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Chen N, Xu X, Guo Y, Zhao M, Li Y, Zhou T, Zhang X, Gao J, Zhu F, Guo C, Shi Y, Wang Q, Wu W, Zhang L, Li Y. Brain Short-Chain Fatty Acids Induce ACSS2 to Ameliorate Depressive-Like Behavior via PPARγ-TPH2 Axis. RESEARCH (WASHINGTON, D.C.) 2024; 7:0400. [PMID: 38939042 PMCID: PMC11210491 DOI: 10.34133/research.0400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 05/10/2024] [Indexed: 06/29/2024]
Abstract
Short-chain fatty acids (SCFAs) have been increasingly evidenced to be important bioactive metabolites of the gut microbiota and transducers in controlling diverse psychiatric or neurological disorders via the microbiota-gut-brain axis. However, the precise mechanism by which brain SCFAs extert multiple beneficial effects is not completely understood. Our previous research has demonstrated that the acetyl-coenzyme A synthetase short-chain family member 2 (ACSS2) is a novel target of the rapid and long-lasting antidepressant responses. Here, we show that micromolar SCFAs significantly augment both total cellular and nuclear ACSS2 to trigger tryptophan hydroxylase 2 (TPH2) promoter histone acetylation and its transcription in SH-SY5Y cells. In chronic-restraint-stress-induced depression mice, neuronal ACSS2 knockdown by stereotaxic injection of adeno-associated virus in the hippocampus abolished SCFA-mediated improvements in depressive-like behaviors of mice, supporting that ACSS2 is required for SCFA-mediated antidepressant responses. Mechanistically, the peroxisome-proliferator-activated receptor gamma (PPARγ) is identified as a novel partner of ACSS2 to activate TPH2 transcription. Importantly, PPARγ is also responsible for SCFA-mediated antidepressant-like effects via ACSS2-TPH2 axis. To further support brain SCFAs as a therapeutic target for antidepressant effects, d-mannose, which is a naturally present hexose, can significantly reverse the dysbiosis of gut microbiota in the chronic-restraint-stress-exposure mice and augment brain SCFAs to protect against the depressive-like behaviors via ACSS2-PPARγ-TPH2 axis. In summary, brain SCFAs can activate ACSS2-PPARγ-TPH2 axis to play the antidepressive-like effects, and d-mannose is suggested to be an inducer of brain SCFAs in resisting depression.
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Affiliation(s)
- Nuo Chen
- Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine,
Shandong University, Jinan, China
| | - Xinyi Xu
- Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine,
Shandong University, Jinan, China
| | - Yaxin Guo
- Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine,
Shandong University, Jinan, China
| | - Ming Zhao
- Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine,
Shandong University, Jinan, China
| | - Yubin Li
- Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine,
Shandong University, Jinan, China
| | - Tian Zhou
- Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine,
Shandong University, Jinan, China
| | - Xinyue Zhang
- Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine,
Shandong University, Jinan, China
| | - Jie Gao
- Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine,
Shandong University, Jinan, China
| | - Faliang Zhu
- Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine,
Shandong University, Jinan, China
| | - Chun Guo
- Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine,
Shandong University, Jinan, China
| | - Yongyu Shi
- Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine,
Shandong University, Jinan, China
| | - Qun Wang
- Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine,
Shandong University, Jinan, China
| | - Wenxian Wu
- Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine,
Shandong University, Jinan, China
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Department of Neurology,
Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Lining Zhang
- Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine,
Shandong University, Jinan, China
| | - Yan Li
- Department of Pathogen Biology, School of Basic Medical Science, Cheeloo College of Medicine,
Shandong University, Jinan, China
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Moțățăianu A, Șerban G, Andone S. The Role of Short-Chain Fatty Acids in Microbiota-Gut-Brain Cross-Talk with a Focus on Amyotrophic Lateral Sclerosis: A Systematic Review. Int J Mol Sci 2023; 24:15094. [PMID: 37894774 PMCID: PMC10606032 DOI: 10.3390/ijms242015094] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Revised: 09/27/2023] [Accepted: 10/06/2023] [Indexed: 10/29/2023] Open
Abstract
Amyotrophic lateral sclerosis is a devastating neurodegenerative disease characterized by the gradual loss of motor neurons in the brain and spinal cord, leading to progressive motor function decline. Unfortunately, there is no effective treatment, and its increasing prevalence is linked to an aging population, improved diagnostics, heightened awareness, and changing lifestyles. In the gastrointestinal system, the gut microbiota plays a vital role in producing metabolites, neurotransmitters, and immune molecules. Short-chain fatty acids, of interest for their potential health benefits, are influenced by a fiber- and plant-based diet, promoting a diverse and balanced gut microbiome. These fatty acids impact the body by binding to receptors on enteroendocrine cells, influencing hormones like glucagon-like peptide-1 and peptide YY, which regulate appetite and insulin sensitivity. Furthermore, these fatty acids impact the blood-brain barrier, neurotransmitter levels, and neurotrophic factors, and directly stimulate vagal afferent nerves, affecting gut-brain communication. The vagus nerve is a crucial link between the gut and the brain, transmitting signals related to appetite, inflammation, and various processes. Dysregulation of this pathway can contribute to conditions like obesity and irritable bowel syndrome. Emerging evidence suggests the complex interplay among these fatty acids, the gut microbiota, and environmental factors influences neurodegenerative processes via interconnected pathways, including immune function, anti-inflammation, gut barrier, and energy metabolism. Embracing a balanced, fiber-rich diet may foster a diverse gut microbiome, potentially impacting neurodegenerative disease risk. Comprehensive understanding requires further research into interventions targeting the gut microbiome and fatty acid production and their potential therapeutic role in neurodegeneration.
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Affiliation(s)
- Anca Moțățăianu
- 1st Neurology Clinic, Mures County Clinical Emergency Hospital, 540136 Târgu Mures, Romania
- Department of Neurology, University of Medicine, Pharmacy, Science and Technology of Târgu Mures ‘George Emil Palade’, 540142 Târgu Mures, Romania
| | - Georgiana Șerban
- Doctoral School, University of Medicine, Pharmacy, Science and Technology of Târgu Mures ‘George Emil Palade’, 540142 Târgu Mures, Romania
| | - Sebastian Andone
- 1st Neurology Clinic, Mures County Clinical Emergency Hospital, 540136 Târgu Mures, Romania
- Department of Neurology, University of Medicine, Pharmacy, Science and Technology of Târgu Mures ‘George Emil Palade’, 540142 Târgu Mures, Romania
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3
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Nguyen HH, Swain MG. Avenues within the gut-liver-brain axis linking chronic liver disease and symptoms. Front Neurosci 2023; 17:1171253. [PMID: 37521690 PMCID: PMC10372440 DOI: 10.3389/fnins.2023.1171253] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 06/09/2023] [Indexed: 08/01/2023] Open
Abstract
Symptoms of fatigue, social withdrawal and mood disturbances are commonly encountered in patients with chronic liver disease and have a detrimental effect on patient quality of life. Treatment options for these symptoms are limited and a current area of unmet medical need. In this review, we will evaluate the potential mechanistic avenues within the gut-liver-brain axis that may be altered in the setting of chronic liver disease that drive the development of these symptoms. Both clinical and pre-clinical studies will be highlighted as we discuss how perturbations in host immune response, microbiome, neural responses, and metabolites composition can affect the central nervous system.
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Affiliation(s)
- Henry H. Nguyen
- University of Calgary Liver Unit, Departments of Medicine and Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Mark G. Swain
- University of Calgary Liver Unit, Department of Medicine, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
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Bastings JJAJ, Venema K, Blaak EE, Adam TC. Influence of the gut microbiota on satiety signaling. Trends Endocrinol Metab 2023; 34:243-255. [PMID: 36870872 DOI: 10.1016/j.tem.2023.02.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 02/09/2023] [Accepted: 02/09/2023] [Indexed: 03/06/2023]
Abstract
Recent studies show a link between the gut microbiota and the regulation of satiety and energy intake, processes that contribute to the development and pathophysiology of metabolic diseases. However, this link is predominantly established in animal and in vitro studies, whereas human intervention studies are scarce. In this review we focus on recent evidence linking satiety and the gut microbiome, with specific emphasis on gut microbial short-chain fatty acids (SCFAs). Based on a systematic search we provide an overview of human studies linking the intake of prebiotics with gut microbial alterations and satiety signaling. Our outcomes highlight the importance of in-depth examination of the gut microbiota in relation to satiety and provide insights into recent and future studies in this field.
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Affiliation(s)
- Jacco J A J Bastings
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Koen Venema
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands; Centre for Healthy Eating and Food Innovation, Maastricht University, Campus Venlo, Venlo, The Netherlands
| | - Ellen E Blaak
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands.
| | - Tanja C Adam
- Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, Maastricht, The Netherlands
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Menees KB, Otero BA, Tansey MG. Microbiome influences on neuro-immune interactions in neurodegenerative disease. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2022; 167:25-57. [PMID: 36427957 DOI: 10.1016/bs.irn.2022.07.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Mounting evidence points to a role for the gut microbiome in a wide range of central nervous system diseases and disorders including depression, multiple sclerosis, Alzheimer's disease, Parkinson's disease, and autism spectrum disorder. Moreover, immune system involvement has also been implicated in these diseases, specifically with inflammation being central to their pathogenesis. In addition to the reported changes in gut microbiome composition and altered immune states in many neurological diseases, how the microbiome and the immune system interact to influence disease onset and progression has recently garnered much attention. This chapter provides a review of the literature related to gut microbiome influences on neuro-immune interactions with a particular focus on neurological diseases. Gut microbiome-derived mediators, including short-chain fatty acids and other metabolites, lipopolysaccharide, and neurotransmitters, and their impact on neuro-immune interactions as well as routes by which these interactions may occur are also discussed.
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Affiliation(s)
- Kelly B Menees
- Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Brittney A Otero
- Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Malú Gámez Tansey
- Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, United States; Norman Fixel Institute for Neurological Diseases, University of Florida Health, Gainesville, FL, United States.
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6
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Modulation of Adipocyte Metabolism by Microbial Short-Chain Fatty Acids. Nutrients 2021; 13:nu13103666. [PMID: 34684670 PMCID: PMC8538331 DOI: 10.3390/nu13103666] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 10/17/2021] [Accepted: 10/17/2021] [Indexed: 12/13/2022] Open
Abstract
Obesity and its complications—including type 2 diabetes, cardiovascular disease, and certain cancers—constitute a rising global epidemic that has imposed a substantial burden on health and healthcare systems over the years. It is becoming increasingly clear that there is a link between obesity and the gut microbiota. Gut dysbiosis, characterized as microbial imbalance, has been consistently associated with obesity in both humans and animal models, and can be reversed with weight loss. Emerging evidence has shown that microbial-derived metabolites such as short-chain fatty acids (SCFAs)—including acetate, propionate, and butyrate—provide benefits to the host by impacting organs beyond the gut, including adipose tissue. In this review, we summarize what is currently known regarding the specific mechanisms that link gut-microbial-derived SCFAs with adipose tissue metabolism, such as adipogenesis, lipolysis, and inflammation. In addition, we explore indirect mechanisms by which SCFAs can modulate adipose tissue metabolism, such as via perturbation of gut hormones, as well as signaling to the brain and the liver. Understanding how the modulation of gut microbial metabolites such as SCFAs can impact adipose tissue function could lead to novel therapeutic strategies for the prevention and treatment of obesity.
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7
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Yu Y, Zhao F. Microbiota-gut-brain axis in autism spectrum disorder. J Genet Genomics 2021; 48:755-762. [PMID: 34373221 DOI: 10.1016/j.jgg.2021.07.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/27/2021] [Accepted: 07/05/2021] [Indexed: 12/17/2022]
Abstract
Extensive studies, largely during the past decade, identify the dynamic and bidirectional interaction between the bacteria resident in the intestines and their host brain along the "microbiota-gut-brain axis". This interaction modulates the development and function of the central nervous system and is implicated in neurological disorders. As a neurodevelopmental disorder, autism spectrum disorder (ASD) is considered a historically defect in the brain. With accumulating evidence showing how the microorganisms modulate neural activities, more and more research is focusing on the role of the gut microbiota in mitigating ASD symptoms and the underlying mechanisms. In this review, we describe the intricate and crucial pathways via which the gut microbiota communicates with the brain, the microbiota-gut-brain axis, and summarize the specific pathways that mediate the crosstalk of the gut microbiota to the brain in ASD.
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Affiliation(s)
- You Yu
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China
| | - Fangqing Zhao
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
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8
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Gündoğan C, Ergül N, Çakır MS, Kılıçkesmez Ö, Gürsu RU, Aksoy T, Çermik TF. 68Ga-PSMA PET/CT Versus 18F-FDG PET/CT for Imaging of Hepatocellular Carcinoma. Mol Imaging Radionucl Ther 2021; 30:79-85. [PMID: 34082503 PMCID: PMC8185475 DOI: 10.4274/mirt.galenos.2021.92053] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Objectives: This study aimed to compare the metabolic parameters obtained from 18fluorine-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) and gallium-68 (68Ga)-prostate-specific membrane antigen (PSMA) PET/CT and investigate the relationship between serum alpha-fetoprotein and PET scan parameters in patients with hepatocellular carcinoma. Methods: Fourteen patients were recruited after dynamic magnetic resonance imaging (MRI) of the upper abdomen, and 18F-FDG and 68Ga-PSMA PET/CT imaging studies were conducted. Regions of interest (ROIs) were drawn from lesion-free liver tissue, abdominal aorta (A), and right medial gluteal muscle (G) for the background activity. Maximum standard uptake value (SUVmax) of these regions were compared with the SUVmax of primary tumor (T). Results: On visual assessment, five patients (36%) experienced low 18F-FDG uptake in the primary lesion, three patients (21%) experienced moderate uptake, and six patients (43%) experienced high uptake. However, only one patient (7%) showed low 68Ga-PSMA uptake, two patients (14%) showed moderate uptake, and 11 patients (79%) showed high uptake. Four patients with a low 18F-FDG uptake showed high 68Ga-PSMA uptake, while one patient exhibited low uptake with both 18F-FDG and 68Ga-PSMA. The number of lesions on 68Ga-PSMA PET/CT and MRI was significantly higher than 18F-FDG PET/CT (p=0.042 and 0.026, respectively). T/A and T/G values were significantly higher in 68Ga-PSMA than 18F-FDG (p=0.002 and 0.002, respectively). Conclusion: 68Ga-PSMA PET/CT is superior to 18F-FDG PET/CT in the staging of hepatocellular carcinoma. High 68Ga-PSMA uptake could be promising for PSMA-targeted radionuclide treatments.
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Affiliation(s)
- Cihan Gündoğan
- University of Health Sciences Turkey, Gazi Yaşargil Training and Research Hospital, Clinic of Nuclear Medicine, Diyarbakır, Turkey
| | - Nurhan Ergül
- University of Health Sciences Turkey, İstanbul Training and Research Hospital, Clinic of Nuclear Medicine, İstanbul, Turkey
| | - Mehmet Semih Çakır
- University of Health Sciences Turkey, İstanbul Training and Research Hospital, Clinic of Radiology, İstanbul, Turkey
| | - Özgür Kılıçkesmez
- University of Health Sciences Turkey, İstanbul Training and Research Hospital, Clinic of Radiology, İstanbul, Turkey
| | - Rıza Umar Gürsu
- University of Health Sciences Turkey, İstanbul Training and Research Hospital, Clinic of Medical Oncology, İstanbul, Turkey
| | - Tamer Aksoy
- University of Health Sciences Turkey, İstanbul Training and Research Hospital, Clinic of Nuclear Medicine, İstanbul, Turkey
| | - Tevfik Fikret Çermik
- University of Health Sciences Turkey, İstanbul Training and Research Hospital, Clinic of Nuclear Medicine, İstanbul, Turkey
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Skonieczna-Żydecka K, Jakubczyk K, Maciejewska-Markiewicz D, Janda K, Kaźmierczak-Siedlecka K, Kaczmarczyk M, Łoniewski I, Marlicz W. Gut Biofactory-Neurocompetent Metabolites within the Gastrointestinal Tract. A Scoping Review. Nutrients 2020; 12:E3369. [PMID: 33139656 PMCID: PMC7693392 DOI: 10.3390/nu12113369] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/27/2020] [Accepted: 10/29/2020] [Indexed: 12/12/2022] Open
Abstract
The gut microbiota have gained much scientific attention recently. Apart from unravelling the taxonomic data, we should understand how the altered microbiota structure corresponds to functions of this complex ecosystem. The metabolites of intestinal microorganisms, especially bacteria, exert pleiotropic effects on the human organism and contribute to the host systemic balance. These molecules play key roles in regulating immune and metabolic processes. A subset of them affect the gut brain axis signaling and balance the mental wellbeing. Neurotransmitters, short chain fatty acids, tryptophan catabolites, bile acids and phosphatidylcholine, choline, serotonin, and L-carnitine metabolites possess high neuroactive potential. A scoping literature search in PubMed/Embase was conducted up until 20 June 2020, using three major search terms "microbiota metabolites" AND "gut brain axis" AND "mental health". This review aimed to enhance our knowledge regarding the gut microbiota functional capacity, and support current and future attempts to create new compounds for future clinical interventions.
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Affiliation(s)
- Karolina Skonieczna-Żydecka
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, 71-460 Szczecin, Poland; (K.S.-Ż.); (K.J.); (D.M.-M.); (K.J.)
| | - Karolina Jakubczyk
- Department of Surgical Oncology, Medical University of Gdansk, Smoluchowskiego 17, 80-214 Gdańsk, Poland;
| | - Dominika Maciejewska-Markiewicz
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, 71-460 Szczecin, Poland; (K.S.-Ż.); (K.J.); (D.M.-M.); (K.J.)
| | - Katarzyna Janda
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, 71-460 Szczecin, Poland; (K.S.-Ż.); (K.J.); (D.M.-M.); (K.J.)
| | | | - Mariusz Kaczmarczyk
- Department of Clinical and Molecular Biochemistry, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland;
| | - Igor Łoniewski
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, 71-460 Szczecin, Poland; (K.S.-Ż.); (K.J.); (D.M.-M.); (K.J.)
| | - Wojciech Marlicz
- Department of Gastroenterology, Pomeranian Medical University, 71-252 Szczecin, Poland
- The Centre for Digestive Diseases Endoklinika, 70-535 Szczecin, Poland
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10
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Lu RC, She B, Gao WT, Ji YH, Xu DD, Wang QS, Wang SB. Positron-emission tomography for hepatocellular carcinoma: Current status and future prospects. World J Gastroenterol 2019; 25:4682-4695. [PMID: 31528094 PMCID: PMC6718031 DOI: 10.3748/wjg.v25.i32.4682] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 06/30/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality worldwide. Various imaging modalities provide important information about HCC for its clinical management. Since positron-emission tomography (PET) or PET-computed tomography was introduced to the oncologic setting, it has played crucial roles in detecting, distinguishing, accurately staging, and evaluating local, residual, and recurrent HCC. PET imaging visualizes tissue metabolic information that is closely associated with treatment. Dynamic PET imaging and dual-tracer have emerged as complementary techniques that aid in various aspects of HCC diagnosis. The advent of new radiotracers and the development of immuno-PET and PET-magnetic resonance imaging have improved the ability to detect lesions and have made great progress in treatment surveillance. The current PET diagnostic capabilities for HCC and the supplementary techniques are reviewed herein.
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Affiliation(s)
- Ren-Cai Lu
- PET-CT Center, the First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China
| | - Bo She
- PET-CT Center, the First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China
| | - Wen-Tao Gao
- PET-CT Center, the First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China
| | - Yun-Hai Ji
- PET-CT Center, the First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China
| | - Dong-Dong Xu
- PET-CT Center, the First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China
| | - Quan-Shi Wang
- Nanfang PET Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Shao-Bo Wang
- PET-CT Center, the First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China
- Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650093, Yunnan Province, China
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11
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Abstract
Short-chain fatty acids (SCFAs), the main metabolites produced by bacterial fermentation of dietary fibre in the gastrointestinal tract, are speculated to have a key role in microbiota-gut-brain crosstalk. However, the pathways through which SCFAs might influence psychological functioning, including affective and cognitive processes and their neural basis, have not been fully elucidated. Furthermore, research directly exploring the role of SCFAs as potential mediators of the effects of microbiota-targeted interventions on affective and cognitive functioning is sparse, especially in humans. This Review summarizes existing knowledge on the potential of SCFAs to directly or indirectly mediate microbiota-gut-brain interactions. The effects of SCFAs on cellular systems and their interaction with gut-brain signalling pathways including immune, endocrine, neural and humoral routes are described. The effects of microbiota-targeted interventions such as prebiotics, probiotics and diet on psychological functioning and the putative mediating role of SCFA signalling will also be discussed, as well as the relationship between SCFAs and psychobiological processes. Finally, future directions to facilitate direct investigation of the effect of SCFAs on psychological functioning are outlined.
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12
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Mulders RJ, de Git KCG, Schéle E, Dickson SL, Sanz Y, Adan RAH. Microbiota in obesity: interactions with enteroendocrine, immune and central nervous systems. Obes Rev 2018; 19:435-451. [PMID: 29363272 DOI: 10.1111/obr.12661] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 11/27/2017] [Accepted: 11/27/2017] [Indexed: 02/06/2023]
Abstract
Western diets, with high consumption of simple sugars and saturated fats, contribute to the rise in the prevalence of obesity. It now seems clear that high-fat diets cause obesity, at least in part, by modifying the composition and function of the microorganisms that colonize in the gastrointestinal tract, the microbiota. The exact pathways by which intestinal microbiota contribute to obesity remain largely unknown. High-fat diet-induced alterations in intestinal microbiota have been suggested to increase energy extraction, intestinal permeability and systemic inflammation while decreasing the capability to generate obesity-suppressing short-chain fatty acids. Moreover, by increasing systemic inflammation, microglial activation and affecting vagal nerve activity, 'obese microbiota' indirectly influence hypothalamic gene expression and promote overeating. Because the potential of intestinal microbiota to induce obesity has been recognized, multiple ways to modify its composition and function are being investigated to provide novel preventive and therapeutic strategies against diet-induced obesity.
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Affiliation(s)
- R J Mulders
- Master's Programme Science and Business Management, Utrecht University, Utrecht, The Netherlands
| | - K C G de Git
- Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - E Schéle
- Institute for Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - S L Dickson
- Institute for Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Y Sanz
- Microbial Ecology, Nutrition and Health Research Group, Institute of Agrochemistry and Food Technology, National Research Council (IATA-CSIC), Valencia, Spain
| | - R A H Adan
- Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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14
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Ktsoyan ZA, Mkrtchyan MS, Zakharyan MK, Mnatsakanyan AA, Arakelova KA, Gevorgyan ZU, Sedrakyan AM, Hovhannisyan AI, Arakelyan AA, Aminov RI. Systemic Concentrations of Short Chain Fatty Acids Are Elevated in Salmonellosis and Exacerbation of Familial Mediterranean Fever. Front Microbiol 2016; 7:776. [PMID: 27252692 PMCID: PMC4877380 DOI: 10.3389/fmicb.2016.00776] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Accepted: 05/09/2016] [Indexed: 12/22/2022] Open
Abstract
Gut microbiota-produced short chain fatty acids (SCFAs) play an important role in the normal human metabolism and physiology. Although the gradients of SCFAs from the large intestine, where they are largely produced, to the peripheral blood as well as the main routes of SCFA metabolism by different organs are known well for the healthy state, there is a paucity of information regarding how these are affected in disease. In particular, how the inflammation caused by infection or autoinflammatory disease affect the concentration of SCFAs in the peripheral venous blood. In this work, we revealed that diseases caused either by infectious agents (two Salmonella enterica serovars, S. Enteritidis, and S. Typhimurium) or by the exacerbation of an autoinflammatory disease, familial Mediterranean fever (FMF), both result in a significantly elevated systemic concentration of SCFAs. In the case of salmonellosis the concentration of SCFAs in peripheral blood was significantly and consistently higher, from 5- to 20-fold, compared to control. In the case of FMF, however, a significant increase of SCFAs in the peripheral venous blood was detected only in the acute phase of the disease, with a lesser impact in remission. It seems counterintuitive that the dysbiotic conditions, with a reduced number of gut microorganisms, produce such an effect. This phenomenon, however, must be appraised within the context of how the inflammatory diseases affect the normal physiology. We discuss a number of factors that may contribute to the “leak” and persistence of gut-produced SCFAs into the systemic circulation in infectious and autoinflammatory diseases.
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Affiliation(s)
- Zhanna A Ktsoyan
- Institute of Molecular Biology of National Academy of Sciences of Republic of Armenia Yerevan, Armenia
| | - Mkhitar S Mkrtchyan
- Institute of Molecular Biology of National Academy of Sciences of Republic of Armenia Yerevan, Armenia
| | - Magdalina K Zakharyan
- Institute of Molecular Biology of National Academy of Sciences of Republic of Armenia Yerevan, Armenia
| | - Armine A Mnatsakanyan
- Clinical Hospital of Infectious Diseases Nork, Ministry of Health of Republic of Armenia Yerevan, Armenia
| | - Karine A Arakelova
- Institute of Molecular Biology of National Academy of Sciences of Republic of Armenia Yerevan, Armenia
| | - Zaruhi U Gevorgyan
- Clinical Hospital of Infectious Diseases Nork, Ministry of Health of Republic of Armenia Yerevan, Armenia
| | - Anahit M Sedrakyan
- Institute of Molecular Biology of National Academy of Sciences of Republic of Armenia Yerevan, Armenia
| | - Alvard I Hovhannisyan
- Institute of Molecular Biology of National Academy of Sciences of Republic of Armenia Yerevan, Armenia
| | - Arsen A Arakelyan
- Institute of Molecular Biology of National Academy of Sciences of Republic of Armenia Yerevan, Armenia
| | - Rustam I Aminov
- School of Medicine and Dentistry, University of Aberdeen Aberdeen, UK
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15
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Leisser A, Pruscha K, Ubl P, Wadsak W, Mayerhöfer M, Mitterhauser M, Hacker M, Kramer G, Shariat S, Karanikas G, Hartenbach M, Haug AR. Evaluation of fatty acid synthase in prostate cancer recurrence: SUV of [(11) C]acetate PET as a prognostic marker. Prostate 2015; 75:1760-7. [PMID: 26282590 DOI: 10.1002/pros.23061] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2015] [Accepted: 07/28/2015] [Indexed: 11/12/2022]
Abstract
AIM High levels of fatty acid synthase have shown to correlate with the aggressiveness of prostate cancer. As [(11) C]acetate exhibits a close correlation with the level of fatty acid synthase, we aimed to assess whether the SUV in [(11) C]acetate PET serves as a suitable prognostic marker in patients with recurrent prostate cancer. MATERIALS AND METHODS In 123 consecutive patients, examined between 2010 and 2014, the maximum standardized uptake value (SUVmax) of local recurrences as well as lymph node and bone metastases was measured. Choosing the spleen as a standard for relatively high physiological uptake, a ratio of tumor to spleen uptake (SUVts) was calculated for standardizing the uptake, too. The corresponding initial Gleason scores (GS) and serum-PSA levels around the time of the performed PET/CT for each patient were retrospectively collected and PSA doubling together with PSA velocity were determined. For further analysis patients were divided with regard to their initial Gleason score (≤3 + 4 and ≥ 4 + 3). The median of PSA velocity was calculated to separate patients with a high and low PSA velocity and Mann-Whitney U or Student's t-test were used, testing for significant differences. For correlation Spearmen-Rho test was used. RESULTS PET was positive for recurrence in 82/123 patients. PSA was significantly higher in PET-positive than in negative patients (5.9 vs. 3.2 ng/ml; P = 0.006). Initial Gleason score did not differ in PET negative and positive patients (P = 0.3), whereas PSA velocity was markedly higher in PET positive patients (0.4 vs. 0.1 ng/ml/month; P = 0.01). Median SUVmax of PET positive patients was 5.23 (mean 5.78; range 0.9-16.8) and meadian SUVts was 0.78 (mean 0.84, range 0.14-2.50). SUVts was significantly higher in patients with high PSA velocity (SUVts 0.76 vs. 0.92; P = 0.009), whereas SUVmax failed statistical significance (5.4 vs. 6.3 ng/ml/month; P = 0.08). Patients with a high SUVmax proved to have a significantly higher median Gleason score compared to low uptake 8.0 vs. 7.0; P = 0.004). Vice versa both SUVmax (GS 6: 5.0; GS 7: 5.6; GS 8: 5.7; GS 9: 6.5; r = 0.30, P = 0.008) and SUVts (GS 6: 0.63; GS 7: 0.68; GS 8: 0.85; GS 9: 0.89; r = 0.30, P = 0.006) significantly correlated with Gleason score. Patients with a Gleason score ≤ 3 + 4 had a significantly lower SUVmax (4.8 vs. 5.7; P = 0.02) and SUVts (0.67 vs. 0.85; P = 0.02) as compared to a Gleason score ≥ 4 + 3. CONCLUSION [(11) C]acetate uptake demonstrated to correlate with initial Gleason score. Furthermore, patients with a high PSA velocity proved to have higher [(11) C]acetate uptake in tumor lesions.
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Affiliation(s)
- Asha Leisser
- Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria
| | - Konstatin Pruscha
- Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria
| | - Philipp Ubl
- Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria
| | - Wolfgang Wadsak
- Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria
| | - Marius Mayerhöfer
- Department of Biomedical Imaging and Image-guided Therapy, Division of General and Paediatric Radiology, Medical University of Vienna, Vienna, Austria
| | - Markus Mitterhauser
- Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria
| | - Marcus Hacker
- Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria
| | - Gero Kramer
- Department of Urology, Medical University of Vienna, Vienna, Austria
| | - Shahrokh Shariat
- Department of Urology, Medical University of Vienna, Vienna, Austria
| | - Georgios Karanikas
- Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria
| | - Markus Hartenbach
- Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria
| | - Alexander R Haug
- Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria
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16
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Nilaweera TD, Saeed M, Kohen A. Targeting the de novo biosynthesis of thymidylate for the development of a PET probe for pancreatic cancer imaging. Biochemistry 2015; 54:1287-93. [PMID: 25581782 DOI: 10.1021/bi501481n] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The development of cancer-specific probes for imaging by positron emission tomography (PET) is gaining impetus in cancer research and clinical oncology. One of the hallmarks of most cancer cells is incessant DNA replication, which requires the continuous synthesis of nucleotides. Thymidylate synthase (TSase) is unique in this context because it is the only enzyme in humans that is responsible for the de novo biosynthesis of the DNA building block 2'-deoxy-thymidylate (dTMP). TSase catalyzes the reductive methylation of 2'-deoxy-uridylate (dUMP) to dTMP using (R)-N(5),N(10)-methylene-5,6,7,8-tetrahydrofolate (MTHF) as a cofactor. Not surprisingly, several human cancers overexpress TSase, which makes it a common target for chemotherapy (e.g., 5-fluorouracil). We envisioned that [(11)C]-MTHF might be a PET probe that could specifically label cancerous cells. Using stable radiotracer [(14)C]-MTHF, we had initially found increased uptake by breast and colon cancer cell lines. In the current study, we examined the uptake of this radiotracer in human pancreatic cancer cell lines MIAPaCa-2 and PANC-1 and found predominant radiolabeling of cancerous versus normal pancreatic cells. Furthermore, uptake of the radiotracer is dependent on the intracellular level of the folate pool, cell cycle phase, expression of folate receptors on the cell membrane, and cotreatment with the common chemotherapeutic drug methotrexate (MTX, which blocks the biosynthesis of endogenous MTHF). These results point toward [(11)C]-MTHF being used as PET probe with broad specificity and being able to control its signal through MTX co-administration.
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Affiliation(s)
- Thushani D Nilaweera
- Department of Chemistry, University of Iowa , Iowa City, Iowa 52242, United States
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17
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Abstract
In recent years, there has been a renewed interest in the role of dietary fibre in obesity management. Much of this interest stems from animal and human studies which suggest that an increased intake of fermentable fibre can suppress appetite and improve weight management. A growing number of reports have demonstrated that the principal products of colonic fermentation of dietary fibre, SCFA, contribute to energy homeostasis via effects on multiple cellular metabolic pathways and receptor-mediated mechanisms. In particular, over the past decade it has been identified that a widespread receptor system exists for SCFA. These G-protein-coupled receptors, free fatty acid receptor (FFAR) 2 and FFAR3 are expressed in numerous tissue sites, including the gut epithelium and adipose tissue. Investigations using FFAR2- or FFAR3-deficient animal models suggest that SCFA-mediated stimulation of these receptors enhances the release of the anorectic hormones peptide tyrosine tyrosine and glucagon-like peptide-1 from colonic L cells and leptin from adipocytes. In addition, the SCFA acetate has recently been shown to have a direct role in central appetite regulation. Furthermore, the SCFA propionate is a known precursor for hepatic glucose production, which has been reported to suppress feeding behaviour in ruminant studies through the stimulation of hepatic vagal afferents. The present review therefore proposes that an elevated colonic production of SCFA could stimulate numerous hormonal and neural signals at different organ and tissue sites that would cumulatively suppress short-term appetite and energy intake.
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18
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Eo JS, Paeng JC, Lee DS. Nuclear imaging for functional evaluation and theragnosis in liver malignancy and transplantation. World J Gastroenterol 2014; 20:5375-5388. [PMID: 24833867 PMCID: PMC4017052 DOI: 10.3748/wjg.v20.i18.5375] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 10/23/2013] [Accepted: 11/05/2013] [Indexed: 02/06/2023] Open
Abstract
Currently, nuclear imaging such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) is increasingly used in the management of liver malignancy. 18F-fluorodeoxyglucose (FDG)-PET is the most widely used nuclear imaging in liver malignancy as in other cancers, and has been reported to be effective in diagnosis, response monitoring, recurrence evaluation, and prognosis prediction. Other PET imaging such as 11C-acetate PET is also used complementarily to FDG-PET in diagnosis of liver malignancy. Additionally, image-based evaluation of regional hepatic function can be performed using nuclear imaging. Those imaging modalities are also effective for candidate selection, treatment planning, and perioperative evaluation in liver surgery and transplantation. Recently, nuclear imaging has been actively adopted in the transarterial radioembolization therapy of liver malignancy, according to the concept of theragnosis. With the development of new hybrid imaging technologies such as PET/magnetic resonance imaging and SPECT/CT, nuclear imaging is expected to be more useful in the management of liver malignancy, particularly regarding liver surgery and transplantation. In this review, the efficacy and roles of nuclear imaging methods in diagnosis, transplantation and theragnosis are discussed.
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19
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Anastasovska J, Arora T, Sanchez Canon GJ, Parkinson JRC, Touhy K, Gibson GR, Nadkarni NA, So PW, Goldstone AP, Thomas EL, Hankir MK, Van Loo J, Modi N, Bell JD, Frost G. Fermentable carbohydrate alters hypothalamic neuronal activity and protects against the obesogenic environment. Obesity (Silver Spring) 2012; 20:1016-23. [PMID: 22322344 DOI: 10.1038/oby.2012.6] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Obesity has become a major global health problem. Recently, attention has focused on the benefits of fermentable carbohydrates on modulating metabolism. Here, we take a system approach to investigate the physiological effects of supplementation with oligofructose-enriched inulin (In). We hypothesize that supplementation with this fermentable carbohydrate will not only lead to changes in body weight and composition, but also to modulation in neuronal activation in the hypothalamus. Male C57BL/6 mice were maintained on a normal chow diet (control) or a high fat (HF) diet supplemented with either oligofructose-enriched In or corn starch (Cs) for 9 weeks. Compared to HF+Cs diet, In supplementation led to significant reduction in average daily weight gain (mean ± s.e.m.: 0.19 ± 0.01 g vs. 0.26 ± 0.02 g, P < 0.01), total body adiposity (24.9 ± 1.2% vs. 30.7 ± 1.4%, P < 0.01), and lowered liver fat content (11.7 ± 1.7% vs. 23.8 ± 3.4%, P < 0.01). Significant changes were also observed in fecal bacterial distribution, with increases in both Bifidobacteria and Lactobacillius and a significant increase in short chain fatty acids (SCFA). Using manganese-enhanced MRI (MEMRI), we observed a significant increase in neuronal activation within the arcuate nucleus (ARC) of animals that received In supplementation compared to those fed HF+Cs diet. In conclusion, we have demonstrated for the first time, in the same animal, a wide range of beneficial metabolic effects following supplementation of a HF diet with oligofructose-enriched In, as well as significant changes in hypothalamic neuronal activity.
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Affiliation(s)
- Jelena Anastasovska
- Metabolic and Molecular Imaging Group, MRC Clinical Sciences Centre, Imperial College London, London, UK
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20
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Saeed M, Sheff D, Kohen A. Novel positron emission tomography tracer distinguishes normal from cancerous cells. J Biol Chem 2011; 286:33872-8. [PMID: 21832075 DOI: 10.1074/jbc.m111.275446] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Development of tumor-specific probes for imaging by positron emission tomography has broad implications in clinical oncology, such as diagnosis, staging, and monitoring therapeutic responses in patients, as well as in biomedical research. Thymidylate synthase (TSase)-based de novo biosynthesis of DNA is an important target for drug development. Increased DNA replication in proliferating cancerous cells requires TSase activity, which catalyzes the reductive methylation of dUMP to dTMP using (R)-N(5),N(10)-methylene-5,6,7,8-tetrahydrofolate (MTHF) as a cofactor. In principle, radiolabeled MTHF can be used as a substrate for this reaction to identify rapidly dividing cells. In this proof-of-principle study, actively growing (log phase) breast cancer (MCF7, MDA-MB-231, and hTERT-HME1), normal breast (human mammary epithelial and MCF10A), colon cancer (HT-29), and normal colon (FHC) cells were incubated with [(14)C]MTHF in culture medium from 30 min to 2 h, and uptake of radiotracer was measured. Cancerous cell lines incorporated significantly more radioactivity than their normal counterparts. The uptake of radioactively labeled MTHF depended upon a combination of cell doubling time, folate receptor status, S phase percentage, and TSase expression in the cells. These findings suggest that the recently synthesized [(11)C]MTHF may serve as a new positron emission tomography tracer for cancer imaging.
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Affiliation(s)
- Muhammad Saeed
- Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, USA
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21
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Runkle AC, Shao X, Tluczek LJM, Henderson BD, Hockley BG, Scott PJH. Automated production of [11C]acetate and [11C]palmitate using a modified GE Tracerlab FX(C-Pro). Appl Radiat Isot 2011; 69:691-8. [PMID: 21256039 DOI: 10.1016/j.apradiso.2011.01.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2010] [Revised: 12/22/2010] [Accepted: 01/03/2011] [Indexed: 11/16/2022]
Abstract
As researchers explore new applications for positron emission tomography radiopharmaceuticals, the demand for effective and readily available radiopharmaceuticals continues to increase. The syntheses of two such radiopharmaceuticals, [(11)C]acetate and [(11)C]palmitate, can be automated on the GE Tracerlab FX(C-Pro) by utilizing Grignard reactions. Radiochemical purities of the [(11)C]acetate and the [(11)C]palmitate products were high (>98% and >99.9%, respectively) with average non-corrected yields of 18% (n = 3) and 10% (n = 5), respectively. These data comprise the validation trials for site qualification of clinical production of both radiopharmaceuticals.
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Affiliation(s)
- Adam C Runkle
- Department of Radiology, University of Michigan Medical School, Ann Arbor, 48109, USA
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