Correlations between the frequency of TIGIT+ CD4+ T and TIGIT+ Treg cells and AFP were analyzed using Spearman's rank correlation test. With the degree of cancerous differentiation from high to low, the expression levels of TIGIT and CD155 were upregulated in the cancerous tissues from patients with HCC. TIGIT+ CD4+ T cell and TIGIT+ Treg cell frequencies were decreased in peripheral blood from postoperative patients with HCC. The increased expression of TIGIT was positively correlated with the level of AFP. These results indicate that co-inhibitory receptor TIGIT may be involved in the pathogenesis of HCC and represent a novel target for the diagnosis and treatment of HCC.
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Affiliation(s)
- Xiangguo Duan
- Department of Laboratory Medicine, College of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
| | - Juanxi Liu
- Department of Laboratory Medicine, College of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
| | - Jianjian Cui
- Department of Clinical Laboratory, Ningxia Chinese Medicine Research Center, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
| | - Bin Ma
- Department of Oncology Surgery, The First People's Hospital of Yinchuan, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
| | - Qiunan Zhou
- Department of Laboratory Medicine, College of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
| | - Xiaojuan Yang
- Department of Laboratory Medicine, College of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
| | - Zhenhui Lu
- Department of Laboratory Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
| | - Yong Du
- Department of Laboratory Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
| | - Chunxia Su
- Department of Pathogen Biology and Immunology, School of Basic Medical Science, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
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Samaraweera AV, Sandamalika WMG, Liyanage DS, Lee S, Priyathilaka TT, Lee J. Molecular characterization and functional analysis of glutathione S-transferase kappa 1 (GSTκ1) from the big belly seahorse (Hippocampus abdominalis): Elucidation of its involvement in innate immune responses. FISH & SHELLFISH IMMUNOLOGY 2019; 92:356-366. [PMID: 31200074 DOI: 10.1016/j.fsi.2019.06.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 06/03/2019] [Accepted: 06/09/2019] [Indexed: 06/09/2023]
Abstract
Glutathione S-transferases (GSTs) are essential enzymes for the bioactivation of xenobiotics through the conjugation of the thiol group of glutathione (GSH). In this study, a kappa class of GST was identified from the big belly seahorse (Hippocampus abdominalis) (HaGSTκ1) and its biochemical and functional properties were analyzed. HaGSTκ1 has 231 amino acids encoded by a 696 bp open reading frame (ORF). The protein has a predicted molecular mass of 26.04 kDa and theoretical isoelectric point (pI) of 8.28. It comprised a thioredoxin domain, disulfide bond formation protein A (DsbA) general fold, and Ser15 catalytic site as well as GSH-binding and polypeptide-binding sites. Phylogenetic analysis revealed that HaGSTκ1 is closely clustered with the kappa class of GSTs from teleost fishes. The recombinant (rHaGSTκ1) protein exhibited activity toward 1-chloro-2,4-dinitrobenzene (CDNB), 4-nitrobenzyl (4-NBC), and 4-nitrophenethyl bromide (4-NPB) but not 1,2-dichloro-4-nitrobenzene (DCNB). The optimum pH and temperature were 8 and 30 °C, respectively, for the catalysis of CDNB and the universal substrate of GSTs. The rHaGSTκ1 activity was efficiently inhibited in the presence of Cibacron blue (CB) as compared with hematin. Most prominent expression of HaGSTκ1 was observed in the liver and kidney among the fourteen different tissues of normal seahorse. After challenge with lipopolysaccharide (LPS), polyinosinic-polycytidylic (poly I:C), gram-negative Edwardsiella tarda, and gram-positive Streptococcus iniae, HaGSTκ1 expression was significantly modulated in the liver and blood tissues. Altogether, our study proposes the plausible important role of HaGSTκ1 in innate immunity and detoxification of harmful xenobiotics.
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Affiliation(s)
- Anushka Vidurangi Samaraweera
- Department of Marine Life Sciences & Fish Vaccine Research Center, Jeju National University, Jeju Self-Governing Province, 63243, Republic of Korea
| | - W M Gayashani Sandamalika
- Department of Marine Life Sciences & Fish Vaccine Research Center, Jeju National University, Jeju Self-Governing Province, 63243, Republic of Korea
| | - D S Liyanage
- Department of Marine Life Sciences & Fish Vaccine Research Center, Jeju National University, Jeju Self-Governing Province, 63243, Republic of Korea; Marine Science Institute, Jeju National University, Jeju Self-Governing Province, 63333, Republic of Korea
| | - Sukkyoung Lee
- Department of Marine Life Sciences & Fish Vaccine Research Center, Jeju National University, Jeju Self-Governing Province, 63243, Republic of Korea; Marine Science Institute, Jeju National University, Jeju Self-Governing Province, 63333, Republic of Korea
| | - Thanthrige Thiunuwan Priyathilaka
- Department of Marine Life Sciences & Fish Vaccine Research Center, Jeju National University, Jeju Self-Governing Province, 63243, Republic of Korea.
| | - Jehee Lee
- Department of Marine Life Sciences & Fish Vaccine Research Center, Jeju National University, Jeju Self-Governing Province, 63243, Republic of Korea; Marine Science Institute, Jeju National University, Jeju Self-Governing Province, 63333, Republic of Korea.
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Rossi E, Schinzari G, Zizzari IG, Maiorano BA, Pagliara MM, Sammarco MG, Fiorentino V, Petrone G, Cassano A, Rindi G, Bria E, Blasi MA, Nuti M, Tortora G. Immunological Backbone of Uveal Melanoma: Is There a Rationale for Immunotherapy? Cancers (Basel) 2019; 11:cancers11081055. [PMID: 31357439 PMCID: PMC6721347 DOI: 10.3390/cancers11081055] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 07/17/2019] [Accepted: 07/24/2019] [Indexed: 12/27/2022] Open
Abstract
No standard treatment has been established for metastatic uveal melanoma (mUM). Immunotherapy is commonly used for this disease even though UM has not been included in phase III clinical trials with checkpoint inhibitors. Unfortunately, only a minority of patients obtain a clinical benefit with immunotherapy. The immunological features of mUM were reviewed in order to understand if immunotherapy could still play a role for this disease.
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Affiliation(s)
- Ernesto Rossi
- Medical Oncology, Fondazione Policlinico Universitario, A. Gemelli IRCCS, 00168 Rome, Italy.
| | - Giovanni Schinzari
- Medical Oncology, Fondazione Policlinico Universitario, A. Gemelli IRCCS, 00168 Rome, Italy
- Medical Oncology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Ilaria Grazia Zizzari
- Laboratory of Tumor Immunology and Cell Therapy, Department of Experimental Medicine, Policlinico Umberto I, "Sapienza" University, 00162 Rome, Italy
| | - Brigida Anna Maiorano
- Medical Oncology, Fondazione Policlinico Universitario, A. Gemelli IRCCS, 00168 Rome, Italy
| | - Monica Maria Pagliara
- Ophtalmology, Fondazione Policlinico Universitario, A. Gemelli IRCCS, 00168 Rome, Italy
| | - Maria Grazia Sammarco
- Ophtalmology, Fondazione Policlinico Universitario, A. Gemelli IRCCS, 00168 Rome, Italy
| | - Vincenzo Fiorentino
- Pathology, Fondazione Policlinico Universitario, A. Gemelli IRCCS, 00168 Rome, Italy
| | - Gianluigi Petrone
- Pathology, Fondazione Policlinico Universitario, A. Gemelli IRCCS, 00168 Rome, Italy
| | - Alessandra Cassano
- Medical Oncology, Fondazione Policlinico Universitario, A. Gemelli IRCCS, 00168 Rome, Italy
- Medical Oncology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Guido Rindi
- Pathology, Fondazione Policlinico Universitario, A. Gemelli IRCCS, 00168 Rome, Italy
| | - Emilio Bria
- Medical Oncology, Fondazione Policlinico Universitario, A. Gemelli IRCCS, 00168 Rome, Italy
- Medical Oncology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | | | - Marianna Nuti
- Laboratory of Tumor Immunology and Cell Therapy, Department of Experimental Medicine, Policlinico Umberto I, "Sapienza" University, 00162 Rome, Italy
| | - Giampaolo Tortora
- Medical Oncology, Fondazione Policlinico Universitario, A. Gemelli IRCCS, 00168 Rome, Italy
- Medical Oncology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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Ren W, Badgery W, Ding Y, Guo H, Gao Y, Zhang J. Hepatic transcriptome profile of sheep (Ovis aries) in response to overgrazing: novel genes and pathways revealed. BMC Genet 2019; 20:54. [PMID: 31272371 PMCID: PMC6610972 DOI: 10.1186/s12863-019-0760-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 06/26/2019] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Overgrazing is a major factor that causes steppe degradation in Inner Mongolian, resulting in extensive ecosystem damage. Scarcity of grass means sheep are smaller and therefore mutton and cashmere production is greatly reduced, which has resulted in massive annual economic losses. Liver is the primary metabolic organ in mammals. It is also the key source of energy supply and detoxification of metabolites in animals, has a close relationship with animal growth. However, investigations on the responses of sheep induced by consequence of overgrazing, particularly those relating to liver-related molecular mechanisms and related metabolic pathways, remain elusive. RESULTS The body weight daily gain of sheep, immune organ indices (liver and spleen), and serum parameters related to immune response, protein synthesis and energy supply (IgG, albumin, glucose and non-esterified fatty acid) were significantly lower in the overgrazing group. Other serum parameters including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, blood urea nitrogen and interleukin-6 were significantly higher in the overgrazing group. For the RNA-Seq results, we identified approximately 50 differentially expressed genes, of which half of were up-regulated and the other half were down-regulated (overgrazing group versus light grazing group). Bioinformatics analysis identified two enriched KEGG pathways including peroxisome proliferator-activated receptor (PPAR) signaling pathway (related to lipolysis) and ECM-receptor interaction (related to liver injury and apoptosis). Additionally, several of the down-regulated genes were related to detoxification and immune response. CONCLUSIONS Overall, based on the high-throughput RNA sequencing profile integrated with the results of serum biochemical analyses, consequences of lower forage availability and quality under overgrazing condition induced altered expression levels of genes participating in energy metabolism (particularly lipid metabolism) and detoxification and immune responses, causing lipolysis and impaired health status, which might be key reasons for the reduced growth performance of sheep. This investigation provides a novel foundation for the development of sheep hepatic gene interactive networks that are a response to the degraded forage availability under overgrazing condition.
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Affiliation(s)
- Weibo Ren
- Key Laboratory of Forage Grass, Ministry of Agriculture, Institute of Grassland Research, Chinese Academy of Agricultural Sciences, Hohhot, 010010, Inner Mongolia, China
| | - Warwick Badgery
- NSW Department of Primary Industries, Orange Agricultural Institute, Orange, NSW, 2800, Australia
| | - Yong Ding
- Key Laboratory of Forage Grass, Ministry of Agriculture, Institute of Grassland Research, Chinese Academy of Agricultural Sciences, Hohhot, 010010, Inner Mongolia, China
| | - Huiqin Guo
- College of Life Sciences, Inner Mongolia Agricultural University, Hohhot, 010019, Inner Mongolia, China
| | - Yang Gao
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, 130018, Jilin, China
| | - Jize Zhang
- Key Laboratory of Forage Grass, Ministry of Agriculture, Institute of Grassland Research, Chinese Academy of Agricultural Sciences, Hohhot, 010010, Inner Mongolia, China.
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50
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Chen X, Xiang L, Jia G, Liu G, Zhao H, Huang Z. Effects of dietary leucine on antioxidant activity and expression of antioxidant and mitochondrial-related genes in longissimus dorsi muscle and liver of piglets. Anim Sci J 2019; 90:990-998. [PMID: 31251457 DOI: 10.1111/asj.13249] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Revised: 05/19/2019] [Accepted: 05/29/2019] [Indexed: 12/28/2022]
Abstract
The study was conducted to investigate the effects of dietary leucine on antioxidant activity and expression of antioxidant- and mitochondrial-related genes in longissimus dorsi muscle and liver of piglets. Three diets were formulated with different levels of supplemented leucine (0%, 0.25%, 0.5%). Results showed that supplementation of 0.25% leucine significantly increased antisuperoxide anion (ASA) and antihydroxyl radical (AHR) levels and activities of total superoxide dismutade (T-SOD), glutathione peroxidase (GPx), glutathione S-transferase (GST), and total antioxidant capacity (T-AOC) in serum, longissimus dorsi muscle and liver of piglets as compared with the control group. The SOD2, catalase (CAT), GPx, GST, glutathione reductase (GR), and nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA levels in longissimus dorsi muscle and liver were significantly increased by 0.25% leucine supplementation. However, the malondialdehyde (MDA) content and the mRNA level of Kelch-like ECH-associated protein 1 (Keap1) exhibited an opposite tendency. Additionally, supplementation of 0.25% leucine significantly increased the mRNA levels of mitochondrial-related genes in longissimus dorsi muscle and liver of piglets. Results suggested that supplementation of 0.25% leucine improved antioxidant activity and mitochondrial biogenesis and function of piglets, which was related to the increase in antioxidant enzymes activities and upregulation of expression of antioxidant- and mitochondrial-related genes.
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Affiliation(s)
- Xiaoling Chen
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China
| | - Lu Xiang
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China
| | - Gang Jia
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China
| | - Guangmang Liu
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China
| | - Hua Zhao
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China
| | - Zhiqing Huang
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China
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