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Luo Z, Liu Y, Wang X, Fan F, Yang Z, Luo D. Exploring tryptophan metabolism: The transition from disturbed balance to diagnostic and therapeutic potential in metabolic diseases. Biochem Pharmacol 2024; 230:116554. [PMID: 39332693 DOI: 10.1016/j.bcp.2024.116554] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 09/04/2024] [Accepted: 09/23/2024] [Indexed: 09/29/2024]
Abstract
The rapidly rising prevalence of metabolic diseases has turned them into an escalating global health concern. By producing or altering metabolic products, the gut microbiota plays a pivotal role in maintaining human health and influencing disease development. These metabolites originate from the host itself or the external environment. In the system of interactions between microbes and the host, tryptophan (Trp) plays a central role in metabolic processes. As the amino acid in the human body that must be obtained through dietary intake, it is crucial for various physiological functions. Trp can be metabolized in the gut into three main products: The gut microbiota regulates the transformation of 5-hydroxytryptamine (5-HT, serotonin), kynurenine (Kyn), and various indole derivatives. It has been revealed that a substantial correlation exists between alterations in Trp metabolism and the initiation and progression of metabolic disorders, including obesity, diabetes, non-alcoholic fatty liver disease, and atherosclerosis, but Trp metabolites have not been comprehensively reviewed in metabolic diseases. As such, this review summarizes and analyzes the latest research, emphasizing the importance of further studying Trp metabolism within the gut microbiota to understand and treat metabolic diseases. This carries potential significance for improving human health and may introduce new therapeutic strategies.
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Affiliation(s)
- Zhizhong Luo
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
| | - Yuqing Liu
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
| | - Xin Wang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
| | - Faxin Fan
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
| | - Zhenzhen Yang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
| | - Duosheng Luo
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China.
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Arto C, Rusu EC, Clavero-Mestres H, Barrientos-Riosalido A, Bertran L, Mahmoudian R, Aguilar C, Riesco D, Chicote JU, Parada D, Martínez S, Sabench F, Richart C, Auguet T. Metabolic profiling of tryptophan pathways: Implications for obesity and metabolic dysfunction-associated steatotic liver disease. Eur J Clin Invest 2024; 54:e14279. [PMID: 38940215 DOI: 10.1111/eci.14279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 06/12/2024] [Indexed: 06/29/2024]
Abstract
BACKGROUND AND AIMS The rise in obesity highlights the need for improved therapeutic strategies, particularly in addressing metabolic dysfunction-associated steatotic liver disease (MASLD). We aim to assess the role of tryptophan metabolic pathways in the pathogenesis of obesity and in the different histological stages of MASLD. MATERIALS AND METHODS We used ultra-high performance liquid chromatography to quantify circulating levels of 15 tryptophan-related metabolites from the kynurenine, indole and serotonin pathways. A cohort of 76 subjects was analysed, comprising 18 subjects with normal weight and 58 with morbid obesity, these last being subclassified into normal liver (NL), simple steatosis (SS) and metabolic dysfunction-associated steatohepatitis (MASH). Then, we conducted gene expression analysis of hepatic IDO-1 and kynyrenine-3-monooxygenase (KMO). RESULTS Key findings in obesity revealed a distinct metabolic signature characterized by a higher concentration of different kynurenine-related metabolites, a decrease in indole-3-acetic acid and indole-3-propionic acid, and an alteration in the serotonin pathway. Elevated tryptophan levels were associated with MASLD presence (37.659 (32.577-39.823) μM of tryptophan in NL subjects; 41.522 (38.803-45.276) μM in patients with MASLD). Overall, pathway fluxes demonstrated an induction of tryptophan catabolism via the serotonin pathway in SS subjects and into the kynurenine pathway in MASH. We found decreased IDO-1 and KMO hepatic expression in NL compared to SS. CONCLUSIONS We identified a distinctive metabolic signature in obesity marked by changes in tryptophan catabolic pathways, discernible through altered metabolite profiles. We observed stage-specific alterations in tryptophan catabolism fluxes in MASLD, highlighting the potential utility of targeting these pathways in therapeutic interventions.
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Affiliation(s)
- Carmen Arto
- Servei Medicina Interna, Hospital Sant Pau i Santa Tecla de Tarragona, Tarragona, Spain
| | - Elena Cristina Rusu
- Departament de Medicina i Cirurgia, Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain
| | - Helena Clavero-Mestres
- Departament de Medicina i Cirurgia, Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain
| | - Andrea Barrientos-Riosalido
- Departament de Medicina i Cirurgia, Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain
| | - Laia Bertran
- Departament de Medicina i Cirurgia, Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain
| | - Razieh Mahmoudian
- Departament de Medicina i Cirurgia, Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain
| | - Carmen Aguilar
- Departament de Medicina i Cirurgia, Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain
| | - David Riesco
- Departament de Medicina i Cirurgia, Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain
- Servei Medicina Interna, Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain
| | - Javier Ugarte Chicote
- Departament de Medicina i Cirurgia, Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain
- Servei Anatomia Patològica, Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain
| | - David Parada
- Departament de Medicina i Cirurgia, Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain
- Servei Anatomia Patològica, Hospital Sant Joan de Reus, Avinguda Doctor Josep Laporte, Reus, Spain
| | - Salomé Martínez
- Departament de Medicina i Cirurgia, Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain
- Servei Anatomia Patològica, Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain
| | - Fàtima Sabench
- Departament de Medicina i Cirurgia, Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain
- Departament de Medicina i Cirurgia, Servei de Cirurgia, Hospital Sant Joan de Reus, URV, IISPV, Avinguda Doctor Josep Laporte, Reus, Spain
| | - Cristóbal Richart
- Departament de Medicina i Cirurgia, Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain
| | - Teresa Auguet
- Departament de Medicina i Cirurgia, Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain
- Servei Medicina Interna, Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain
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Lashgari NA, Roudsari NM, Shayan M, Niazi Shahraki F, Hosseini Y, Momtaz S, Abdolghaffari AH. IDO/Kynurenine; novel insight for treatment of inflammatory diseases. Cytokine 2023; 166:156206. [PMID: 37120946 DOI: 10.1016/j.cyto.2023.156206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 03/26/2023] [Accepted: 04/04/2023] [Indexed: 05/02/2023]
Abstract
Inflammation and oxidative stress play pivotal roles in pathogenesis of many diseases including cancer, type 2 diabetes, cardiovascular disease, atherosclerosis, neurological diseases, and inflammatory diseases such as inflammatory bowel disease (IBD). Inflammatory mediators such as interleukins (ILs), interferons (INF-s), and tumor necrosis factor (TNF)-α are related to an extended chance of inflammatory diseases initiation or progression due to the over expression of the nuclear factor Kappa B (NF-κB), signal transducer of activators of transcription (STAT), nod-like receptor family protein 3 (NLRP), toll-like receptors (TLR), mitogen-activated protein kinase (MAPK), and mammalian target of rapamycin (mTOR) pathways. These pathways are completely interconnected. Theindoleamine 2,3 dioxygenase (IDO) subset of the kynurenine (KYN) (IDO/KYN), is a metabolic inflammatory pathway involved in production of nicotinamide adenine dinucleotide (NAD + ). It has been shown that IDO/KYN actively participates in inflammatory processes and can increase the secretion of cytokines that provoke inflammatory diseases. Data were extracted from clinical and animal studies published in English between 1990-April 2022, which were collected from PubMed, Google Scholar, Scopus, and Cochrane library. IDO/KYN is completely associated with inflammatory-related pathways, thus leading to the production of cytokines such as TNF-α, IL-1β, and IL-6, and ultimately development and progression of various inflammatory disorders. Inhibition of the IDO/KYN pathway might be a novel therapeutic option for inflammatory diseases. Herein, we gathered data on probable interactions of the IDO/KYN pathway with induction of some inflammatory diseases.
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Affiliation(s)
- Naser-Aldin Lashgari
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Nazanin Momeni Roudsari
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maryam Shayan
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Faezeh Niazi Shahraki
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Yasamin Hosseini
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Saeideh Momtaz
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran; Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), and Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
| | - Amir Hossein Abdolghaffari
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
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Shirakami Y, Kato J, Maeda T, Ideta T, Imai K, Sakai H, Shiraki M, Shimizu M. Skeletal muscle atrophy is exacerbated by steatotic and fibrotic liver-derived TNF-α in senescence-accelerated mice. J Gastroenterol Hepatol 2023; 38:800-808. [PMID: 36890117 DOI: 10.1111/jgh.16171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 01/15/2023] [Accepted: 03/04/2023] [Indexed: 03/10/2023]
Abstract
BACKGROUND AND AIM Although liver diseases, including non-alcoholic steatohepatitis, are associated with skeletal muscle atrophy, the mechanism behind their association has not been fully elucidated. In this study, the effects of aging and non-alcoholic steatohepatitis on the skeletal muscle, and the interaction between the liver and muscle were investigated using a diet-induced non-alcoholic steatohepatitis model in senescence-accelerated mice. METHODS A total of four groups of senescence-accelerated mice and the control mice were fed either a non-alcoholic steatohepatitis-inducing or control diet, and their livers and skeletal muscles were removed for examinations. RESULTS In the senescence-accelerated/non-alcoholic steatohepatitis group, serum level of alanine aminotransferase was markedly elevated and histopathology of non-alcoholic steatohepatitis was significant. Skeletal muscles were also markedly atrophied. The expression of the ubiquitin ligase Murf1 in the muscle was significantly increased with muscle atrophy, while that of Tnfa was not significantly different. In contrast, the hepatic Tnfa expression and serum TNF-α levels were significantly increased in the senescence-accelerated/non-alcoholic steatohepatitis group. These results suggest that liver-derived TNF-α might promote muscle atrophy associated with steatohepatitis and aging through Murf-1. The metabolomic analysis of skeletal muscle indicated higher spermidine and lower tryptophan levels in the steatohepatitis-diet group. CONCLUSIONS The findings of this study revealed an aspect of liver-muscle interaction, which might be important in developing treatments for sarcopenia associated with liver diseases.
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Affiliation(s)
- Yohei Shirakami
- Department of Gastroenterology, Graduate School of Medicine, Gifu University, Gifu, Japan
| | - Junichi Kato
- Department of Gastroenterology, Graduate School of Medicine, Gifu University, Gifu, Japan
| | - Toshihide Maeda
- Department of Gastroenterology, Graduate School of Medicine, Gifu University, Gifu, Japan
| | - Takayasu Ideta
- Department of Gastroenterology, Graduate School of Medicine, Gifu University, Gifu, Japan
| | - Kenji Imai
- Department of Gastroenterology, Graduate School of Medicine, Gifu University, Gifu, Japan
| | - Hiroyasu Sakai
- Department of Gastroenterology, Graduate School of Medicine, Gifu University, Gifu, Japan
| | - Makoto Shiraki
- Department of Gastroenterology, Graduate School of Medicine, Gifu University, Gifu, Japan
| | - Masahito Shimizu
- Department of Gastroenterology, Graduate School of Medicine, Gifu University, Gifu, Japan
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Li X, Shan K, Li C, Zhou G. Intermittent Protein Diets Alter Hepatic Lipid Accumulation by Changing Tryptophan Metabolism in a Fast-Response Manner. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:3261-3272. [PMID: 36634216 DOI: 10.1021/acs.jafc.2c06576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
In modern life, the fluctuation of dietary protein levels is common, in particular, for low-income populations. However, its effect on human health is little known. Alternating changes of low and high casein or pork protein were used to simulate the fluctuation of dietary protein content in mice. Hepatic lipid accumulation showed a fast response to alternating changes of low- and high-protein diets. Correspondingly, some gut microbiota and tryptophan metabolite composition also showed a fast response to dietary protein changes. The fast response of 3-hydroxykynurenine (3-HK) was proven to inhibit hepatic lipid accumulation in vitro. Therefore, intermittent protein diets modulated hepatic lipid accumulation through 3-HK. These findings highlighted the sensitivity of hepatic lipid accumulation to dietary protein levels.
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Affiliation(s)
- Xiaohui Li
- Key Laboratory of Meat Processing and Quality Control, Ministry of Education; Key Laboratory of Meat Processing, Ministry of Agriculture and Rural Affairs; Jiangsu Synergistic Innovation Center of Meat Processing and Quality Control, College of Food Science and Technology, Nanjing Agricultural University, 210095Nanjing, P. R. China
| | - Kai Shan
- Key Laboratory of Meat Processing and Quality Control, Ministry of Education; Key Laboratory of Meat Processing, Ministry of Agriculture and Rural Affairs; Jiangsu Synergistic Innovation Center of Meat Processing and Quality Control, College of Food Science and Technology, Nanjing Agricultural University, 210095Nanjing, P. R. China
| | - Chunbao Li
- Key Laboratory of Meat Processing and Quality Control, Ministry of Education; Key Laboratory of Meat Processing, Ministry of Agriculture and Rural Affairs; Jiangsu Synergistic Innovation Center of Meat Processing and Quality Control, College of Food Science and Technology, Nanjing Agricultural University, 210095Nanjing, P. R. China
| | - Guanghong Zhou
- Key Laboratory of Meat Processing and Quality Control, Ministry of Education; Key Laboratory of Meat Processing, Ministry of Agriculture and Rural Affairs; Jiangsu Synergistic Innovation Center of Meat Processing and Quality Control, College of Food Science and Technology, Nanjing Agricultural University, 210095Nanjing, P. R. China
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Yoshimura K, Tamano Y, Nguyen Canh H, Zihan L, Le Thanh D, Sato Y, Terashima T, Shimoda S, Harada K. A novel pathologic marker, indoleamine 2,3-dioxygenase 1, for the cholangiopathy of immune checkpoint inhibitors-induced immune mediated hepatotoxicity as adverse events and the prediction of additional ursodeoxycholic acid treatment. Med Mol Morphol 2023; 56:106-115. [PMID: 36599971 DOI: 10.1007/s00795-022-00344-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 12/16/2022] [Indexed: 01/06/2023]
Abstract
Immune-related adverse events (irAE) has been clarified according the usage of immune checkpoint inhibitors(ICI). We primarily found indoleamine 2,3-dioxygenase 1(IDO-1) as a histologic biomarker for the cholangiopathy of primary biliary cholangitis(PBC). In this study, we evaluated the utility of IDO-1 in identifying ICI-induced immune-mediated hepatotoxicity(IMH). Immunostaining for IDO-1 using liver sections of PBC, ICI-induced IMH and controls, revealed that IDO-1 expression in bile ducts is mostly restricted in PBC and ICI-induced IMH. In ICI-induced IMH, IDO-1-positive bile ducts is found in 2/2 cases of cholangitis type and also positive/focal ducts in 11/15 cases of hepatitis type. Moreover, in 8/13 positive/focal cases, ursodeoxycholic acid as well as steroids were needed to improve liver dysfunction, but just one case (1/4) in IDO-1-negative cases. One IDO-1 positive case of hepatitis type did not receive additional UDCA, but biliary enzymes worsen. In vitro study using cultured human biliary epithelial cells revealed that IDO-1 induction was found with the stimulation of IFN-γ. In conclusion, the presence of IDO-1-positive cells is found in bile ducts in hepatitic type as well as sclerosing cholangitis of ICI-induced IMH. IDO-1 is surely a valuable pathologic marker for diagnosing ICI-induced IMH and also for predicting an additional need of UDCA in clinical practice.
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Affiliation(s)
- Kaori Yoshimura
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan
| | - Yuko Tamano
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan
| | - Hiep Nguyen Canh
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan
| | - Li Zihan
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan
| | - Dong Le Thanh
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan
| | - Yasunori Sato
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan
| | - Takeshi Terashima
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Shinji Shimoda
- Internal Medicine, Karatsu Red Cross Hospital, Karatsu, Japan
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan.
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Najimi M, Michel S, Binda MM, Gellynck K, Belmonte N, Mazza G, Gordillo N, Vainilovich Y, Sokal E. Human Allogeneic Liver-Derived Progenitor Cells Significantly Improve NAFLD Activity Score and Fibrosis in Late-Stage NASH Animal Model. Cells 2022; 11:cells11182854. [PMID: 36139429 PMCID: PMC9497074 DOI: 10.3390/cells11182854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 09/05/2022] [Accepted: 09/06/2022] [Indexed: 11/26/2022] Open
Abstract
Accumulated experimental and clinical evidence supports the development of human allogeneic liver-derived progenitor cells (HALPCs) to treat fibro-inflammatory liver diseases. The aim of the present study was to evaluate their therapeutic effect in a non-alcoholic steatohepatitis (NASH)-STAM mouse model. The immune signaling characteristics of HALPCs were first assessed in vitro. Upon inflammation treatment, HALPCs secreted large amounts of potent bioactive prostaglandin E2 and indoleamine 2,3-dioxygenase, which significantly reduced CD4+ T-lymphocyte proliferation and secretion of proinflammatory cytokines. In vivo, HALPCs were intravenously administered as single or triple shots (of a dose of 12.5 × 106 cells/kg BW) in STAM mice. Transplantation of HALPCs was associated with a significant decrease in the NAFLD activity score at an early stage and in both inflammation and hepatocyte ballooning scores in late-stage NASH. Sirius red staining analyses revealed decreased collagen deposition in the pericentral region at both stages of NASH. Altogether, these findings showed the anti-inflammatory and anti-fibrotic features of HALPCs in an in vivo NASH model, which suggests their potential to reverse the progression of this chronic fibro-inflammatory disease.
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Affiliation(s)
- Mustapha Najimi
- Cellaïon, 1435 Mont-Saint-Guibert, Belgium
- UCLouvain, Laboratory of Pediatric Hepatology and Cell Therapy (PEDI), Institute of Experimental and Clinical Research (IREC), 1200 Brussels, Belgium
- Correspondence: (M.N.); (E.S.); Tel.: +32-10-39-43-00 (M.N.)
| | | | | | | | | | | | | | | | - Etienne Sokal
- Cellaïon, 1435 Mont-Saint-Guibert, Belgium
- UCLouvain, Laboratory of Pediatric Hepatology and Cell Therapy (PEDI), Institute of Experimental and Clinical Research (IREC), 1200 Brussels, Belgium
- Correspondence: (M.N.); (E.S.); Tel.: +32-10-39-43-00 (M.N.)
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Interactions between Tryptophan Metabolism, the Gut Microbiome and the Immune System as Potential Drivers of Non-Alcoholic Fatty Liver Disease (NAFLD) and Metabolic Diseases. Metabolites 2022; 12:metabo12060514. [PMID: 35736447 PMCID: PMC9227929 DOI: 10.3390/metabo12060514] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/30/2022] [Accepted: 05/31/2022] [Indexed: 02/01/2023] Open
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing and therefore is its burden of disease as NALFD is a risk factor for cirrhosis and is associated with other metabolic conditions such as type II diabetes, obesity, dyslipidaemia and atherosclerosis. Linking these cardiometabolic diseases is a state of low-grade inflammation, with higher cytokines and c-reactive protein levels found in individuals with NAFLD, obesity and type II diabetes. A possible therapeutic target to decrease this state of low-grade inflammation is the metabolism of the essential amino-acid tryptophan. Its three main metabolic pathways (kynurenine pathway, indole pathway and serotonin/melatonin pathway) result in metabolites such as kynurenic acid, xanturenic acid, indole-3-propionic acid and serotonin/melatonin. The kynurenine pathway is regulated by indoleamine 2,3-dioxygenase (IDO), an enzyme that is upregulated by pro-inflammatory molecules such as INF, IL-6 and LPS. Higher activity of IDO is associated with increased inflammation and fibrosis in NAFLD, as well with increased glucose levels, obesity and atherosclerosis. On the other hand, increased concentrations of the indole pathway metabolites, regulated by the gut microbiome, seem to result in more favorable outcomes. This narrative review summarizes the interactions between tryptophan metabolism, the gut microbiome and the immune system as potential drivers of cardiometabolic diseases in NAFLD.
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Genetic Deficiency of Indoleamine 2,3-dioxygenase Aggravates Vascular but Not Liver Disease in a Nonalcoholic Steatohepatitis and Atherosclerosis Comorbidity Model. Int J Mol Sci 2022; 23:ijms23095203. [PMID: 35563591 PMCID: PMC9099704 DOI: 10.3390/ijms23095203] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 04/30/2022] [Accepted: 05/04/2022] [Indexed: 02/05/2023] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is a chronic liver disease that increases cardiovascular disease risk. Indoleamine 2,3-dioxygenase-1 (IDO1)-mediated tryptophan (Trp) metabolism has been proposed to play an immunomodulatory role in several diseases. The potential of IDO1 to be a link between NASH and cardiovascular disease has never been investigated. Using Apoe−/− and Apoe−/−Ido1−/− mice that were fed a high-fat, high-cholesterol diet (HFCD) to simultaneously induce NASH and atherosclerosis, we found that Ido1 deficiency significantly accelerated atherosclerosis after 7 weeks. Surprisingly, Apoe−/−Ido1−/− mice did not present a more aggressive NASH phenotype, including hepatic lipid deposition, release of liver enzymes, and histopathological parameters. As expected, a lower L-kynurenine/Trp (Kyn/Trp) ratio was found in the plasma and arteries of Apoe−/−Ido1−/− mice compared to controls. However, no difference in the hepatic Kyn/Trp ratio was found between the groups. Hepatic transcript analyses revealed that HFCD induced a temporal increase in tryptophan 2,3-dioxygenase (Tdo2) mRNA, indicating an alternative manner to maintain Trp degradation during NASH development in both Apoe−/− and Apoe−/−Ido1−/mice−. Using HepG2 hepatoma cell and THP1 macrophage cultures, we found that iron, TDO2, and Trp degradation may act as important mediators of cross-communication between hepatocytes and macrophages regulating liver inflammation. In conclusion, we show that Ido1 deficiency aggravates atherosclerosis, but not liver disease, in a newly established NASH and atherosclerosis comorbidity model. Our data indicate that the overexpression of TDO2 is an important mechanism that helps in balancing the kynurenine pathway and inflammation in the liver, but not in the artery wall, which likely determined disease outcome in these two target tissues.
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Gudd CLC, Possamai LA. The Role of Myeloid Cells in Hepatotoxicity Related to Cancer Immunotherapy. Cancers (Basel) 2022; 14:1913. [PMID: 35454819 PMCID: PMC9027811 DOI: 10.3390/cancers14081913] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/03/2022] [Accepted: 04/06/2022] [Indexed: 11/23/2022] Open
Abstract
Drug-related hepatotoxicity is an emerging clinical challenge with the widening use of immunotherapeutic agents in the field of oncology. This is an important complication to consider as more immune oncological targets are being identified to show promising results in clinical trials. The application of these therapeutics may be complicated by the development of immune-related adverse events (irAEs), a serious limitation often requiring high-dose immunosuppression and discontinuation of cancer therapy. Hepatoxicity presents one of the most frequently encountered irAEs and a better understanding of the underlying mechanism is crucial for the development of alternative therapeutic interventions. As a novel drug side effect, the immunopathogenesis of the condition is not completely understood. In the liver, myeloid cells play a central role in the maintenance of homeostasis and promotion of inflammation. Recent research has identified myeloid cells to be associated with hepatic adverse events of various immune modulatory monoclonal antibodies. In this review article, we provide an overview of the role of myeloid cells in the immune pathogenesis during hepatoxicity related to cancer immunotherapies and highlight potential treatment options.
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Affiliation(s)
- Cathrin L. C. Gudd
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK;
| | - Lucia A. Possamai
- Department of Metabolism, Digestion & Reproduction, Imperial College London, London SW7 2AZ, UK
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11
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Chen J, Vitetta L, Henson JD, Hall S. Intestinal Dysbiosis, the Tryptophan Pathway and Nonalcoholic Steatohepatitis. Int J Tryptophan Res 2022; 15:11786469211070533. [PMID: 35153490 PMCID: PMC8829707 DOI: 10.1177/11786469211070533] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 12/07/2021] [Indexed: 12/15/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) progresses from simple steatosis to steatohepatitis (NASH), which may then progress to the development of cirrhosis and hepatocarcinoma. NASH is characterized by both steatosis and inflammation. Control of inflammation in NASH is a key step for the prevention of disease progression to severe sequalae. Intestinal dysbiosis has been recognized to be an important causal factor in the pathogenesis of NASH, involving both the accumulation of lipids and aggravation of inflammation. The effects of gut dysbiosis are mediated by adverse shifts of various intestinal commensal bacterial genera and their associated metabolites such as butyrate, tryptophan, and bile acids. In this review, we focus on the roles of tryptophan and its metabolites in NASH in association with intestinal dysbiosis and discuss possible therapeutic implications.
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Affiliation(s)
- Jiezhong Chen
- Research Department, Medlab Clinical, Sydney, NSW, Australia
| | - Luis Vitetta
- Research Department, Medlab Clinical, Sydney, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | - Jeremy D Henson
- Research Department, Medlab Clinical, Sydney, NSW, Australia
- Faculty of Medicine, Prince of Wales Clinical School, The University of New South Wales, Sydney, NSW, Australia
| | - Sean Hall
- Research Department, Medlab Clinical, Sydney, NSW, Australia
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Xu L, Ling J, Su C, Su YW, Xu Y, Jiang Z. Emerging Roles on Immunological Effect of Indoleamine 2,3-Dioxygenase in Liver Injuries. Front Med (Lausanne) 2021; 8:756435. [PMID: 34869457 PMCID: PMC8636938 DOI: 10.3389/fmed.2021.756435] [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: 09/10/2021] [Accepted: 10/22/2021] [Indexed: 11/13/2022] Open
Abstract
Indoleamine 2,3-dioxygenase (IDO) is one of the initial rate-limiting enzymes of the kynurenine pathway (KP), which causes immune suppression and induction of T cell anergy. It is associated with the imbalance of immune homeostasis in numerous diseases including cancer, chronic viral infection, allergy, and autoimmune diseases. Recently, IDO has extended its role to liver field. In this review, we summarize the dysregulation and potentials of IDO in the emerging field of liver injuries, as well as current challenges for IDO targets. In particular, we discuss unexpected conclusions against previous work published. IDO is induced by pro-inflammatory cytokines in liver dysfunction and exerts an immunosuppressive effect, whereas the improvement of liver injury may require consideration of multiple factors besides IDO.
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Affiliation(s)
- Lingyan Xu
- Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Jiawei Ling
- Institute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Hong Kong, China
| | - Chang Su
- Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Yu-Wen Su
- Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
- School of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Yan Xu
- Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Zhenzhou Jiang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China
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Llewellyn HP, Arat S, Gao J, Wen J, Xia S, Kalabat D, Oziolor E, Virgen-Slane R, Affolter T, Ji C. T cells and monocyte-derived myeloid cells mediate immunotherapy-related hepatitis in a mouse model. J Hepatol 2021; 75:1083-1095. [PMID: 34242700 DOI: 10.1016/j.jhep.2021.06.037] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 05/14/2021] [Accepted: 06/20/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs) which are more severe when ICIs are used in combination. We aimed to use a mouse model to elucidate the molecular mechanisms of immune-related hepatitis, one of the common irAEs associated with ICIs. METHODS Immune phenotyping and molecular profiling were performed on Pdcd1-/- mice treated with anti-CTLA4 and/or the IDO1 inhibitor epacadostat or a 4-1BB agonistic antibody. RESULTS ICI combination-induced hepatitis and 4-1BB agonist-mediated hepatitis share similar features yet maintain distinct immune signatures. Both were characterized by an expansion of periportal infiltrates and pan-zonal inflammation albeit with different morphologic characteristics. In both cases, infiltrates were predominantly CD4+ and CD8+ T cells with upregulated T-cell activation markers, ICOS and CD44. Depletion of CD8+ T cells abolished ICI-mediated hepatitis. Single-cell transcriptomics revealed that the hepatitis induced by combination ICIs is associated with a robust immune activation signature in all subtypes of T cells and T helper 1 skewing. Expression profiling revealed a central role for IFNγ and liver monocyte-derived macrophages in promoting a pro-inflammatory T-cell response to ICI combination and 4-1BB agonism. CONCLUSION We developed a novel mouse model which offers significant value in yielding deeper mechanistic insight into immune-mediated liver toxicity associated with various immunotherapies. LAY SUMMARY Hepatitis is one of the common immune-related adverse events in cancer patients receiving immune checkpoint inhibitor (ICI) therapy. The mechanisms of ICI-induced hepatitis are not well understood. In this paper, we identify key molecular mechanisms mediating immune intracellular crosstalk between liver T cells and macrophages in response to ICI in a mouse model.
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Affiliation(s)
- Heather P Llewellyn
- Global Biomarkers, Drug Safety Research and Development (DSRD), La Jolla, CA, USA
| | - Seda Arat
- Global Pathology and Investigative Toxicology, DSRD, Groton, CT, USA
| | - Jingjin Gao
- Oncology Research Unit, Pfizer, La Jolla, CA, USA
| | - Ji Wen
- Oncology Research Unit, Pfizer, La Jolla, CA, USA
| | - Shuhua Xia
- Global Pathology and Investigative Toxicology, DSRD, Groton, CT, USA
| | - Dalia Kalabat
- Global Pathology and Investigative Toxicology, DSRD, Groton, CT, USA
| | - Elias Oziolor
- Global Pathology and Investigative Toxicology, DSRD, Groton, CT, USA
| | - Richard Virgen-Slane
- Global Biomarkers, Drug Safety Research and Development (DSRD), La Jolla, CA, USA
| | | | - Changhua Ji
- Regulatory and Immunosafety Strategy, DSRD, Pfizer, La Jolla, CA, USA.
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Chen CT, Wu PH, Hu CC, Nien HC, Wang JT, Sheu JC, Chow LP. Aberrant Upregulation of Indoleamine 2,3-Dioxygenase 1 Promotes Proliferation and Metastasis of Hepatocellular Carcinoma Cells via Coordinated Activation of AhR and β-Catenin Signaling. Int J Mol Sci 2021; 22:ijms222111661. [PMID: 34769098 PMCID: PMC8583706 DOI: 10.3390/ijms222111661] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 10/15/2021] [Accepted: 10/25/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. Chronic liver inflammation due to hepatitis virus infection and other major effectors is a major risk factor of HCC. Indoleamine 2,3-dioxygenase 1 (IDO1), a heme enzyme highly expressed upon stimulation with proinflammatory cytokines such as interferon-γ (IFN-γ), is activated to modulate the tumor microenvironment and potentially crucial in the development of certain cancer types. Earlier studies have majorly reported an immunomodulatory function of IDO1. However, the specific role of IDO1 in cancer cells, particularly HCC, remains to be clarified. Analysis of The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA LIHC) dataset in the current study revealed a significant correlation between IDO1 expression and HCC. We further established inducible IDO1-expressing cell models by coupling lentivirus-mediated knockdown and IFN-γ induction of IDO1 in normal and HCC cells. In functional assays, proliferation and motility-related functions of HCC cells were compromised upon suppression of IDO1, which may partially be rescued by its enzymatic product, kynurenine (KYN), while normal hepatocytes were not affected. Aryl hydrocarbon receptor (AhR), a reported endogenous KYN receptor, is suggested to participate in tumorigenesis. In mechanistic studies, IDO1 activation promoted both AhR and β-catenin activity and nuclear translocation. Immunofluorescence staining and co-immunoprecipitation assays further disclosed interactions between AhR and β-catenin. In addition, we identified a Src-PTEN-PI3K/Akt-GSK-3β axis involved in β-catenin stabilization and activation following IDO1-mediated AhR activation. IDO1-induced AhR and β-catenin modulated the expression of proliferation- and EMT-related genes to facilitate growth and metastasis of HCC cells. Our collective findings provide a mechanistic basis for the design of more efficacious IDO1-targeted therapy for HCC.
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Affiliation(s)
- Chih-Ta Chen
- Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Rd, Taipei 100, Taiwan; (C.-T.C.); (P.-H.W.); (C.-C.H.)
| | - Pei-Hua Wu
- Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Rd, Taipei 100, Taiwan; (C.-T.C.); (P.-H.W.); (C.-C.H.)
| | - Chia-Chi Hu
- Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Rd, Taipei 100, Taiwan; (C.-T.C.); (P.-H.W.); (C.-C.H.)
| | - Hsiao-Ching Nien
- Department of Family Medicine, National Taiwan University Hospital, Taipei 100, Taiwan;
- Liver Disease Prevention and Treatment Research Foundation, Taipei 100, Taiwan;
| | - Jin-Town Wang
- Department of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan;
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan
| | - Jin-Chuan Sheu
- Liver Disease Prevention and Treatment Research Foundation, Taipei 100, Taiwan;
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan
| | - Lu-Ping Chow
- Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Rd, Taipei 100, Taiwan; (C.-T.C.); (P.-H.W.); (C.-C.H.)
- Correspondence: ; Tel.: +886-223-123-456 (ext. 88214); Fax: +886-223-958-814
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15
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Rojas IY, Moyer BJ, Ringelberg CS, Wilkins OM, Pooler DB, Ness DB, Coker S, Tosteson TD, Lewis LD, Chamberlin MD, Tomlinson CR. Kynurenine-Induced Aryl Hydrocarbon Receptor Signaling in Mice Causes Body Mass Gain, Liver Steatosis, and Hyperglycemia. Obesity (Silver Spring) 2021; 29:337-349. [PMID: 33491319 PMCID: PMC10782555 DOI: 10.1002/oby.23065] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 09/22/2020] [Accepted: 09/23/2020] [Indexed: 12/30/2022]
Abstract
OBJECTIVE The aryl hydrocarbon receptor (AHR) plays a key role in obesity. In vitro studies revealed that the tryptophan metabolite kynurenine (Kyn) activates AHR signaling in cultured hepatocytes. The objective of this study was to determine whether Kyn activated the AHR in mice to induce obesity. METHODS Mice were fed a low-fat diet and the same diet supplemented with Kyn. Body mass, liver status, and the expression of identified relevant genes were determined. RESULTS Kyn caused mice to gain significant body mass, develop fatty liver and hyperglycemia, and increase expression levels of cytochrome P450 1B1 and stearoyl-CoA desaturase 1. The hyperglycemia was accompanied with decreased insulin levels, which may have been due to the repression of genes involved in insulin secretion. Kyn plasma concentrations and BMI were measured in female patients, and a significant association was observed between Kyn and age in patients with obesity but not in patients who were lean. CONCLUSIONS Results show that (1) Kyn or a metabolite thereof is a ligand responsible for inducing AHR-based obesity, fatty liver, and hyperglycemia in mice; (2) plasma Kyn levels increase with age in women with obesity but not in lean women; and (3) an activated AHR is necessary but not sufficient to attain obesity, a status that also requires fat in the diet.
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Affiliation(s)
- Itzel Y. Rojas
- Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Benjamin J. Moyer
- Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Carol S. Ringelberg
- Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Owen M. Wilkins
- Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Darcy B. Pooler
- Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA
- Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Dylan B. Ness
- Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA
- Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Shodeinde Coker
- Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA
- Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA
- Department of Medicine, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Tor D. Tosteson
- Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA
- Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA
- Department of Biomedical Data Science, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Lionel D. Lewis
- Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA
- Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA
- Department of Medicine, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Mary D. Chamberlin
- Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA
- Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA
- Department of Medicine, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Craig R. Tomlinson
- Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA
- Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA
- Department of Molecular & Systems Biology, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA
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Mo C, Xie S, Liu B, Zhong W, Zeng T, Huang S, Lai Y, Deng G, Zhou C, Yan W, Chen Y, Huang S, Gao L, Lv Z. Indoleamine 2,3-dioxygenase 1 limits hepatic inflammatory cells recruitment and promotes bile duct ligation-induced liver fibrosis. Cell Death Dis 2021; 12:16. [PMID: 33414436 PMCID: PMC7791029 DOI: 10.1038/s41419-020-03277-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 11/18/2020] [Accepted: 11/24/2020] [Indexed: 02/06/2023]
Abstract
Liver fibrosis is a course of chronic liver dysfunction, can develop into cirrhosis and hepatocellular carcinoma. Inflammatory insult owing to pathogenic factors plays a crucial role in the pathogenesis of liver fibrosis. Indoleamine 2,3-dioxygenase 1 (IDO1) can affect the infiltration of immune cells in many pathology processes of diseases, but its role in liver fibrosis has not been elucidated completely. Here, the markedly elevated protein IDO1 in livers was identified, and dendritic cells (DCs) immune-phenotypes were significantly altered after BDL challenge. A distinct hepatic population of CD11c+DCs was decreased and presented an immature immune-phenotype, reflected by lower expression levels of co-stimulatory molecules (CD40, MHCII). Frequencies of CD11c+CD80+, CD11c+CD86+, CD11c+MHCII+, and CD11c+CD40+ cells in splenic leukocytes were reduced significantly. Notably, IDO1 overexpression inhibited hepatic, splenic CD11c+DCs maturation, mature DCs-mediated T-cell proliferation and worsened liver fibrosis, whereas above pathological phenomena were reversed in IDO1-/- mice. Our data demonstrate that IDO1 affects the process of immune cells recruitment via inhibiting DCs maturation and subsequent T cells proliferation, resulting in the promotion of hepatic fibrosis. Thus, amelioration of immune responses in hepatic and splenic microenvironment by targeting IDO1 might be essential for the therapeutic effects on liver fibrosis.
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Affiliation(s)
- Chan Mo
- School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Shuwen Xie
- School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Bin Liu
- Department of Emergency, Guangzhou Red Cross Hospital, Medical College, Jinan University, 510220, Guangzhou, China
| | - Weichao Zhong
- Shenzhen Traditional Chinese Medicine Hospital, No.1, Fuhua Road, Futian District, 518033, Shenzhen, Guangdong, People's Republic of China
| | - Ting Zeng
- School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Sha Huang
- School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Yuqi Lai
- School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Guanghui Deng
- School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Chuying Zhou
- School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Weixin Yan
- School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Yuyao Chen
- School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Shaohui Huang
- School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Lei Gao
- School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China.
- The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China.
- Guangdong Provincial Key Laboratory of Shock and Microcirculation, Southern Medical University, 510515, Guangzhou, People's Republic of China.
| | - Zhiping Lv
- School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China.
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Correlation of Indoleamine-2,3-Dioxygenase and Chronic Kidney Disease: A Pilot Study. J Immunol Res 2021; 2021:8132569. [PMID: 33506062 PMCID: PMC7806403 DOI: 10.1155/2021/8132569] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Revised: 11/28/2020] [Accepted: 12/19/2020] [Indexed: 12/13/2022] Open
Abstract
Objective To explore the correlation of indoleamine-2,3-dioxygenase (IDO) and chronic kidney disease (CKD). Methods A total of 154 CKD patients and 42 non-CKD patients were recruited. Patients were grouped into ACR1~ACR3 (<30 mg/g, 30-300 mg/g, and >300 mg/g). Biomarkers in different groups were compared by ANOVA. Correlation was calculated by Pearson or Spearman analysis and binary logistic regression. The ROC curve was also performed. Results The levels of albumin, serum creatinine (sCr), and IDO in non-CKD patients were significantly different from those in CKD3-CKD5 stages (p < 0.05). IDO was correlated with age, proteinuria, ACR, and eGFR (p < 0.01). After adjusting for CKD-related indices, ln(IDO) was an independent risk factor for CKD (3.48, p < 0.05). The analysis of ROC curve revealed a best cutoff for IDO was 0.0466 and yielded a sensitivity of 83.8% and a specificity of 75%. Hemoglobin, total protein, and albumin in the ACR1 group were significantly higher than those in the ACR2 and ACR3 groups (p < 0.01), while sCr and IDO levels were significantly lower than those in the ACR2 and ACR3 groups (p < 0.01 or p < 0.05). After adjusting for CKD-related indices, ln(IDO) was still an independent risk factor for ACR (OR = 2.7, p < 0.05). The analysis of ROC curve revealed a best cutoff for IDO was 0.075 and yielded a sensitivity of 71.9% and a specificity of 72.2%. Conclusion IDO may be a promising biomarker to predict CKD and assess kidney function.
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Zhou Q, Shi Y, Chen C, Wu F, Chen Z. A narrative review of the roles of indoleamine 2,3-dioxygenase and tryptophan-2,3-dioxygenase in liver diseases. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:174. [PMID: 33569476 PMCID: PMC7867903 DOI: 10.21037/atm-20-3594] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Indoleamine 2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) are induced by several immune factors, such as interferon-γ, and act as intracellular enzymes that catabolize essential amino acid tryptophan into kynurenine and other downstream metabolites, including kynurenic acid (KYNA), xanthurenic acid (XA) and so on. IDO and TDO work as a double-edge sword. On one hand, they exert the immunomodulatory effects, especially immunosuppressive effects on the microenvironment including infections, pregnancy, tumor cells escape and transplantation. TDO plays the major role under basal conditions, while IDO comes into play under different circumstances of immune activation, thus IDO has a wider spectrum of immune regulation. On the other hand, these enzymes also inhibit pathogens such as Chlamydia pneumoniae, Staphylococcus aureus, Toxoplasma gondii and so on. Moreover, IDO regulates metabolic health through shaping intestinal microbiota. Recently, these enzymes have attracted more and more attention in liver diseases. Several studies have indicated that IDO and TDO can modulate viral hepatitis, autoimmune liver diseases, non-alcoholic fatty liver disease (NAFLD), liver cirrhosis, liver cancer even liver transplantation. Targeting them or their antagonists may provide novel therapeutic treatments for liver diseases. In this review, we will discuss the exact roles that IDO and TDO play in diverse hepatic diseases.
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Affiliation(s)
- Qihui Zhou
- Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yu Shi
- Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Chao Chen
- Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Fengtian Wu
- Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Zhi Chen
- Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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Thompson DS, Bourdon C, Massara P, Boyne MS, Forrester TE, Gonzales GB, Bandsma RHJ. Childhood severe acute malnutrition is associated with metabolomic changes in adulthood. JCI Insight 2020; 5:141316. [PMID: 33201860 PMCID: PMC7819749 DOI: 10.1172/jci.insight.141316] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 11/11/2020] [Indexed: 12/28/2022] Open
Abstract
BACKGROUNDSevere acute malnutrition (SAM) is a major contributor to global mortality in children under 5 years. Mortality has decreased; however, the long-term cardiometabolic consequences of SAM and its subtypes, severe wasting (SW) and edematous malnutrition (EM), are not well understood. We evaluated the metabolic profiles of adult SAM survivors using targeted metabolomic analyses.METHODSThis cohort study of 122 adult SAM survivors (SW = 69, EM = 53) and 90 age-, sex-, and BMI-matched community participants (CPs) quantified serum metabolites using direct flow injection mass spectrometry combined with reverse-phase liquid chromatography. Univariate and sparse partial least square discriminant analyses (sPLS-DAs) assessed differences in metabolic profiles and identified the most discriminative metabolites.RESULTSSeventy-seven metabolite variables were significant in distinguishing between SAM survivors (28.4 ± 8.8 years, 24.0 ± 6.1 kg/m2) and CPs (28.4 ± 8.9 years, 23.3 ± 4.4 kg/m2) (mean ± SDs) in univariate and sPLS-DA models. Compared with CPs, SAM survivors had less liver fat; higher branched-chain amino acids (BCAAs), urea cycle metabolites, and kynurenine/tryptophan (KT) ratio (P < 0.001); and lower β-hydroxybutyric acid and acylcarnitine/free carnitine ratio (P < 0.001), which were both associated with hepatic steatosis (P < 0.001). SW and EM survivors had similar metabolic profiles as did stunted and nonstunted SAM survivors.CONCLUSIONAdult SAM survivors have distinct metabolic profiles that suggest reduced β-oxidation and greater risk of type 2 diabetes (BCAAs, KT ratio, urea cycle metabolites) compared with CPs. This indicates that early childhood SAM exposure has long-term metabolic consequences that may worsen with age and require targeted clinical management.FUNDINGHealth Research Council of New Zealand, Caribbean Public Health Agency, Centre for Global Child Health at the Hospital for Sick Children. DST is an Academic Fellow and a Restracomp Fellow at the Centre for Global Child Health. GBG is a postdoctoral fellow of the Research Foundation Flanders.
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Affiliation(s)
- Debbie S. Thompson
- Translational Medicine Program, Hospital for Sick Children, Toronto, Canada
- Centre for Global Child Health, Hospital for Sick Children, Toronto, Canada
- Caribbean Institute for Health Research, The University of the West Indies, Kingston, Jamaica
| | - Celine Bourdon
- Translational Medicine Program, Hospital for Sick Children, Toronto, Canada
- The Childhood Acute Illness & Nutrition Network, Nairobi, Kenya
| | - Paraskevi Massara
- Translational Medicine Program, Hospital for Sick Children, Toronto, Canada
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Canada
| | - Michael S. Boyne
- Caribbean Institute for Health Research, The University of the West Indies, Kingston, Jamaica
- Department of Medicine, The University of the West Indies, Kingston, Jamaica
| | | | - Gerard Bryan Gonzales
- Translational Medicine Program, Hospital for Sick Children, Toronto, Canada
- Gastroenterology, Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Wageningen, the Netherlands
| | - Robert H. J. Bandsma
- Translational Medicine Program, Hospital for Sick Children, Toronto, Canada
- Centre for Global Child Health, Hospital for Sick Children, Toronto, Canada
- The Childhood Acute Illness & Nutrition Network, Nairobi, Kenya
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Canada
- Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, Canada
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20
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Lu Y, Shao M, Xiang H, Zheng P, Wu T, Ji G. Integrative transcriptomics and metabolomics explore the mechanism of kaempferol on improving nonalcoholic steatohepatitis. Food Funct 2020; 11:10058-10069. [PMID: 33135718 DOI: 10.1039/d0fo02123g] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Kaempferol has been confirmed to be effective in improving metabolic diseases such as diabetes and obesity. However, its effect and mechanism in nonalcoholic steatohepatitis (NASH) are unclear. We aim to confirm whether kaempferol could improve NASH and find the corresponding differential genes and metabolites. Transcriptomics combined with metabolomics was used to investigate the alterations in genes and metabolites expression after kaempferol treatment in mice with high-fat-diet-induced NASH. The results showed that kaempferol reduced the level of alanine transaminase (ALT), low-density lipoprotein cholesterol (LDL-C), and total cholesterol (TC) in serum and triglyceride (TG), lipid droplets, and inflammatory cell infiltration in liver. Further, 277 differentially expressed genes (DEGs) were identified through liver transcriptomics and the five most obvious DEGs were found to be CYP2b9, Cyp4a12b, Mup17, Mup7, and Mup16, which revealed that HFD induced fatty acid degradation, ribosome, and glyoxylic acid and dicarboxylic acid metabolism. Nine serum metabolites (methylcysteine, l-tryptophan, adrenic acid, d-2-hydroxyglutaric acid, tartaric acid, p-cresol sulfate, l-alanine, l-tryosine, and glutaconic acid) and 3 liver differential metabolites (gallic acid, γ-lindenic acid, and l-phenylalanine) were also identified, while the pathways were mainly involved in phenylalanine, tyrosine, and tryptophan biosynthesis; and phenylalanine metabolism. Integrating transcriptomics and metabolomics analyses indicated that kaempferol possesses the ability to improve NASH associated with energy metabolism, lipid metabolism, oxidative stress, and inflammation-related pathways. This study provides a powerful means of multiomics data integration and reveals the potent therapy and biomarkers for kaempferol.
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Affiliation(s)
- Yifei Lu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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21
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Ahmad MI, Ijaz MU, Hussain M, Haq IU, Zhao D, Li C. High-Fat Proteins Drive Dynamic Changes in Gut Microbiota, Hepatic Metabolome, and Endotoxemia-TLR-4-NFκB-Mediated Inflammation in Mice. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:11710-11725. [PMID: 33034193 DOI: 10.1021/acs.jafc.0c02570] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
The responses of gut microbiota to dietary proteins have been studied previously. However, the effects of dietary proteins supplemented with a high-fat diet (HFD) on the metabolite biomarkers associated with non-alcoholic fatty liver disease (NAFLD) are not well understood. To understand the underlying mechanisms, C57BL/6J mice were fed with either a low-fat diet with casein (LFC) or an HFD with casein (HFC), fish (HFF), or mutton proteins (HFM), and their cecal microbiota and liver metabolites were analyzed. At the phylum level, the HFD group had a relatively higher abundance of Firmicutes compared to the LFC-diet group. At the genus level, the HFF-diet group had the highest abundance of Lactobacillus and Akkermansia compared to the HFC- and HFM-diet groups. Furthermore, mice fed with the HFF diet had significantly reduced levels of hepatic metabolites involved in oxidative stress and bile acid metabolism. Thus, meat proteins in HFD interact in the host to create distinct responses in the gut microbiota and its metabolites.
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Affiliation(s)
- Muhammad Ijaz Ahmad
- Key Laboratory of Meat Processing and Quality Control, MOE; Key Laboratory of Meat Processing, MARA; Jiangsu Collaborative Innovation Center of Meat Production and Processing, Quality and Safety Control; College of Food Science and Technology, Nanjing Agricultural University, 210095 Nanjing, China
| | - Muhammad Umair Ijaz
- Key Laboratory of Meat Processing and Quality Control, MOE; Key Laboratory of Meat Processing, MARA; Jiangsu Collaborative Innovation Center of Meat Production and Processing, Quality and Safety Control; College of Food Science and Technology, Nanjing Agricultural University, 210095 Nanjing, China
| | - Muzhair Hussain
- Key Laboratory of Meat Processing and Quality Control, MOE; Key Laboratory of Meat Processing, MARA; Jiangsu Collaborative Innovation Center of Meat Production and Processing, Quality and Safety Control; College of Food Science and Technology, Nanjing Agricultural University, 210095 Nanjing, China
| | - Ijaz Ul Haq
- Key Laboratory of Meat Processing and Quality Control, MOE; Key Laboratory of Meat Processing, MARA; Jiangsu Collaborative Innovation Center of Meat Production and Processing, Quality and Safety Control; College of Food Science and Technology, Nanjing Agricultural University, 210095 Nanjing, China
| | - Di Zhao
- Key Laboratory of Meat Processing and Quality Control, MOE; Key Laboratory of Meat Processing, MARA; Jiangsu Collaborative Innovation Center of Meat Production and Processing, Quality and Safety Control; College of Food Science and Technology, Nanjing Agricultural University, 210095 Nanjing, China
| | - Chunbao Li
- Key Laboratory of Meat Processing and Quality Control, MOE; Key Laboratory of Meat Processing, MARA; Jiangsu Collaborative Innovation Center of Meat Production and Processing, Quality and Safety Control; College of Food Science and Technology, Nanjing Agricultural University, 210095 Nanjing, China
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22
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Zeltser N, Meyer I, Hernandez GV, Trahan MJ, Fanter RK, Abo-Ismail M, Glanz H, Strand CR, Burrin DG, La Frano MR, Manjarín R, Maj M. Neurodegeneration in juvenile Iberian pigs with diet-induced nonalcoholic fatty liver disease. Am J Physiol Endocrinol Metab 2020; 319:E592-E606. [PMID: 32744096 PMCID: PMC7864229 DOI: 10.1152/ajpendo.00120.2020] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The objective of this study was to investigate whether juvenile Iberian pigs with diet-induced nonalcoholic fatty liver disease (NAFLD), cholestasis, and gut dysbiosis would develop histological and metabolic markers of neurodegeneration in the frontal cortex (FC) and whether supplementing probiotics would influence the response to the diet. Twenty-eight juvenile Iberian pigs were fed for 10 wk either a control (CON) or high-fructose high-fat (HFF) diet with or without a commercial probiotic mixture. Compared with CON, HFF-fed pigs had a decreased number of neurons and an increase in reactive astrocytes in FC tissue. There was also a decrease in one-carbon metabolites choline and betaine and a marked accumulation of bile acids, cholesteryl esters, and polyol pathway intermediates in FC of HFF-fed pigs, which were associated with markers of neurodegeneration and accentuated with the severity of NAFLD. Betaine depletion in FC tissue was negatively correlated with choline-derived phospholipids in colon content, whereas primary conjugated bile acids in FC were associated with cholestasis. Plasma kynurenine-to-tryptophan quotient, as a marker of indoleamine 2,3-dioxygenase activity, and intestinal dysbiosis were also correlated with neuronal loss and astrogliosis. Recognition memory test and FC levels of amyloid-β and phosphorylated Tau did not differ between diets, whereas probiotics increased amyloid-β and memory loss in HFF-fed pigs. In conclusion, our results show evidence of neurodegeneration in FC of juvenile Iberian pigs and establish a novel pediatric model to investigate the role of gut-liver-brain axis in diet-induced NAFLD.
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Affiliation(s)
- Nicole Zeltser
- Department of Animal Science, California Polytechnic State University, San Luis Obispo, California
| | - Isabell Meyer
- Institute of Animal Science, University of Bonn, Bonn, Germany
| | - Gabriella V Hernandez
- Department of Animal Science, California Polytechnic State University, San Luis Obispo, California
| | - Matthew J Trahan
- Department of Biological Sciences, California Polytechnic State University, San Luis Obispo, California
| | - Rob K Fanter
- College of Agriculture, Food, and Environmental Sciences, California Polytechnic State University, San Luis Obispo, California
- Center for Health Research, California Polytechnic State University, San Luis Obispo, California
| | - Mohammed Abo-Ismail
- Department of Animal Science, California Polytechnic State University, San Luis Obispo, California
| | - Hunter Glanz
- Department of Statistics, California Polytechnic State University, San Luis Obispo, California
| | - Christine R Strand
- Department of Biological Sciences, California Polytechnic State University, San Luis Obispo, California
| | - Douglas G Burrin
- United States Department of Agriculture-Agricultural Research Services, Children's Nutrition Research Center, Section of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Michael R La Frano
- Center for Health Research, California Polytechnic State University, San Luis Obispo, California
- Department of Food Science and Nutrition, California Polytechnic State University, San Luis Obispo, California
| | - Rodrigo Manjarín
- Department of Animal Science, California Polytechnic State University, San Luis Obispo, California
| | - Magdalena Maj
- Department of Biological Sciences, California Polytechnic State University, San Luis Obispo, California
- Center for Applications in Biotechnology, California Polytechnic State University, San Luis Obispo, California
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23
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Ketelhuth DFJ. The immunometabolic role of indoleamine 2,3-dioxygenase in atherosclerotic cardiovascular disease: immune homeostatic mechanisms in the artery wall. Cardiovasc Res 2020; 115:1408-1415. [PMID: 30847484 DOI: 10.1093/cvr/cvz067] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Revised: 01/30/2019] [Accepted: 03/05/2019] [Indexed: 01/05/2023] Open
Abstract
Coronary heart disease and stroke, the two most common cardiovascular diseases worldwide, are triggered by complications of atherosclerosis. Atherosclerotic plaques are initiated by a maladaptive immune response triggered by accumulation of lipids in the artery wall. Hence, disease is influenced by several non-modifiable and modifiable risk factors, including dyslipidaemia, hypertension, smoking, and diabetes. Indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in the kynurenine pathway of tryptophan (Trp) degradation, is modulated by inflammation and regarded as a key molecule driving immunotolerance and immunosuppressive mechanisms. A large body of evidence indicates that IDO-mediated Trp metabolism is involved directly or indirectly in atherogenesis. This review summarizes evidence from basic and clinical research showing that IDO is a major regulatory enzyme involved in the maintenance of immunohomeostasis in the vascular wall, as well as current knowledge about promising targets for the development of new anti-atherosclerotic drugs.
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Affiliation(s)
- Daniel F J Ketelhuth
- Cardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.,Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, Univ. of Southern Denmark, J. B. Winsløws Vej 21(3), Odense C, Denmark
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24
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Berge RK, Cacabelos D, Señarís R, Nordrehaug JE, Nygård O, Skorve J, Bjørndal B. Hepatic steatosis induced in C57BL/6 mice by a non-ß oxidizable fatty acid analogue is associated with reduced plasma kynurenine metabolites and a modified hepatic NAD +/NADH ratio. Lipids Health Dis 2020; 19:94. [PMID: 32410680 PMCID: PMC7227213 DOI: 10.1186/s12944-020-01271-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 04/29/2020] [Indexed: 01/14/2023] Open
Abstract
Background Non-alcoholic fatty liver disease is often associated with obesity, insulin resistance, dyslipidemia, and the metabolic syndrome in addition to mitochondrial dysfunction and nicotinamide adenine dinucleotide (NAD+) deficiency. The aim of this study was to investigate how inhibition of mitochondrial fatty acid oxidation using the compound tetradecylthiopropionic acid (TTP) would affect hepatic triacylglycerol level and plasma levels of kynurenine (Kyn) metabolites and nicotinamide. Methods 12 C57BL/6 mice were fed a control diet, or an intervention diet supplemented with 0.9% (w/w) tetradecylthiopropionic acid for 14 days. Blood and liver samples were collected, enzyme activities and gene expression were analyzed in liver, in addition to fatty acid composition. Metabolites in the tryptophan/kynurenine pathway and total antioxidant status were measured in plasma. Results Dietary treatment with tetradecylthiopropionic acid for 2 weeks induced fatty liver accompanied by decreased mitochondrial fatty acid oxidation. The liver content of the oxidized form of NAD+ was increased, as well as the ratio of NAD+/NADH, and these changes were associated by increased hepatic mRNA levels of NAD synthetase and nicotinamide mononucleotide adenyltransferase-3. The downstream metabolites of kynurenine were reduced in plasma whereas the plasma nicotinamide content was increased. Some effects on inflammation and oxidative stress was observed in the liver, while the plasma antioxidant capacity was increased. This was accompanied by a reduced plasma ratio of kynurenine/tryptophan. In addition, a significant decrease in the inflammation-related arachidonic fatty acid in liver was observed. Conclusion Fatty liver induced by short-time treatment with tetradecylthiopropionic acid decreased the levels of kynurenine metabolites but increased the plasma levels of NAD+ and nicotinamide. These changes are most likely not associated with increased inflammation and oxidative stress. Most probably the increase of NAD+ and nicotinamide are generated through the Preiss Handler pathway and/or salvage pathway and not through the de novo pathway. The take home message is that non-alcoholic fatty liver disease is associated with the metabolic syndrome in addition to mitochondrial dysfunction and nicotinamide adenine dinucleotide (NAD+) deficiency. Inducing fatty liver in mice by inhibition of fatty acid oxidation resulted in a concomitant change in kynurenine metabolites increasing the plasma levels of nicotinamides and the hepatic NAD+/NADH ratio, probably without affecting the de novo pathway of kynurenines.
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Affiliation(s)
- Rolf K Berge
- Department of Clinical Science, University of Bergen, Bergen, Norway. .,Department of Heart Disease, Haukeland University Hospital, Bergen, Norway.
| | - Daniel Cacabelos
- Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
| | - Rosa Señarís
- Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
| | - Jan Erik Nordrehaug
- Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Heart Disease, Stavanger University Hospital, Stavanger, Norway
| | - Ottar Nygård
- Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Heart Disease, Haukeland University Hospital, Bergen, Norway.,KG Jebsen Centre for Diabetes Research, University of Bergen, Bergen, Norway
| | - Jon Skorve
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Bodil Bjørndal
- Department of Clinical Science, University of Bergen, Bergen, Norway
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25
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Oates JR, McKell MC, Moreno-Fernandez ME, Damen MSMA, Deepe GS, Qualls JE, Divanovic S. Macrophage Function in the Pathogenesis of Non-alcoholic Fatty Liver Disease: The Mac Attack. Front Immunol 2019; 10:2893. [PMID: 31921154 PMCID: PMC6922022 DOI: 10.3389/fimmu.2019.02893] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 11/26/2019] [Indexed: 12/15/2022] Open
Abstract
Obesity is a prevalent predisposing factor to non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in the developed world. NAFLD spectrum of disease involves progression from steatosis (NAFL), to steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). Despite clinical and public health significance, current FDA approved therapies for NAFLD are lacking in part due to insufficient understanding of pathogenic mechanisms driving disease progression. The etiology of NAFLD is multifactorial. The induction of both systemic and tissue inflammation consequential of skewed immune cell metabolic state, polarization, tissue recruitment, and activation are central to NAFLD progression. Here, we review the current understanding of the above stated cellular and molecular processes that govern macrophage contribution to NAFLD pathogenesis and how adipose tissue and liver crosstalk modulates macrophage function. Notably, the manipulation of such events may lead to the development of new therapies for NAFLD.
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Affiliation(s)
- Jarren R Oates
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States.,Division of Immunobiology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, United States.,Immunology Graduate Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Melanie C McKell
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States.,Immunology Graduate Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, United States.,Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Maria E Moreno-Fernandez
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States.,Division of Immunobiology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Michelle S M A Damen
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States.,Division of Immunobiology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - George S Deepe
- Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Joseph E Qualls
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States.,Immunology Graduate Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, United States.,Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Senad Divanovic
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States.,Division of Immunobiology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, United States.,Immunology Graduate Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, United States.,Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
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26
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Sorgdrager FJH, Naudé PJW, Kema IP, Nollen EA, Deyn PPD. Tryptophan Metabolism in Inflammaging: From Biomarker to Therapeutic Target. Front Immunol 2019; 10:2565. [PMID: 31736978 PMCID: PMC6833926 DOI: 10.3389/fimmu.2019.02565] [Citation(s) in RCA: 240] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 10/16/2019] [Indexed: 12/12/2022] Open
Abstract
Inflammation aims to restore tissue homeostasis after injury or infection. Age-related decline of tissue homeostasis causes a physiological low-grade chronic inflammatory phenotype known as inflammaging that is involved in many age-related diseases. Activation of tryptophan (Trp) metabolism along the kynurenine (Kyn) pathway prevents hyperinflammation and induces long-term immune tolerance. Systemic Trp and Kyn levels change upon aging and in age-related diseases. Moreover, modulation of Trp metabolism can either aggravate or prevent inflammaging-related diseases. In this review, we discuss how age-related Kyn/Trp activation is necessary to control inflammaging and alters the functioning of other metabolic faiths of Trp including Kyn metabolites, microbiota-derived indoles and nicotinamide adenine dinucleotide (NAD+). We explore the potential of the Kyn/Trp ratio as a biomarker of inflammaging and discuss how intervening in Trp metabolism might extend health- and lifespan.
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Affiliation(s)
- Freek J H Sorgdrager
- European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.,Laboratory of Neurochemistry and Behavior, Department of Biomedical Sciences, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.,Department of Neurology and Alzheimer Center, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.,Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Petrus J W Naudé
- Department of Neurology and Alzheimer Center, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.,Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, Groningen, Netherlands
| | - Ido P Kema
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Ellen A Nollen
- European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Peter P De Deyn
- Laboratory of Neurochemistry and Behavior, Department of Biomedical Sciences, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.,Department of Neurology and Alzheimer Center, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.,Department of Neurology, Memory Clinic of Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium
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27
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Increased fatty acid oxidation and mitochondrial proliferation in liver are associated with increased plasma kynurenine metabolites and nicotinamide levels in normolipidemic and carnitine-depleted rats. Biochim Biophys Acta Mol Cell Biol Lipids 2019; 1865:158543. [PMID: 31676443 DOI: 10.1016/j.bbalip.2019.158543] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 10/15/2019] [Accepted: 10/25/2019] [Indexed: 11/20/2022]
Abstract
Dysregulation of the tryptophan (Trp)-NAD+ pathway has been related to several pathological conditions, and the metabolites in this pathway are known to influence mitochondrial respiration and redox status. The aim of this project was to investigate if stimulation of beta-oxidation and mitochondrial proliferation by the mitochondrial-targeted compound 2-(tridec-12-yn-1-ylthio)acetic acid (1-triple TTA) would influence metabolites of the Trp-Kyn-NAD+ pathway. We wished to investigate how carnitine depletion by meldonium-treatment influenced these metabolites. After dietary treatment of male Wistar rats with 1-triple TTA for three weeks, increased hepatic mitochondrial- and peroxisomal fatty acid oxidation resulted. The plasma content of total carnitines decreased compared to control animals, whereas hepatic genes involved in CoA biosynthesis were upregulated by 1-triple TTA treatment. The plasma Trp level and individual metabolites in the kynurenine pathway were increased by 1-triple TTA, associated with decreased hepatic gene expression of indoleamine2,3-dioxygenase. 1-triple TTA treatment increased conversion of Trp to nicotinamide (Nam) as the plasma content of quinolinic acid, Nam and N1-methylnicotinamide (mNam) increased, accompanied with suppression of hepatic gene expression of α-amino-α-carboxymuconate-ε-semialdehyde decarboxylase. A positive correlation between mitochondrial fatty acid oxidation and Trp-derivatives was found. Almost identical results were obtained by 1-triple TTA in the presence of meldonium, which alone exerted minor effects. Moreover, the plasma Kyn:Trp ratio (KTR) correlated negatively to mitochondrial function. Whether increased flux through the Trp-NAD+ pathway increased redox status and lowered inflammation locally and systemically should be considered.
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28
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Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the first and rate-limiting reaction of l-tryptophan (Trp) conversion into l-kynurenine (Kyn). The depletion of Trp, and the accumulation of Kyn have been proposed as mechanisms that contribute to the suppression of the immune response-primarily evidenced by in vitro study. IDO1 is therefore considered to be an immunosuppressive modulator and quantification of IDO1 metabolism may be critical to understanding its role in select immunopathologies, including autoimmune- and oncological-conditions, as well as for determining the potency of IDO1 enzyme inhibitors. Because tryptophan 2,3-dioxygenase (TDO), and to a significantly lesser extent, IDO2, also catabolize Trp into Kyn, it's important to differentiate the contribution of each enzyme to Trp catabolism and Kyn generation. Moreover, a great variety of detection methods have been developed for the quantification of Trp metabolites, but choosing the suitable protocol remains challenging. Here, we review the differential expression of IDO1/TDO/IDO2 in normal and malignant tissues, followed by a comprehensive analysis of methodologies for quantifying Trp and Kyn in vitro and in vivo, with an emphasis on the advantages/disadvantages for each application.
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29
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Affolter T, Llewellyn HP, Bartlett DW, Zong Q, Xia S, Torti V, Ji C. Inhibition of immune checkpoints PD-1, CTLA-4, and IDO1 coordinately induces immune-mediated liver injury in mice. PLoS One 2019; 14:e0217276. [PMID: 31112568 PMCID: PMC6528985 DOI: 10.1371/journal.pone.0217276] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 05/08/2019] [Indexed: 12/18/2022] Open
Abstract
Cancer cells harness immune checkpoints such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and indoleamine 2,3-dioxygenase 1 (IDO1) to evade immune control. Checkpoint inhibitors have demonstrated durable anti-tumor efficacy in human and preclinical models. Liver toxicity is one of the common immune-related adverse events associated with checkpoint inhibitors (CPIs) and its frequency and severity often increase significantly during CPI combination therapies. We aim to develop a mouse model to elucidate the immune mechanisms of CPI-associated liver toxicity. Co-administration of CTLA-4 blocking antibody, 9D9, and/or an IDO1 inhibitor, epacadostat in wild-type and PD-1-/- mice (to simulate the effect of PD1 blockade) synergistically induced liver injury and immune cell infiltration. Infiltrated cells were primarily composed of CD8+ T cells and positively associated with hepatocyte necrosis. Strikingly, sites of hepatocyte necrosis were frequently surrounded by clusters of mononuclear immune cells. CPI treatments resulted in increased expression of genes associated with hepatocyte cell death, leukocyte migration and T cell activation in the liver. In conclusion, blockade of immune checkpoints PD-1, CTLA-4, and IDO1 act synergistically to enhance T cell infiltration and activity in the liver, leading to hepatocyte death.
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Affiliation(s)
- Timothy Affolter
- Global Pathology, Pfizer Drug Safety Research and Development, La Jolla, California, United States of America
| | - Heather P. Llewellyn
- Global Pathology, Pfizer Drug Safety Research and Development, La Jolla, California, United States of America
| | - Derek W. Bartlett
- Medicine Design, Pfizer Worldwide Research and Development, La Jolla, California, United States of America
| | - Qing Zong
- Biomarkers, Pfizer Drug Safety Research and Development, La Jolla, California, United States of America
| | - Shuhua Xia
- Investigative Toxicology, Drug Safety Research and Development, Groton, Connecticut, United States of America
| | - Vince Torti
- General Toxicology, Drug Safety Research and Development La Jolla, California, United States of America
| | - Changhua Ji
- Global Pathology, Pfizer Drug Safety Research and Development, La Jolla, California, United States of America
- * E-mail:
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30
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Liu XJ, Zhang CE, Yu XH, Liu RX, Qin XM, Jia JD, Ma ZJ. Serum metabonomics characterization of liver fibrosis induced by bile duct-ligated in rats and the intervention effects of herb compound 861. J LIQ CHROMATOGR R T 2019. [DOI: 10.1080/10826076.2019.1574815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Affiliation(s)
- Xiao-Jie Liu
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, P. R. China
| | - Cong-En Zhang
- Beijing Friendship Hospital, Capital Medical University, Beijing, P. R. China
| | - Xiao-Hong Yu
- Beijing Friendship Hospital, Capital Medical University, Beijing, P. R. China
| | - Rui-Xia Liu
- Beijing Friendship Hospital, Capital Medical University, Beijing, P. R. China
| | - Xue-Mei Qin
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, P. R. China
| | - Ji-Dong Jia
- Beijing Friendship Hospital, Capital Medical University, Beijing, P. R. China
- Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis
| | - Zhi-Jie Ma
- Beijing Friendship Hospital, Capital Medical University, Beijing, P. R. China
- Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis
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Abstract
PURPOSE OF REVIEW So far, the tryptophan catabolites generated in the kynurenine pathway have been mainly studied in relation to oncologic and mental health disorders. The current review provides an update on the emerging biomedical interest for kynurenine pathway activity in the field of energy homeostasis and metabolic diseases. RECENT FINDINGS Kynurenine pathway enzymes are expressed in tissues relevant for energy homeostasis such as fat, skeletal muscle, liver and endocrine pancreas, blood vessel and heart, and are regulated by nutritional and inflammatory signals. Kynurenine pathway metabolites have been proposed as biomarkers for initiation and progression of atherosclerosis and diabetes. Exercise training activation of kynurenine pathway in skeletal muscles increases lipid metabolism and thermogenesis, and it limits weight gain, inflammation, insulin resistance, and glucose intolerance in rodents fed a high-fat diet. Manipulation of kynurenine pathway metabolism through administration of enzyme inhibitors or kynurenine pathway metabolites can serve as novel therapeutic strategy for atherosclerosis, obesity, glucose intolerance, or impaired insulin secretion. SUMMARY Although we are far from a complete understanding of the role of kynurenine pathway in the modulation of energy homeostasis, targeting kynurenine pathway harbors high potential to expand the range of therapies to prevent and treat metabolic diseases.
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Affiliation(s)
- Jun-Jun Liu
- Laboratoire B2PE (Biologie et Pathologie du Pancréas Endocrine), Unité BFA (Biologie Fonctionnelle et Adaptive), Université Paris-Diderot, Sorbonne-Paris-Cité, Paris, France
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Aguiar SLF, Miranda MCG, Guimarães MAF, Santiago HC, Queiroz CP, Cunha PDS, Cara DC, Foureaux G, Ferreira AJ, Cardoso VN, Barros PA, Maioli TU, Faria AMC. High-Salt Diet Induces IL-17-Dependent Gut Inflammation and Exacerbates Colitis in Mice. Front Immunol 2018; 8:1969. [PMID: 29379505 PMCID: PMC5775230 DOI: 10.3389/fimmu.2017.01969] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Accepted: 12/19/2017] [Indexed: 01/26/2023] Open
Abstract
Excess intake of sodium is often associated with high risk for cardiovascular disease. More recently, some studies on the effects of high-salt diets (HSDs) have also demonstrated that they are able to activate Th17 cells and increase severity of autoimmune diseases. The purpose of the present study was to evaluate the effects of a diet supplemented with NaCl in the colonic mucosa at steady state and during inflammation. We showed that consumption of HSD by mice triggered a gut inflammatory reaction associated with IL-23 production, recruitment of neutrophils, and increased frequency of the IL-17-producing type 3 innate lymphoid cells (ILC3) in the colon. Moreover, gut inflammation was not observed in IL-17–/– mice but it was present, although at lower grade, in RAG−/− mice suggesting that the inflammatory effects of HSD was dependent on IL-17 but only partially on Th17 cells. Expression of SGK1, a kinase involved in sodium homeostasis, increased 90 min after ingestion of 50% NaCl solution and decreased 3 weeks after HSD consumption. Colitis induced by oral administration of either dextran sodium sulfate or 2,4,6-trinitrobenzenesulfonic acid was exacerbated by HSD consumption and this effect was associated with increased frequencies of RORγt+ CD4+ T cells and neutrophils in the colon. Therefore, our results demonstrated that consumption of HSD per se triggered a histologically detectable inflammation in the colon and also exacerbated chemically induced models of colitis in mice by a mechanism dependent on IL-17 production most likely by both ILC3 and Th17 cells.
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Affiliation(s)
- Sarah Leão Fiorini Aguiar
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Mariana Camila Gonçalves Miranda
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Mauro Andrade Freitas Guimarães
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Helton Costa Santiago
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Camila Pereira Queiroz
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Pricila da Silva Cunha
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Denise Carmona Cara
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Giselle Foureaux
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Anderson José Ferreira
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Valbert Nascimento Cardoso
- Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Patrícia Aparecida Barros
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Tatiani Uceli Maioli
- Departamento de Nutrição, Escola de Enfermagem, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Ana Maria Caetano Faria
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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Chaves Filho AJM, Lima CNC, Vasconcelos SMM, de Lucena DF, Maes M, Macedo D. IDO chronic immune activation and tryptophan metabolic pathway: A potential pathophysiological link between depression and obesity. Prog Neuropsychopharmacol Biol Psychiatry 2018; 80:234-249. [PMID: 28595944 DOI: 10.1016/j.pnpbp.2017.04.035] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Revised: 04/03/2017] [Accepted: 04/10/2017] [Indexed: 12/12/2022]
Abstract
Obesity and depression are among the most pressing health problems in the contemporary world. Obesity and depression share a bidirectional relationship, whereby each condition increases the risk of the other. By inference, shared pathways may underpin the comorbidity between obesity and depression. Activation of cell-mediated immunity (CMI) is a key factor in the pathophysiology of depression. CMI cytokines, including IFN-γ, TNFα and IL-1β, induce the catabolism of tryptophan (TRY) by stimulating indoleamine 2,3-dioxygenase (IDO) resulting in the synthesis of kynurenine (KYN) and other tryptophan catabolites (TRYCATs). In the CNS, TRYCATs have been related to oxidative damage, inflammation, mitochondrial dysfunction, cytotoxicity, excitotoxicity, neurotoxicity and lowered neuroplasticity. The pathophysiology of obesity is also associated with a state of aberrant inflammation that activates aryl hydrocarbon receptor (AHR), a pathway involved in the detection of intracellular or environmental changes as well as with increases in the production of TRYCATs, being KYN an agonists of AHR. Both AHR and TRYCATS are involved in obesity and related metabolic disorders. These changes in the TRYCAT pathway may contribute to the onset of neuropsychiatric symptoms in obesity. This paper reviews the role of immune activation, IDO stimulation and increased TRYCAT production in the pathophysiology of depression and obesity. Here we suggest that increased synthesis of detrimental TRYCATs is implicated in comorbid obesity and depression and is a new drug target to treat both diseases.
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Affiliation(s)
- Adriano José Maia Chaves Filho
- Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil; Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil
| | - Camila Nayane Carvalho Lima
- Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil; Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil
| | - Silvânia Maria Mendes Vasconcelos
- Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil; Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil
| | - David Freitas de Lucena
- Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil; Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil
| | - Michael Maes
- Impact Strategic Research Center, Deakin University, Geelong, Australia; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, Brazil
| | - Danielle Macedo
- Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil; Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil.
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Polyzos KA, Ketelhuth DFJ. The role of the kynurenine pathway of tryptophan metabolism in cardiovascular disease. Hamostaseologie 2017; 35:128-36. [DOI: 10.5482/hamo-14-10-0052] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Accepted: 12/18/2014] [Indexed: 12/14/2022] Open
Abstract
SummaryCoronary heart disease and stroke, the deadliest forms of cardiovascular disease (CVD), are mainly caused by atherosclerosis, a chronic inflammatory disease of the artery wall driven by maladaptive immune responses in the vessel wall. Various risk factors for CVD influence this pathogenic process, including diabetes mellitus, hypertension, dyslipidaemia, and obesity. Indoleamine 2,3-dioxygenase (IDO), an enzyme catalyzing the rate-limiting step in the kynurenine pathway of tryptophan degradation, is strongly induced by inflammation in several tissues, including the artery wall. An increasing body of evidence indicates that IDO promotes immune tolerance, decreases inflammation, and functions as a homeostatic mechanism against excessive immune reactions.This review provides an overview of the emerging field of the kynurenine pathway of tryptophan degradation in CVD, emphasizing the role of IDO-mediated tryptophan metabolism and its metabolites in the modulation of ‘classical’ cardiovascular risk factors, such as hypertension, obesity, lipid metabolism, diabetes mellitus, and in the development of atherosclerotic CVD.
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Asghar K, Farooq A, Zulfiqar B, Rashid MU. Indoleamine 2,3-dioxygenase: As a potential prognostic marker and immunotherapeutic target for hepatocellular carcinoma. World J Gastroenterol 2017; 23:2286-2293. [PMID: 28428708 PMCID: PMC5385395 DOI: 10.3748/wjg.v23.i13.2286] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Revised: 02/23/2017] [Accepted: 03/15/2017] [Indexed: 02/06/2023] Open
Abstract
Tumor cells induce an immunosuppressive microenvironment which leads towards tumor immune escape. Understanding the intricacy of immunomodulation by tumor cells is essential for immunotherapy. Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive enzyme which mediates tumor immune escape in various cancers including hepatocellular carcinoma (HCC). IDO up-regulation in HCC may lead to recruitment of regulatory T-cells into tumor microenvironment and therefore inhibit local immune responses and promote metastasis. HCC associated fibroblasts stimulate natural killer cells dysfunction through prostaglandin E2 and subsequently IDO promotes favorable condition for tumor metastasis. IDO up-regulation induces immunosuppression and may enhance the risk of hepatitis C virus and hepatitis B virus induced HCC. Therefore, IDO inhibitors as adjuvant therapeutic agents may have clinical implications in HCC. This review proposes future prospects of IDO not only as a therapeutic target but also as a prognostic marker for HCC.
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Wang D, Wang X, Zhang P, Wang Y, Zhang R, Yan J, Zhou Z, Zhu W. The fate of technical-grade chlordane in mice fed a high-fat diet and its roles as a candidate obesogen. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2017; 222:532-542. [PMID: 28041837 DOI: 10.1016/j.envpol.2016.11.028] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Revised: 10/14/2016] [Accepted: 11/09/2016] [Indexed: 06/06/2023]
Abstract
Epidemiological studies indicate that exposure to persistent organic pollutants is positively associated with the prevalence of obesity. To delineate the potential role of technical-grade chlordane in obesity development, chlordane metabolism and chlordane-induced metabolic changes were investigated in mice fed high-fat diet (HFD) over a 6-week period. Gas chromatography-electron capture detector analysis showed that HFD induced more accumulation of technical chlordane in the liver, muscle and adipose tissue. The enantioselectivities of oxychlordane in selected tissues were also influenced by HFD. 1H NMR-based liver metabolome indicated that technical chlordane can enhance the metabolic alterations induced by HFD. Compared with the low-fat diet (LFD) group, no differences were observed in the LFD + chlordane group. However, as many as 16 metabolites were significantly different between the HFD group and HFD + chlordane group. Moreover, compared to the LFD + chlordane group, the abundances of 24 metabolites significantly increased or decreased in the HFD + chlordane group. Twenty metabolites were altered in the HFD group compared to the LFD group. Tryptophan profiling suggested that both chlordane and HFD can disturb tryptophan catabolism. These interactions between technical chlordane and HFD suggest that technical chlordane is a candidate obesogen.
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Affiliation(s)
- Dezhen Wang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, Yuanmingyuan West Road 2, Beijing 100193, PR China
| | - Xinru Wang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, Yuanmingyuan West Road 2, Beijing 100193, PR China
| | - Ping Zhang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, Yuanmingyuan West Road 2, Beijing 100193, PR China
| | - Yao Wang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, Yuanmingyuan West Road 2, Beijing 100193, PR China
| | - Renke Zhang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, Yuanmingyuan West Road 2, Beijing 100193, PR China
| | - Jin Yan
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, Yuanmingyuan West Road 2, Beijing 100193, PR China
| | - Zhiqiang Zhou
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, Yuanmingyuan West Road 2, Beijing 100193, PR China
| | - Wentao Zhu
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, Yuanmingyuan West Road 2, Beijing 100193, PR China.
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Yu E, Ruiz-Canela M, Guasch-Ferré M, Zheng Y, Toledo E, Clish CB, Salas-Salvadó J, Liang L, Wang DD, Corella D, Fitó M, Gómez-Gracia E, Lapetra J, Estruch R, Ros E, Cofán M, Arós F, Romaguera D, Serra-Majem L, Sorlí JV, Hu FB, Martinez-Gonzalez MA. Increases in Plasma Tryptophan Are Inversely Associated with Incident Cardiovascular Disease in the Prevención con Dieta Mediterránea (PREDIMED) Study. J Nutr 2017; 147:314-322. [PMID: 28179491 DOI: 10.3945/jn/116.241711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 10/17/2016] [Accepted: 01/09/2017] [Indexed: 01/11/2025] Open
Abstract
Background: During development of cardiovascular disease (CVD), interferon-γ-mediated inflammation accelerates degradation of tryptophan into downstream metabolites. A Mediterranean diet (MedDiet) consisting of a high intake of extra-virgin olive oil (EVOO), nuts, fruits, vegetables, and cereals has been demonstrated to lower the risk of CVD. The longitudinal relation between tryptophan and its downstream metabolites and CVD in the context of a MedDiet is unstudied.Objective: We sought to investigate the relation between metabolites in the tryptophan-kynurenine pathway and CVD in the context of a MedDiet pattern.Methods: We used a case-cohort design nested in the Prevención con Dieta Mediterránea randomized controlled trial. There were 231 CVD cases (stroke, myocardial infarction, cardiovascular death) among 985 participants over a median of 4.7 y of follow-up [mean ± SD age: 67.6 ± 6.1 y; 53.7% women; mean ± SD body mass index (in kg/m2): 29.7 ± 3.7]. We assessed plasma tryptophan, kynurenine, kynurenic acid, 3-hydroxyanthranilic acid, and quinolinic acid concentrations at baseline and after 1 y of intervention with a MedDiet. We combined these metabolites in a kynurenine risk score (KRS) by weighting each metabolite by the adjusted coefficient of its associations with CVD. Cox models were used in the primary analysis.Results: Increases in tryptophan after 1 y were associated with a lower risk of composite CVD (HR per SD: 0.79; 95% CI: 0.63, 0.98). The baseline kynurenic acid concentration was associated with a higher risk of myocardial infarction and coronary artery disease death but not stroke. A higher KRS was more strongly associated with CVD in the control group than in the 2 intervention groups (P-interaction = 0.003). Adjustment for changes in plasma tryptophan attenuated the inverse association between MedDiet+EVOO and CVD.Conclusions: An increase in the plasma tryptophan concentration was significantly associated with a decreased risk of CVD. A MedDiet may counteract the deleterious effects of a high kynurenine risk score.
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Affiliation(s)
| | - Miguel Ruiz-Canela
- Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain
- Navarra Institute for Health Research, Pamplona, Spain
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | - Marta Guasch-Ferré
- Departments of Nutrition
- Navarra Institute for Health Research, Pamplona, Spain
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | | | - Estefania Toledo
- Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain
- Navarra Institute for Health Research, Pamplona, Spain
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | - Clary B Clish
- Broad Institute of MIT and Harvard University, Cambridge, MA
| | - Jordi Salas-Salvadó
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Human Nutrition Unit, Faculty of Medicine and Health Sciences, Institut d'Investigació Sanitària Pere Virgili, Rovira i Virgili University, Reus, Spain
| | | | | | - Dolores Corella
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Department of Preventive Medicine, University of Valencia, Valencia, Spain
| | - Montse Fitó
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Cardiovascular and Nutrition Research Group, Institut de Recerca Hospital del Mar, Barcelona, Spain
| | | | - José Lapetra
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Department of Family Medicine, Unit Research, Distrito Sanitario Atención Primaria Sevilla, Sevilla, Spain
| | - Ramón Estruch
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Department of Internal Medicine Institut d'Investigacions Biomèdiques August Pi Sunyer, Hospital Clinic, and
| | - Emilio Ros
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Lipid Clinic, Department of Endocrinology and Nutrition and University of Barcelona, Barcelona, Spain
| | - Montserrat Cofán
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Lipid Clinic, Department of Endocrinology and Nutrition and University of Barcelona, Barcelona, Spain
| | - Fernando Arós
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Department of Cardiology, University Hospital of Álava, Vitoria, Spain
| | - Dora Romaguera
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Health Research Institute of Palma, University Hospital Son Espases, Palma de Mallorca, Spain
| | - Lluis Serra-Majem
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Research Institute of Biomedical and Health Sciences, University of Las Palmas de Gran Canaria, Las Palmas, Spain; and
| | - Jose V Sorlí
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Cardiovascular and Nutrition Research Group, Institut de Recerca Hospital del Mar, Barcelona, Spain
| | - Frank B Hu
- Departments of Nutrition
- Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
- Channing Division for Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Miguel A Martinez-Gonzalez
- Departments of Nutrition,
- Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain
- Navarra Institute for Health Research, Pamplona, Spain
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
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38
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Yu E, Ruiz-Canela M, Guasch-Ferré M, Zheng Y, Toledo E, Clish CB, Salas-Salvadó J, Liang L, Wang DD, Corella D, Fitó M, Gómez-Gracia E, Lapetra J, Estruch R, Ros E, Cofán M, Arós F, Romaguera D, Serra-Majem L, Sorlí JV, Hu FB, Martinez-Gonzalez MA. Increases in Plasma Tryptophan Are Inversely Associated with Incident Cardiovascular Disease in the Prevención con Dieta Mediterránea (PREDIMED) Study. J Nutr 2017; 147:314-322. [PMID: 28179491 PMCID: PMC5320398 DOI: 10.3945/jn.116.241711] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 10/17/2016] [Accepted: 01/09/2017] [Indexed: 12/16/2022] Open
Abstract
Background: During development of cardiovascular disease (CVD), interferon-γ-mediated inflammation accelerates degradation of tryptophan into downstream metabolites. A Mediterranean diet (MedDiet) consisting of a high intake of extra-virgin olive oil (EVOO), nuts, fruits, vegetables, and cereals has been demonstrated to lower the risk of CVD. The longitudinal relation between tryptophan and its downstream metabolites and CVD in the context of a MedDiet is unstudied.Objective: We sought to investigate the relation between metabolites in the tryptophan-kynurenine pathway and CVD in the context of a MedDiet pattern.Methods: We used a case-cohort design nested in the Prevención con Dieta Mediterránea randomized controlled trial. There were 231 CVD cases (stroke, myocardial infarction, cardiovascular death) among 985 participants over a median of 4.7 y of follow-up [mean ± SD age: 67.6 ± 6.1 y; 53.7% women; mean ± SD body mass index (in kg/m2): 29.7 ± 3.7]. We assessed plasma tryptophan, kynurenine, kynurenic acid, 3-hydroxyanthranilic acid, and quinolinic acid concentrations at baseline and after 1 y of intervention with a MedDiet. We combined these metabolites in a kynurenine risk score (KRS) by weighting each metabolite by the adjusted coefficient of its associations with CVD. Cox models were used in the primary analysis.Results: Increases in tryptophan after 1 y were associated with a lower risk of composite CVD (HR per SD: 0.79; 95% CI: 0.63, 0.98). The baseline kynurenic acid concentration was associated with a higher risk of myocardial infarction and coronary artery disease death but not stroke. A higher KRS was more strongly associated with CVD in the control group than in the 2 intervention groups (P-interaction = 0.003). Adjustment for changes in plasma tryptophan attenuated the inverse association between MedDiet+EVOO and CVD.Conclusions: An increase in the plasma tryptophan concentration was significantly associated with a decreased risk of CVD. A MedDiet may counteract the deleterious effects of a high kynurenine risk score.
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Affiliation(s)
| | - Miguel Ruiz-Canela
- Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain
- Navarra Institute for Health Research, Pamplona, Spain
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | - Marta Guasch-Ferré
- Departments of Nutrition
- Navarra Institute for Health Research, Pamplona, Spain
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | | | - Estefania Toledo
- Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain
- Navarra Institute for Health Research, Pamplona, Spain
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | - Clary B Clish
- Broad Institute of MIT and Harvard University, Cambridge, MA
| | - Jordi Salas-Salvadó
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Human Nutrition Unit, Faculty of Medicine and Health Sciences, Institut d'Investigació Sanitària Pere Virgili, Rovira i Virgili University, Reus, Spain
| | | | | | - Dolores Corella
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Department of Preventive Medicine, University of Valencia, Valencia, Spain
| | - Montse Fitó
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Cardiovascular and Nutrition Research Group, Institut de Recerca Hospital del Mar, Barcelona, Spain
| | | | - José Lapetra
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Department of Family Medicine, Unit Research, Distrito Sanitario Atención Primaria Sevilla, Sevilla, Spain
| | - Ramón Estruch
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Department of Internal Medicine Institut d'Investigacions Biomèdiques August Pi Sunyer, Hospital Clinic, and
| | - Emilio Ros
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Lipid Clinic, Department of Endocrinology and Nutrition and University of Barcelona, Barcelona, Spain
| | - Montserrat Cofán
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Lipid Clinic, Department of Endocrinology and Nutrition and University of Barcelona, Barcelona, Spain
| | - Fernando Arós
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Department of Cardiology, University Hospital of Álava, Vitoria, Spain
| | - Dora Romaguera
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Health Research Institute of Palma, University Hospital Son Espases, Palma de Mallorca, Spain
| | - Lluis Serra-Majem
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Research Institute of Biomedical and Health Sciences, University of Las Palmas de Gran Canaria, Las Palmas, Spain; and
| | - Jose V Sorlí
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Cardiovascular and Nutrition Research Group, Institut de Recerca Hospital del Mar, Barcelona, Spain
| | - Frank B Hu
- Departments of Nutrition
- Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
- Channing Division for Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Miguel A Martinez-Gonzalez
- Departments of Nutrition,
- Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain
- Navarra Institute for Health Research, Pamplona, Spain
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
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Di Giovanni V, Bourdon C, Wang DX, Seshadri S, Senga E, Versloot CJ, Voskuijl W, Semba RD, Trehan I, Moaddel R, Ordiz MI, Zhang L, Parkinson J, Manary MJ, Bandsma RH. Metabolomic Changes in Serum of Children with Different Clinical Diagnoses of Malnutrition. J Nutr 2016; 146:2436-2444. [PMID: 27807038 PMCID: PMC5118769 DOI: 10.3945/jn.116.239145] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 08/28/2016] [Accepted: 10/04/2016] [Indexed: 12/04/2022] Open
Abstract
Background: Mortality in children with severe acute malnutrition (SAM) remains high despite standardized rehabilitation protocols. Two forms of SAM are classically distinguished: kwashiorkor and marasmus. Children with kwashiorkor have nutritional edema and metabolic disturbances, including hypoalbuminemia and hepatic steatosis, whereas marasmus is characterized by severe wasting. The metabolic changes underlying these phenotypes have been poorly characterized, and whether homeostasis is achieved during hospital stay is unclear. Objectives: We aimed to characterize metabolic differences between children with marasmus and kwashiorkor at hospital admission and after clinical stabilization and to compare them with stunted and nonstunted community controls. Methods: We studied children aged 9–59 mo from Malawi who were hospitalized with SAM (n = 40; 21 with kwashiorkor and 19 with marasmus) or living in the community (n = 157; 78 stunted and 79 nonstunted). Serum from patients with SAM was obtained at hospital admission and 3 d after nutritional stabilization and from community controls. With the use of targeted metabolomics, 141 metabolites, including amino acids, biogenic amines, acylcarnitines, sphingomyelins, and phosphatidylcholines, were measured. Results: At admission, most metabolites (128 of 141; 91%) were lower in children with kwashiorkor than in those with marasmus, with significant differences in several amino acids and biogenic amines, including those of the kynurenine-tryptophan pathway. Several phosphatidylcholines and some acylcarnitines also differed. Patients with SAM had profiles that were profoundly different from those of stunted and nonstunted controls, even after clinical stabilization. Amino acids and biogenic amines generally improved with nutritional rehabilitation, but most sphingomyelins and phosphatidylcholines did not. Conclusions: Children with kwashiorkor were metabolically distinct from those with marasmus, and were more prone to severe metabolic disruptions. Children with SAM showed metabolic profiles that were profoundly different from stunted and nonstunted controls, even after clinical stabilization. Therefore, metabolic recovery in children with SAM likely extends beyond discharge, which may explain the poor long-term outcomes in these children. This trial was registered at isrctn.org as ISRCTN13916953.
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Affiliation(s)
| | | | | | | | | | | | - Wieger Voskuijl
- Department of Pediatrics and Child Health, and.,Global Child Health Group, Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, Netherlands
| | - Richard D Semba
- Wilmer Eye Institute, John Hopkins University School of Medicine, Baltimore, MD
| | - Indi Trehan
- Department of Pediatrics and Child Health, and.,National Institute of Aging, NIH, Baltimore, MD
| | | | - M Isabel Ordiz
- Department of Pediatrics, Washington University in St. Louis, St. Louis, MO; and
| | - Ling Zhang
- Department of Physiology and Experimental Medicine
| | - John Parkinson
- Program in Molecular Structure and Function.,Department of Biochemistry and Department of Molecular Genetics, University of Toronto, Toronto, Canada
| | - Mark J Manary
- School of Public Health and Family Medicine, College of Medicine, University of Malawi, Blantyre, Malawi.,Department of Pediatrics, Washington University in St. Louis, St. Louis, MO; and
| | - Robert Hj Bandsma
- Department of Physiology and Experimental Medicine, .,Division of Gastroenterology, Hepatology and Nutrition, and.,Centre for Global Child Health, Hospital for Sick Children, Toronto, Canada.,Department of Biomedical Sciences
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40
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Larkin PB, Sathyasaikumar KV, Notarangelo FM, Funakoshi H, Nakamura T, Schwarcz R, Muchowski PJ. Tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase 1 make separate, tissue-specific contributions to basal and inflammation-induced kynurenine pathway metabolism in mice. BIOCHIMICA ET BIOPHYSICA ACTA 2016; 1860:2345-2354. [PMID: 27392942 PMCID: PMC5808460 DOI: 10.1016/j.bbagen.2016.07.002] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Revised: 06/25/2016] [Accepted: 07/04/2016] [Indexed: 01/06/2023]
Abstract
BACKGROUND In mammals, the majority of the essential amino acid tryptophan is degraded via the kynurenine pathway (KP). Several KP metabolites play distinct physiological roles, often linked to immune system functions, and may also be causally involved in human diseases including neurodegenerative disorders, schizophrenia and cancer. Pharmacological manipulation of the KP has therefore become an active area of drug development. To target the pathway effectively, it is important to understand how specific KP enzymes control levels of the bioactive metabolites in vivo. METHODS Here, we conducted a comprehensive biochemical characterization of mice with a targeted deletion of either tryptophan 2,3-dioxygenase (TDO) or indoleamine 2,3-dioxygenase (IDO), the two initial rate-limiting enzymes of the KP. These enzymes catalyze the same reaction, but differ in biochemical characteristics and expression patterns. We measured KP metabolite levels and enzyme activities and expression in several tissues in basal and immune-stimulated conditions. RESULTS AND CONCLUSIONS Although our study revealed several unexpected downstream effects on KP metabolism in both knockout mice, the results were essentially consistent with TDO-mediated control of basal KP metabolism and a role of IDO in phenomena involving stimulation of the immune system.
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Affiliation(s)
- Paul B Larkin
- Gladstone Institute of Neurological Disease, San Francisco, CA, USA; Neuroscience Graduate Program, University of California, San Francisco, CA, USA
| | - Korrapati V Sathyasaikumar
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Francesca M Notarangelo
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Hiroshi Funakoshi
- Center for Advanced Research and Education (CARE), Asahikawa Medical University, 1-1-1- Higashinijo Midorigaoka, Asahikawa 078-8510, Japan
| | | | - Robert Schwarcz
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Paul J Muchowski
- Gladstone Institute of Neurological Disease, San Francisco, CA, USA; Neuroscience Graduate Program, University of California, San Francisco, CA, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, CA, USA; The Taube-Koret Center for Huntington's Disease Research, San Francisco, CA, USA.
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Inhibition of the aryl hydrocarbon receptor prevents Western diet-induced obesity. Model for AHR activation by kynurenine via oxidized-LDL, TLR2/4, TGFβ, and IDO1. Toxicol Appl Pharmacol 2016; 300:13-24. [PMID: 27020609 DOI: 10.1016/j.taap.2016.03.011] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Revised: 03/11/2016] [Accepted: 03/21/2016] [Indexed: 12/25/2022]
Abstract
Obesity is an increasingly urgent global problem, yet, little is known about its causes and less is known how obesity can be effectively treated. We showed previously that the aryl hydrocarbon receptor (AHR) plays a role in the regulation of body mass in mice fed Western diet. The AHR is a ligand-activated nuclear receptor that regulates genes involved in a number of biological pathways, including xenobiotic metabolism and T cell polarization. This study was an investigation into whether inhibition of the AHR prevents Western diet-based obesity. Male C57Bl/6J mice were fed control and Western diets with and without the AHR antagonist α-naphthoflavone or CH-223191, and a mouse hepatocyte cell line was used to delineate relevant cellular pathways. Studies are presented showing that the AHR antagonists α-naphthoflavone and CH-223191 significantly reduce obesity and adiposity and ameliorates liver steatosis in male C57Bl/6J mice fed a Western diet. Mice deficient in the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) were also resistant to obesity. Using an AHR-directed, luciferase-expressing mouse hepatocyte cell line, we show that the transforming growth factor β1 (TGFβ1) signaling pathway via PI3K and NF-κB and the toll-like receptor 2/4 (TLR2/4) signaling pathway stimulated by oxidized low-density lipoproteins via NF-κB, each induce luciferase expression; however, TLR2/4 signaling was significantly reduced by inhibition of IDO1. At physiological levels, kynurenine but not kynurenic acid (both tryptophan metabolites and known AHR agonists) activated AHR-directed luciferase expression. We propose a hepatocyte-based model, in which kynurenine production is increased by enhanced IDO1 activity stimulated by TGFβ1 and TLR2/4 signaling, via PI3K and NF-κB, to perpetuate a cycle of AHR activation to cause obesity; and inhibition of the AHR, in turn, blocks the cycle's output to prevent obesity. The AHR with its broad ligand binding specificity is a promising candidate for a potentially simple therapeutic approach for the prevention and treatment of obesity and associated complications.
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42
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Ohno T, Shimizu M, Shirakami Y, Miyazaki T, Ideta T, Kochi T, Kubota M, Sakai H, Tanaka T, Moriwaki H. Preventive effects of astaxanthin on diethylnitrosamine-induced liver tumorigenesis in C57/BL/KsJ-db/db obese mice. Hepatol Res 2016; 46:E201-9. [PMID: 26147624 DOI: 10.1111/hepr.12550] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Revised: 06/11/2015] [Accepted: 06/30/2015] [Indexed: 12/17/2022]
Abstract
AIM Obesity and its related metabolic abnormalities, including oxidative stress and adipokine imbalance, are involved in liver carcinogenesis. The aim of the present study was to examine the effects of astaxanthin, a powerful biological antioxidant, on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in C57BL/KsJ-db/db (db/db) obese mice. METHODS Male db/db mice were given a single i.p. injection of DEN (25 mg/kg bodyweight) at 2 weeks of age, and, subsequently, from 4 weeks of age, they were fed a diet containing 200 p.p.m. astaxanthin throughout the experiment. RESULTS Twenty weeks of astaxanthin administration significantly inhibited the development of hepatocellular neoplasms (liver cell adenoma and hepatocellular carcinoma) and the hepatic expression of cyclin D1 mRNA compared with the basal diet group in DEN-treated db/db mice. Astaxanthin administration in DEN-treated experimental mice markedly reduced the derivatives of reactive oxygen metabolites/biological antioxidant potential ratio, which is a serum marker of oxidative stress, while increasing the mRNA expression of the antioxidant enzymes superoxide dismutase 2 and glutathione peroxidase 1 in the liver and white adipose tissue. The serum levels of adiponectin increased after astaxanthin administration in these mice. CONCLUSION Dietary astaxanthin prevented the development of liver tumorigenesis in obese mice by improving oxidative stress and ameliorating serum adiponectin level. Therefore, astaxanthin may be useful in the chemoprevention of liver tumorigenesis in obese individuals.
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Affiliation(s)
- Tomohiko Ohno
- Departments of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Masahito Shimizu
- Departments of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Yohei Shirakami
- Departments of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Tsuneyuki Miyazaki
- Departments of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Takayasu Ideta
- Departments of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Takahiro Kochi
- Departments of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Masaya Kubota
- Departments of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Hiroyasu Sakai
- Departments of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Takuji Tanaka
- Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Hisataka Moriwaki
- Departments of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
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Shibata Y, Hara T, Nagano J, Nakamura N, Ohno T, Ninomiya S, Ito H, Tanaka T, Saito K, Seishima M, Shimizu M, Moriwaki H, Tsurumi H. The Role of Indoleamine 2,3-Dioxygenase in Diethylnitrosamine-Induced Liver Carcinogenesis. PLoS One 2016; 11:e0146279. [PMID: 26727596 PMCID: PMC4699706 DOI: 10.1371/journal.pone.0146279] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Accepted: 12/15/2015] [Indexed: 12/16/2022] Open
Abstract
Indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing intracellular enzyme of the L-kynurenine pathway, causes preneoplastic cells and tumor cells to escape the immune system by inducing immune tolerance; this mechanism might be associated with the development and progression of human malignancies. In the present study, we investigated the role of IDO in diethylnitrosamine (DEN)-induced hepatocarcinogenesis by using IDO-knockout (KO) mice. To induce hepatocellular carcinoma (HCC), hepatic adenoma, and preneoplastic hepatocellular lesions termed foci of cellular alteration (FCA), male IDO-wild-type (WT) and IDO-KO mice with a C57BL/6J background received a single intraperitoneal injection of DEN at 2 weeks of age. The mice were sacrificed to evaluate the development of FCA and hepatocellular neoplasms. HCC overexpressed IDO and L-kynurenine compared to surrounding normal tissue in the DEN-treated IDO-WT mice. The number and cell proliferative activity of FCAs, and the incidence and multiplicity of HCC were significantly greater in the IDO-WT than in the IDO-KO mice. The expression levels of the IDO protein, of L-kynurenine, and of IFN-γ, COX-2, TNF-α, and Foxp3 mRNA were also significantly increased in the DEN-induced hepatic tumors that developed in the IDO-WT mice. The mRNA expression levels of CD8, perforin and granzyme B were markedly increased in hepatic tumors developed in IDO-KO mice. Moreover, Foxp3-positive inflammatory cells had infiltrated into the livers of DEN-treated IDO-WT mice, whereas fewer cells had infiltrated into the livers of IDO-KO mice. Induction of IDO and elevation of L-kynurenine might play a critical role in both the early and late phase of liver carcinogenesis. Our findings suggest that inhibition of IDO might offer a promising strategy for the prevention of liver cancer.
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MESH Headings
- Adenoma/chemically induced
- Adenoma/enzymology
- Adenoma/immunology
- Animals
- CD8 Antigens/biosynthesis
- CD8 Antigens/genetics
- Cyclooxygenase 2/biosynthesis
- Cyclooxygenase 2/genetics
- Diethylnitrosamine
- Disease Progression
- Forkhead Transcription Factors/biosynthesis
- Forkhead Transcription Factors/genetics
- Gene Expression Regulation, Neoplastic
- Granzymes/biosynthesis
- Granzymes/genetics
- Immune Tolerance
- Indoleamine-Pyrrole 2,3,-Dioxygenase/deficiency
- Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics
- Indoleamine-Pyrrole 2,3,-Dioxygenase/physiology
- Interferon-gamma/biosynthesis
- Interferon-gamma/genetics
- Kynurenine/biosynthesis
- Kynurenine/physiology
- Liver Neoplasms, Experimental/chemically induced
- Liver Neoplasms, Experimental/enzymology
- Liver Neoplasms, Experimental/immunology
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Neoplasm Proteins/genetics
- Neoplasm Proteins/physiology
- Pore Forming Cytotoxic Proteins/biosynthesis
- Pore Forming Cytotoxic Proteins/genetics
- Precancerous Conditions/chemically induced
- Precancerous Conditions/enzymology
- T-Lymphocytes, Cytotoxic/immunology
- T-Lymphocytes, Regulatory/immunology
- Tumor Necrosis Factor-alpha/biosynthesis
- Tumor Necrosis Factor-alpha/genetics
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Affiliation(s)
- Yuhei Shibata
- First Departments of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Takeshi Hara
- First Departments of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Junji Nagano
- First Departments of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Nobuhiko Nakamura
- First Departments of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Tomohiko Ohno
- First Departments of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Soranobu Ninomiya
- First Departments of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Hiroyasu Ito
- Departments of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Takuji Tanaka
- Departments of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Kuniaki Saito
- Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, Japan
| | - Mitsuru Seishima
- Departments of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Masahito Shimizu
- First Departments of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Hisataka Moriwaki
- First Departments of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Hisashi Tsurumi
- First Departments of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
- * E-mail:
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Zhai L, Spranger S, Binder DC, Gritsina G, Lauing KL, Giles FJ, Wainwright DA. Molecular Pathways: Targeting IDO1 and Other Tryptophan Dioxygenases for Cancer Immunotherapy. Clin Cancer Res 2015; 21:5427-33. [PMID: 26519060 PMCID: PMC4681601 DOI: 10.1158/1078-0432.ccr-15-0420] [Citation(s) in RCA: 247] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Accepted: 10/15/2015] [Indexed: 01/12/2023]
Abstract
Indoleamine 2, 3-dioxygenase 1 (IDO1), IDO2, and tryptophan 2, 3-dioxygenase (TDO) comprise a family of enzymes that catalyze the first- and rate-limiting step associated with the catabolic conversion of tryptophan (Trp) into kynurenine (Kyn). Through subsequent enzymatic and spontaneous reactions, Kyn is further converted into the energetic substrates, NAD(+) and ATP, to fuel cellular metabolic functions. Coincidently, the depletion of Trp and accumulation of Kyn has been demonstrated to induce effector T-cell apoptosis/dysfunction and immunosuppressive regulatory T-cell induction, respectively. Similar to other immune checkpoints, IDO1 and TDO are suggested to be important targets for immunotherapeutic intervention. This is represented by the recent growth of efforts to inhibit the Trp-to-Kyn pathway as a means to control immunosuppression. Inhibitors currently in clinical trials, INCB024360, GDC-0919, indoximod, and an IDO1 peptide-based vaccine, are being evaluated for their efficacy against a wide range of cancers including melanoma, glioblastoma, non-small cell lung, pancreatic, and/or breast cancer, as well as metastatic disease. Despite the rapid development of potent clinical grade inhibitors, strategic questions remain. Here, we review the state of the literature with respect to current therapeutic inhibitors of tryptophan catabolism, evaluation of those efforts preclinically and clinically, compensatory changes that occur with therapeutic targeting, as well as newly recognized signaling features that raise critical questions to the field. Given the rapidly evolving interest in determining how IDO1/TDO, and to an unknown extent, IDO2, can be targeted for increasing cancer immunotherapeutic efficacy, we present a brief but comprehensive analysis that addresses critical questions, while highlighting the mechanics that remain to be explored.
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Affiliation(s)
- Lijie Zhai
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Stefani Spranger
- Department of Pathology, The University of Chicago, Chicago, Illinois
| | - David C Binder
- Department of Pathology, The University of Chicago, Chicago, Illinois. Committee on Cancer Biology, The University of Chicago, Chicago, Illinois
| | - Galina Gritsina
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Kristen L Lauing
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Francis J Giles
- Northwestern Medicine Developmental Therapeutics Institute, Northwestern University, Chicago, Illinois. Division of Hematology and Oncology, Northwestern University, Chicago, Illinois. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois
| | - Derek A Wainwright
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Northwestern Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
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Increased Sensitivity to Binge Alcohol-Induced Gut Leakiness and Inflammatory Liver Disease in HIV Transgenic Rats. PLoS One 2015; 10:e0140498. [PMID: 26484872 PMCID: PMC4618849 DOI: 10.1371/journal.pone.0140498] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Accepted: 09/25/2015] [Indexed: 12/16/2022] Open
Abstract
The mechanisms of alcohol-mediated advanced liver injury in HIV-infected individuals are poorly understood. Thus, this study was aimed to investigate the effect of binge alcohol on the inflammatory liver disease in HIV transgenic rats as a model for simulating human conditions. Female wild-type (WT) or HIV transgenic rats were treated with three consecutive doses of binge ethanol (EtOH) (3.5 g/kg/dose oral gavages at 12-h intervals) or dextrose (Control). Blood and liver tissues were collected at 1 or 6-h following the last dose of ethanol or dextrose for the measurements of serum endotoxin and liver pathology, respectively. Compared to the WT, the HIV rats showed increased sensitivity to alcohol-mediated gut leakiness, hepatic steatosis and inflammation, as evidenced with the significantly elevated levels of serum endotoxin, hepatic triglycerides, histological fat accumulation and F4/80 staining. Real-time PCR analysis revealed that hepatic levels of toll-like receptor-4 (TLR4), leptin and the downstream target monocyte chemoattractant protein-1 (MCP-1) were significantly up-regulated in the HIV-EtOH rats, compared to all other groups. Subsequent experiments with primary cultured cells showed that both hepatocytes and hepatic Kupffer cells were the sources of the elevated MCP-1 in HIV-EtOH rats. Further, TLR4 and MCP-1 were found to be upregulated by leptin. Collectively, these results show that HIV rats, similar to HIV-infected people being treated with the highly active anti-retroviral therapy (HAART), are more susceptible to binge alcohol-induced gut leakiness and inflammatory liver disease than the corresponding WT, possibly due to additive or synergistic interaction between binge alcohol exposure and HIV infection. Based on these results, HIV transgenic rats can be used as a surrogate model to study the molecular mechanisms of many disease states caused by heavy alcohol intake in HIV-infected people on HAART.
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Lai YS, Chen WC, Kuo TC, Ho CT, Kuo CH, Tseng YJ, Lu KH, Lin SH, Panyod S, Sheen LY. Mass-Spectrometry-Based Serum Metabolomics of a C57BL/6J Mouse Model of High-Fat-Diet-Induced Non-alcoholic Fatty Liver Disease Development. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2015; 63:7873-7884. [PMID: 26262841 DOI: 10.1021/acs.jafc.5b02830] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Obesity, dyslipidemia, insulin resistance, oxidative stress, and inflammation are key clinical risk factors for the progression of non-alcoholic fatty liver disease (NAFLD). Currently, there is no comprehensive metabolic profile of a well-established animal model that effectively mimics the etiology and pathogenesis of NAFLD in humans. Here, we report the pathophysiological and metabolomic changes associated with NAFLD development in a C57BL/6J mouse model in which NAFLD was induced by feeding a high-fat diet (HFD) for 4, 8, 12, and 16 weeks. Serum metabolomic analysis was conducted using ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) and gas chromatography-mass spectrometry (GC-MS) to establish a metabolomic profile. Analysis of the metabolomic profile in combination with principal component analysis revealed marked differences in metabolites between the control and HFD group depending upon NAFLD severity. A total of 30 potential biomarkers were strongly associated with the development of NAFLD. Among these, 11 metabolites were mainly related to carbohydrate metabolism, hepatic biotransformation, collagen synthesis, and gut microbial metabolism, which are characteristics of obesity, as well as significantly increased serum glucose, total cholesterol, and hepatic triglyceride levels during the onset of NAFLD (4 weeks). At 8 weeks, 5 additional metabolites that are chiefly involved in perturbation of lipid metabolism and insulin secretion were found to be associated with hyperinsulinemia, hyperlipidemia, and hepatic steatosis in the mid-term of NAFLD progression. At the end of 12 and 16 weeks, 14 additional metabolites were predominantly correlated to abnormal bile acid synthesis, oxidative stress, and inflammation, representing hepatic inflammatory infiltration during NAFLD development. These results provide potential biomarkers for early risk assessment of NAFLD and further insights into NAFLD development.
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Affiliation(s)
| | | | | | - Chi-Tang Ho
- Department of Food Science, Rutgers University , New Brunswick, New Jersey 08901, United States
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Maeta A, Sano M, Fukuwatari T, Shibata K. Simultaneous measurement of nicotinamide and its catabolites, nicotinamide N-oxide, N1-methyl-2-pyridone-5-carboxamide, and N1-methyl-4-pyridone-3-carboxamide, in mice urine. Biosci Biotechnol Biochem 2014; 78:1306-9. [DOI: 10.1080/09168451.2014.918495] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Abstract
Nicotinamide N-oxide is a major nicotinamide catabolite in mice but not in humans and rats. A high-performance liquid chromatographic method for the simultaneous measurement of nicotinamide, nicotinamide N-oxide, N1-methyl-2-pyridone-5-carboxamide, and N1-methyl-4-pyridone-3-carboxamide in mice urine was developed by modifying the mobile phase of a reported method for measurement of nicotinamide N-oxide.
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Affiliation(s)
- Akihiro Maeta
- Department of Nutrition, School of Human Cultures, The University of Shiga Prefecture, Hikone, Japan
| | - Mitsue Sano
- Department of Nutrition, School of Human Cultures, The University of Shiga Prefecture, Hikone, Japan
| | - Tsutomu Fukuwatari
- Department of Nutrition, School of Human Cultures, The University of Shiga Prefecture, Hikone, Japan
| | - Katsumi Shibata
- Department of Nutrition, School of Human Cultures, The University of Shiga Prefecture, Hikone, Japan
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Effect of tryptophan supplementation on diet-induced non-alcoholic fatty liver disease in mice. Br J Nutr 2014; 112:1-7. [PMID: 24708895 DOI: 10.1017/s0007114514000440] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Intestinal serotonin (5-hydroxytrypamine, 5-HT) metabolism is thought to play a role in gut functions by regulating motility, permeability and other functions of the intestine. In the present study, we investigated the effect of tryptophan (TRP), the precursor of 5-HT, supplementation on intestinal barrier functions and non-alcoholic fatty liver disease (NAFLD). An established mouse model of NAFLD induced by feeding a fructose-rich diet (N group) was used in the present study. TRP was administered orally for 8 weeks to C57BL/6J control or NAFLD mice. NAFLD-related liver parameters (hepatic TAG and Oil Red O staining), intestinal barrier parameters (tight-junction protein occludin and portal plasma lipopolysaccharides (LPS)) and 5-HT-related parameters (5-HT, 5-HT transporter (SERT) and motility) were measured. We observed reduced duodenal occludin protein concentrations (P= 0·0007), high portal plasma LPS concentrations (P= 0·005) and an elevated liver weight:body weight ratio (P= 0·01) in the N group compared with the parameters in the control group. TRP supplementation led to an increase in occludin concentrations (P= 0·0009) and consecutively reduced liver weight:body weight ratio (P= 0·009) as well as overall hepatic fat accumulation in the N group (P= 0·05). In addition, the N group exhibited reduced SERT protein expression (P= 0·002), which was normalised by TRP supplementation (P= 0·02). For the first time, our data indicate that oral TRP supplementation attenuates experimental NAFLD in mice. The underlying mechanisms are not clear, but probably involve stabilisation of the intestinal barrier in the upper small intestine and amelioration of the dysregulated intestinal serotonergic system.
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Lee S, Yang G, Mulligan W, Gipp J, Bushman W. Ventral prostate fibrosis in the Akita mouse is associated with macrophage and fibrocyte infiltration. J Diabetes Res 2014; 2014:939053. [PMID: 25019092 PMCID: PMC4074948 DOI: 10.1155/2014/939053] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Accepted: 04/23/2014] [Indexed: 02/06/2023] Open
Abstract
A higher incidence of lower urinary tract symptoms (LUTS) among diabetic men is unexplained. Recently, prostate inflammation and fibrosis have been implicated as major contributing factors to bladder outlet obstruction and LUTS. We characterized the inflammatory cell infiltrate and collagen content of the anterior, dorsal, and ventral lobes of 18-week-old DBA2J.Ins2-Akita mice (Akita) and age-matched control mice. We performed hematoxylin and eosin staining to score tissue injury and inflammation, picrosirius red staining to quantitate collagen content, and immunostaining to identify monocytes/macrophages and infiltrating fibrocytes. We observed significantly greater numbers of monocytes/macrophages and fibrocytes specifically in the ventral prostate of the Akita mice and found that this was associated with significant greater collagen content specifically in the ventral prostate of the Akita mice. These observations support the inference that diabetes elicits monocyte/macrophage infiltration and collagen accumulation in the prostate and suggest that further study of Akita mice may inform translational studies of diabetes in the genesis prostatic inflammation, prostatic fibrosis, and LUTS.
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Affiliation(s)
- Sanghee Lee
- Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53717, USA
- Cellular and Molecular Biology Program, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI 53706, USA
| | - Guang Yang
- Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53717, USA
| | - William Mulligan
- Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53717, USA
| | - Jerry Gipp
- Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53717, USA
| | - Wade Bushman
- Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53717, USA
- Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53717, USA
- *Wade Bushman:
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