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Sun P, Wang M, Chai X, Liu YX, Li L, Zheng W, Chen S, Zhu X, Zhao S. Disruption of tryptophan metabolism by high-fat diet-triggered maternal immune activation promotes social behavioral deficits in male mice. Nat Commun 2025; 16:2105. [PMID: 40025041 DOI: 10.1038/s41467-025-57414-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 02/20/2025] [Indexed: 03/04/2025] Open
Abstract
Diet-related maternal obesity has been implicated in neurodevelopmental disorders in progeny. Although the precise mechanisms and effective interventions remain uncertain, our research elucidates some of these complexities. We established that a prenatal high-fat diet triggered maternal immune activation (MIA), marked by elevated serum lipopolysaccharide levels and inflammatory-cytokine overproduction, which dysregulated the maternal tryptophan metabolism promoting the accumulation of neurotoxic kynurenine metabolites in the embryonic brain. Interventions aimed at mitigating MIA or blocking the kynurenine pathway effectively rescued the male mice social performance. Furthermore, excessive kynurenine metabolites initiated oxidative stress response causing neuronal migration deficits in the fetal neocortex, an effect that was mitigated by administering the glutathione synthesis precursor N-Acetylcysteine, underscoring the central role of maternal immune-metabolic homeostasis in male mice behavioral outcomes. Collectively, our study accentuated the profound influence of maternal diet-induced immuno-metabolic dysregulation on fetal brain development and provided the preventive strategies for addressing neurodevelopmental disorders.
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Affiliation(s)
- Penghao Sun
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
| | - Mengli Wang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
| | - Xuejun Chai
- College of Basic Medicine, Xi'an Medical University, Xi'an, Shaanxi, China.
| | - Yong-Xin Liu
- Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, Guangdong, China
| | - Luqi Li
- Life Science Research Core Services, Northwest A&F University, Yangling, Shaanxi, China
| | - Wei Zheng
- College of Resources and Environment Sciences, Northwest A&F University, Yangling, Shaanxi, China
| | - Shulin Chen
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
| | - Xiaoyan Zhu
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China.
| | - Shanting Zhao
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China.
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Mohiti S, Christensen J, Landler NE, Sørensen IM, Thomassen JQ, Bjergfelt SS, Hansen D, Feldt-Rasmussen B, Bro S, Ebrahimi-Mameghani M, Biering-Sørensen T, Bisgaard LS, Christoffersen C. Serum tryptophan and kynurenine levels and risk of heart failure among patients with chronic kidney disease. Clin Nutr 2025; 47:14-20. [PMID: 39978230 DOI: 10.1016/j.clnu.2025.01.028] [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: 08/12/2024] [Revised: 01/20/2025] [Accepted: 01/25/2025] [Indexed: 02/22/2025]
Abstract
BACKGROUND AND AIMS Chronic kidney disease (CKD) is often complicated by heart failure (HF), leading to increased mortality. Emerging evidence suggests that Tryptophan metabolites, through the Kynurenine pathway (KP), play a significant role in HF pathophysiology. Therefore, we explored the association of Tryptophan (TRP), Kynurenine (KYN), and the Kynurenine to Tryptophan ratio (KTR) with HF in CKD, hypothesizing a link between KP alterations and HF occurrence in this population. METHODS 673 non-dialysis patients aged 30 to 75 with CKD stages 1-5 were included. Incident HF data were collected through medical record reviews, and the median follow-up time was 3.9 years. Serum concentrations of KYN and TRP were measured using High-Performance Liquid Chromatography (HPLC). RESULTS Patients with more advanced stages of CKD had higher levels of KYN and KTR, and lower levels of TRP (p < 0.001). Following adjustments for age, sex, BMI, hypertension, and hypercholesterolemia, serum KYN and KTR remained significantly associated with prevalent HF in patients with CKD (p = 0.012, p = 0.028 respectively). Furthermore, Cox-regression analysis indicated that KTR concentration was associated with incident HF after adjusting for confounders such as age, sex, BMI, hypertension, hypercholesterolemia and diabetes (p = 0.019). CONCLUSION In conclusion, the present analysis suggests that changes in the kynurenine pathway may be a new biomarker for HF in patients with CKD. Thus, KTR concentration might be associated with prevalent and future HF in patients with CKD. Further research is needed to understand the mechanisms and potential of these metabolites in refining HF risk prediction and prevention in CKD patients.
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Affiliation(s)
- Sara Mohiti
- Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Student Research Committee, School of Nutrition & Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jacob Christensen
- Center for Translational Cardiology and Pragmatic Randomized Trials (CTCPR), Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Cardiovascular Non-Invasive Imaging Research Laboratory, Department of Cardiology, Copenhagen University Hospital - Herlev and Gentofte, Denmark
| | - Nino E Landler
- Center for Translational Cardiology and Pragmatic Randomized Trials (CTCPR), Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Cardiovascular Non-Invasive Imaging Research Laboratory, Department of Cardiology, Copenhagen University Hospital - Herlev and Gentofte, Denmark
| | - Ida Mh Sørensen
- Department of Nephrology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Denmark
| | - Jesper Qvist Thomassen
- Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Sasha S Bjergfelt
- Department of Nephrology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Department of Biomedical Sciences, University of Copenhagen, Denmark
| | - Ditte Hansen
- Department of Nephrology, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark
| | - Bo Feldt-Rasmussen
- Department of Nephrology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Denmark
| | - Susanne Bro
- Department of Nephrology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Mehrangiz Ebrahimi-Mameghani
- Nutrition Research Center, Department of Biochemistry and Diet Therapy, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Tor Biering-Sørensen
- Center for Translational Cardiology and Pragmatic Randomized Trials (CTCPR), Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Cardiovascular Non-Invasive Imaging Research Laboratory, Department of Cardiology, Copenhagen University Hospital - Herlev and Gentofte, Denmark; Steno Diabetes Center Copenhagen, Denmark; Department of Cardiology, Copenhagen University Hospital - Rigshospitalet, Denmark
| | - Line S Bisgaard
- Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Department of Biomedical Sciences, University of Copenhagen, Denmark.
| | - Christina Christoffersen
- Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Department of Biomedical Sciences, University of Copenhagen, Denmark.
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Sun S, Hu F, Sang Y, Wang S, Liu X, Shi J, Cao H, Tao F, Liu K. Dysregulated tryptophan metabolism contributes to metabolic syndrome in Chinese community-dwelling older adults. BMC Endocr Disord 2025; 25:7. [PMID: 39780122 PMCID: PMC11708088 DOI: 10.1186/s12902-024-01826-8] [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: 09/02/2024] [Accepted: 12/27/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND As the prevalence of metabolic syndrome (MetS) rises among older adults, the associated risks of cardiovascular diseases and diabetes significantly increase, and it is closely linked to various metabolic processes in the body. Dysregulation of tryptophan (TRP) metabolism, particularly alterations in the kynurenine (KYN) and serotonin pathways, has been linked to the onset of chronic inflammation, oxidative stress, and insulin resistance, key contributors to the development of MetS. We aim to investigate the relationship between the TRP metabolites and the risk of MetS in older adults. METHODS Ultra-performance liquid chromatography tandem mass spectrometry was used to detect TRP and its seven metabolites in a study involving 986 participants. Physical examination included the following indicators: blood pressure, body mass index, triglyceride levels, and high-density lipoprotein cholesterol (HDL-C) levels. Multiple linear regression, restricted cubic spline curve, binary logistic analysis, and sex-stratified analysis were used to explore the relationship between the metabolites and the risk of MetS in older adults. RESULTS The results indicated that, after adjusting for covariates, higher levels of TRP, KYN, kynurenic acid (KA), and xanthurenic acid (XA) were risk factors for MetS (P for trend < 0.05). By contrast, higher ratios of 5-hydroxytryptamine to TRP and indole-3-propionic acid to TRP were protective factors against MetS (P for trend < 0.05). CONCLUSIONS TRP and its metabolites may serve as potential indicators for assessing and managing MetS in older adults, complementing existing biomarkers. CLINICAL TRIAL NUMBER Not applicable.
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Affiliation(s)
- Shujing Sun
- School of Public Health, Anhui Medical University, No. 81 Meishan Road, Hefei, Anhui, 230032, China
| | - Fangting Hu
- School of Public Health, Anhui Medical University, No. 81 Meishan Road, Hefei, Anhui, 230032, China
| | - Yanru Sang
- School of Public Health, Anhui Medical University, No. 81 Meishan Road, Hefei, Anhui, 230032, China
| | - Sheng Wang
- Center for Scientific Research, Anhui Medical University, Hefei, Anhui, 230032, China
| | - Xuechun Liu
- Hefei Hospital affiliated to Anhui Medical University (Hefei Second People's Hospital), Hefei, Anhui, 230011, China
| | - Jiafeng Shi
- School of Public Health, Anhui Medical University, No. 81 Meishan Road, Hefei, Anhui, 230032, China
| | - Hongjuan Cao
- Lu'an Center of Disease Control and Prevention, Lu'an, Anhui, 237000, China
| | - Fangbiao Tao
- School of Public Health, Anhui Medical University, No. 81 Meishan Road, Hefei, Anhui, 230032, China
- Center for Big Data and Population Health, Institute of Health and Medicine, Hefei, Anhui, 230032, China
| | - Kaiyong Liu
- School of Public Health, Anhui Medical University, No. 81 Meishan Road, Hefei, Anhui, 230032, China.
- Center for Big Data and Population Health, Institute of Health and Medicine, Hefei, Anhui, 230032, China.
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Ryan KM, Corrigan M, Murphy TM, McLoughlin DM, Harkin A. Gene expression of kynurenine pathway enzymes in depression and following electroconvulsive therapy. Acta Neuropsychiatr 2024:1-10. [PMID: 39417574 DOI: 10.1017/neu.2024.34] [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] [Indexed: 10/19/2024]
Abstract
OBJECTIVE This study aimed to investigate changes in mRNA expression of the kynurenine pathway (KP) enzymes tryptophan 2, 3-dioxygenase (TDO), indoleamine 2, 3-dioxygenase 1 and 2 (IDO1, IDO2), kynurenine aminotransferase 1 and 2 (KAT1, KAT2), kynurenine monooxygenase (KMO) and kynureninase (KYNU) in medicated patients with depression (n = 74) compared to age- and sex-matched healthy controls (n = 55) and in patients with depression after electroconvulsive therapy (ECT). Associations with mood score (24-item Hamilton Depression Rating Scale, HAM-D24), plasma KP metabolites and selected glucocorticoid and inflammatory immune markers known to regulate KP enzyme expression were also explored. METHODS HAM-D24 was used to evaluate depression severity. Whole blood mRNA expression was assessed using quantitative real-time polymerase chain reaction. RESULTS KAT1, KYNU and IDO2 were significantly reduced in patient samples compared to control samples, though results did not survive statistical adjustment for covariates or multiple comparisons. ECT did not alter KP enzyme mRNA expression. Changes in IDO1 and KMO and change in HAM-D24 score post-ECT were negatively correlated in subgroups of patients with unipolar depression (IDO1 only), psychotic depression and ECT responders and remitters. Further exploratory correlative analyses revealed altered association patterns between KP enzyme expression, KP metabolites, NR3C1 and IL-6 in depressed patients pre- and post-ECT. CONCLUSION Further studies are warranted to determine if KP measures have sufficient sensitivity, specificity and predictive value to be integrated into stress and immune associated biomarker panels to aid patient stratification at diagnosis and in predicting treatment response to antidepressant therapy.
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Affiliation(s)
- Karen M Ryan
- Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland
- Department of Psychiatry, St. Patrick's University Hospital, Trinity College Dublin, Dublin, Ireland
| | - Myles Corrigan
- Neuropsychopharmacology Research Group, School of Pharmacy and Pharmaceutical Sciences & Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland
| | - Therese M Murphy
- School of Biological, Sports and Health Sciences, Technological University Dublin, Dublin, Ireland
| | - Declan M McLoughlin
- Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland
- Department of Psychiatry, St. Patrick's University Hospital, Trinity College Dublin, Dublin, Ireland
| | - Andrew Harkin
- Neuropsychopharmacology Research Group, School of Pharmacy and Pharmaceutical Sciences & Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland
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Kim SM, Oh S, Lee SS, Park S, Hur YM, Ansari A, Lee G, Paik MJ, You YA, Kim YJ. Maternal Diet during Pregnancy Alters the Metabolites in Relation to Metabolic and Neurodegenerative Diseases in Young Adult Offspring. Int J Mol Sci 2024; 25:11046. [PMID: 39456828 PMCID: PMC11508017 DOI: 10.3390/ijms252011046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 10/06/2024] [Accepted: 10/12/2024] [Indexed: 10/28/2024] Open
Abstract
Maternal nutrition during the critical period of pregnancy increases the susceptibility of offspring to the development of diseases later in life. This study aimed to analyze metabolite profiles to investigate the effect of maternal diet during pregnancy on changes in offspring plasma metabolites and to identify correlations with metabolic parameters. Pregnant Sprague-Dawley rats were exposed to under- and overnutrition compared to controls, and their offspring were fed a standard diet after birth. Plasma metabolism was profiled in offspring at 16 weeks of age using liquid chromatography-mass spectrometry (LC-MS/MS) and gas chromatography-tandem mass spectrometry (GC-MS/MS). We analyzed 80 metabolites to identify distinct metabolites and metabolic and neurodegenerative disease-associated metabolites that were sex-differentially altered in each group compared to controls (p < 0.05, VIP score > 1.0). Specifically, changes in 3-indolepropionic acid, anthranilic acid, linoleic acid, and arachidonic acid, which are involved in tryptophan and linoleic acid metabolism, were observed in male offspring and correlated with plasma leptin levels in male offspring. Our results suggest that fatty acids involved in tryptophan and linoleic acid metabolism, which are altered by the maternal diet during pregnancy, may lead to an increased risk of metabolic and neurodegenerative diseases in the early life of male offspring.
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Affiliation(s)
- Soo-Min Kim
- Department of Obstetrics and Gynecology, Ewha Medical Research Institute, College of Medicine, Ewha Womans University Mokdong Hospital, Seoul 07985, Republic of Korea; (S.-M.K.); (S.P.); (Y.-M.H.); (A.A.); (G.L.)
- Graduate Program in System Health Science and Engineering, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Songjin Oh
- College of Pharmacy, Sunchon National University, Suncheon 57922, Republic of Korea; (S.O.); (S.S.L.); (M.-J.P.)
| | - Sang Suk Lee
- College of Pharmacy, Sunchon National University, Suncheon 57922, Republic of Korea; (S.O.); (S.S.L.); (M.-J.P.)
| | - Sunwha Park
- Department of Obstetrics and Gynecology, Ewha Medical Research Institute, College of Medicine, Ewha Womans University Mokdong Hospital, Seoul 07985, Republic of Korea; (S.-M.K.); (S.P.); (Y.-M.H.); (A.A.); (G.L.)
| | - Young-Min Hur
- Department of Obstetrics and Gynecology, Ewha Medical Research Institute, College of Medicine, Ewha Womans University Mokdong Hospital, Seoul 07985, Republic of Korea; (S.-M.K.); (S.P.); (Y.-M.H.); (A.A.); (G.L.)
| | - AbuZar Ansari
- Department of Obstetrics and Gynecology, Ewha Medical Research Institute, College of Medicine, Ewha Womans University Mokdong Hospital, Seoul 07985, Republic of Korea; (S.-M.K.); (S.P.); (Y.-M.H.); (A.A.); (G.L.)
| | - Gain Lee
- Department of Obstetrics and Gynecology, Ewha Medical Research Institute, College of Medicine, Ewha Womans University Mokdong Hospital, Seoul 07985, Republic of Korea; (S.-M.K.); (S.P.); (Y.-M.H.); (A.A.); (G.L.)
- Graduate Program in System Health Science and Engineering, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Man-Jeong Paik
- College of Pharmacy, Sunchon National University, Suncheon 57922, Republic of Korea; (S.O.); (S.S.L.); (M.-J.P.)
| | - Young-Ah You
- Department of Obstetrics and Gynecology, Ewha Medical Research Institute, College of Medicine, Ewha Womans University Mokdong Hospital, Seoul 07985, Republic of Korea; (S.-M.K.); (S.P.); (Y.-M.H.); (A.A.); (G.L.)
| | - Young Ju Kim
- Department of Obstetrics and Gynecology, Ewha Medical Research Institute, College of Medicine, Ewha Womans University Mokdong Hospital, Seoul 07985, Republic of Korea; (S.-M.K.); (S.P.); (Y.-M.H.); (A.A.); (G.L.)
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Mirzababaei A, Mahmoodi M, Keshtkar A, Ebrahimi S, Pashayee-Khamene F, Abaj F, Radmehr M, Khalili P, Mehri Hajmir M, Mirzaei K. The interaction between dietary nitrates/nitrites intake and gut microbial metabolites on metabolic syndrome: a cross-sectional study. Front Public Health 2024; 12:1398460. [PMID: 39328991 PMCID: PMC11425044 DOI: 10.3389/fpubh.2024.1398460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 08/12/2024] [Indexed: 09/28/2024] Open
Abstract
Background Metabolic syndrome (MetS) prevalence has increased globally.The evidence shows thatdiet and gut microbial metabolites includingtrimethylamine N-oxide (TMAO) and kynurenine (KYN) play an important role in developing MetS. However, there is a lack of evidence on associations between between diet and these metabolites. This study aimed to investigate the interaction between dietary nitrate/nitrite and gut microbial metabolites (TMAO, KYN) on MetS and its components. Methods This cross-sectional study included 250 adults aged 20-50 years. Dietary intake was assessed using food frequency questionnaires (FFQ), and serum TMAO and KYN levels were measured. MetS was defined usingthe National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III) criteria. Result The ATPIII index revealed an 11% prevalence of metabolic syndrome among the study participants. After adjusting for confounders, significant positive interactions were found: High animal-source nitrate intake and high TMAO levels with elevated triglycerides (TG) (p interaction = 0.07) and abdominal obesity (p interaction = 0.08). High animal-source nitrate intake and high KYN levels with increased TG (p interaction = 0.01) and decreased high-density lipoprotein cholesterol (HDL) (p interaction = 0.01).Individuals with high animal-source nitrite intake and high TMAO levels showed increased risk of hypertriglyceridemia (OR: 1.57, 95%CI: 0.35-2.87, p = 0.05), hypertension (OR: 1.53, 95%CI: 0.33-2.58, p = 0.06), and lower HDL (OR: 1.96, 95%CI: 0.42-2.03, p = 0.04). Similarly, high animal-source nitrite intake with high KYN levels showed lower HDL (OR: 2.44, 95%CI: 1.92-3.89, p = 0.07) and increased risk of hypertension (OR: 2.17,95%CI: 1.69-3.40, p = 0.05). Conversely, Negative interactions were found between high plant-source nitrate/nitrite intake with high KYN and TMAO levels on MetS and some components. Conclusion There is an interaction between dietary nitrate/nitrite source (animal vs. plant) and gut microbial metabolites (TMAO and KYN) on the risk of of MetS and its components. These findings highlight the importance of considering diet, gut microbiome metabolites, and their interactions in MetS risk assessment.
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Affiliation(s)
- Atieh Mirzababaei
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Mahmoodi
- Department of Cellular and Molecular Nutrition, School of Nutritional Science and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbasali Keshtkar
- Department of Disaster and Emergency Health, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Sara Ebrahimi
- Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Geelong, VIC, Australia
| | | | - Faezeh Abaj
- Department of Nutrition, Dietetics and Food, Monash University, Clayton, VIC, Australia
| | - Mina Radmehr
- Department of Nutrition, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Pardis Khalili
- Department of Nutrition, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Mahya Mehri Hajmir
- Department of Exercise and Nutrition Sciences, Milken Institute School of Public Health, The George Washington University, Washington, DC, United States
| | - Khadijeh Mirzaei
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
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Vints WAJ, Šeikinaitė J, Gökçe E, Kušleikienė S, Šarkinaite M, Valatkeviciene K, Česnaitienė VJ, Verbunt J, Levin O, Masiulis N. Resistance exercise effects on hippocampus subfield volumes and biomarkers of neuroplasticity and neuroinflammation in older adults with low and high risk of mild cognitive impairment: a randomized controlled trial. GeroScience 2024; 46:3971-3991. [PMID: 38478179 PMCID: PMC11226571 DOI: 10.1007/s11357-024-01110-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 02/25/2024] [Indexed: 07/07/2024] Open
Abstract
Physical exercise is suggested to promote hippocampal neuroplasticity by increasing circulating neurotrophic and anti-inflammatory factors. Our aim was to explore the interplay between the effect of progressive resistance exercise on blood biomarker levels, hippocampal neurometabolite levels and hippocampal volume in older adults with a low compared to a high risk of mild cognitive impairment (MCI). Seventy apparently healthy male/female older adults (aged 60-85 years old) were randomly allocated to a 12 week lower limb progressive resistance or no intervention, stratified for low (< 26/30) or high (≥ 26/30) Montreal Cognitive Assessment (MoCA) score, indicating MCI risk. Outcome measures were blood levels of insulin-like growth factor-1 (IGF-1), interleukin-6 (IL-6) or kynurenine (KYN); hippocampal total and subfield volumes of the cornu ammonis 1 (CA1) and 4 (CA4), subiculum, presubiculum, and dentate gyrus measured with magnetic resonance imaging (MRI); and hippocampus neurometabolites including total N-acetylaspartate (NAA), myo-inositol (mIns), and total creatine (Cr) measured with proton magnetic resonance spectroscopy (1H-MRS). We evaluated the intervention effect, cognitive status effect, their interaction and the bivariate relationship between exercise-induced changes between the outcome measures. Higher kynurenine levels (p = 0.015) and lower subiculum volumes (p = 0.043) were found in older adults with high MCI risk compared to older adults with low MCI risk. Exercise-induced CA1 volume changes were negatively correlated with hippocampal tNAA/mIns level changes (r = -0.605, p = 0.006). This study provides valuable insight in the multifactorial processes related to resistance training in older adults with low or high MCI risk.
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Affiliation(s)
- Wouter A J Vints
- Department of Health Promotion and Rehabilitation, Lithuanian Sports University, Kaunas, Lithuania.
- Department of Rehabilitation Medicine Research School CAPHRI, Maastricht University, Maastricht, The Netherlands.
- Centre of Expertise in Rehabilitation and Audiology, Adelante Zorggroep, Hoensbroek, The Netherlands.
| | - Julija Šeikinaitė
- Department of Rehabilitation, Physical and Sports Medicine, Institute of Health Science, Vilnius University, Vilnius, Lithuania
| | - Evrim Gökçe
- Sports Rehabilitation Laboratory, Ankara City Hospital, 06800, Ankara, Turkey
| | - Simona Kušleikienė
- Department of Health Promotion and Rehabilitation, Lithuanian Sports University, Kaunas, Lithuania
| | - Milda Šarkinaite
- Department of Radiology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Kristina Valatkeviciene
- Department of Radiology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Vida J Česnaitienė
- Department of Health Promotion and Rehabilitation, Lithuanian Sports University, Kaunas, Lithuania
| | - Jeanine Verbunt
- Department of Rehabilitation Medicine Research School CAPHRI, Maastricht University, Maastricht, The Netherlands
- Centre of Expertise in Rehabilitation and Audiology, Adelante Zorggroep, Hoensbroek, The Netherlands
| | - Oron Levin
- Department of Health Promotion and Rehabilitation, Lithuanian Sports University, Kaunas, Lithuania
- Motor Control & Neuroplasticity Research Group, Group Biomedical Sciences, Catholic University Leuven, Heverlee, Belgium
| | - Nerijus Masiulis
- Department of Health Promotion and Rehabilitation, Lithuanian Sports University, Kaunas, Lithuania
- Department of Rehabilitation, Physical and Sports Medicine, Institute of Health Science, Vilnius University, Vilnius, Lithuania
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Melnik BC, Weiskirchen R, Stremmel W, John SM, Schmitz G. Risk of Fat Mass- and Obesity-Associated Gene-Dependent Obesogenic Programming by Formula Feeding Compared to Breastfeeding. Nutrients 2024; 16:2451. [PMID: 39125332 PMCID: PMC11314333 DOI: 10.3390/nu16152451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 07/21/2024] [Accepted: 07/25/2024] [Indexed: 08/12/2024] Open
Abstract
It is the purpose of this review to compare differences in postnatal epigenetic programming at the level of DNA and RNA methylation and later obesity risk between infants receiving artificial formula feeding (FF) in contrast to natural breastfeeding (BF). FF bears the risk of aberrant epigenetic programming at the level of DNA methylation and enhances the expression of the RNA demethylase fat mass- and obesity-associated gene (FTO), pointing to further deviations in the RNA methylome. Based on a literature search through Web of Science, Google Scholar, and PubMed databases concerning the dietary and epigenetic factors influencing FTO gene and FTO protein expression and FTO activity, FTO's impact on postnatal adipogenic programming was investigated. Accumulated translational evidence underscores that total protein intake as well as tryptophan, kynurenine, branched-chain amino acids, milk exosomal miRNAs, NADP, and NADPH are crucial regulators modifying FTO gene expression and FTO activity. Increased FTO-mTORC1-S6K1 signaling may epigenetically suppress the WNT/β-catenin pathway, enhancing adipocyte precursor cell proliferation and adipogenesis. Formula-induced FTO-dependent alterations of the N6-methyladenosine (m6A) RNA methylome may represent novel unfavorable molecular events in the postnatal development of adipogenesis and obesity, necessitating further investigations. BF provides physiological epigenetic DNA and RNA regulation, a compelling reason to rely on BF.
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Affiliation(s)
- Bodo C. Melnik
- Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, D-49076 Osnabrück, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany;
| | - Wolfgang Stremmel
- Praxis for Internal Medicine, Beethovenstrasse 2, D-76530 Baden-Baden, Germany;
| | - Swen Malte John
- Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, D-49076 Osnabrück, Germany
- Institute for Interdisciplinary Dermatological Prevention and Rehabilitation (iDerm), University of Osnabrück, D-49076 Osnabrück, Germany;
| | - Gerd Schmitz
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital of Regensburg, D-93053 Regensburg, Germany;
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9
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Cui Y, Auclair H, He R, Zhang Q. GPCR-mediated regulation of beige adipocyte formation: Implications for obesity and metabolic health. Gene 2024; 915:148421. [PMID: 38561165 DOI: 10.1016/j.gene.2024.148421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 03/10/2024] [Accepted: 03/29/2024] [Indexed: 04/04/2024]
Abstract
Obesity and its associated complications pose a significant burden on health. The non-shivering thermogenesis (NST) and metabolic capacity properties of brown adipose tissue (BAT), which are distinct from those of white adipose tissue (WAT), in combating obesity and its related metabolic diseases has been well documented. However, beige adipose tissue, the third and relatively novel type of adipose tissue, which emerges in extensive presence of WAT and shares similar favorable metabolic properties with BAT, has garnered considerable attention in recent years. In this review, we focused on the role of G protein-coupled receptors (GPCRs), the largest receptor family and the most successful class of drug targets in humans, in the induction of beige adipocytes. More importantly, we highlight researchers' clinical treatment attempts to ameliorate obesity and other related metabolic diseases through the formation and activation of beige adipose tissue. In summary, this review provides valuable insights into the formation of beige adipose tissue and the involvement of GPCRs, based on the latest advancements in scientific research.
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Affiliation(s)
- Yuanxu Cui
- Animal Zoology Department, Kunming Medical University, Kunming, China; Science and Technology Achievement Incubation Center, Kunming Medical University, Kunming, China
| | - Hugo Auclair
- Faculty of Medicine, François-Rabelais University, Tours, France
| | - Rong He
- Animal Zoology Department, Kunming Medical University, Kunming, China
| | - Qiang Zhang
- Animal Zoology Department, Kunming Medical University, Kunming, China.
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10
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Reininghaus EZ, Lenger M, Schönthaler EMD, Fellendorf FT, Stross T, Schwarz M, Moll N, Reininghaus B, Dalkner N. Changes in tryptophan breakdown associated with response to multimodal treatment in depression. Front Psychiatry 2024; 15:1380620. [PMID: 38974918 PMCID: PMC11224482 DOI: 10.3389/fpsyt.2024.1380620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 06/03/2024] [Indexed: 07/09/2024] Open
Abstract
Background Research on depression showed that dysregulations in tryptophan (TRP), kynurenine (KYN), and its KYN pathway metabolites are key aspects in the development and maintenance of depressive symptoms. In our previous reports, we described sex-specific changes in TRP breakdown as well as changes in KYN and KYN/TRP in association with treatment response and inflammatory and metabolic parameters. However, results of treatment effects on KYN pathway metabolites as well as how pathway changes are related to treatment response remain sparse. Objective We investigated potential changes of KYN and KYN pathway metabolites in association with therapeutic response of individuals with depression during a six-week multimodal psychiatric rehabilitation program. Methods 87 participants were divided into treatment responders and non-responders (48 responders, 39 non-responders; 38 male, 49 female; M age = 51.09; SD age = 7.70) using scores of psychological questionnaires. KYN pathway metabolites serum concentrations as well as their ratios were collected using high performance liquid chromatography. Changes over time (time of admission (t1) vs. time of discharge (t2)) were calculated using repeated measure analyses of (co)variance. Results Non-responders exhibited higher levels of 3-Hydroxyanthralinic acid (3-HAA), nicotinic acid (NA), and 3-HAA/KYN, independently of measurement time. NA levels decreased, while 3-HAA levels increased over time in both groups, independently of treatment response. 3-HK/KYN levels decreased, while KYN levels increased in non-responders, but not in responders over time. Discussion The results indicate that some compounds of the KYN pathway metabolites can be altered through multimodal long-term interventions in association with treatment response. Especially the pathway degrading KYN further down to 3-HAA and 3-HK/KYN might be decisive for treatment response in depression.
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Affiliation(s)
- Eva Z. Reininghaus
- Clinical Division of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria
| | - Melanie Lenger
- Clinical Division of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria
| | - Elena M. D. Schönthaler
- Clinical Division of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria
| | - Frederike T. Fellendorf
- Clinical Division of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria
| | - Tatjana Stross
- Clinical Division of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria
| | - Markus Schwarz
- Institute of Laboratory Medicine, University Hospital, Ludwig-Maximilian University (LMU), Munich, Munich, Germany
| | - Natalie Moll
- Institute of Laboratory Medicine, University Hospital, Ludwig-Maximilian University (LMU), Munich, Munich, Germany
| | - Bernd Reininghaus
- Clinical Division of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria
| | - Nina Dalkner
- Clinical Division of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria
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11
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Hernandez N, Lokhnygina Y, Ramaker ME, Ilkayeva O, Muehlbauer MJ, Crawford ML, Grant RP, Hsia DS, Jain N, Bain JR, Armstrong S, Newgard CB, Freemark M, Gumus Balikcioglu P. Sex Differences in Branched-chain Amino Acid and Tryptophan Metabolism and Pathogenesis of Youth-onset Type 2 Diabetes. J Clin Endocrinol Metab 2024; 109:e1345-e1358. [PMID: 38066593 PMCID: PMC10940256 DOI: 10.1210/clinem/dgad708] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Indexed: 03/16/2024]
Abstract
OBJECTIVES Insulin resistance is associated with elevations in plasma branched-chain amino acids (BCAAs). BCAAs compete with aromatic amino acids including tryptophan for uptake into β cells. To explore relationships between BCAAs and tryptophan metabolism, adiposity, and glucose tolerance, we compared urine metabolites in overweight/obese youth with type 2 diabetes (T2D) with those in nondiabetic overweight/obese and lean youth. METHODS Metabolites were measured in 24-hour and first-morning urine samples of 56 nondiabetic adolescents with overweight/obesity, 42 adolescents with T2D, and 43 lean controls, aged 12 to 21 years. Group differences were assessed by Kruskal Wallis or ANOVA. RESULTS Groups were comparable for age, pubertal status, and ethnicity. Youth with T2D were predominantly female and had highest percent body fat. BCAAs, branched-chain ketoacids (BCKAs), tryptophan, and kynurenine were higher in urine of subjects with T2D. There were no differences between lean controls and nondiabetic youth with overweight/obesity. T2D was associated with diversion of tryptophan from the serotonin to the kynurenine pathway, with higher urinary kynurenine/serotonin ratio and lower serotonin/tryptophan and 5-HIAA/kynurenine ratios. Urinary BCAAs, BCKAs, tryptophan, and ratios reflecting diversion to the kynurenine pathway correlated positively with metrics of body fat and hemoglobin A1c. Increases in these metabolites in the obese T2D group were more pronounced and statistically significant only in adolescent girls. CONCLUSION Increases in urinary BCAAs and BCKAs in adolescent females with T2D are accompanied by diversion of tryptophan metabolism from the serotonin to the kynurenine pathway. These adaptations associate with higher risks of T2D in obese adolescent females than adolescent males.
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Affiliation(s)
- Natalie Hernandez
- Division of Pediatric Endocrinology and Diabetes, Duke University Medical Center, Durham, NC 27710, USA
| | - Yuliya Lokhnygina
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC 27710, USA
- Duke Clinical Research Institute, Duke University Medical Center, Durham, NC 27701, USA
| | - Megan Elizabeth Ramaker
- Duke Molecular Physiology Institute (DMPI), Duke University Medical Center, Durham, NC 27701, USA
| | - Olga Ilkayeva
- Duke Molecular Physiology Institute (DMPI), Duke University Medical Center, Durham, NC 27701, USA
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27705, USA
- Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC 27710, USA
| | - Michael J Muehlbauer
- Duke Molecular Physiology Institute (DMPI), Duke University Medical Center, Durham, NC 27701, USA
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27705, USA
| | - Matthew L Crawford
- Department of Research and Development, LabCorp, Burlington, NC 27215, USA
| | - Russell P Grant
- Department of Research and Development, LabCorp, Burlington, NC 27215, USA
| | - Daniel S Hsia
- Clinical Trials Unit, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA
| | - Nina Jain
- Division of Endocrinology, Department of Pediatrics, University of North Carolina, Chapel Hill, NC 27514, USA
| | - James R Bain
- Duke Molecular Physiology Institute (DMPI), Duke University Medical Center, Durham, NC 27701, USA
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27705, USA
- Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC 27710, USA
| | - Sarah Armstrong
- Duke Clinical Research Institute, Duke University Medical Center, Durham, NC 27701, USA
- Division of General Pediatrics and Adolescent Health, Duke University Medical Center, Durham, NC 27710, USA
- Department of Family Medicine and Community Health, Duke University Medical Center, Durham, NC 27710, USA
- Department of Population Health Sciences, Duke University Medical Center, Durham, NC 27710, USA
| | - Christopher B Newgard
- Duke Molecular Physiology Institute (DMPI), Duke University Medical Center, Durham, NC 27701, USA
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27705, USA
- Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC 27710, USA
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
| | - Michael Freemark
- Division of Pediatric Endocrinology and Diabetes, Duke University Medical Center, Durham, NC 27710, USA
- Duke Molecular Physiology Institute (DMPI), Duke University Medical Center, Durham, NC 27701, USA
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27705, USA
| | - Pinar Gumus Balikcioglu
- Division of Pediatric Endocrinology and Diabetes, Duke University Medical Center, Durham, NC 27710, USA
- Duke Molecular Physiology Institute (DMPI), Duke University Medical Center, Durham, NC 27701, USA
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27705, USA
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12
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Conte C, Cipponeri E, Roden M. Diabetes Mellitus, Energy Metabolism, and COVID-19. Endocr Rev 2024; 45:281-308. [PMID: 37934800 PMCID: PMC10911957 DOI: 10.1210/endrev/bnad032] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 08/30/2023] [Accepted: 11/01/2023] [Indexed: 11/09/2023]
Abstract
Obesity, diabetes mellitus (mostly type 2), and COVID-19 show mutual interactions because they are not only risk factors for both acute and chronic COVID-19 manifestations, but also because COVID-19 alters energy metabolism. Such metabolic alterations can lead to dysglycemia and long-lasting effects. Thus, the COVID-19 pandemic has the potential for a further rise of the diabetes pandemic. This review outlines how preexisting metabolic alterations spanning from excess visceral adipose tissue to hyperglycemia and overt diabetes may exacerbate COVID-19 severity. We also summarize the different effects of SARS-CoV-2 infection on the key organs and tissues orchestrating energy metabolism, including adipose tissue, liver, skeletal muscle, and pancreas. Last, we provide an integrative view of the metabolic derangements that occur during COVID-19. Altogether, this review allows for better understanding of the metabolic derangements occurring when a fire starts from a small flame, and thereby help reducing the impact of the COVID-19 pandemic.
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Affiliation(s)
- Caterina Conte
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome 00166, Italy
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Milan 20099, Italy
| | - Elisa Cipponeri
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Milan 20099, Italy
| | - Michael Roden
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf 40225, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf 40225, Germany
- German Center for Diabetes Research, Partner Düsseldorf, Neuherberg 85764, Germany
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13
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Bakker L, Choe K, Eussen SJPM, Ramakers IHGB, van den Hove DLA, Kenis G, Rutten BPF, Verhey FRJ, Köhler S. Relation of the kynurenine pathway with normal age: A systematic review. Mech Ageing Dev 2024; 217:111890. [PMID: 38056721 DOI: 10.1016/j.mad.2023.111890] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 11/21/2023] [Accepted: 11/29/2023] [Indexed: 12/08/2023]
Abstract
BACKGROUND The kynurenine pathway (KP) is gaining more attention as a common pathway involved in age-related conditions. However, which changes in the KP occur due to normal ageing is still largely unclear. The aim of this systematic review was to summarize the available evidence for associations of KP metabolites with age. METHODS We used an broad search strategy and included studies up to October 2023. RESULTS Out of 8795 hits, 55 studies were eligible for the systematic review. These studies suggest that blood levels of tryptophan decrease with age, while blood and cerebrospinal fluid levels of kynurenine and its ratio with tryptophan increase. Studies investigating associations between cerebrospinal fluid and blood levels of kynurenic acid and quinolinic acid with age reported either positive or non-significant findings. However, there is a large heterogeneity across studies. Additionally, most studies were cross-sectional, and only few studies investigated associations with other downstream kynurenines. CONCLUSIONS This systematic review suggests that levels of kynurenines are positively associated with age. Larger and prospective studies are needed that also investigate a more comprehensive panel of KP metabolites and changes during the life-course.
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Affiliation(s)
- Lieke Bakker
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs) and European Graduate School of Neuroscience (EURON), Faculty of Health, Medicine and Life Sciences (FHML) Maastricht University, 6229 ER Maastricht, the Netherlands; Alzheimer Center Limburg, Maastricht University, 6229 ET Maastricht, the Netherlands
| | - Kyonghwan Choe
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs) and European Graduate School of Neuroscience (EURON), Faculty of Health, Medicine and Life Sciences (FHML) Maastricht University, 6229 ER Maastricht, the Netherlands
| | - Simone J P M Eussen
- Department of Epidemiology, Maastricht University, 6229 HA Maastricht, the Netherlands; School for Cardiovascular Diseases (CARIM) and Care and Public Health Research Institute (CAPHRI), 6229 ER Maastricht, the Netherlands
| | - Inez H G B Ramakers
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs) and European Graduate School of Neuroscience (EURON), Faculty of Health, Medicine and Life Sciences (FHML) Maastricht University, 6229 ER Maastricht, the Netherlands; Alzheimer Center Limburg, Maastricht University, 6229 ET Maastricht, the Netherlands
| | - Daniel L A van den Hove
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs) and European Graduate School of Neuroscience (EURON), Faculty of Health, Medicine and Life Sciences (FHML) Maastricht University, 6229 ER Maastricht, the Netherlands; Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, 97080 Wuerzburg, Germany
| | - Gunter Kenis
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs) and European Graduate School of Neuroscience (EURON), Faculty of Health, Medicine and Life Sciences (FHML) Maastricht University, 6229 ER Maastricht, the Netherlands
| | - Bart P F Rutten
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs) and European Graduate School of Neuroscience (EURON), Faculty of Health, Medicine and Life Sciences (FHML) Maastricht University, 6229 ER Maastricht, the Netherlands; Alzheimer Center Limburg, Maastricht University, 6229 ET Maastricht, the Netherlands
| | - Frans R J Verhey
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs) and European Graduate School of Neuroscience (EURON), Faculty of Health, Medicine and Life Sciences (FHML) Maastricht University, 6229 ER Maastricht, the Netherlands; Alzheimer Center Limburg, Maastricht University, 6229 ET Maastricht, the Netherlands
| | - Sebastian Köhler
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs) and European Graduate School of Neuroscience (EURON), Faculty of Health, Medicine and Life Sciences (FHML) Maastricht University, 6229 ER Maastricht, the Netherlands; Alzheimer Center Limburg, Maastricht University, 6229 ET Maastricht, the Netherlands.
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14
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Mirzababaei A, Mahmoodi M, Keshtkar A, Ashraf H, Abaj F, Soveid N, Hajmir MM, Radmehr M, Khalili P, Mirzaei K. Serum levels of trimethylamine N-oxide and kynurenine novel biomarkers are associated with adult metabolic syndrome and its components: a case-control study from the TEC cohort. Front Nutr 2024; 11:1326782. [PMID: 38321994 PMCID: PMC10844432 DOI: 10.3389/fnut.2024.1326782] [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: 10/24/2023] [Accepted: 01/02/2024] [Indexed: 02/08/2024] Open
Abstract
Background Epidemiologic research suggests that gut microbiota alteration (dysbiosis) may play a role in the pathogenesis of metabolic syndrome (MetS). Dysbiosis can influence Trimethylamine N-oxide (TMAO) a gut microbiota-derived metabolite, as well as kynurenine pathways (KP), which are known as a new marker for an early predictor of chronic diseases. Hence, the current study aimed to investigate the association between KYN and TMAO with MetS and its components. Methods This case-control study was conducted on 250 adults aged 18 years or over of Tehran University of Medical Sciences (TUMS) Employee's Cohort study (TEC) in the baseline phase. Data on the dietary intakes were collected using a validated dish-based food frequency questionnaire (FFQ) and dietary intakes of nitrite and nitrate were estimated using FFQ with 144 items. MetS was defined according to the NCEP ATP criteria. Serum profiles TMAO and KYN were measured by standard protocol. Result The mean level of TMAO and KYN in subjects with MetS was 51.49 pg/mL and 417.56 nmol/l. High levels of TMAO (≥30.39 pg/mL) with MetS were directly correlated, after adjusting for confounding factors, the odds of MetS in individuals 2.37 times increased (OR: 2.37, 95% CI: 1.31-4.28, P-value = 0.004), also, high levels of KYN (≥297.18 nmol/L) increased odds of Mets+ 1.48 times, which is statistically significant (OR: 1.48, 95% CI: 0.83-2.63, P-value = 0.04). High levels of TMAO compared with the reference group increased the odds of hypertriglyceridemia and low HDL in crude and adjusted models (P < 0.05). Additionally, there was a statistically significant high level of KYN increased odds of abdominal obesity (P < 0.05). Conclusion Our study revealed a positive association between serum TMAO and KYN levels and MetS and some of its components. For underlying mechanisms and possible clinical implications of the differences. Prospective studies in healthy individuals are necessary.
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Affiliation(s)
- Atieh Mirzababaei
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Mahmoodi
- Department of Cellular and Molecular Nutrition, School of Nutritional Science and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbasali Keshtkar
- Department of Disaster and Emergency Health, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Haleh Ashraf
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Faezeh Abaj
- Department of Nutrition, Dietetics and Food, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia
| | - Neda Soveid
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahya Mehri Hajmir
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Mina Radmehr
- Department of Nutrition, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Pardis Khalili
- Department of Nutrition, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Khadijeh Mirzaei
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
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15
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Yanko R, Levashov M, Chaka OG, Nosar V, Khasabov SG, Khasabova I. Tryptophan Prevents the Development of Non-Alcoholic Fatty Liver Disease. Diabetes Metab Syndr Obes 2023; 16:4195-4204. [PMID: 38152280 PMCID: PMC10752026 DOI: 10.2147/dmso.s444278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 12/18/2023] [Indexed: 12/29/2023] Open
Abstract
Purpose The main aim of this research is to study the protective effects of tryptophan on the histomorphological and biochemical abnormalities in the liver caused by a high-calorie diet (HCD), as well as its ability to normalize mitochondrial functions in order to prevent the development of non-alcoholic fatty liver disease (NAFLD). Methods The study was conducted in male Wistar rats aged 3 months at the start of the experiment. Control animals (group I) were fed a standard diet. Group II experimental animals were fed a diet with an excess of fat (45%) and carbohydrates (31%) for 12 weeks. Group III experimental animals also received L-tryptophan at a dose of 80 mg/kg body weight in addition to the HCD. The presence of NAFLD, functional activity, physiological regeneration, and the state of the liver parenchyma and connective tissue were assessed using physiological, morphological, histo-morphometric, biochemical, and biophysical research methods. Results HCD induced the development of NAFLD, which is characterized by an increase in liver weight, hypertrophy of hepatocytes and an increase in the concentration of lipids, cholesterol and triglycerides in liver tissue. Increased alanine aminotransferase activity in the liver of obese rats also confirm hepatocytes damage. Tryptophan added to the diet lowered the severity of NAFLD by reducing fat accumulation and violations of bioelectric properties, and prevented a decrease in mitochondrial ATP synthesis. Conclusion The addition of tryptophan can have a potential positive effect on the liver, reducing the severity of structural, biochemical, mitochondrial and bioelectric damage caused by HCD.
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Affiliation(s)
- Roman Yanko
- Department of Clinical Physiology of Connective Tissue, Bogomoletz Institute of Physiology National Academy of Sciences of Ukraine, Kiev, Ukraine
| | - Mikhail Levashov
- Department of Clinical Physiology of Connective Tissue, Bogomoletz Institute of Physiology National Academy of Sciences of Ukraine, Kiev, Ukraine
| | - Olena Georgievna Chaka
- Department of Clinical Physiology of Connective Tissue, Bogomoletz Institute of Physiology National Academy of Sciences of Ukraine, Kiev, Ukraine
| | - Valentina Nosar
- Department of Clinical Physiology of Connective Tissue, Bogomoletz Institute of Physiology National Academy of Sciences of Ukraine, Kiev, Ukraine
| | - Sergey G Khasabov
- Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN, USA
| | - Iryna Khasabova
- Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN, USA
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16
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Wang M, Feng X, Zhao Y, Lan Y, Xu H. Indole-3-acetamide from gut microbiota activated hepatic AhR and mediated the remission effect of Lactiplantibacillus plantarum P101 on alcoholic liver injury in mice. Food Funct 2023; 14:10535-10548. [PMID: 37947440 DOI: 10.1039/d3fo03585a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2023]
Abstract
Alcoholic liver disease is a prevalent condition resulting from excessive alcohol consumption, characterized by hepatic lipid accumulation and inflammation. This study delved into the protective effects and mechanisms of L. plantarum P101 on alcoholic liver injury in mice. As a result, L. plantarum P101 intervention reduced ALT and AST release, indicative of hepatocyte injury alleviation, while enhancing the activity of the antioxidant enzymes SOD and CAT. A reduction in pro-inflammatory cytokine TNF-α and an increase in anti-inflammatory cytokine IL-10 levels were observed in the L. plantarum P101-intervened mouse liver, signifying reduced inflammation within the mice. Furthermore, L. plantarum P101 intervention altered the gut microbial composition, primarily marked by an increase in Bacteroidota abundance, along with significant enrichment of beneficial bacteria, including Coprostanoligenes, Blautia and Lactiplantibacillus. Correlation analysis unveiled connections between serum tryptophan metabolites and the altered gut microbiota genera, suggesting that gut microbiota-driven effects may extend to extraintestinal organs through their metabolites. Intriguingly, serum indole-3-acetamide (IAM) was elevated by L. plantarum P101-regulated gut microbiota. Subsequently, the role of IAM in ameliorating alcoholic injury was explored using HepG2 cells, where it bolstered cell viability and attenuated EtOH-induced oxidative damage. Concomitantly, IAM activated the gene and protein expression of AhR in cells. Likewise, hepatic AhR expression in mice subjected to L. plantarum P101 significantly up-regulated, possibly instigated by gut microbiota-mediated IAM. Collectively, L. plantarum P101 orchestrates a modulation of gut microbiota and its metabolites, particularly IAM, to activate AhR, thereby alleviating alcoholic liver injury.
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Affiliation(s)
- Mengqi Wang
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, P.R. China.
| | - Xiaoyan Feng
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, P.R. China.
| | - Yu Zhao
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, P.R. China.
| | - Yuzhi Lan
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, P.R. China.
| | - Hengyi Xu
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, P.R. China.
- International Institute of Food Innovation, Nanchang University, Nanchang 330299, P.R. China
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Hu Y, Li J, Wang B, Zhu L, Li Y, Ivey KL, Lee KH, Eliassen AH, Chan A, Huttenhower C, Hu FB, Qi Q, Rimm EB, Sun Q. Interplay between diet, circulating indolepropionate concentrations and cardiometabolic health in US populations. Gut 2023; 72:2260-2271. [PMID: 37739776 PMCID: PMC10841831 DOI: 10.1136/gutjnl-2023-330410] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 08/23/2023] [Indexed: 09/24/2023]
Abstract
OBJECTIVES To identify indolepropionate (IPA)-predicting gut microbiota species, investigate potential diet-microbiota interactions, and examine the prospective associations of circulating IPA concentrations with type 2 diabetes (T2D) and coronary heart disease (CHD) risk in free-living individuals. DESIGN We included 287 men from the Men's Lifestyle Validation Study, a substudy of the Health Professionals Follow-Up Study (HPFS), who provided up to two pairs of faecal samples and two blood samples. Diet was assessed using 7-day diet records. Associations between plasma concentrations of tryptophan metabolites and T2D CHD risk were examined in 13 032 participants from Nurses' Health Study (NHS), NHSII and HPFS. RESULTS We identified 17 microbial species whose abundance was significantly associated with plasma IPA concentrations. A significant association between higher tryptophan intake and higher IPA concentrations was only observed among men who had higher fibre intake and a higher microbial species score consisting of the 17 species (p-interaction<0.01). Dietary and plasma concentrations of tryptophan and most kynurenine pathway metabolites were positively associated with T2D risk (HRQ5 vs Q1 ranged from 1.17 to 1.46) while a significant inverse association was found for IPA (HRQ5 vs Q1 (95% CI) 0.70 (0.56 to 0.88)). No associations were found in CHD for any plasma tryptophan metabolites. CONCLUSIONS Specific microbial species and dietary fibre jointly predicted significantly higher circulating IPA concentrations at higher tryptophan intake. Dietary and plasma tryptophan, as well as its kynurenine pathway metabolites, demonstrated divergent associations from those for IPA, which was significantly predictive of lower risk of T2D.
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Affiliation(s)
- Yang Hu
- Department of Nutrition, Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA
| | - Jun Li
- Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Biqi Wang
- Department of Medicine, UMASS Medical School, Worcester, Massachusetts, USA
| | - Lu Zhu
- Department of Nutrition, Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA
| | - Yanping Li
- Department of Nutrition, Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA
| | - Kerry L Ivey
- Department of Nutrition, Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA
| | - Kyu Ha Lee
- Department of Nutrition, Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA
- Department of Epidemiology, Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA
- Department of Biostatistics, Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA
| | - A Heather Eliassen
- Department of Epidemiology, Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Andrew Chan
- Clinical and Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
- Immunology and Infectious Diseases, Harvard University T. H. Chan School of Public Health, Boston, Boston, Massachusetts, USA
| | - Curtis Huttenhower
- Department of Biostatistics, Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA
- Immunology and Infectious Diseases, Harvard University T. H. Chan School of Public Health, Boston, Boston, Massachusetts, USA
- Eli and Edythe L. Broad Institute of Harvard and MIT, Flinders University College of Nursing and Health Sciences, Cambridge, MA, USA
| | - Frank B Hu
- Department of Nutrition, Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA
- Department of Epidemiology, Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Qibin Qi
- Department of Epidemiology and Population Health, Yeshiva University Albert Einstein College of Medicine, Bronx, New York, USA
| | - Eric B Rimm
- Department of Nutrition, Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA
- Department of Epidemiology, Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Qi Sun
- Department of Nutrition, Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA
- Department of Epidemiology, Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
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18
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Diedrich JD, Gonzalez-Pons R, Medeiros HCD, Ensink E, Liby KT, Wellberg EA, Lunt SY, Bernard JJ. Adipocyte-derived kynurenine stimulates malignant transformation of mammary epithelial cells through the aryl hydrocarbon receptor. Biochem Pharmacol 2023; 216:115763. [PMID: 37625554 PMCID: PMC10587895 DOI: 10.1016/j.bcp.2023.115763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 08/17/2023] [Accepted: 08/21/2023] [Indexed: 08/27/2023]
Abstract
Anti-hormone therapies are not efficacious for reducing the incidence of triple negative breast cancer (TNBC), which lacks both estrogen and progesterone receptors. While the etiology of this aggressive breast cancer subtype is unclear, visceral obesity is a strong risk factor for both pre- and post-menopausal cases. The mechanism by which excessive deposition of visceral adipose tissue (VAT) promotes the malignant transformation of hormone receptor-negative mammary epithelial cells is currently unknown. We developed a novel in vitro system of malignant transformation in which non-tumorigenic human breast epithelial cells (MCF-10A) grow in soft agar when cultured with factors released from VAT. These cells, which acquire the capacity for 3D growth, show elevated aryl hydrocarbon receptor (AhR) protein and AhR target genes, suggesting that AhR activity may drive malignant transformation by VAT. AhR is a ligand-dependent transcription factor that generates biological responses to exogenous carcinogens and to the endogenous tryptophan pathway metabolite, kynurenine. The serum kynurenine to tryptophan ratio has been shown to be elevated in patients with obesity. Herein, we demonstrate that AhR inhibitors or knockdown of AhR in MCF-10A cells prevents VAT-induced malignant transformation. Specifically, VAT-induced transformation is inhibited by Kyn-101, an inhibitor for the endogenous ligand binding site of AhR. Mass spectrometry analysis demonstrates that adipocytes metabolize tryptophan and release kynurenine, which is taken up by MCF-10A cells and activates the AhR to induce CYP1B1 and promote malignant transformation. This novel hormone receptor-independent mechanism of malignant transformation suggests targeting AhR for TNBC prevention in the context of visceral adiposity.
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Affiliation(s)
- Jonathan D Diedrich
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824 USA
| | - Romina Gonzalez-Pons
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824 USA
| | - Hyllana C D Medeiros
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824 USA
| | - Elliot Ensink
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824 USA
| | - Karen T Liby
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824 USA
| | - Elizabeth A Wellberg
- Department of Pathology, University of Oklahoma Health Sciences Center, Stephenson Cancer Center, Harold Hamm Diabetes Center, Oklahoma City, OK, USA
| | - Sophia Y Lunt
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824 USA; Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, MI 48824 USA
| | - Jamie J Bernard
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824 USA; Department of Medicine, Michigan State University, East Lansing, MI 48824 USA.
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19
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Shu L, Wang Y, Huang W, Fan S, Pan J, Lv Q, Wang L, Wang Y, Xu J, Yan H, Bai Y, Wang Y, Li Y. Integrating Metabolomics and Network Pharmacology to Explore the Mechanism of Tongmai Yangxin Pills in Ameliorating Doxorubicin-Induced Cardiotoxicity. ACS OMEGA 2023; 8:18128-18139. [PMID: 37251132 PMCID: PMC10210219 DOI: 10.1021/acsomega.3c01441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 04/25/2023] [Indexed: 05/31/2023]
Abstract
Doxorubicin (DOX) is a broad-spectrum chemotherapeutic drug used in clinical treatment of malignant tumors. It has a high anticancer activity but also high cardiotoxicity. The aim of this study was to explore the mechanism of Tongmai Yangxin pills (TMYXPs) in ameliorating DOX-induced cardiotoxicity through integrated metabolomics and network pharmacology. In this study, first, an ultrahigh-performance liquid chromatography-quadrupole-time-of-flight/mass spectrometry (UPLC-Q-TOF/MS) metabonomics strategy was established to obtain metabolite information and potential biomarkers were determined after data processing. Second, network pharmacological analysis was used to evaluate the active components, drug-disease targets, and key pathways of TMYXPs to alleviate DOX-induced cardiotoxicity. Targets from the network pharmacology analysis and metabolites from plasma metabolomics were jointly analyzed to select crucial metabolic pathways. Finally, the related proteins were verified by integrating the above results and the possible mechanism of TMYXPs to alleviate DOX-induced cardiotoxicity was studied. After metabolomics data processing, 17 different metabolites were screened, and it was found that TMYXPs played a role in myocardial protection mainly by affecting the tricarboxylic acid (TCA) cycle of myocardial cells. A total of 71 targets and 20 related pathways were screened out with network pharmacological analysis. Based on the combined analysis of 71 targets and different metabolites, TMYXPs probably played a role in myocardial protection through regulating upstream proteins of the insulin signaling pathway, MAPK signaling pathway, and p53 signaling pathway, as well as the regulation of metabolites related to energy metabolism. They then further affected the downstream Bax/Bcl-2-Cyt c-caspase-9 axis, inhibiting the myocardial cell apoptosis signaling pathway. The results of this study may contribute to the clinical application of TMYXPs in DOX-induced cardiotoxicity.
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Affiliation(s)
- Lexin Shu
- School
of Chinese Materia Medica, Tianjin University
of Traditional Chinese Medicine, Tianjin 301617, China
| | - Yuming Wang
- School
of Chinese Materia Medica, Tianjin University
of Traditional Chinese Medicine, Tianjin 301617, China
| | - Wei Huang
- School
of Chinese Materia Medica, Tianjin University
of Traditional Chinese Medicine, Tianjin 301617, China
| | - Simiao Fan
- School
of Chinese Materia Medica, Tianjin University
of Traditional Chinese Medicine, Tianjin 301617, China
| | - Junhua Pan
- Hainan
Province Key Laboratory for Drug Preclinical Study of Pharmacology
and Toxicology Research, Hainan Medical
University, Haikou 571199, China
| | - Qingbo Lv
- Institute
of Traditional Chinese Medicine, Tianjin University of Traditional
Chinese Medicine, Tianjin 301617, China
| | - Lin Wang
- Tianjin
Zhongxin Pharmaceutical Group Co., Ltd., Le Ren Tang Pharmaceutical
Factory, Tianjin 301617, China
| | - Yujing Wang
- Tianjin
Zhongxin Pharmaceutical Group Co., Ltd., Le Ren Tang Pharmaceutical
Factory, Tianjin 301617, China
| | - Jinpeng Xu
- Tianjin
Zhongxin Pharmaceutical Group Co., Ltd., Tianjin 301617, China
| | - Haifeng Yan
- Institute
of Traditional Chinese Medicine, Tianjin University of Traditional
Chinese Medicine, Tianjin 301617, China
| | - Yuchao Bai
- School
of Chinese Materia Medica, Tianjin University
of Traditional Chinese Medicine, Tianjin 301617, China
| | - Yi Wang
- Institute
of Traditional Chinese Medicine, Tianjin University of Traditional
Chinese Medicine, Tianjin 301617, China
| | - Yubo Li
- School
of Chinese Materia Medica, Tianjin University
of Traditional Chinese Medicine, Tianjin 301617, China
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20
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Wang ME, Hodge AM, Li SX, Southey MC, Giles GG, Dugué PA. Adiposity and plasma concentrations of kynurenine pathway metabolites and traditional markers of inflammation. Obes Res Clin Pract 2023:S1871-403X(23)00028-5. [PMID: 37121824 DOI: 10.1016/j.orcp.2023.04.004] [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: 02/06/2023] [Revised: 04/12/2023] [Accepted: 04/14/2023] [Indexed: 05/02/2023]
Abstract
AIM The kynurenine pathway is increasingly recognised to play a role in inflammation and disease. We assessed the cross-sectional and longitudinal associations of adiposity measures (body mass index, waist-hip ratio, waist circumference and fat mass ratio) with plasma concentrations of kynurenine pathway metabolites and traditional markers of inflammation. METHODS We used data from 970 Melbourne Collaborative Cohort Study participants who had plasma markers measured at baseline (median age 59 years) and follow-up (median age 70 years). Linear regression was used to assess cross-sectional and longitudinal associations between four adiposity measures and concentrations of i) nine kynurenine pathway metabolites; ii) two derived markers; iii) eight traditional inflammatory markers. RESULTS Cross-sectionally, most kynurenine metabolites were strongly associated with adiposity measures at both time points; associations were generally stronger than for most inflammation markers except CRP (e.g. body mass index at baseline, quinolinic acid (per S.D. β = 0.30, 95%CI: 0.24-0.36, P = 10-21), kynurenine (β = 0.25, 95%CI: 0.19-0.31, P = 10-16) and CRP (β = 0.31, 95%CI: 0.25-0.37, P = 10-24), and remained largely unchanged after adjustment for confounders. Longitudinally, changes in adiposity measures over approximately a decade were positively associated with changes in kynurenine metabolite concentrations (in particular for 3-hydroxyanthranilic acid, kynurenine and quinolinic acid), and more strongly so than for other markers of inflammation, including CRP. CONCLUSIONS In middle-aged and older adults, plasma concentrations of kynurenine metabolites are strongly associated with adiposity, both cross-sectionally and longitudinally. Our study demonstrates that kynurenine metabolites may be valuable markers to monitor the adverse consequences of obesity.
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Affiliation(s)
- Mengmei E Wang
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia
| | - Allison M Hodge
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia; Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia
| | - Sherly X Li
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia; Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia; Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Melissa C Southey
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia; Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia; Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, Australia
| | - Graham G Giles
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia; Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia
| | - Pierre-Antoine Dugué
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia; Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
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21
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Vints WA, Kušleikienė S, Sheoran S, Valatkevičienė K, Gleiznienė R, Himmelreich U, Pääsuke M, Česnaitienė VJ, Levin O, Verbunt J, Masiulis N. Body fat and components of sarcopenia relate to inflammation, brain volume and neurometabolism in older adults. Neurobiol Aging 2023; 127:1-11. [PMID: 37004309 DOI: 10.1016/j.neurobiolaging.2023.02.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 12/27/2022] [Accepted: 02/24/2023] [Indexed: 03/06/2023]
Abstract
Obesity and sarcopenia are associated with cognitive impairments at older age. Current research suggests that blood biomarkers may mediate this body-brain crosstalk, altering neurometabolism and brain structure eventually resulting in cognitive performance changes. Seventy-four older adults (60-85 years old) underwent bio-impedance body composition analysis, handgrip strength measurements, 8-Foot Up-and-Go (8UG) test, Montreal Cognitive Assessment (MoCA), blood analysis of interleukin-6 (IL-6), kynurenine, and insulin-like growth factor-1 (IGF-1), as well as brain magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H-MRS), estimating neurodegeneration and neuroinflammation. Normal fat% or overweight was associated with larger total gray matter volume compared to underweight or obesity in older adults and obesity was associated with higher N-acetylaspartate/Creatine levels in the sensorimotor and dorsolateral prefrontal cortex. Muscle strength, not muscle mass/physical performance, corresponded to lower kynurenine and higher N-acetylaspartate/Creatine levels in the dorsal posterior cingulate and dorsolateral prefrontal cortex. The inflammatory and neurotrophic blood biomarkers did not significantly mediate these body-brain associations. This study used a multimodal approach to comprehensively assess the proposed mechanism of body-brain crosstalk.
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22
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Kupjetz M, Patt N, Joisten N, Ueland PM, McCann A, Gonzenbach R, Bansi J, Zimmer P. The serum kynurenine pathway metabolic profile is associated with overweight and obesity in multiple sclerosis. Mult Scler Relat Disord 2023; 72:104592. [PMID: 36881945 DOI: 10.1016/j.msard.2023.104592] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 02/24/2023] [Indexed: 03/05/2023]
Abstract
BACKGROUND Overweight and obesity increase multiple sclerosis (MS) susceptibility, disease severity, and disability progression. Kynurenine pathway (KP) dysregulation is present in overweight and obesity, and in MS. Since the effect of overweight and obesity on KP dysregulation in persons with MS (pwMS) remains to be established, this study primarily aims to explore the effect of overweight and obesity on the serum KP metabolic profile in pwMS. METHODS This cross-sectional study represents a secondary analysis of a randomized clinical trial at Valens rehabilitation clinic, Switzerland. Registration was performed on 22 April 2020 at clinicaltrials.gov (NCT04356248, https://clinicaltrials.gov/ct2/show/NCT04356248). The first participant was enrolled on 13 July 2020. Based on body mass index (BMI), 106 MS inpatients (Expanded Disability Status Scale (EDSS) score ≤ 6.5) were dichotomised to a lean group (LG, BMI < 25 kg/m2), and an overweight/obese group (OG, BMI ≥ 25 kg/m2). Targeted metabolomics (LC-MS/MS) was performed to determine serum concentrations of tryptophan (TRP), KP downstream metabolites, and neopterin (Neopt). Correlations between BMI, kynurenine-to-TRP ratio (KTR), and serum concentrations of TRP, KP downstream metabolites, and Neopt were calculated. ANCOVA was used to determine differences in KTR, and serum concentrations of TRP, KP downstream metabolites and Neopt between OG and LG, and across MS phenotypes. RESULTS Higher BMI correlated with higher KTR (r = 0.425, p <0.001) and serum concentrations of most KP downstream metabolites, but not with EDSS score. Higher KTR (r = 0.470, p < .001) and serum concentrations of most KP downstream metabolites correlated with a higher serum concentration of Neopt. The OG (n = 44, 59% female, 51.68 (9.98) years, EDSS: 4.71 (1.37)) revealed higher KTR (0.026 (0.007) vs. 0.022 (0.006), p=.001) and serum concentrations of most KP downstream metabolites than the LG (n = 62, 71% female, 48.37 (9.63) years, EDSS: 4.60 (1.29)). KP metabolic profiles did not differ between MS phenotypes. CONCLUSION Overweight and obesity are associated with a systemic elevation of KP metabolic flux and an accumulation of most KP downstream metabolites in pwMS. Further research is needed to clarify if KP involvement serves as a mechanism linking overweight and obesity with symptom expression, disease severity, and disability progression in pwMS.
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Affiliation(s)
- Marie Kupjetz
- Department of Performance and Health (Sports Medicine), Institute of Sport and Sport Science, TU Dortmund University, Otto-Hahn-Str. 3, 44227 Dortmund, Germany
| | - Nadine Patt
- Department of Neurology, Clinics of Valens, Rehabilitation Centre Valens, Taminaplatz 1, 7317 Valens, Switzerland
| | - Niklas Joisten
- Department of Performance and Health (Sports Medicine), Institute of Sport and Sport Science, TU Dortmund University, Otto-Hahn-Str. 3, 44227 Dortmund, Germany
| | - Per Magne Ueland
- Bevital AS, Laboratoriebygget, 9 etg, Jonas Lies vei 87, 5021 Bergen, Norway
| | - Adrian McCann
- Bevital AS, Laboratoriebygget, 9 etg, Jonas Lies vei 87, 5021 Bergen, Norway
| | - Roman Gonzenbach
- Department of Neurology, Clinics of Valens, Rehabilitation Centre Valens, Taminaplatz 1, 7317 Valens, Switzerland
| | - Jens Bansi
- Department of Neurology, Clinics of Valens, Rehabilitation Centre Valens, Taminaplatz 1, 7317 Valens, Switzerland; Department of Health, OST - Eastern Switzerland University of Applied Sciences, Rosenbergstrasse 59, 9000 Sankt Gallen, Switzerland
| | - Philipp Zimmer
- Department of Performance and Health (Sports Medicine), Institute of Sport and Sport Science, TU Dortmund University, Otto-Hahn-Str. 3, 44227 Dortmund, Germany.
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23
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Alberts C, Owe-Larsson M, Urbanska EM. New Perspective on Anorexia Nervosa: Tryptophan-Kynurenine Pathway Hypothesis. Nutrients 2023; 15:nu15041030. [PMID: 36839388 PMCID: PMC9967350 DOI: 10.3390/nu15041030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 02/14/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
Anorexia nervosa (AN), affecting up to 4% of all females and 0.3% of all males globally, remains the neuropsychiatric disorder with the highest mortality rate. However, the response to the current therapeutic options is rarely satisfactory. Considering the devastating prognosis of survival among patients with AN, further research aimed at developing novel, more effective therapies for AN is essential. Brain and serum tryptophan is mostly converted along the kynurenine pathway into multiple neuroactive derivatives, whereas only 1-2% is used for the synthesis of serotonin. This narrative review provides an update on the experimental and clinical research data concerning the metabolism of tryptophan along the kynurenine pathway in anorexia nervosa based on the available literature. We propose that in AN, lower levels of L-kynurenine and kynurenic acid result in diminished stimulation of the aryl hydrocarbon receptor, which could contribute to abnormally low body weight. The impact of L-kynurenine supplementation on anorexia in animal models and the effects of changes in tryptophan and downstream kynurenines on the clinical progression of AN require further investigation. Moreover, prospective clinical studies on larger cohorts of restrictive and binge-eating/purging AN patients and assessing the potential benefit of L-kynurenine as an add-on therapeutic agent, should follow.
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Affiliation(s)
- Charl Alberts
- Department of Experimental and Clinical Pharmacology, Medical University of Lublin, Jaczewskiego 8B, 20-059 Lublin, Poland
| | - Maja Owe-Larsson
- Department of Histology and Embryology, Center of Biostructure Research, Medical University of Warsaw, Chałubińskiego 5, 02-004 Warsaw, Poland
- Laboratory of Center for Preclinical Research, Department of Experimental and Clinical Physiology, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland
| | - Ewa M. Urbanska
- Laboratory of Cellular and Molecular Pharmacology, Department of Experimental and Clinical Pharmacology, Medical University of Lublin, Jaczewskiego 8B, 20-059 Lublin, Poland
- Correspondence:
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24
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Jeong S, Jang HB, Kim HJ, Lee HJ. Identification of Biomarkers Related to Metabolically Unhealthy Obesity in Korean Obese Adolescents: A Cross-Sectional Study. CHILDREN (BASEL, SWITZERLAND) 2023; 10:children10020322. [PMID: 36832451 PMCID: PMC9955165 DOI: 10.3390/children10020322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 01/25/2023] [Accepted: 02/02/2023] [Indexed: 02/11/2023]
Abstract
BACKGROUND The current study aimed to screen for relationships and different potential metabolic biomarkers involved between metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) in adolescents. METHODS The study included 148 obese adolescents aged between 14 and 16. The study participants were divided into MUO and MHO groups based on the age-specific adolescent metabolic syndrome (MetS) criteria of the International Diabetes Federation. The current study was conducted to investigate the clinical and metabolic differences between the MHO and MUO groups. Multivariate analyses were conducted to investigate the metabolites as independent predictors for the odds ratio and the presence of the MetS. RESULTS There were significant differences in the three acylcarnitines, five amino acids, glutamine/glutamate ratio, three biogenic amines, two glycerophospholipids, and the triglyceride-glucose index between the MUO group and those in the MHO group. Moreover, several metabolites were associated with the prevalence of MUO. Additionally, several metabolites were inversely correlated with MHO in the MUO group. CONCLUSIONS In this study, the biomarkers found in this study have the potential to reflect the clinical outcomes of the MUO group. These biomarkers will lead to a better understanding of MetS in obese adolescents.
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Affiliation(s)
| | | | | | - Hye-Ja Lee
- Correspondence: ; Tel.: +82-43-719-8452; Fax: +82-43-719-8709
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25
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Rigamonti AE, Frigerio G, Caroli D, De Col A, Cella SG, Sartorio A, Fustinoni S. A Metabolomics-Based Investigation of the Effects of a Short-Term Body Weight Reduction Program in a Cohort of Adolescents with Obesity: A Prospective Interventional Clinical Study. Nutrients 2023; 15:529. [PMID: 36771236 PMCID: PMC9921209 DOI: 10.3390/nu15030529] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 01/10/2023] [Accepted: 01/14/2023] [Indexed: 01/20/2023] Open
Abstract
Metabolomics applied to assess the response to a body weight reduction program (BWRP) may generate valuable information concerning the biochemical mechanisms/pathways underlying the BWRP-induced cardiometabolic benefits. The aim of the present study was to establish the BWRP-induced changes in the metabolomic profile that characterizes the obese condition. In particular, a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) targeted metabolomic approach was used to determine a total of 188 endogenous metabolites in the plasma samples of a cohort of 42 adolescents with obesity (female/male = 32/10; age = 15.94 ± 1.33 year; body mass index standard deviation score (BMI SDS) = 2.96 ± 0.46) who underwent a 3-week BWRP, including hypocaloric diet, physical exercise, nutritional education, and psychological support. The BWRP was capable of significantly improving body composition (e.g., BMI SDS, p < 0.0001), glucometabolic homeostasis (e.g., glucose, p < 0.0001), and cardiovascular function (e.g., diastolic blood pressure, p = 0.016). A total of 64 metabolites were significantly reduced after the intervention (at least p < 0.05), including 53 glycerophospholipids (23 PCs ae, 21 PCs aa, and 9 lysoPCs), 7 amino acids (tyrosine, phenylalanine, arginine, citrulline, tryptophan, glutamic acid, and leucine), the biogenic amine kynurenine, 2 sphingomyelins, and (free) carnitine (C0). On the contrary, three metabolites were significantly increased after the intervention (at least p < 0.05)-in particular, glutamine, trans-4-hydroxyproline, and the octadecenoyl-carnitine (C18:1). In conclusion, when administered to adolescents with obesity, a short-term BWRP is capable of changing the metabolomic profile in the plasma.
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Affiliation(s)
- Antonello E. Rigamonti
- Department of Clinical Sciences and Community Health, University of Milan, 20129 Milan, Italy
| | - Gianfranco Frigerio
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 6 Avenue Du Swing, L-4367 Belvaux, Luxembourg
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Diana Caroli
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 28824 Piancavallo-Verbania, Italy
| | - Alessandra De Col
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 28824 Piancavallo-Verbania, Italy
| | - Silvano G. Cella
- Department of Clinical Sciences and Community Health, University of Milan, 20129 Milan, Italy
| | - Alessandro Sartorio
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 28824 Piancavallo-Verbania, Italy
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 20145 Milan, Italy
| | - Silvia Fustinoni
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
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Aarsland TIM, Instanes JT, Posserud MBR, Ulvik A, Kessler U, Haavik J. Changes in Tryptophan-Kynurenine Metabolism in Patients with Depression Undergoing ECT-A Systematic Review. Pharmaceuticals (Basel) 2022; 15:1439. [PMID: 36422569 PMCID: PMC9694349 DOI: 10.3390/ph15111439] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 11/03/2022] [Accepted: 11/11/2022] [Indexed: 10/29/2023] Open
Abstract
The kynurenine pathway of tryptophan (Trp) metabolism generates multiple biologically active metabolites (kynurenines) that have been implicated in neuropsychiatric disorders. It has been suggested that modulation of kynurenine metabolism could be involved in the therapeutic effect of electroconvulsive therapy (ECT). We performed a systematic review with aims of summarizing changes in Trp and/or kynurenines after ECT and assessing methodological issues. The inclusion criterium was measures of Trp and/or kynurenines before and after ECT. Animal studies and studies using Trp administration or Trp depletion were excluded. Embase, MEDLINE, PsycInfo and PubMed were searched, most recently in July 2022. Outcomes were levels of Trp, kynurenines and ratios before and after ECT. Data on factors affecting Trp metabolism and ECT were collected for interpretation and discussion of the reported changes. We included 17 studies with repeated measures for a total of 386 patients and 27 controls. Synthesis using vote counting based on the direction of effect found no evidence of effect of ECT on any outcome variable. There were considerable variations in design, patient characteristics and reported items. We suggest that future studies should include larger samples, assess important covariates and determine between- and within-subject variability. PROSPERO (CRD42020187003).
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Affiliation(s)
| | | | - Maj-Britt Rocio Posserud
- Department of Clinical Medicine, University of Bergen, 5020 Bergen, Norway
- Division of Psychiatry, Haukeland University Hospital, 5021 Bergen, Norway
| | - Arve Ulvik
- Bevital A/S, Laboratoriebygget, 5020 Bergen, Norway
| | - Ute Kessler
- Department of Clinical Medicine, University of Bergen, 5020 Bergen, Norway
- Division of Psychiatry, Haukeland University Hospital, 5021 Bergen, Norway
| | - Jan Haavik
- Department of Biomedicine, University of Bergen, 5020 Bergen, Norway
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The Role of Tryptophan Dysmetabolism and Quinolinic Acid in Depressive and Neurodegenerative Diseases. Biomolecules 2022; 12:biom12070998. [PMID: 35883554 PMCID: PMC9313172 DOI: 10.3390/biom12070998] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 07/04/2022] [Accepted: 07/14/2022] [Indexed: 02/04/2023] Open
Abstract
Emerging evidence suggests that neuroinflammation is involved in both depression and neurodegenerative diseases. The kynurenine pathway, generating metabolites which may play a role in pathogenesis, is one of several competing pathways of tryptophan metabolism. The present article is a narrative review of tryptophan metabolism, neuroinflammation, depression, and neurodegeneration. A disturbed tryptophan metabolism with increased activity of the kynurenine pathway and production of quinolinic acid may result in deficiencies in tryptophan and derived neurotransmitters. Quinolinic acid is an N-methyl-D-aspartate receptor agonist, and raised levels in CSF, together with increased levels of inflammatory cytokines, have been reported in mood disorders. Increased quinolinic acid has also been observed in neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and HIV-related cognitive decline. Oxidative stress in connection with increased indole-dioxygenase (IDO) activity and kynurenine formation may contribute to inflammatory responses and the production of cytokines. Increased formation of quinolinic acid may occur at the expense of kynurenic acid and neuroprotective picolinic acid. While awaiting ongoing research on potential pharmacological interventions on tryptophan metabolism, adequate protein intake with appropriate amounts of tryptophan and antioxidants may offer protection against oxidative stress and provide a balanced set of physiological receptor ligands.
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Adipocyte-derived kynurenine promotes obesity and insulin resistance by activating the AhR/STAT3/IL-6 signaling. Nat Commun 2022; 13:3489. [PMID: 35715443 PMCID: PMC9205899 DOI: 10.1038/s41467-022-31126-5] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 06/02/2022] [Indexed: 02/05/2023] Open
Abstract
Aberrant amino acid metabolism is a common event in obesity. Particularly, subjects with obesity are characterized by the excessive plasma kynurenine (Kyn). However, the primary source of Kyn and its impact on metabolic syndrome are yet to be fully addressed. Herein, we show that the overexpressed indoleamine 2,3-dioxygenase 1 (IDO1) in adipocytes predominantly contributes to the excessive Kyn, indicating a central role of adipocytes in Kyn metabolism. Depletion of Ido1 in adipocytes abrogates Kyn accumulation, protecting mice against obesity. Mechanistically, Kyn impairs lipid homeostasis in adipocytes via activating the aryl hydrocarbon receptor (AhR)/Signal transducer and activator of transcription 3 /interleukin-6 signaling. Genetic ablation of AhR in adipocytes abolishes the effect of Kyn. Moreover, supplementation of vitamin B6 ameliorated Kyn accumulation, protecting mice from obesity. Collectively, our data support that adipocytes are the primary source of increased circulating Kyn, while elimination of accumulated Kyn could be a viable strategy against obesity. Kynurenine, a tryptophan metabolite, is increased in the circulating plasma of obese individuals, but the source has been unclear. Here, the authors show in mice that mature adipocytes produce kynurenine, with vitamin B6 administration preventing accumulation and protecting against high-fat diet.
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Orozco-Ruiz X, Anesi A, Mattivi F, Breteler MMB. Branched-Chain and Aromatic Amino Acids Related to Visceral Adipose Tissue Impact Metabolic Health Risk Markers. J Clin Endocrinol Metab 2022; 107:e2896-e2905. [PMID: 35325166 DOI: 10.1210/clinem/dgac160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT Visceral (VAT) and subcutaneous adipose tissue (SAT) function as endocrine organs capable of influencing metabolic health across adiposity levels. OBJECTIVE We aimed to investigate whether metabolites associated with VAT and SAT impact metabolic health through metabolite concentrations. METHODS Analyses are based on 1790 participants from the population-based Rhineland Study. We assessed plasma levels of methionine (Met), branched-chain amino acids (BCAA), aromatic amino acids (AAA), and their metabolic downstream metabolites with liquid chromatography-mass spectrometry. VAT and SAT volumes were assessed by magnetic resonance imaging (MRI). Metabolically healthy and unhealthy phenotypes were defined using Wildman criteria. RESULTS Metabolically unhealthy participants had higher concentrations of BCAA than metabolically healthy participants (P < 0.001). In metabolically unhealthy participants, VAT volumes were significantly associated with levels of L-isoleucine, L-leucine, indole-3-lactic acid, and indole-3-propionic acid (in log SD units: β = 0.16, P = 0.003; β = 0.12, P = 0.038; β = 0.11, P = 0.035 and β = -0.16, P = 0.010, respectively). Higher concentrations of certain BCAA and AAA-downstream metabolites significantly increased the odds of cardiometabolic risk markers. The relation between VAT volume and cardiometabolic risk markers was mediated by BCAA (indirect effects 3.7%-11%, P = 0.02 to < 0.0001), while the effect of VAT on systemic inflammation was mediated through higher kynurenine concentrations (indirect effect 6.4%, P < 0.0001). CONCLUSION Larger volumes of VAT in metabolically unhealthy individuals are associated with altered concentrations of circulating BCAA and AAA-downstream metabolites, increasing the odds of cardiometabolic risk markers. This suggests that these metabolites are involved in the mechanisms that underlie the relationship of abdominal VAT with metabolic health.
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Affiliation(s)
- Ximena Orozco-Ruiz
- Population Health Sciences, German Center for Neurodegenerative diseases (DZNE), 53127 Bonn, Germany
| | - Andrea Anesi
- Department of Food Quality and Nutrition, Research and Innovation Centre, Fondazione Edmund Mach (FEM), 38010 San Michele all'Adige, Italy
| | - Fulvio Mattivi
- Department of Food Quality and Nutrition, Research and Innovation Centre, Fondazione Edmund Mach (FEM), 38010 San Michele all'Adige, Italy
- University of Trento, Department of Cellular, Computational and Integrative Biology (CIBIO), 38123 Povo, Italy
| | - Monique M B Breteler
- Population Health Sciences, German Center for Neurodegenerative diseases (DZNE), 53127 Bonn, Germany
- Institute for Medical Biometry, Informatics and Epidemiology (IMBIE), Faculty of Medicine, University of Bonn, 53127 Bonn, Germany
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Oliveira LA, Della Lucia CM, Rezende FAC, Ferreira LG, Anastácio LR, Souza TCDM, Daniel MM, Liboredo JC. Food Craving and Its Associated Factors during COVID-19 Outbreak in Brazil. AMERICAN JOURNAL OF HEALTH EDUCATION 2022. [DOI: 10.1080/19325037.2022.2071360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Jamshed L, Debnath A, Jamshed S, Wish JV, Raine JC, Tomy GT, Thomas PJ, Holloway AC. An Emerging Cross-Species Marker for Organismal Health: Tryptophan-Kynurenine Pathway. Int J Mol Sci 2022; 23:6300. [PMID: 35682980 PMCID: PMC9181223 DOI: 10.3390/ijms23116300] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 05/26/2022] [Accepted: 05/30/2022] [Indexed: 02/01/2023] Open
Abstract
Tryptophan (TRP) is an essential dietary amino acid that, unless otherwise committed to protein synthesis, undergoes metabolism via the Tryptophan-Kynurenine (TRP-KYN) pathway in vertebrate organisms. TRP and its metabolites have key roles in diverse physiological processes including cell growth and maintenance, immunity, disease states and the coordination of adaptive responses to environmental and dietary cues. Changes in TRP metabolism can alter the availability of TRP for protein and serotonin biosynthesis as well as alter levels of the immune-active KYN pathway metabolites. There is now considerable evidence which has shown that the TRP-KYN pathway can be influenced by various stressors including glucocorticoids (marker of chronic stress), infection, inflammation and oxidative stress, and environmental toxicants. While there is little known regarding the role of TRP metabolism following exposure to environmental contaminants, there is evidence of linkages between chemically induced metabolic perturbations and altered TRP enzymes and KYN metabolites. Moreover, the TRP-KYN pathway is conserved across vertebrate species and can be influenced by exposure to xenobiotics, therefore, understanding how this pathway is regulated may have broader implications for environmental and wildlife toxicology. The goal of this narrative review is to (1) identify key pathways affecting Trp-Kyn metabolism in vertebrates and (2) highlight consequences of altered tryptophan metabolism in mammals, birds, amphibians, and fish. We discuss current literature available across species, highlight gaps in the current state of knowledge, and further postulate that the kynurenine to tryptophan ratio can be used as a novel biomarker for assessing organismal and, more broadly, ecosystem health.
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Affiliation(s)
- Laiba Jamshed
- Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON L8S 4K1, Canada; (L.J.); (A.D.); (S.J.)
| | - Amrita Debnath
- Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON L8S 4K1, Canada; (L.J.); (A.D.); (S.J.)
| | - Shanza Jamshed
- Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON L8S 4K1, Canada; (L.J.); (A.D.); (S.J.)
| | - Jade V. Wish
- Department of Chemistry, Centre for Oil and Gas Research and Development (COGRAD), University of Manitoba, 586 Parker Building, 144 Dysart Rd., Winnipeg, MB R3T 2N2, Canada; (J.V.W.); (G.T.T.)
| | - Jason C. Raine
- Quesnel River Research Centre, University of Northern British Columbia, Prince George, BC V2N 4Z9, Canada;
| | - Gregg T. Tomy
- Department of Chemistry, Centre for Oil and Gas Research and Development (COGRAD), University of Manitoba, 586 Parker Building, 144 Dysart Rd., Winnipeg, MB R3T 2N2, Canada; (J.V.W.); (G.T.T.)
| | - Philippe J. Thomas
- Environment and Climate Change Canada, National Wildlife Research Centre, Ottawa, ON K1A 0H3, Canada;
| | - Alison C. Holloway
- Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON L8S 4K1, Canada; (L.J.); (A.D.); (S.J.)
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Tan KML, Tint MT, Kothandaraman N, Yap F, Godfrey KM, Lee YS, Tan KH, Gluckman PD, Chong YS, Chong MFF, Eriksson JG, Cameron-Smith D. Association of plasma kynurenine pathway metabolite concentrations with metabolic health risk in prepubertal Asian children. Int J Obes (Lond) 2022; 46:1128-1137. [PMID: 35173282 PMCID: PMC7612806 DOI: 10.1038/s41366-022-01085-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 01/26/2022] [Accepted: 01/28/2022] [Indexed: 11/08/2022]
Abstract
BACKGROUND The tryptophan-kynurenine (KYN) pathway is linked to obesity-related systemic inflammation and metabolic health. The pathway generates multiple metabolites, with little available data on their relationships to early markers of increased metabolic disease risk in children. The aim of this study was to examine the association of multiple KYN pathway metabolites with metabolic risk markers in prepubertal Asian children. METHODS Fasting plasma concentrations of KYN pathway metabolites were measured using liquid chromatography-tandem mass spectrometry in 8-year-old children (n = 552) from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) prospective mother-offspring cohort study. The child's weight and height were used to ascertain overweight and obesity using local body mass index (BMI)-for-age percentile charts. Body fat percentage was measured by quantitative magnetic resonance. Abdominal circumference, systolic and diastolic blood pressure, homeostatic model assessment for insulin resistance (HOMA-IR), triglyceride, and HDL-cholesterol were used for the calculation of Metabolic syndrome scores (MetS). Serum triglyceride, BMI, gamma-glutamyl transferase (GGT), and abdominal circumference were used in the calculation of the Fatty liver index (FLI). Associations were examined using multivariable regression analyses. RESULTS In overweight or obese children (n = 93; 16.9% of the cohort), all KYN pathway metabolites were significantly increased, relative to normal weight children. KYN, kynurenic acid (KA), xanthurenic acid (XA), hydroxyanthranilic acid (HAA) and quinolinic acid (QA) all showed significant positive associations with body fat percentage (B(95% CI) = 0.32 (0.22,0.42) for QA), HOMA-IR (B(95% CI) = 0.25 (0.16,0.34) for QA), and systolic blood pressure (B(95% CI) = 0.14(0.06,0.22) for QA). All KYN metabolites except 3-hydroxykynurenine (HK) significantly correlated with MetS (B (95% CI) = 0.29 (0.21,0.37) for QA), and FLI (B (95% CI) = 0.30 (0.21,0.39) for QA). CONCLUSIONS Higher plasma concentrations of KYN pathway metabolites are associated with obesity and with increased risk for metabolic syndrome and fatty liver in prepubertal Asian children.
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Affiliation(s)
- Karen Mei-Ling Tan
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Department of Laboratory Medicine, National University Hospital, Singapore, Singapore
| | - Mya-Thway Tint
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Human Potential Translational Research Programme, Yong Loo Lin School of Medicine (YLLSOM), National University of Singapore, Singapore, Singapore
| | - Narasimhan Kothandaraman
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Fabian Yap
- Duke-National University of Singapore (NUS) Medical School, Singapore, Singapore
- Department of Pediatric Endocrinology, KK Women's and Children's Hospital, Singapore, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Keith M Godfrey
- MRC Lifecourse Epidemiology Centre, University of Southampton, Southampton, UK
- NIHR Southampton Biomedical Research Centre, University of Southampton and University of Southampton Hospital, Southampton, UK
| | - Yung Seng Lee
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Khoo Teck Puat - National University Children's Medical Institute (KTPCMI), National University Health System, Singapore, Singapore
| | - Kok Hian Tan
- Duke-National University of Singapore (NUS) Medical School, Singapore, Singapore
- Perinatal Audit and Epidemiology, Department of Maternal Fetal Medicine, KK Women's and Children's Hospital, Singapore, Singapore
| | - Peter D Gluckman
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Liggins Institute, University of Auckland, Auckland, New Zealand
| | - Yap-Seng Chong
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine (YLLSOM), National University of Singapore, Singapore, Singapore
| | - Mary F F Chong
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore
| | - Johan G Eriksson
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Human Potential Translational Research Programme, Yong Loo Lin School of Medicine (YLLSOM), National University of Singapore, Singapore, Singapore
- Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine (YLLSOM), National University of Singapore, Singapore, Singapore
- Folkhälsan Research Center, Helsinki, Finland
- Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland
| | - David Cameron-Smith
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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The Kynurenine Pathway in Obese Middle-Aged Women with Normoglycemia and Type 2 Diabetes. Metabolites 2022; 12:metabo12060492. [PMID: 35736425 PMCID: PMC9230031 DOI: 10.3390/metabo12060492] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 05/23/2022] [Accepted: 05/28/2022] [Indexed: 11/28/2022] Open
Abstract
We examined the relationships of tryptophan (Trp) and the metabolites of the kynurenine pathway (KP) to the occurrence of type 2 diabetes (T2D) and metabolic risk factors in obese middle-aged women. The study included 128 obese women divided into two subgroups: a normoglycemic group (NG, n = 65) and a T2D group (n = 63). The concentrations of serum tryptophan (Trp), kynurenine (Kyn), 3-hydroxykynurenine (3HKyn), quinolinic acid (QA), and kynurenic acid (Kyna) were analyzed using ultra-high-performance liquid chromatography coupled with electrospray ionization/triple quadrupole mass spectrometry. Blood biochemical parameters and anthropometric parameters were measured. The women with T2D had significantly higher Trp, Kyna, Kyna/QA ratio, and Kyna/3HKyn ratio values than the NG women. Logistic regression analysis showed that the concentrations of Trp and Kyna and the values of the Kyna/3HKyn ratio were most strongly associated with T2D occurrence, even after controlling for confounding factors. The model with Trp level and Kyna/3HKyn ratio accounted for 20% of the variation in the presence of T2D. We also showed a different pattern of correlations between kynurenines and metabolic factors in the NG and T2D women, which was mostly reflected in the stronger relationship between BMI and KP metabolites in the NG obese women. An increase in Trp and Kyna levels with an accompanying increase in Kyna/3HKyn ratio value is associated with the occurrence of T2D in obese middle-aged women.
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Jovanovic F, Sudhakar A, Knezevic NN. The Kynurenine Pathway and Polycystic Ovary Syndrome: Inflammation as a Common Denominator. Int J Tryptophan Res 2022; 15:11786469221099214. [PMID: 35620306 PMCID: PMC9128055 DOI: 10.1177/11786469221099214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 04/20/2022] [Indexed: 11/17/2022] Open
Abstract
Polycystic ovary syndrome (PCOS) is a complex metabolic disorder commonly seen in females of reproductive age. The pathophysiology of PCOS is multifactorial and includes dysfunction in ovarian steroidogenesis and folliculogenesis, impaired gonadotropin levels, insulin resistance, gut microbiota imbalance, genetic predisposition, and lifestyle preferences. Low-grade inflammatory conditions such as obesity and impaired glucose tolerance are common metabolic disturbances in women with PCOS. A growing body of literature suggests strong evidence rendering PCOS in close proximity with chronic inflammation as documented by high levels of serum white blood cells, C-reactive protein, and various proinflammatory cytokines seen in this condition. Inflammation seems to be the most common metabolic denominator between the kynurenine pathway and PCOS. The association of tryptophan and kynurenine pathway has already been well documented in mood disorders, neurodegenerative diseases, chronic pain conditions, and different inflammatory states. In this manuscript, we describe the influence of sex steroid hormones on different enzymes of the KP; inflammatory nature of PCOS and CRP as a marker of IDO/TDO activity; and the effects of altered gut flora in women with PCOS. This review provides a novel view of the available evidence of tryptophan and downstream metabolites in PCOS in the context of underlying inflammation.
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Affiliation(s)
- Filip Jovanovic
- Department of Internal Medicine, Merit Health Wesley, Hattiesburg, MS, USA
| | - Aboorva Sudhakar
- Department of Internal Medicine, Merit Health Wesley, Hattiesburg, MS, USA
| | - Nebojsa Nick Knezevic
- Department of Anesthesiology, Advocate Illinois Masonic Medical Center, Chicago, USA
- Department of Anesthesiology, University of Illinois, Chicago, USA
- Department of Surgery, University of Illinois, Chicago, USA
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35
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Tan KML, Tint MT, Kothandaraman N, Michael N, Sadananthan SA, Velan SS, Fortier MV, Yap F, Tan KH, Gluckman PD, Chong YS, Chong MFF, Lee YS, Godfrey KM, Eriksson JG, Cameron-Smith D. The Kynurenine Pathway Metabolites in Cord Blood Positively Correlate With Early Childhood Adiposity. J Clin Endocrinol Metab 2022; 107:e2464-e2473. [PMID: 35150259 PMCID: PMC9113811 DOI: 10.1210/clinem/dgac078] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT The kynurenine pathway generates metabolites integral to energy metabolism, neurotransmission, and immune function. Circulating kynurenine metabolites positively correlate with adiposity in children and adults, yet it is not known whether this relationship is present already at birth. OBJECTIVE In this prospective longitudinal study, we investigate the relationship between cord blood kynurenine metabolites and measures of adiposity from birth to 4.5 years. METHODS Liquid chromatography-tandem mass spectrometry was used to quantify cord blood kynurenine metabolites in 812 neonates from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) study. Fat percentage was measured by air displacement plethysmography and abdominal adipose tissue compartment volumes; superficial (sSAT) and deep subcutaneous (dSAT) and internal adipose tissue were quantified by magnetic resonance imaging at early infancy in a smaller subset of neonates, and again at 4 to 4.5 years of age. RESULTS Cord blood kynurenine metabolites appeared to be higher in female newborns, higher in Indian newborns compared with Chinese newborns, and higher in infants born by cesarean section compared with vaginal delivery. Kynurenine, xanthurenic acid, and quinolinic acid were positively associated with birthweight, but not with subsequent weight during infancy and childhood. Quinolinic acid was positively associated with sSAT at birth. Kynurenic acid and quinolinic acid were positively associated with fat percentage at 4 years. CONCLUSION Several cord blood kynurenine metabolite concentrations were positively associated with birthweight, with higher kynurenic acid and quinolinic acid correlating to higher percentage body fat in childhood, suggesting these cord blood metabolites as biomarkers of early childhood adiposity.
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Affiliation(s)
- Karen Mei-Ling Tan
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), 117609, Singapore
- Department of Laboratory Medicine, National University Hospital, 119074, Singapore
| | - Mya-Thway Tint
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), 117609, Singapore
- Department of Obstetrics and Gynaecology, Human Potential Translational Research Programme, Yong Loo Lin School of Medicine (YLLSOM), National University of Singapore, 119228, Singapore
| | - Narasimhan Kothandaraman
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), 117609, Singapore
| | - Navin Michael
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), 117609, Singapore
| | - Suresh Anand Sadananthan
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), 117609, Singapore
| | - S Sendhil Velan
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), 117609, Singapore
- Institute of Bioengineering and Bioimaging (IBB), Agency for Science Technology and Research, 138669, Singapore
| | - Marielle V Fortier
- Department of Diagnostic and Interventional Imaging, KK Women’s and Children’s Hospital, 229899, Singapore
| | - Fabian Yap
- Duke-National University of Singapore (NUS) Medical School, 169857, Singapore
- Department of Pediatric Endocrinology, KK Women’s and Children’s Hospital, 229899, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, 636921, Singapore
| | - Kok Hian Tan
- Duke-National University of Singapore (NUS) Medical School, 169857, Singapore
- Perinatal Audit and Epidemiology, Department of Maternal Fetal Medicine, KK Women’s and Children’s Hospital, 119228, Singapore
| | - Peter D Gluckman
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), 117609, Singapore
- Liggins Institute, University of Auckland, Auckland 1023, New Zealand
| | - Yap-Seng Chong
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), 117609, Singapore
- Department of Obstetrics and Gynaecology, Human Potential Translational Research Programme, Yong Loo Lin School of Medicine (YLLSOM), National University of Singapore, 119228, Singapore
- Yong Loo Lin School of Medicine (YLLSOM), National University of Singapore, 117597, Singapore
| | - Mary F F Chong
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), 117609, Singapore
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, 117549, Singapore
| | - Yung Seng Lee
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), 117609, Singapore
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, 119228, Singapore
- Khoo Teck Puat – National University Children’s Medical Institute, National University Health System, 119074, Singapore
| | - Keith M Godfrey
- MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton SO16 6YD, United Kingdom
- NIHR Southampton Biomedical Research Centre, University of Southampton Hospital, Southampton SO16 6YD, United Kingdom
| | - Johan G Eriksson
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), 117609, Singapore
- Department of Obstetrics and Gynaecology, Human Potential Translational Research Programme, Yong Loo Lin School of Medicine (YLLSOM), National University of Singapore, 119228, Singapore
- Folkhälsan Research Center, 00250 Helsinki, Finland
- Department of General Practice and Primary Health Care, University of Helsinki, 00290 Helsinki, Finland
| | - David Cameron-Smith
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), 117609, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117596, Singapore
- Correspondence: Professor David Cameron Smith, Singapore Institute for Clinical Sciences, Brenner Centre for Molecular Medicine, Agency for Science, Technology and Research, 30 Medical Drive 117609, Singapore.
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Is Poor Lithium Response in Individuals with Bipolar Disorder Associated with Increased Degradation of Tryptophan along the Kynurenine Pathway? Results of an Exploratory Study. J Clin Med 2022; 11:jcm11092517. [PMID: 35566641 PMCID: PMC9103936 DOI: 10.3390/jcm11092517] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 04/15/2022] [Accepted: 04/27/2022] [Indexed: 11/17/2022] Open
Abstract
Bipolar disorder is associated with an inflammation-triggered elevated catabolism of tryptophan to the kynurenine pathway, which impacts psychiatric symptoms and outcomes. The data indicate that lithium exerts anti-inflammatory effects by inhibiting indoleamine-2,3-dioxygenase (IDO)-1 activity. This exploratory study aimed to investigate the tryptophan catabolism in individuals with bipolar disorder (n = 48) compared to healthy controls (n = 48), and the associations with the response to mood stabilizers such as lithium, valproate, or lamotrigine rated with the Retrospective Assessment of the Lithium Response Phenotype Scale (or the Alda scale). The results demonstrate an association of a poorer response to lithium with higher levels of kynurenine, kynurenine/tryptophan ratio as a proxy for IDO-1 activity, as well as quinolinic acid, which, overall, indicates a pro-inflammatory state with a higher degradation of tryptophan towards the neurotoxic branch. The treatment response to valproate and lamotrigine was not associated with the levels of the tryptophan metabolites. These findings support the anti-inflammatory properties of lithium. Furthermore, since quinolinic acid has neurotoxic features via the glutamatergic pathway, they also strengthen the assumption that the clinical drug response might be associated with biochemical processes. The relationship between the lithium response and the measurements of the tryptophan to the kynurenine pathway is of clinical relevance and may potentially bring advantages towards a personalized medicine approach to bipolar disorder that allows for the selection of the most effective mood-stabilizing drug.
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Gazi MA, Siddique MA, Alam MA, Hossaini F, Hasan MM, Fahim SM, Wahid BZ, Kabir MM, Das S, Mahfuz M, Ahmed T. Plasma Kynurenine to Tryptophan Ratio Is Not Associated with Undernutrition in Adults but Reduced after Nutrition Intervention: Results from a Community-Based Study in Bangladesh. Nutrients 2022; 14:nu14091708. [PMID: 35565678 PMCID: PMC9104876 DOI: 10.3390/nu14091708] [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: 03/14/2022] [Revised: 04/14/2022] [Accepted: 04/19/2022] [Indexed: 12/10/2022] Open
Abstract
Infections and persistent immunological activation are linked to increased kynurenine (KYN) and the KYN-to-Tryptophan (TRP) or KT ratio and may be critical factors in undernutrition. We sought to determine the association between the KT ratio and adult malnutrition, as well as investigate if nutritional supplementation had any influence on the decrease of the KT ratio. A total of 525 undernourished adults aged 18–45 years were recruited and provided a nutrition intervention for 60 feeding days. TRP and KYN concentrations were determined from plasma samples using LC-MS/MS. At baseline, the median (interquartile range (IQR)) TRP, KYN and KT ratios were 24.1 (17.6, 34.3) µmol/L, 0.76 (0.53, 1.18) µmol/L and 30.9 (24.5, 41.7), respectively. Following intervention, the median (IQR) KYN and KT ratios were significantly reduced to 0.713 (0.46, 1.12) µmol/L and 27.5 (21.3, 35.8). The KT ratio was found to be inversely linked with adult BMI (coefficient: −0.09; 95% CI: −0.18, 0.004; p-value = 0.06) but not statistically significant. Additionally, Plasma CRP was correlated positively, while LRP1 was inversely correlated with the KT ratio. Our data suggest that in Bangladeshi adults, the KT ratio is not related to the pathophysiology of malnutrition but correlated with inflammatory and anti-inflammatory biomarkers, and the ratio can be reduced by a nutrition intervention.
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Affiliation(s)
- Md. Amran Gazi
- Nutrition and Clinical Services Division, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka 1212, Bangladesh; (M.A.G.); (M.A.A.); (F.H.); (M.M.H.); (S.M.F.); (B.Z.W.); (S.D.); (T.A.)
| | - Md. Abdullah Siddique
- Emerging Infections and Parasitology Laboratory, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka 1212, Bangladesh; (M.A.S.); (M.M.K.)
| | - Md. Ashraful Alam
- Nutrition and Clinical Services Division, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka 1212, Bangladesh; (M.A.G.); (M.A.A.); (F.H.); (M.M.H.); (S.M.F.); (B.Z.W.); (S.D.); (T.A.)
| | - Farzana Hossaini
- Nutrition and Clinical Services Division, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka 1212, Bangladesh; (M.A.G.); (M.A.A.); (F.H.); (M.M.H.); (S.M.F.); (B.Z.W.); (S.D.); (T.A.)
| | - Md. Mehedi Hasan
- Nutrition and Clinical Services Division, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka 1212, Bangladesh; (M.A.G.); (M.A.A.); (F.H.); (M.M.H.); (S.M.F.); (B.Z.W.); (S.D.); (T.A.)
| | - Shah Mohammad Fahim
- Nutrition and Clinical Services Division, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka 1212, Bangladesh; (M.A.G.); (M.A.A.); (F.H.); (M.M.H.); (S.M.F.); (B.Z.W.); (S.D.); (T.A.)
| | - Barbie Zaman Wahid
- Nutrition and Clinical Services Division, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka 1212, Bangladesh; (M.A.G.); (M.A.A.); (F.H.); (M.M.H.); (S.M.F.); (B.Z.W.); (S.D.); (T.A.)
| | - Md. Mamun Kabir
- Emerging Infections and Parasitology Laboratory, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka 1212, Bangladesh; (M.A.S.); (M.M.K.)
| | - Subhasish Das
- Nutrition and Clinical Services Division, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka 1212, Bangladesh; (M.A.G.); (M.A.A.); (F.H.); (M.M.H.); (S.M.F.); (B.Z.W.); (S.D.); (T.A.)
| | - Mustafa Mahfuz
- Nutrition and Clinical Services Division, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka 1212, Bangladesh; (M.A.G.); (M.A.A.); (F.H.); (M.M.H.); (S.M.F.); (B.Z.W.); (S.D.); (T.A.)
- Faculty of Medicine and Life Sciences, University of Tampere, 33100 Tampere, Finland
- Correspondence:
| | - Tahmeed Ahmed
- Nutrition and Clinical Services Division, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka 1212, Bangladesh; (M.A.G.); (M.A.A.); (F.H.); (M.M.H.); (S.M.F.); (B.Z.W.); (S.D.); (T.A.)
- Department of Global Health, University of Washington, Seattle, WA 98195, USA
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Novak Kujundžić R. COVID-19: Are We Facing Secondary Pellagra Which Cannot Simply Be Cured by Vitamin B3? Int J Mol Sci 2022; 23:ijms23084309. [PMID: 35457123 PMCID: PMC9032523 DOI: 10.3390/ijms23084309] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/11/2022] [Accepted: 04/12/2022] [Indexed: 02/07/2023] Open
Abstract
Immune response to SARS-CoV-2 and ensuing inflammation pose a huge challenge to the host’s nicotinamide adenine dinucleotide (NAD+) metabolism. Humans depend on vitamin B3 for biosynthesis of NAD+, indispensable for many metabolic and NAD+-consuming signaling reactions. The balance between its utilization and resynthesis is vitally important. Many extra-pulmonary symptoms of COVID-19 strikingly resemble those of pellagra, vitamin B3 deficiency (e.g., diarrhoea, dermatitis, oral cavity and tongue manifestations, loss of smell and taste, mental confusion). In most developed countries, pellagra is successfully eradicated by vitamin B3 fortification programs. Thus, conceivably, it has not been suspected as a cause of COVID-19 symptoms. Here, the deregulation of the NAD+ metabolism in response to the SARS-CoV-2 infection is reviewed, with special emphasis on the differences in the NAD+ biosynthetic pathway’s efficiency in conditions predisposing for the development of serious COVID-19. SARS-CoV-2 infection-induced NAD+ depletion and the elevated levels of its metabolites contribute to the development of a systemic disease. Acute liberation of nicotinamide (NAM) in antiviral NAD+-consuming reactions potentiates “NAM drain”, cooperatively mediated by nicotinamide N-methyltransferase and aldehyde oxidase. “NAM drain” compromises the NAD+ salvage pathway’s fail-safe function. The robustness of the host’s NAD+ salvage pathway, prior to the SARS-CoV-2 infection, is an important determinant of COVID-19 severity and persistence of certain symptoms upon resolution of infection.
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Affiliation(s)
- Renata Novak Kujundžić
- Laboratory for Epigenomics, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
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Bengesser SA, Hohenberger H, Tropper B, Dalkner N, Birner A, Fellendorf FT, Platzer M, Rieger A, Maget A, Hamm C, Queissner R, Pilz R, Bauer K, Lenger M, Mörkl S, Wagner-Skacel J, Kapfhammer HP, Meier-Allard N, Stracke A, Holasek SJ, Murphy L, Reininghaus EZ. Gene expression analysis of MAOA and the clock gene ARNTL in individuals with bipolar disorder compared to healthy controls. World J Biol Psychiatry 2022; 23:287-294. [PMID: 34468263 DOI: 10.1080/15622975.2021.1973816] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 07/30/2021] [Accepted: 08/24/2021] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Circadian rhythms are associated with bipolar disorder (BD). This cross-sectional study aimed at investigating ARNTL and MAOA gene expression differences (1) between individuals with BD and controls, (2) between affective episodes, and (3) the relationship between ARNTL and MAOA expression. METHODS ARNTL and MAOA gene expression in peripheral mononuclear blood cells were analysed from fasting blood samples (BD n = 81, controls n = 54) with quantitative real-time PCR operating on TaqMan® assays (normalised to 18S RNA expression). ANCOVAs corrected for age, sex, body mass index, and medication was used to evaluate expression differences and correlation analyses for the relation between ARNTL and MAOA expression. RESULTS ARNTL gene expression differed between affective episodes (F(2,78) = 3.198, p = 0.047, Partial Eta2= 0.083), but not between BD and controls (n.s.). ARNTL and MAOA expression correlated positively in BD (r = 0.704, p < 0.001) and in controls (r = 0.932, p < 0.001). MAOA expression differed neither between BD and controls nor between affective episodes (n.s.). DISCUSSION Clock gene expression changes were observed in different affective states of BD. More precisely, ARNTL gene expression was significantly higher in euthymia than in depression. ARNTL and MAOA gene expression correlated significantly in BD and in controls, which emphasises the strong concatenation between circadian rhythms and neurotransmitter breakdown.
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Affiliation(s)
- S A Bengesser
- Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria
| | - H Hohenberger
- Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria
| | - B Tropper
- Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria
| | - N Dalkner
- Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria
| | - A Birner
- Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria
| | - F T Fellendorf
- Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria
| | - M Platzer
- Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria
| | - A Rieger
- Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria
| | - A Maget
- Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria
| | - C Hamm
- Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria
| | - R Queissner
- Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria
| | - R Pilz
- Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria
| | - K Bauer
- Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria
| | - M Lenger
- Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria
| | - S Mörkl
- Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria
| | - J Wagner-Skacel
- Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria
| | - H P Kapfhammer
- Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria
| | - N Meier-Allard
- Otto Loewi Research Center, Chair of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria
| | - A Stracke
- Otto Loewi Research Center, Chair of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria
| | - S J Holasek
- Otto Loewi Research Center, Chair of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria
| | - L Murphy
- CAMH Pharmacogenetic Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada
| | - E Z Reininghaus
- Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria
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40
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Wang W, Wang X, Liu L, Liu Z, Han T, Sun C, Yang X. Dietary tryptophan and the risk of obesity and type 2 diabetes: Total effect and mediation effect of sleep duration. Obesity (Silver Spring) 2022; 30:515-523. [PMID: 35088560 DOI: 10.1002/oby.23343] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/29/2021] [Accepted: 11/02/2021] [Indexed: 12/17/2022]
Abstract
OBJECTIVE The aims of this study were to examine the effects of tryptophan consumption on obesity and type 2 diabetes (T2D) risk and whether sleep duration mediates these effects. METHODS Overall, data of 7,908 participants were obtained from the China Health and Nutrition Survey (1997-2011). A total of 6,373 and 4,398 participants who reported sleep duration and had blood samples, respectively, were incorporated into subgroup analyses. Multivariate Cox regression models were used to assess the associations between tertiles of tryptophan intake with obesity and T2D. General linear regression models were used to evaluate the effect of tryptophan on sleep time and plasma biomarkers. RESULTS Dietary tryptophan was significantly associated with decreased risk of obesity and T2D risk (hazard ratio tertile 3 to tertile 1 : 0.602 [95% CI: 0.500-0.724]; 0.693 [95% CI: 0.565-0.850]). Sleep duration was significantly higher, and hemoglobin A1c, total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B-100 (APO-B) were lower in the high tertile of tryptophan compared with the low tertile (p < 0.05). In addition, mediation effects on the associations of tryptophan intake with obesity and T2D risk were observed for sleep duration (estimated mediation percentage: 31.902% and 37.391%). CONCLUSIONS Dietary tryptophan showed advantageous effects on obesity and T2D risk. Furthermore, sleep duration potentially mediated for these effects.
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Affiliation(s)
- Weiqi Wang
- National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, People's Republic of China
| | - Xinyue Wang
- National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, People's Republic of China
| | - Lin Liu
- National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, People's Republic of China
| | - Zengjiao Liu
- National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, People's Republic of China
| | - Tianshu Han
- National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, People's Republic of China
| | - Changhao Sun
- National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, People's Republic of China
| | - Xue Yang
- National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, People's Republic of China
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Song X, Wang L, Liu Y, Zhang X, Weng P, Liu L, Zhang R, Wu Z. The gut microbiota–brain axis: Role of the gut microbial metabolites of dietary food in obesity. Food Res Int 2022; 153:110971. [DOI: 10.1016/j.foodres.2022.110971] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 01/27/2022] [Accepted: 01/30/2022] [Indexed: 12/13/2022]
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Lischka J, Schanzer A, Baumgartner M, de Gier C, Greber-Platzer S, Zeyda M. Tryptophan Metabolism Is Associated with BMI and Adipose Tissue Mass and Linked to Metabolic Disease in Pediatric Obesity. Nutrients 2022; 14:nu14020286. [PMID: 35057467 PMCID: PMC8781866 DOI: 10.3390/nu14020286] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 01/03/2022] [Accepted: 01/07/2022] [Indexed: 12/27/2022] Open
Abstract
The obesity epidemic has contributed to an escalating prevalence of metabolic diseases in children. Overnutrition leads to increased tryptophan uptake and availability. An association between the induction of the tryptophan catabolic pathway via indoleamine 2,3-dioxygenase (IDO) activity and obesity-related inflammation has been observed. This study aimed to investigate the impact of pediatric obesity on tryptophan metabolism and the potential relationship with metabolic disease. In this prospective cohort study, plasma kynurenine, tryptophan, and serotonin levels were measured by ELISA, and IDO activity was estimated by calculating the kynurenine/tryptophan ratio in a clinically characterized population with severe obesity (BMI ≥ 97th percentile) aged 9 to 19 (n = 125). IDO activity and its product kynurenine correlated with BMI z-score and body fat mass, whereas concentrations of serotonin, the alternative tryptophan metabolite, negatively correlated with these measures of adiposity. Kynurenine and tryptophan, but not serotonin levels, were associated with disturbed glucose metabolism. Tryptophan concentrations negatively correlated with adiponectin and were significantly higher in prediabetes and metabolically unhealthy obesity. In conclusion, BMI and body fat mass were associated with increased tryptophan catabolism via the kynurenine pathway and decreased serotonin production in children and adolescents with severe obesity. The resulting elevated kynurenine levels may contribute to metabolic disease in obesity.
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Vints WAJ, Kušleikiene S, Sheoran S, Šarkinaite M, Valatkevičiene K, Gleizniene R, Kvedaras M, Pukenas K, Himmelreich U, Cesnaitiene VJ, Levin O, Verbunt J, Masiulis N. Inflammatory Blood Biomarker Kynurenine Is Linked With Elevated Neuroinflammation and Neurodegeneration in Older Adults: Evidence From Two 1H-MRS Post-Processing Analysis Methods. Front Psychiatry 2022; 13:859772. [PMID: 35479493 PMCID: PMC9035828 DOI: 10.3389/fpsyt.2022.859772] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 03/11/2022] [Indexed: 12/21/2022] Open
Abstract
RATIONALE AND OBJECTIVES Pro-inflammatory processes have been argued to play a role in conditions associated with cognitive decline and neurodegeneration, like aging and obesity. Only a limited number of studies have tried to measure both peripheral and central biomarkers of inflammation and examined their interrelationship. The primary aim of this study was to examine the hypothesis that chronic peripheral inflammation would be associated with neurometabolic changes that indicate neuroinflammation (the combined elevation of myoinositol and choline), brain gray matter volume decrease, and lower cognitive functioning in older adults. MATERIALS AND METHODS Seventy-four older adults underwent bio-impedance body composition analysis, cognitive testing with the Montreal Cognitive Assessment (MoCA), blood serum analysis of inflammatory markers interleukin-6 (IL-6) and kynurenine, magnetic resonance imaging (MRI), and proton magnetic resonance spectroscopy (1H-MRS) of the brain. Neurometabolic findings from both Tarquin and LCModel 1H-MRS post-processing software packages were compared. The regions of interest for MRI and 1H-MRS measurements were dorsal posterior cingulate cortex (DPCC), left hippocampal cortex (HPC), left medial temporal cortex (MTC), left primary sensorimotor cortex (SM1), and right dorsolateral prefrontal cortex (DLPFC). RESULTS Elevated serum kynurenine levels were associated with signs of neuroinflammation, specifically in the DPCC, left SM1 and right DLPFC, and signs of neurodegeneration, specifically in the left HPC, left MTC and left SM1, after adjusting for age, sex and fat percentage (fat%). Elevated serum IL-6 levels were associated with increased Glx levels in left HPC, left MTC, and right DLPFC, after processing the 1H-MRS data with Tarquin. Overall, the agreement between Tarquin and LCModel results was moderate-to-strong for tNAA, tCho, mIns, and tCr, but weak to very weak for Glx. Peripheral inflammatory markers (IL-6 and kynurenine) were not associated with older age, higher fat%, decreased brain gray matter volume loss or decreased cognitive functioning within a cohort of older adults. CONCLUSION Our results suggest that serum kynurenine may be used as a peripheral inflammatory marker that is associated with neuroinflammation and neurodegeneration, although not linked to cognition. Future studies should consider longitudinal analysis to assess the causal inferences between chronic peripheral and neuroinflammation, brain structural and neurometabolic changes, and cognitive decline in aging.
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Affiliation(s)
- Wouter A J Vints
- Department of Health Promotion and Rehabilitation, Lithuanian Sports University, Kaunas, Lithuania.,Department of Rehabilitation Medicine Research School Caphri, Maastricht University, Maastricht, Netherlands.,Centre of Expertise in Rehabilitation and Audiology, Adelante Zorggroep, Hoensbroek, Netherlands
| | - Simona Kušleikiene
- Department of Health Promotion and Rehabilitation, Lithuanian Sports University, Kaunas, Lithuania
| | - Samrat Sheoran
- Department of Health Promotion and Rehabilitation, Lithuanian Sports University, Kaunas, Lithuania
| | - Milda Šarkinaite
- Department of Radiology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Kristina Valatkevičiene
- Department of Radiology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Rymante Gleizniene
- Department of Radiology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Mindaugas Kvedaras
- Department of Health Promotion and Rehabilitation, Lithuanian Sports University, Kaunas, Lithuania
| | - Kazimieras Pukenas
- Department of Health Promotion and Rehabilitation, Lithuanian Sports University, Kaunas, Lithuania
| | - Uwe Himmelreich
- Biomedical MRI Unit, Department of Imaging and Pathology, Group Biomedical Sciences, Catholic University Leuven, Leuven, Belgium
| | - Vida J Cesnaitiene
- Department of Health Promotion and Rehabilitation, Lithuanian Sports University, Kaunas, Lithuania
| | - Oron Levin
- Department of Health Promotion and Rehabilitation, Lithuanian Sports University, Kaunas, Lithuania.,Movement Control & Neuroplasticity Research Group, Group Biomedical Sciences, Catholic University Leuven, Heverlee, Belgium
| | - Jeanine Verbunt
- Department of Rehabilitation Medicine Research School Caphri, Maastricht University, Maastricht, Netherlands.,Centre of Expertise in Rehabilitation and Audiology, Adelante Zorggroep, Hoensbroek, Netherlands
| | - Nerijus Masiulis
- Department of Health Promotion and Rehabilitation, Lithuanian Sports University, Kaunas, Lithuania.,Department of Rehabilitation, Physical and Sports Medicine, Institute of Health Science, Vilnius University, Vilnius, Lithuania
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Sudar-Milovanovic E, Gluvic Z, Obradovic M, Zaric B, Isenovic ER. Tryptophan Metabolism in Atherosclerosis and Diabetes. Curr Med Chem 2022; 29:99-113. [PMID: 34269660 DOI: 10.2174/0929867328666210714153649] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 06/07/2021] [Accepted: 06/11/2021] [Indexed: 02/08/2023]
Abstract
The essential amino acid tryptophan (Trp) undergoes catabolism through several pathways, producing biologically active metabolites that significantly impact physiological processes. The metabolic pathway responsible for the majority of Trp catabolism is the kynurenine synthesis pathway (KP). Serotonin and melatonin are among the most essential Trp pathways degradation products. It has emerged that a strong relationship exists between alterations in Trp metabolism and the onset and progression of atherosclerosis and diabetes. Atherosclerosis is a chronic inflammatory disease of the small and medium arteries wall caused by maladaptive local immune responses, which underpins several cardiovascular diseases (CVD). Systemic low-grade immune-mediated inflammation is implicated in atherosclerosis where pro-inflammatory cytokines, such as interferon-γ (IFN-γ), play a significant role. IFN-γ upregulates the enzyme indoleamine 2,3-dioxygenase (IDO), decreasing serum levels of the Trp and increasing metabolite levels of kynurenine. Increased IDO expression and activity could accelerate the atherosclerosis process. Therefore, activated IDO inhibition could offer possible treatment options regarding atherosclerosis management. Diabetes is a chronic metabolic disease characterized by hyperglycemia that, over time, leads to severe damage to the heart, blood vessels, eyes, kidneys, and peripheral nerves. Trp serum levels and lower activity of IDO were higher in future type 2 diabetes (T2DM) patients. This article reviews recent findings on the link between mammalian Trp metabolism and its role in atherosclerosis and diabetes and outlines the intervention strategies.
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Affiliation(s)
- Emina Sudar-Milovanovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade,Serbia
| | - Zoran Gluvic
- Clinic for Internal Medicine, Department of Endocrinology and Diabetes, Zemun Clinical Hospital, School of Medicine, University of Belgrade, Belgrade,Serbia
| | - Milan Obradovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade,Serbia
| | - Bozidarka Zaric
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade,Serbia
| | - Esma R Isenovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade,Serbia
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Tryptophan Metabolism in Bipolar Disorder in a Longitudinal Setting. Antioxidants (Basel) 2021; 10:antiox10111795. [PMID: 34829665 PMCID: PMC8615217 DOI: 10.3390/antiox10111795] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 11/02/2021] [Accepted: 11/08/2021] [Indexed: 11/17/2022] Open
Abstract
Immune-mediated inflammatory processes and oxidative stress are involved in the aetiopathogenesis of bipolar disorder (BD) and weight-associated comorbidities. Tryptophan breakdown via indoleamine 2,3-dioxygenase-1 (IDO-1) along the kynurenine axis concomitant with a pro-inflammatory state was found to be more active in BD, and associated with overweight/obesity. This study aimed to investigate tryptophan metabolism in BD compared to controls (C), stratified by weight classes, in a longitudinal setting, dependent on the incidence of BD episodes. Peripheral tryptophan, kynurenine, and neopterin were assessed in the serum of 226 BD individuals and 142 C. Three samples in a longitudinal assessment were used for 75 BD individuals. Results showed a higher kynurenine/tryptophan in both BD compared to C and overweight compared to normal weight persons. Levels remained stable over time. In the longitudinal course, no differences were found between individuals who were constantly euthymic or not, or who had an illness episode or had none. Findings indicate that tryptophan, kynurenine, and IDO-1 activity may play a role in pathophysiology in BD but are not necessarily associated with clinical manifestations. Accelerated tryptophan breakdown along the kynurenine axis may be facilitated by being overweight. This may increase the risk of accumulation of neurotoxic metabolites, impacting BD symptomatology, cognition, and somatic comorbidities.
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IDO activity forecasts obesity in males and premenopausal females in a 10-year follow-up study:The Cardiovascular Risk in Young Finns Study. Atherosclerosis 2021; 336:32-38. [PMID: 34628102 DOI: 10.1016/j.atherosclerosis.2021.09.018] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 09/12/2021] [Accepted: 09/16/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS Indoleamine 2,3-dioxygenase (IDO) is an intracellular enzyme associated with artery wall inflammation. Previous studies have verified correlation between IDO activity and early signs of atherosclerosis especially in females. We aimed to elucidate the relationship between an estimate of IDO activity and atherosclerotic risk factors related to non-alchohol-fatty liver (NAFLD) in a 6- and 10-year follow-up. METHODS Estimates of IDO activity along with complete risk factor data were measured from females (n = 506; age 24-39) and males (n = 421; age 24-39) in 2001. Risk factor measurements were conducted again in 2007 and 2011. Statistical examinations were carried out by Pearson correlation and risk ratio analysis. RESULTS In females, age-adjusted IDO correlated with body mass index (BMI) (p = 0.0008), waist (p = 0.0009), C-reactive protein (CRP) (p = 0.0014) and logarithmically modified triglycerides (p = 0.0488) in 2007. Correlation remained significant with BMI (p = 0.0007) and waist (p = 0.0063) in 2011. In males, age-adjusted IDO correlated with waist (p = 0.0367) and high-density lipoprotein cholesterol (HDL-C) (p = 0.0489) in 2007. Correlation remained significant with HDL-C (p = 0.0348) in 2011. In risk ratio analysis, relationship between IDO and obesity was confirmed in females after 10 years (RR = 1.026, p = 0.0147, 95% CI) and in males after 6 and 10 years (RR = 1.019, p = 0.0091, 95% CI and RR = 1.015, p = 0.0404, 95% CI, respectively) when the data was adjusted for age and BMI. CONCLUSIONS IDO activity correlated with obesity and factors related to NAFLD, namely obesity of visceral type, hypertriglyceridemia and CRP (in females), well-characterized risk factors for diabetes and atherosclerosis in 6- and 10-year follow-up in males and premenopausal females.
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Nazario-Yepiz NO, Fernández Sobaberas J, Lyman R, Campbell MR, Shankar V, Anholt RRH, Mackay TFC. Physiological and metabolomic consequences of reduced expression of the Drosophila brummer triglyceride Lipase. PLoS One 2021; 16:e0255198. [PMID: 34547020 PMCID: PMC8454933 DOI: 10.1371/journal.pone.0255198] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 09/07/2021] [Indexed: 11/18/2022] Open
Abstract
Disruption of lipolysis has widespread effects on intermediary metabolism and organismal phenotypes. Defects in lipolysis can be modeled in Drosophila melanogaster through genetic manipulations of brummer (bmm), which encodes a triglyceride lipase orthologous to mammalian Adipose Triglyceride Lipase. RNAi-mediated knock-down of bmm in all tissues or metabolic specific tissues results in reduced locomotor activity, altered sleep patterns and reduced lifespan. Metabolomic analysis on flies in which bmm is downregulated reveals a marked reduction in medium chain fatty acids, long chain saturated fatty acids and long chain monounsaturated and polyunsaturated fatty acids, and an increase in diacylglycerol levels. Elevated carbohydrate metabolites and tricarboxylic acid intermediates indicate that impairment of fatty acid mobilization as an energy source may result in upregulation of compensatory carbohydrate catabolism. bmm downregulation also results in elevated levels of serotonin and dopamine neurotransmitters, possibly accounting for the impairment of locomotor activity and sleep patterns. Physiological phenotypes and metabolomic changes upon reduction of bmm expression show extensive sexual dimorphism. Altered metabolic states in the Drosophila model are relevant for understanding human metabolic disorders, since pathways of intermediary metabolism are conserved across phyla.
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Affiliation(s)
- Nestor O. Nazario-Yepiz
- Department of Biochemistry and Genetics and Center for Human Genetics, Clemson University, Greenwood, South Carolina, United States of America
| | - Jaime Fernández Sobaberas
- Department of Biochemistry and Genetics and Center for Human Genetics, Clemson University, Greenwood, South Carolina, United States of America
| | - Roberta Lyman
- Department of Biochemistry and Genetics and Center for Human Genetics, Clemson University, Greenwood, South Carolina, United States of America
| | - Marion R. Campbell
- Department of Biochemistry and Genetics and Center for Human Genetics, Clemson University, Greenwood, South Carolina, United States of America
| | - Vijay Shankar
- Department of Biochemistry and Genetics and Center for Human Genetics, Clemson University, Greenwood, South Carolina, United States of America
| | - Robert R. H. Anholt
- Department of Biochemistry and Genetics and Center for Human Genetics, Clemson University, Greenwood, South Carolina, United States of America
| | - Trudy F. C. Mackay
- Department of Biochemistry and Genetics and Center for Human Genetics, Clemson University, Greenwood, South Carolina, United States of America
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Metabonomic Study on the Plasma of High-Fat Diet-Induced Dyslipidemia Rats Treated with Ge Gen Qin Lian Decoction by Ultrahigh-Performance Liquid Chromatography-Mass Spectrometry. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:6692456. [PMID: 34194524 PMCID: PMC8203394 DOI: 10.1155/2021/6692456] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 05/07/2021] [Accepted: 05/21/2021] [Indexed: 01/03/2023]
Abstract
Gegen Qinlian decoction (GGQLD) has a definite effect on T2DM in clinic, and it has the effect of lowering blood sugar, improving insulin resistance, and improving the blood lipid level of rats with dyslipidemia, but the intervention mechanism of GGQLD on dyslipidemia has not been clarified. The changes in endogenous metabolites in the plasma of high-fat diet-induced dyslipidemia rats treated with Ge Gen Qin Lian Decoction (GGQLD) were studied to elucidate the therapeutic effects and mechanism of action of GGQLD in dyslipidemia. Based on ultrahigh-performance liquid chromatography coupled with quadrupole-time-of-flight tandem mass spectrometry (UHPLC-Q-TOF-MS), the metabolic profiles of rat serum samples were collected. The rat model of dyslipidemia was induced by a 60% fat-fed high-fat diet. After feeding the rats with a high-fat diet for 4 weeks, dyslipidemia appeared. After 5 weeks of GGQLD (14.85 g kg−1) administration, the metabonomics of rats' plasma samples in the normal group, model group, and administration group were analyzed. Mass profiler professional (MPP), SIMCA-P 14.1, and Graphpad prism 6.0 software were used combined with METLIN biological database and human metabolite database HMDB to screen and identify endogenous biomarkers. Metaboanalyst 4.0 software was used by combining with HMDB and KEGG databases; the enrichment and metabolic pathway of biomarkers were analyzed to explore the metabolic mechanism of dyslipidemia rats induced by high-fat diet and the intervention mechanism of Gegen Qinlian decoction. After 5 weeks of administration of GGQLD, the levels of serum TC and TG were significantly decreased (P < 0.05, P < 0.01), while HDL-C and LDL-C were not significantly affected. After administration, the food intake of rats in the administration group decreased gradually, and the change trend of body weight gradually slowed down. The metabonomics of rat plasma samples results showed that 23 potential biomarkers including α-linolenic acid, arachidonic acid, and lysophosphatidylcholine were significantly changed in positive ion mode. Studies have shown that GGQLD has a significant lipid-lowering effect on dyslipidemia rats induced by a high-fat diet, and its preventive mechanism is related to tryptophan metabolism, fatty acid biosynthesis, α-linolenic acid metabolism, arachidonic acid, and glycerophosphatidyl metabolism pathway.
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Huang X, Chen X, Zhao S, Hou J, Huang L, Xu J, Wang W, He M, Shen O, Zhang J. Metabolomic Profiles of Shift Workers and Day Workers: A Cross-Sectional Study. Obesity (Silver Spring) 2021; 29:1074-1082. [PMID: 34029446 DOI: 10.1002/oby.23164] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 02/21/2021] [Accepted: 02/22/2021] [Indexed: 11/08/2022]
Abstract
OBJECTIVE The purpose of this study was to characterize the metabolomic profiles of shift workers and day workers and to discover the effect of shift work on workers' metabolic health. METHODS A total of 824 participants aged 25 to 55 years were recruited, and 485 (275 shift workers and 210 day workers) completed the study. The mean age of the shift workers was 37.32 (5.53) years old, and that of day workers was 36.50 (7.83) years old. Serum and salivary samples were collected for the detection of key biochemical indicators (melatonin, cholesterol, and low-density lipoprotein cholesterol) and for metabolome profile analyses. RESULTS Compared with female day workers, female shift workers had a higher BMI, waist circumference, and hip circumference. Correspondingly, we identified 76 significant metabolites (false discovery rate < 0.05) in shift workers, including L-tryptophan, acylcarnitines, and several fatty acids. Three pathways that presented significant differences were biosynthesis of unsaturated fatty acids, linoleic acid metabolism, and ubiquinone and other terpenoid-quinone biosynthesis. CONCLUSIONS Compared with day workers, shift workers were more prone to weight gain and central obesity and were at a higher risk for impaired lipid metabolism with disrupted circadian rhythms.
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Affiliation(s)
- Xinru Huang
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Xiaoyi Chen
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Shiyu Zhao
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Jiaojiao Hou
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Li Huang
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Jie Xu
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Wei Wang
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Mengting He
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Ouxi Shen
- Department of Occupational Health, Suzhou Industrial Park Center for Disease Control and Prevention, Suzhou, Jiangsu, China
| | - Jie Zhang
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, China
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou, Jiangsu, China
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Steiner J, Dobrowolny H, Guest PC, Bernstein HG, Fuchs D, Roeser J, Summergrad P, Oxenkrug GF. Plasma Anthranilic Acid and Leptin Levels Predict HAM-D Scores in Depressed Women. Int J Tryptophan Res 2021; 14:11786469211016474. [PMID: 34045868 PMCID: PMC8138296 DOI: 10.1177/11786469211016474] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 04/18/2021] [Indexed: 11/24/2022] Open
Abstract
Objectives: Major depressive disorder (MDD) is associated with dysregulations of leptin
and tryptophan–kynurenine (Trp–Kyn) (TKP) pathways. Leptin, a
pro-inflammatory cytokine, activates Trp conversion into Kyn. However,
leptin association with down-stream Kyn metabolites in MDD is unknown. Methods: Fasting plasma samples from 29 acutely ill drug-naïve (n = 16) or currently
non-medicated (⩾6 weeks; n = 13) MDD patients were analyzed for leptin, Trp,
Kyn, its down-stream metabolites (anthranilic [AA], kynurenic [KYNA],
xanthurenic [XA] acids and 3-hydroxykynurenine [3HK]), C-reactive protein
(CRP), neopterin, body mass index (BMI), and insulin resistance (HOMA-IR).
Depression severity was assessed by HAM-D-21. Results: In female (n = 14) (but not in male) patients HAM-D-21 scores correlated with
plasma levels of AA (but not other Kyn metabolites) (rho = −0.644,
P = .009) and leptin (Spearman’s rho = −0.775,
P = .001). Inclusion of AA into regression analysis
improved leptin prediction of HAM-D from 48.5% to 65.9%. Actual HAM-D scores
highly correlated with that calculated by formula: HAM-D = 34.8518−(0.5660 ×
leptin [ng/ml] + 0.4159 × AA [nmol/l]) (Rho = 0.84, P =
.00015). In male (n = 15) (but not in female) patients leptin correlated
with BMI, waist circumference/hip ratio, CRP, and HOMA-IR. Conclusions: Present findings of gender specific AA/Leptin correlations with HAM-D are
important considering that AA and leptin are transported from plasma into
brain, and that AA formation is catalyzed by
kynureninase—the only TKP gene associated with depression
according to genome-wide analysis. High correlation between predicted and
actual HAM-D warrants further evaluation of plasma AA and leptin as an
objective laboratory test for the assessment of depression severity in
female MDD patients
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Affiliation(s)
- Johann Steiner
- Laboratory of Translational Psychiatry, University of Magdeburg, Magdeburg, Saxony-Anhalt, Germany.,Department of Psychiatry and Psychotherapy, University of Magdeburg, Magdeburg, Germany.,Center for Behavioral Brain Sciences, Magdeburg, Germany
| | - Henrik Dobrowolny
- Laboratory of Translational Psychiatry, University of Magdeburg, Magdeburg, Saxony-Anhalt, Germany.,Department of Psychiatry and Psychotherapy, University of Magdeburg, Magdeburg, Germany
| | - Paul C Guest
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, University of Campinas, Campinas, Brazil
| | - Hans-Gert Bernstein
- Laboratory of Translational Psychiatry, University of Magdeburg, Magdeburg, Saxony-Anhalt, Germany.,Department of Psychiatry and Psychotherapy, University of Magdeburg, Magdeburg, Germany
| | - Dietmar Fuchs
- Institute of Biological Chemistry, Biocenter of the Medical University of Innsbruck, Innsbruck, Tyrol, Austria
| | - Julien Roeser
- Charles River Laboratories, South San Francisco, CA, USA
| | - Paul Summergrad
- Department of Psychiatry, Psychiatry and Inflammation Program, Tufts University School of Medicine, Boston, MA, USA
| | - Gregory F Oxenkrug
- Department of Psychiatry, Psychiatry and Inflammation Program, Tufts University School of Medicine, Boston, MA, USA
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