1
|
Salsinha AS, Araújo-Rodrigues H, Dias C, Cima A, Rodríguez-Alcalá LM, Relvas JB, Pintado M. Omega-3 and conjugated fatty acids impact on human microbiota modulation using an in vitro fecal fermentation model. Clin Nutr 2025; 49:102-117. [PMID: 40262394 DOI: 10.1016/j.clnu.2025.04.007] [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: 03/14/2024] [Revised: 03/07/2025] [Accepted: 04/03/2025] [Indexed: 04/24/2025]
Abstract
BACKGROUND & AIMS Gut microbiota has been gaining increasing attention and its important role in the maintenance of a general good health condition is already established. The potential of gut microbiota modulation through diet is an important research focus to be considered. Lipids, as omega-3 fatty acids, are well known for their beneficial role on organs and corresponding diseases. However, their impact on gut microbiota is still poorly defined, and studies on the role of other polyunsaturated fatty acids, such as conjugated linoleic and linolenic acids, are even scarcer. METHODS By using an in vitro human fermentation model, we assessed the effect of omega-3, CLA isomers, and punicic acid on microbiota modulation. RESULTS Fish oil, Omega-3, and CLA samples positively impact Akkermansia spp. and Bifidobacterium spp. growth. Moreover, all the samples supported Roseburia spp. growth after 24 h of fermentation and, importantly, they were able to maintain the Firmicutes: Bacteroidetes ratio near 1. All the bioactive fatty acid samples, except Pomegranate oil, were able to significantly increase butyrate levels compared to those found in the positive control (FOS) sample. Moreover, Fish oil and Omega-3 samples were able to increase the concentration of GABA, alanine, tyrosine, phenylalanine, isoleucine, and leucine between 12 and 24 h of fermentation. CONCLUSIONS The impact of the assessed polyunsaturated fatty acids in gut microbiota has been observed in its impact on key bacteria (Akkermansia, Bifidobacterium, and Roseburia) as well as their metabolic byproducts, including butyrate and amino acids, which could potentially play a role in modulating the gut-brain axis.
Collapse
Affiliation(s)
- Ana Sofia Salsinha
- Universidade Católica Portuguesa, CBQF - Centro de Biotecnologia e Química Fina -Laboratório Associado, Escola Superior de Biotecnologia, Rua de Diogo Botelho, 1327, 4169-005 Porto, Portugal; Instituto de Investigação e Inovação em Saúde and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto - Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
| | - Helena Araújo-Rodrigues
- Universidade Católica Portuguesa, CBQF - Centro de Biotecnologia e Química Fina -Laboratório Associado, Escola Superior de Biotecnologia, Rua de Diogo Botelho, 1327, 4169-005 Porto, Portugal; Instituto de Investigação e Inovação em Saúde and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto - Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
| | - Cindy Dias
- Universidade Católica Portuguesa, CBQF - Centro de Biotecnologia e Química Fina -Laboratório Associado, Escola Superior de Biotecnologia, Rua de Diogo Botelho, 1327, 4169-005 Porto, Portugal
| | - André Cima
- Universidade Católica Portuguesa, CBQF - Centro de Biotecnologia e Química Fina -Laboratório Associado, Escola Superior de Biotecnologia, Rua de Diogo Botelho, 1327, 4169-005 Porto, Portugal
| | - Luís Miguel Rodríguez-Alcalá
- Universidade Católica Portuguesa, CBQF - Centro de Biotecnologia e Química Fina -Laboratório Associado, Escola Superior de Biotecnologia, Rua de Diogo Botelho, 1327, 4169-005 Porto, Portugal
| | - João B Relvas
- Instituto de Investigação e Inovação em Saúde and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto - Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; Departamento de Biomedicina, Faculdade de Medicina da Universidade do Porto (FMUP), 4200-319 Porto, Portugal
| | - Manuela Pintado
- Universidade Católica Portuguesa, CBQF - Centro de Biotecnologia e Química Fina -Laboratório Associado, Escola Superior de Biotecnologia, Rua de Diogo Botelho, 1327, 4169-005 Porto, Portugal.
| |
Collapse
|
2
|
Li Z, Liu H. Microbe-dependent and independent effects of diet on metabolic inflammation in glucose metabolism regulation. Food Chem 2025; 488:144852. [PMID: 40413951 DOI: 10.1016/j.foodchem.2025.144852] [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: 02/26/2025] [Revised: 05/18/2025] [Accepted: 05/19/2025] [Indexed: 05/27/2025]
Abstract
Diet can contribute to the development of metabolic disease including type 2 diabetes (T2D) by inducing metabolic inflammation. While the gut microbiota mediates the effects of diet, the diet can also exert its effects independent of gut microbes. The microbe-dependent and -independent effects of diet on inflammation remain to be elucidated. This review examines recent advances and dissects the specifics of both gut microbe-dependent and independent mechanisms through which diet impacts inflammation and glucose metabolism. We delineate how diet interacts with the gut microbiome and induces metabolic inflammation. We also describe the direct effects of dietary components and their related metabolites on the immune system, and explore how diet-induced sterile inflammation may contribute to metabolic disorders. It is important to consider both microbe-dependent and independent pathways when developing therapeutic approaches aimed at preventing T2D.
Collapse
Affiliation(s)
- Zhipeng Li
- State Key Laboratory of Food Science and Resources, China-Canada Joint Laboratory of Food Science and Technology (Nanchang), Nanchang University, Nanchang 330047, China.
| | - Huiying Liu
- The Institute of Translational Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330000, China.
| |
Collapse
|
3
|
Ning X, Zheng H, Tu Y, Guo Q, Ren B, Wu L, Xie J, Liu C. Branched-chain amino acids promote gelatinase secretion from human periodontal ligament stem cells through nuclear factor kappa-B signaling. Arch Oral Biol 2025; 176:106297. [PMID: 40373536 DOI: 10.1016/j.archoralbio.2025.106297] [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: 02/13/2025] [Revised: 05/08/2025] [Accepted: 05/12/2025] [Indexed: 05/17/2025]
Abstract
OBJECTIVE To explore the effects of branched-chain amino acids (BCAAs) on periodontal tissues and regulation of gelatinase secretion by human periodontal ligament stem cells (hPDLSCs). DESIGN The salivary BCAA levels (leucine, isoleucine, and valine) in the clinical participants were measured using mass spectrometry. A local injection model in the periodontium of Sprague Dawley rats was established to investigate the periodontal destruction induced by BCAAs. A BCAA-treatment model of hPDLSCs was established to detect the expression and activity of gelatinase and further explore the potential mechanism by which BCAAs enhance gelatinase secretion. RESULTS Compared to the healthy controls, the salivary levels of leucine (p = 0.0190), isoleucine (p = 0.0351), and valine (p = 0.0072) were significantly elevated in individuals with periodontitis. In vivo experiments revealed that BCAAs aggravated periodontal extracellular matrix degradation and alveolar bone resorption in rats. Three-dimensional reconstruction of the rat maxilla demonstrated an increase in the distance from the cementoenamel junction to the alveolar bone crest (p < 0.0001), and a decrease in the bone volume fraction (p < 0.0001). In vitro experiments demonstrated that BCAAs activate the phosphorylation of nuclear factor kappa-B (NF-κB) signaling pathway in the hPDLSCs and consequently induce the secretion of gelatinases. The absence of any of the components in the BCAAs attenuated this effect. CONCLUSION BCAAs increase gelatinase secretion through the NF-κB (p-p65) signaling pathway, consequently exacerbating periodontal tissue destruction. This provides a novel insight on the role of BCAAs in the host immune-inflammatory response and increases our understanding of the possible involvement of BCAAs in the periodontitis development.
Collapse
Affiliation(s)
- Xinjie Ning
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Huiling Zheng
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Ying Tu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Qiang Guo
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Biao Ren
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Leng Wu
- Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Jing Xie
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
| | - Chengcheng Liu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
| |
Collapse
|
4
|
Pasut A, Lama E, Van Craenenbroeck AH, Kroon J, Carmeliet P. Endothelial cell metabolism in cardiovascular physiology and disease. Nat Rev Cardiol 2025:10.1038/s41569-025-01162-x. [PMID: 40346347 DOI: 10.1038/s41569-025-01162-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/15/2025] [Indexed: 05/11/2025]
Abstract
Endothelial cells are multifunctional cells that form the inner layer of blood vessels and have a crucial role in vasoreactivity, angiogenesis, immunomodulation, nutrient uptake and coagulation. Endothelial cells have unique metabolism and are metabolically heterogeneous. The microenvironment and metabolism of endothelial cells contribute to endothelial cell heterogeneity and metabolic specialization. Endothelial cell dysfunction is an early event in the development of several cardiovascular diseases and has been shown, at least to some extent, to be driven by metabolic changes preceding the manifestation of clinical symptoms. Diabetes mellitus, hypertension, obesity and chronic kidney disease are all risk factors for cardiovascular disease. Changes in endothelial cell metabolism induced by these cardiometabolic stressors accelerate the accumulation of dysfunctional endothelial cells in tissues and the development of cardiovascular disease. In this Review, we discuss the diversity of metabolic programmes that control endothelial cell function in the cardiovascular system and how these metabolic programmes are perturbed in different cardiovascular diseases in a disease-specific manner. Finally, we discuss the potential and challenges of targeting endothelial cell metabolism for the treatment of cardiovascular diseases.
Collapse
Affiliation(s)
- Alessandra Pasut
- Laboratory of Angiogenesis & Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, VIB Center for Cancer Biology, VIB, Leuven, Belgium
| | - Eleonora Lama
- Laboratory of Angiogenesis & Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, VIB Center for Cancer Biology, VIB, Leuven, Belgium
| | - Amaryllis H Van Craenenbroeck
- Division of Nephrology, University Hospitals Leuven, Leuven, Belgium
- Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium
| | - Jeffrey Kroon
- Experimental Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
- Amsterdam Cardiovascular Sciences, Atherosclerosis & Ischaemic Syndromes, Amsterdam, The Netherlands.
| | - Peter Carmeliet
- Laboratory of Angiogenesis & Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, VIB Center for Cancer Biology, VIB, Leuven, Belgium.
- Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates.
| |
Collapse
|
5
|
Muttiah B, Hanafiah A. Gut Microbiota and Cardiovascular Diseases: Unraveling the Role of Dysbiosis and Microbial Metabolites. Int J Mol Sci 2025; 26:4264. [PMID: 40362500 PMCID: PMC12072866 DOI: 10.3390/ijms26094264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2025] [Revised: 04/29/2025] [Accepted: 04/29/2025] [Indexed: 05/15/2025] Open
Abstract
Cardiovascular diseases (CVDs), including heart failure (HF), hypertension, myocardial infarction (MI), and atherosclerosis, are increasingly linked to gut microbiota dysbiosis and its metabolic byproducts. HF, affecting over 64 million individuals globally, is associated with systemic inflammation and gut barrier dysfunction, exacerbating disease progression. Similarly, hypertension and MI correlate with reduced microbial diversity and an abundance of pro-inflammatory bacteria, contributing to vascular inflammation and increased cardiovascular risk. Atherosclerosis is also influenced by gut dysbiosis, with key microbial metabolites such as trimethylamine-N-oxide (TMAO) and short-chain fatty acids (SCFAs) playing crucial roles in disease pathogenesis. Emerging evidence highlights the therapeutic potential of natural compounds, including flavonoids, omega-3 fatty acids, resveratrol, curcumin, and marine-derived bioactives, which modulate the gut microbiota and confer cardioprotective effects. These insights underscore the gut microbiota as a critical regulator of cardiovascular health, suggesting that targeting dysbiosis may offer novel preventive and therapeutic strategies. Further research is needed to elucidate underlying mechanisms and optimize microbiome-based interventions for improved cardiovascular outcomes.
Collapse
Affiliation(s)
- Barathan Muttiah
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
| | - Alfizah Hanafiah
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
- GUT Research Group, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
| |
Collapse
|
6
|
Kuleš J, Rubić I, Rešetar Maslov D, Efendić M, Martinković K, Pongrac E, Šmit I, Potočnjak D, Barić Rafaj R, Mrljak V. Metabolomics Insights into Salivary Profile in Dogs with Babesia canis Infection. Biomolecules 2025; 15:520. [PMID: 40305281 PMCID: PMC12024595 DOI: 10.3390/biom15040520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 03/21/2025] [Accepted: 03/31/2025] [Indexed: 05/02/2025] Open
Abstract
Babesiosis is a significant vector-borne zoonotic disease with major global economic and health implications, affecting various vertebrate hosts. Babesia parasites are auxotrophic for essential nutrients, relying on their hosts for metabolic support. This study investigated salivary metabolomic changes in dogs naturally infected with Babesia canis (N = 14) compared to healthy controls (N = 14) using untargeted and targeted mass spectrometry-based approaches. Saliva, a biofluid rich in metabolites, undergoes alterations in response to systemic diseases, making it a promising medium for studying host-pathogen interactions. Metabolomic profiling was performed using a Dionex UltiMate 3000 UHPLC system coupled with a Thermo Orbitrap Q Exactive mass spectrometer. An untargeted analysis detected 2257 salivary features, of which, 868 were significantly altered, with seven metabolites identified by reference to standards. A targeted analysis revealed significant changes in seven metabolites. Functional bioinformatics indicated disruptions in amino acid, nucleotide, and lipid metabolism, alongside alterations in energy production pathways, and purine metabolism. These findings provide critical insights into the metabolic shifts underlying canine babesiosis, supporting the development of advanced diagnostic and therapeutic strategies in the future. This study highlights the intricate interplay between host and pathogen, particularly in nutrient acquisition and metabolic regulation.
Collapse
Affiliation(s)
- Josipa Kuleš
- Department of Chemistry and Biochemistry, Faculty of Veterinary Medicine, University of Zagreb, 10 000 Zagreb, Croatia;
| | - Ivana Rubić
- Internal Diseases Clinic, Faculty of Veterinary Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (I.R.); (D.R.M.); (M.E.); (E.P.); (I.Š.); (D.P.); (V.M.)
| | - Dina Rešetar Maslov
- Internal Diseases Clinic, Faculty of Veterinary Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (I.R.); (D.R.M.); (M.E.); (E.P.); (I.Š.); (D.P.); (V.M.)
| | - Maša Efendić
- Internal Diseases Clinic, Faculty of Veterinary Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (I.R.); (D.R.M.); (M.E.); (E.P.); (I.Š.); (D.P.); (V.M.)
| | - Krešimir Martinković
- Department for Microbiology and Infectious Diseases with Clinic, Faculty of Veterinary Medicine, University of Zagreb, 10 000 Zagreb, Croatia;
| | - Elizabeta Pongrac
- Internal Diseases Clinic, Faculty of Veterinary Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (I.R.); (D.R.M.); (M.E.); (E.P.); (I.Š.); (D.P.); (V.M.)
| | - Iva Šmit
- Internal Diseases Clinic, Faculty of Veterinary Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (I.R.); (D.R.M.); (M.E.); (E.P.); (I.Š.); (D.P.); (V.M.)
| | - Dalibor Potočnjak
- Internal Diseases Clinic, Faculty of Veterinary Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (I.R.); (D.R.M.); (M.E.); (E.P.); (I.Š.); (D.P.); (V.M.)
| | - Renata Barić Rafaj
- Department of Chemistry and Biochemistry, Faculty of Veterinary Medicine, University of Zagreb, 10 000 Zagreb, Croatia;
| | - Vladimir Mrljak
- Internal Diseases Clinic, Faculty of Veterinary Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (I.R.); (D.R.M.); (M.E.); (E.P.); (I.Š.); (D.P.); (V.M.)
| |
Collapse
|
7
|
Hao QY, Weng J, Zeng TT, Zeng YH, Guo JB, Li SC, Chen YR, Yang PZ, Gao JW, Li ZH. Dietary branched-chain amino acids intake and coronary artery calcium progression: insights from the coronary artery risk development in young adults (CARDIA) study. Eur J Nutr 2025; 64:131. [PMID: 40106011 DOI: 10.1007/s00394-025-03649-2] [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: 11/11/2024] [Accepted: 03/05/2025] [Indexed: 03/22/2025]
Abstract
OBJECTIVE Branched-chain amino acids (BCAA) have been implicated in the risk of cardiovascular disease. However, it is unclear whether dietary BCAA intake, specifically isoleucine, leucine, and valine are associated with coronary artery calcium (CAC) progression. METHODS We included the participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study cohort for the analysis. Dietary intake of BCAA was assessed at year 7 of the study. CAC was measured using standardized computed tomography scans at years 15, 20, and 25. CAC progression was defined as follows: for participants with a baseline CAC of 0, progression was defined as CAC > 0 at follow-up; for those with 0 < baseline CAC < 100, progression was defined as an annualized change of ≥ 10; and for those with baseline CAC ≥ 100, progression was defined as an annualized percent change of ≥ 10%. Multivariate adjusted Cox regression models were utilized to examine the associations between BCAA intake and CAC progression. RESULTS Among 2381 included participants (average age 40.4 ± 3.5 years, 44.9% men), 629 participants (26.4%) exhibited CAC progression during a follow-up period of 8.90 ± 2.03 years. In the fully adjusted model, high intake of total BCAA, and its individual components, isoleucine, leucine, and valine were associated with an increased risk of CAC progression by 35.6% (HR, 1.356 [95% CI, 1.040-1.769]), 30.5% (HR, 1.305 [95% CI, 1.001-1.701]), 30.9% (HR, 1.309 [95% CI, 1.003-1.706]), and 33.9% (HR, 1.339 [95% CI, 1.026-1.747]), respectively, compared to their corresponding low intake groups. The associations were consistent across various subgroups, including age, sex, race, and body mass index, but were stronger in participants without baseline CAC (interaction P < 0.001). These results remained robust in a series of sensitivity analyses. CONCLUSIONS High dietary intake of BCAA, including isoleucine, leucine, and valine, were independently associated with an increased risk of CAC progression. The findings may implication for dietary modifications in primary prevention of subclinical atherosclerosis. REGISTRATION URL: https://www. CLINICALTRIALS gov ; Unique identifier: NCT00005130.
Collapse
Affiliation(s)
- Qing-Yun Hao
- Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jun Weng
- Department of Endoscopy, SunYat-sen University Cancer Center, Guangzhou, China
| | - Ting-Ting Zeng
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yu-Hong Zeng
- Medical Apparatus and Equipment Deployment, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jing-Bin Guo
- Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Shi-Chao Li
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yi-Ran Chen
- Institute of Public Health, Guangzhou Medical University & Guangzhou Center for Disease Control and Prevention, Guangzhou, Guangdong, China
| | - Ping-Zhen Yang
- Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
| | - Jing-Wei Gao
- Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
| | - Ze-Hua Li
- Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
| |
Collapse
|
8
|
Yao S, Marron MM, Farsijani S, Miljkovic I, Tseng GC, Shah RV, Murthy VL, Newman AB. Metabolomic characterization of unintentional weight loss among community-dwelling older Black and White men and women. Aging Cell 2025; 24:e14410. [PMID: 39544124 PMCID: PMC11896220 DOI: 10.1111/acel.14410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 09/27/2024] [Accepted: 10/16/2024] [Indexed: 11/17/2024] Open
Abstract
This study aims to understand the metabolic mechanisms of unintentional weight loss in older adults. We investigated plasma metabolite associations of subsequent weight change over 2 years in 1536 previously weight stable participants (mean age 74.6 years, 50% women, 35% Black) from the Health, Aging and Body Composition (Health ABC) Study. Multinomial logistic regressions were used to examine associations of the 442 metabolites with weight loss with/without an intention and weight gain >3% annually relative to weight stability. The metabolite associations of unintentional weight loss differed from those of intentional weight loss and weight gain. Lower levels of aromatic amino acids, phospholipids, long-chain poly-unsaturated triglycerides, and higher levels of amino acid derivatives, poly-unsaturated fatty acids, and carbohydrates were associated with higher odds of unintentional weight loss after adjusting for age, sex, race, and BMI categories. Prevalent diseases attenuated four and lower mid-thigh muscle mass and poorer appetite each attenuated 2 of 77 identified metabolite associations by >20%, respectively. Other factors (e.g., energy expenditure, diet, and medication) attenuated all associations by <20%. While 16 metabolite associations were attenuated by 20%-48% when adjusting for all these risk factors, 47 metabolite associations remained significant. Altered amino acid metabolism, impaired mitochondrial fatty acid oxidation, and inflammaging implicated by identified metabolites appear to precede unintentional weight loss in Health ABC older adults. Furthermore, these pathways seem to be associated with prevalent diseases especially diabetes, lower muscle mass, and poorer appetite.
Collapse
Affiliation(s)
- Shanshan Yao
- University of PittsburghPittsburghPennsylvaniaUSA
| | | | | | | | | | - Ravi V. Shah
- Vanderbilt University Medical CenterNashvilleTennesseeUSA
| | | | | |
Collapse
|
9
|
Sun W, Lin R, Li Y, Yao Y, Lu B, Yu Y. Circulating branched-chain amino acids and the risk of major adverse cardiovascular events in the UK biobank. Front Endocrinol (Lausanne) 2025; 16:1510910. [PMID: 40052157 PMCID: PMC11882422 DOI: 10.3389/fendo.2025.1510910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 01/21/2025] [Indexed: 03/09/2025] Open
Abstract
Objective To investigate the relationship between circulating branched-chain amino acids (BCAAs) and the risk of major adverse cardiovascular events (MACE) in a national population-based cohort study. Methods UK Biobank, a prospective study involving 22 recruitment centers across the United Kingdom. For this analysis, we included 266,840 participants from the UK Biobank who had available BCAA data and no history of MACE at baseline. Cox regression analysis was conducted to evaluate these associations, adjusting for potential confounders. Results During a 13.80 ± 0.83-year follow-up, 52,598 participants experienced MACE, with the incidence of MACE increasing progressively across quintiles of circulating BCAAs, isoleucine, leucine, and valine. Overall, the fifth quintile exhibited a 7-12% higher MACE risk compared to the second quintile. In males, BCAAs were not associated with MACE risk. However, increased risks were observed for isoleucine (8-12% in higher quintiles), leucine (9% in the first quintile and 6% in the fifth quintile), and valine (8% in the first quintile). In females, higher quintiles of BCAAs, isoleucine, leucine, and valine were associated with increased MACE risk, ranging from 9% to 12%. Among participants under 65y, higher quintiles of BCAAs, isoleucine, and leucine were associated with increased MACE risk, while valine showed no significant association. No association was found in participants aged 65 and older. These analyses were adjusted for multiple potential confounders. Conclusion Generally, higher levels of BCAAs, isoleucine, leucine, and valine were associated with an increased risk of MACE, except in participants older than 65. Additionally, in males, the lowest quintiles of leucine and valine were also associated with an increased risk of MACE.
Collapse
Affiliation(s)
- Wanwan Sun
- Department of Endocrinology, Huashan Hospital Affiliated to Fudan University, Shanghai, China
| | - Ruilang Lin
- Department of Biostatistics, School of Public Health, The Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China
| | - Yiming Li
- Department of Endocrinology, Huashan Hospital Affiliated to Fudan University, Shanghai, China
| | - Ye Yao
- Department of Biostatistics, School of Public Health, The Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China
| | - Bin Lu
- Department of Endocrinology, Huadong Hospital Affiliated to Fudan University, Shanghai, China
| | - Yongfu Yu
- Department of Biostatistics, School of Public Health, The Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China
| |
Collapse
|
10
|
Mallol R, Rombauts A, Abelenda-Alonso G, Gudiol C, Balsalobre M, Carratalà J. Metabolomic profile of severe COVID-19 and a signature predictive of progression towards severe disease status: a prospective cohort study (METCOVID). Sci Rep 2025; 15:4963. [PMID: 39929875 PMCID: PMC11811168 DOI: 10.1038/s41598-025-87288-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 01/17/2025] [Indexed: 02/13/2025] Open
Abstract
Profound metabolomic alterations occur during COVID-19. Early identification of the subset of hospitalised COVID-19 patients at risk of developing severe disease is critical for optimal resource utilization and prompt treatment. This work explores the metabolomic profile of hospitalised adult COVID-19 patients with severe disease, and establishes a predictive signature for disease progression. Within 48 hours of admission, serum samples were collected from 148 hospitalised patients for nuclear magnetic resonance (NMR) spectroscopy. Lipoprotein profiling was performed using the 1H-NMR-based Liposcale test, while low molecular weight metabolites were analysed using one-dimensional Carr-Purcell-Meiboom-Gill pulse spectroscopy and an adaptation of the Dolphin method for lipophilic extracts. Severe COVID-19, per WHO's Clinical Progression Scale, was characterized by altered lipoprotein distribution, elevated signals of glyc-A and glyc-B, a shift towards a catabolic state with elevated levels of branched-chain amino acids, and accumulation of ketone bodies. Furthermore, COVID-19 patients initially presenting with moderate disease but progressing to severe stages exhibited a distinct metabolic signature. Our multivariate model demonstrated a cross-validated AUC of 0.82 and 72% predictive accuracy for severity progression. NMR spectroscopy-based metabolomic profiling enables the identification of moderate COVID-19 patients at risk of disease progression, aiding in resource allocation and early intervention.
Collapse
Affiliation(s)
- Roger Mallol
- Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), 08007, Barcelona, Spain
| | - Alexander Rombauts
- Department of Infectious Diseases, Hospital Universitari de Bellvitge-IDIBELL, 08907, Barcelona, Spain.
| | - Gabriela Abelenda-Alonso
- Department of Infectious Diseases, Hospital Universitari de Bellvitge-IDIBELL, 08907, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - Carlota Gudiol
- Department of Infectious Diseases, Hospital Universitari de Bellvitge-IDIBELL, 08907, Barcelona, Spain
- Department of Medicine, Universitat de Barcelona, 08007, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029, Madrid, Spain
- Institut Català d'Oncologia (ICO), Hospital Duran i Reynals, 08908, Barcelona, Spain
| | - Marc Balsalobre
- Human Environment Research, La Salle-Universitat Ramon Llull, 08022, Barcelona, Spain
| | - Jordi Carratalà
- Department of Infectious Diseases, Hospital Universitari de Bellvitge-IDIBELL, 08907, Barcelona, Spain
- Department of Medicine, Universitat de Barcelona, 08007, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029, Madrid, Spain
| |
Collapse
|
11
|
Deng Y, Zeng L, Lai Y, Ji S, Peng B, Lu H, Wang M, Kwan HY, Wang Q, Zhao X. Branched-chain amino acids levels associated with risk of erectile dysfunction: A Mendelian randomization analysis. Exp Gerontol 2025; 200:112677. [PMID: 39778693 DOI: 10.1016/j.exger.2025.112677] [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: 09/01/2024] [Revised: 12/30/2024] [Accepted: 01/05/2025] [Indexed: 01/11/2025]
Abstract
BACKGROUND Erectile dysfunction (ED) is a prevalent male sexual dysfunction that remarkably impacts patients' quality of life and is also recognized as a precursor to cardiovascular disease (CVD) events. Branched-chain amino acids (BCAAs) are derived from dietary intake and mainly involved in energy metabolism. Previous studies have underscored the association between BCAAs and CVD, but the causal link between BCAAs and ED remains uncertain. METHODS The bidirectional Mendelian randomization (MR) study used the genetic data from genome-wide association studies (GWAS) to identify single nucleotide polymorphisms (SNPs) associated with total BCAAs, leucine, isoleucine, and valine. The genetic data for ED were acquired from the FinnGen study (n = 95,178). The primary method used to assess causal associations was the inverse variance-weighted (IVW) method, supplemented by MR-Egger, weighted median, and simple median analyses. Cochrane's Q test was utilized to evaluate heterogeneity within the results, while the MR-Egger intercept test was utilized to evaluate the Level pleiotropy. A sensitivity analysis was performed employing leave-one-out analysis. RESULTS The MR analysis results indicate a positive correlation between levels of total BCAA (OR = 1.984, 95 % CI = 1.018-3.868, P = 0.044), leucine (OR = 2.277, 95 % CI = 1.121-4.626, P = 0.023), isoleucine (OR = 2.584, 95 % CI = 1.167-5.722, P = 0.019), valine (OR = 1.894, 95 % CI = 1.119-3.206, P = 0.017), and the risk of ED. Sensitivity tests confirmed the accuracy and robustness of the study findings. Moreover, the reverse MR analysis found no association between ED and the BCAAs. CONCLUSION The results of this analysis indicate a positive association between the circulating BCAA concentrations and the risk of ED, but their underlying mechanisms require further investigation.
Collapse
Affiliation(s)
- Yijian Deng
- Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, China
| | - Liying Zeng
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Yigui Lai
- People's Hospital of Yangjiang, Yangjiang 529500, China
| | - Shuai Ji
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Baizhao Peng
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Hanqi Lu
- Dongguan Hospital of Traditional Chinese Medicine, Dongguan, Guangdong 523000, China
| | - Ming Wang
- Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, China
| | - Hiu Yee Kwan
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Qi Wang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China.
| | - Xiaoshan Zhao
- Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, China; School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China.
| |
Collapse
|
12
|
Chaney C, Mansilla L, Kubica M, Pinto-Pacheco B, Dunn K, Bertacchi V, Walker DI, Valeggia C. Contaminant Exposure Profiles Demonstrate Similar Physiological Effects Across Environments Despite Unique Profile Composition in Formosa, Argentina, and Connecticut, USA. Am J Hum Biol 2025; 37:e24178. [PMID: 39463098 DOI: 10.1002/ajhb.24178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 10/01/2024] [Accepted: 10/12/2024] [Indexed: 10/29/2024] Open
Abstract
OBJECTIVE Exposure to environmental contaminants is globally universal. However, communities vary in the specific combination of contaminants to which they are exposed, potentially contributing to variation in human health and creating "locally situated biologies." We investigated how environmental exposures differ across environments by comparing exposure profiles between two contexts that differ markedly across political, economic, and sociocultural factors-Namqom, Formosa, Argentina, and New Haven, Connecticut, United States. METHODS We collected infant urine, maternal urine, and human milk samples from mother-infant dyads in Formosa (n = 13) and New Haven (n = 21). We used untargeted liquid chromatography with high-resolution mass spectrometry (LC-HRMS) to annotate environmental contaminants and endogenous metabolites in these samples, and we analyzed the data using exposome-wide association studies (EWAS) followed by pathway enrichment. RESULTS We found statistically significant differences between the chemical exposure profiles of the Argentinian and US mothers, mostly involving pesticides; however, we observed similarities in the infant urine and human milk environmental contaminant profiles, suggesting that the maternal body may buffer infant exposure through human milk. We also found that infants and mothers were exposed to contaminants that were associated with alterations in amino acid and carbohydrate metabolism. Infants additionally showed alterations in vitamin metabolism, including vitamins B1, B3, and B6. CONCLUSIONS Differences in chemical exposure profiles may be related to structural factors. Despite variation in the composition of exposure profiles between the two study sites, environmental contaminant exposure was associated with similar patterns in human physiology when we considered contaminants comprehensively rather than individually, with implications for metabolic and cardiovascular disease risk as well as infant cognitive development.
Collapse
Affiliation(s)
- Carlye Chaney
- Department of Biology, Washington University in St. Louis, St. Louis, Missouri, USA
- Department of Anthropology, University of Missouri, Columbia, Missouri, USA
- Chaco Area Reproductive Ecology Program, Formosa, Argentina
| | | | - Marcelina Kubica
- The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Brismar Pinto-Pacheco
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Kathryn Dunn
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Victoria Bertacchi
- Department of Anthropology, Yale University, New Haven, Connecticut, USA
| | - Douglas I Walker
- Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA
| | - Claudia Valeggia
- Chaco Area Reproductive Ecology Program, Formosa, Argentina
- Department of Anthropology, Yale University, New Haven, Connecticut, USA
| |
Collapse
|
13
|
Wu Y, Avcilar-Kücükgöze I, Santovito D, Atzler D. Amino Acid Metabolism and Autophagy in Atherosclerotic Cardiovascular Disease. Biomolecules 2024; 14:1557. [PMID: 39766264 PMCID: PMC11673637 DOI: 10.3390/biom14121557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 11/29/2024] [Accepted: 12/04/2024] [Indexed: 01/11/2025] Open
Abstract
Cardiovascular disease is the most common cause of mortality globally, accounting for approximately one out of three deaths. The main underlying pathology is atherosclerosis, a dyslipidemia-driven, chronic inflammatory disease. The interplay between immune cells and non-immune cells is of great importance in the complex process of atherogenesis. During atheroprogression, intracellular metabolic pathways, such as amino acid metabolism, are master switches of immune cell function. Autophagy, an important stress survival mechanism involved in maintaining (immune) cell homeostasis, is crucial during the development of atherosclerosis and is strongly regulated by the availability of amino acids. In this review, we focus on the interplay between amino acids, especially L-leucine, L-arginine, and L-glutamine, and autophagy during atherosclerosis development and progression, highlighting potential therapeutic perspectives.
Collapse
Affiliation(s)
- Yuting Wu
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, 80336 Munich, Germany; (Y.W.); (I.A.-K.)
| | - Irem Avcilar-Kücükgöze
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, 80336 Munich, Germany; (Y.W.); (I.A.-K.)
- DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, 80336 Munich, Germany
| | - Donato Santovito
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, 80336 Munich, Germany; (Y.W.); (I.A.-K.)
- DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, 80336 Munich, Germany
- Institute for Genetic and Biomedical Research (IRGB), Unit of Milan, National Research Council, 20133 Milan, Italy
| | - Dorothee Atzler
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, 80336 Munich, Germany; (Y.W.); (I.A.-K.)
- DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, 80336 Munich, Germany
- Walter Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, 80336 Munich, Germany
| |
Collapse
|
14
|
Zhang H, Leng S, Gao F, Kovalik JP, Tan RS, Wee HN, Chua KV, Ching J, Zhao X, Allen J, Wu Q, Leiner T, Zhong L, Koh AS. Longitudinal aortic strain, ventriculo-arterial coupling and fatty acid oxidation: novel insights into human cardiovascular aging. GeroScience 2024; 46:5459-5471. [PMID: 38514519 PMCID: PMC11493888 DOI: 10.1007/s11357-024-01127-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 03/09/2024] [Indexed: 03/23/2024] Open
Abstract
Aging-induced aortic stiffness has been associated with altered fatty acid metabolism. We studied aortic stiffness using cardiac magnetic resonance (CMR)-assessed ventriculo-arterial coupling (VAC) and novel aortic (AO) global longitudinal strain (GLS) combined with targeted metabolomic profiling. Among community older adults without cardiovascular disease, VAC was calculated as aortic pulse wave velocity (PWV), a marker of arterial stiffness, divided by left ventricular (LV) GLS. AOGLS was the maximum absolute strain measured by tracking the phasic distance between brachiocephalic artery origin and aortic annulus. In 194 subjects (71 ± 8.6 years; 88 women), AOGLS (mean 5.6 ± 2.1%) was associated with PWV (R = -0.3644, p < 0.0001), LVGLS (R = 0.2756, p = 0.0001) and VAC (R = -0.3742, p <0.0001). Stiff aorta denoted by low AOGLS <4.26% (25th percentile) was associated with age (OR 1.13, 95% CI 1.04-1.24, p = 0.007), body mass index (OR 1.12, 95% CI 1.01-1.25, p = 0.03), heart rate (OR 1.04, 95% CI 1.01-1.06, p = 0.011) and metabolites of medium-chain fatty acid oxidation: C8 (OR 1.005, p = 0.026), C10 (OR 1.003, p = 0.036), C12 (OR 1.013, p = 0.028), C12:2-OH/C10:2-DC (OR 1.084, p = 0.032) and C16-OH (OR 0.82, p = 0.006). VAC was associated with changes in long-chain hydroxyl and dicarboxyl carnitines. Multivariable models that included acyl-carnitine metabolites, but not amino acids, significantly increased the discrimination over clinical risk factors for prediction of AOGLS (AUC [area-under-curve] 0.73 to 0.81, p = 0.037) and VAC (AUC 0.78 to 0.87, p = 0.0044). Low AO GLS and high VAC were associated with altered medium-chain and long-chain fatty acid oxidation, respectively, which may identify early metabolic perturbations in aging-associated aortic stiffening. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02791139.
Collapse
Affiliation(s)
- Hongzhou Zhang
- National Heart Centre Singapore, 5 Hospital Drive, Singapore, 169609, Singapore
- Department of Cardiology, the First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China
| | - Shuang Leng
- National Heart Centre Singapore, 5 Hospital Drive, Singapore, 169609, Singapore
- Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore
| | - Fei Gao
- National Heart Centre Singapore, 5 Hospital Drive, Singapore, 169609, Singapore
- Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore
| | - Jean-Paul Kovalik
- Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore
- Singapore General Hospital, 31 Third Hospital Ave, Singapore, 168753, Singapore
| | - Ru-San Tan
- National Heart Centre Singapore, 5 Hospital Drive, Singapore, 169609, Singapore
- Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore
| | - Hai Ning Wee
- Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore
| | - Kee Voon Chua
- Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore
| | - Jianhong Ching
- Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore
- KK Women's and Children's Hospital, 100 Bukit Timah Rd, Singapore, 229899, Singapore
| | - Xiaodan Zhao
- National Heart Centre Singapore, 5 Hospital Drive, Singapore, 169609, Singapore
| | - John Allen
- Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore
| | - Qinghua Wu
- Department of Cardiology, the Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang, 330006, China
| | - Tim Leiner
- Department of Radiology, Mayo Clinic, 200 1st St SW, Rochester, MN, USA
| | - Liang Zhong
- National Heart Centre Singapore, 5 Hospital Drive, Singapore, 169609, Singapore.
- Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore.
| | - Angela S Koh
- National Heart Centre Singapore, 5 Hospital Drive, Singapore, 169609, Singapore.
- Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore.
| |
Collapse
|
15
|
Song Y, Zhou X, Zhao H, Zhao W, Sun Z, Zhu J, Yu Y. Characterizing the role of the microbiota-gut-brain axis in cerebral small vessel disease: An integrative multi‑omics study. Neuroimage 2024; 303:120918. [PMID: 39505226 DOI: 10.1016/j.neuroimage.2024.120918] [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: 04/16/2024] [Revised: 10/22/2024] [Accepted: 11/04/2024] [Indexed: 11/08/2024] Open
Abstract
BACKGROUND Prior efforts have revealed changes in gut microbiome, circulating metabolome, and multimodal neuroimaging features in cerebral small vessel disease (CSVD). However, there is a paucity of research integrating the multi-omic information to characterize the role of the microbiota-gut-brain axis in CSVD. METHODS We collected gut microbiome, fecal and blood metabolome, multimodal magnetic resonance imaging data from 37 CSVD patients with white matter hyperintensities and 46 healthy controls. Between-group comparison was performed to identify the differential gut microbial taxa, followed by performance of multi-stage microbiome-metabolome-neuroimaging-neuropsychology correlation analyses in CSVD patients. RESULTS Our data showed both depleted and enriched gut microbes in CSVD patients. Among the differential microbes, Haemophilus and Akkermansia were associated with a range of metabolites enriched for Aminoacyl-tRNA biosynthesis pathway. Furthermore, the affected metabolites were associated with neuroimaging measures involving gray matter morphology, spontaneous intrinsic brain activity, white matter integrity, and global structural network topology, which were in turn related to cognition and emotion in CSVD patients. CONCLUSION Our findings provide an integrative framework to understand the pathophysiological mechanisms underlying the interplay between gut microbiota dysbiosis and CSVD, highlighting the potential of targeting the microbiota-gut-brain axis as a therapeutic strategy in CSVD patients.
Collapse
Affiliation(s)
- Yu Song
- Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, PR China; Research Center of Clinical Medical Imaging, Anhui Province, Hefei 230032, PR China; Anhui Provincial Institute of Translational Medicine, Hefei 230032, PR China; Anhui Provincial Key Laboratory for Brain Bank Construction and Resource Utilization, Hefei 230032, PR China
| | - Xia Zhou
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, PR China
| | - Han Zhao
- Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, PR China; Research Center of Clinical Medical Imaging, Anhui Province, Hefei 230032, PR China; Anhui Provincial Institute of Translational Medicine, Hefei 230032, PR China; Anhui Provincial Key Laboratory for Brain Bank Construction and Resource Utilization, Hefei 230032, PR China
| | - Wenming Zhao
- Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, PR China; Research Center of Clinical Medical Imaging, Anhui Province, Hefei 230032, PR China; Anhui Provincial Institute of Translational Medicine, Hefei 230032, PR China; Anhui Provincial Key Laboratory for Brain Bank Construction and Resource Utilization, Hefei 230032, PR China
| | - Zhongwu Sun
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, PR China.
| | - Jiajia Zhu
- Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, PR China; Research Center of Clinical Medical Imaging, Anhui Province, Hefei 230032, PR China; Anhui Provincial Institute of Translational Medicine, Hefei 230032, PR China; Anhui Provincial Key Laboratory for Brain Bank Construction and Resource Utilization, Hefei 230032, PR China.
| | - Yongqiang Yu
- Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, PR China; Research Center of Clinical Medical Imaging, Anhui Province, Hefei 230032, PR China; Anhui Provincial Institute of Translational Medicine, Hefei 230032, PR China; Anhui Provincial Key Laboratory for Brain Bank Construction and Resource Utilization, Hefei 230032, PR China.
| |
Collapse
|
16
|
Kong FS, Huang P, Chen JH, Ma Y. The Novel Insight of Gut Microbiota from Mouse Model to Clinical Patients and the Role of NF-κB Pathway in Polycystic Ovary Syndrome. Reprod Sci 2024; 31:3323-3333. [PMID: 38653859 DOI: 10.1007/s43032-024-01562-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 04/12/2024] [Indexed: 04/25/2024]
Abstract
Polycystic Ovary Syndrome (PCOS) is a metabolic disorder characterized by hyperandrogenism and related symptoms in women of reproductive age. Emerging evidence suggests that chronic low-grade inflammation plays a significant role in the development of PCOS. The gut microbiota, a complex bacterial ecosystem, has been extensively studied for various diseases, including PCOS, while the underlying mechanisms are not fully understood. This review comprehensively summarizes the changes in gut microbiota and metabolites observed in PCOS and their potential association with the condition. Additionally, we discuss the role of abnormal nuclear factor κB signaling in the pathogenesis of PCOS. These findings offer valuable insights into the mechanisms of PCOS and may pave the way for the development of control and therapeutic strategies for this condition in clinical practice. By bridging the gap between mouse models and clinical patients, this review contributes to a better understanding of the interplay between gut microbiota and inflammation in PCOS, thus paving new ways for future investigations and interventions.
Collapse
Affiliation(s)
- Fan-Sheng Kong
- Department of Pediatrics, Affiliated Hospital of Jiangnan University, Wuxi, 214122, Jiangsu, China
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Panwang Huang
- Department of Pediatrics, Affiliated Hospital of Jiangnan University, Wuxi, 214122, Jiangsu, China
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Jian-Huan Chen
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China.
- Joint Primate Research Center for Chronic Diseases, Institute of Zoology of Guangdong Academy of Science, Jiangnan University, Wuxi, Jiangsu, China.
- Jiangnan University Brain Institute, Wuxi, Jiangsu, China.
| | - Yaping Ma
- Department of Pediatrics, Affiliated Hospital of Jiangnan University, Wuxi, 214122, Jiangsu, China.
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China.
| |
Collapse
|
17
|
Singh D, Menghini P, Rodriguez-Palacios A, Martino LD, Cominelli F, Basson AR. Leucine-Enriched Diet Reduces Fecal MPO but Does Not Protect Against DSS Colitis in a Mouse Model of Crohn's Disease-like Ileitis. Int J Mol Sci 2024; 25:11748. [PMID: 39519299 PMCID: PMC11545852 DOI: 10.3390/ijms252111748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 10/24/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024] Open
Abstract
Understanding the complex link between inflammation, gut health, and dietary amino acids is becoming increasingly important in the pathophysiology of inflammatory bowel disease (IBD). This study tested the hypothesis that a leucine-rich diet could attenuate inflammation and improve gut health in a mouse model of IBD. Specifically, we investigated the effects of a leucine-rich diet on dextran sulfate sodium (DSS)-induced colitis in germ-free (GF) SAMP1/YitFC (SAMP) mice colonized with human gut microbiota (hGF-SAMP). hGF-SAMP mice were fed one of four different diets: standard mouse diet (CHOW), American diet (AD), leucine-rich AD (AD + AA), or leucine-rich CHOW diet (CH + AA). Body weight, myeloperoxidase (MPO) activity, gut permeability, colonoscopy scores, and histological analysis were measured. Mice on a leucine-rich CHOW diet showed a decrease in fecal MPO prior to DSS treatment as compared to those on a regular diet (p > 0.05); however, after week five, prior to DSS, this effect had diminished. Following DSS treatment, there was no significant difference in gut permeability, fecal MPO activity, or body weight changes between the leucine-supplemented and control groups. These findings suggest that while a leucine-rich diet may transiently affect fecal MPO levels in hGF-SAMP mice, it does not confer protection against DSS-induced colitis symptoms or mitigate inflammation in the long term.
Collapse
Affiliation(s)
- Drishtant Singh
- Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA;
- Division of Gastroenterology & Liver Diseases, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; (P.M.); (A.R.-P.); (F.C.)
| | - Paola Menghini
- Division of Gastroenterology & Liver Diseases, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; (P.M.); (A.R.-P.); (F.C.)
- Digestive Health Research Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
| | - Alexander Rodriguez-Palacios
- Division of Gastroenterology & Liver Diseases, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; (P.M.); (A.R.-P.); (F.C.)
- Digestive Health Research Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
- Mouse Models Core, Silvio O’Conte Cleveland Digestive Diseases Research Core Center, Cleveland, OH 44106, USA
- Germ-Free and Gut Microbiome Core, Digestive Health Research Institute, Case Western Reserve University, Cleveland, OH 44106, USA
- Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Luca Di Martino
- Case Digestive Health Research Institute, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA;
- Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Fabio Cominelli
- Division of Gastroenterology & Liver Diseases, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; (P.M.); (A.R.-P.); (F.C.)
- Digestive Health Research Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
- Mouse Models Core, Silvio O’Conte Cleveland Digestive Diseases Research Core Center, Cleveland, OH 44106, USA
- Germ-Free and Gut Microbiome Core, Digestive Health Research Institute, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Abigail Raffner Basson
- Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA;
- Division of Gastroenterology & Liver Diseases, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; (P.M.); (A.R.-P.); (F.C.)
- Digestive Health Research Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
| |
Collapse
|
18
|
Prechtl L, Carrard J, Gallart-Ayala H, Borreggine R, Teav T, Königstein K, Wagner J, Knaier R, Infanger D, Streese L, Hinrichs T, Hanssen H, Ivanisevic J, Schmidt-Trucksäss A. Circulating amino acid signature features urea cycle alterations associated with coronary artery disease. Sci Rep 2024; 14:25848. [PMID: 39468229 PMCID: PMC11519371 DOI: 10.1038/s41598-024-76835-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Accepted: 10/17/2024] [Indexed: 10/30/2024] Open
Abstract
Coronary artery disease (CAD) remains a leading cause of death worldwide and imposes a substantial socioeconomic burden on healthcare. Improving risk stratification in clinical practice could help to combat this burden. As amino acids are biologically active metabolites whose involvement in CAD remains largely unknown, this study investigated associations between circulating amino acid levels and CAD phenotypes. A high-coverage quantitative liquid chromatography-mass spectrometry approach was applied to acquire the serum amino acids profile of age- and sex-coarsened-matched patients with CAD (n = 46, 66.9 years, 74.7% male) and healthy individuals (n = 120, 67.4 years, 74.7% male) from the COmPLETE study. Multiple linear regressions were performed to investigate associations between amino acid levels and (a) the health status (CAD vs. healthy), (b) the number of affected coronary arteries, or (c) the left ventricular ejection fraction. Regressions were adjusted for age, sex, daily physical activity, sampling, and fasting time. Urea cycle amino acids (ornithine, citrulline, homocitrulline, aspartate, and arginine) were significantly and negatively associated with CAD, the number of affected coronary arteries, and the left ventricular ejection fraction. Lysine, histidine, and the glutamine/glutamate ratio were also significantly and negatively associated with the CAD phenotypes. Overall, patients with CAD displayed lower levels of urea cycle amino acids, highlighting a potential role for urea cycle amino acid profiling in cardiovascular risk stratification.Trial registrationThe study was registered on https://www.clinicaltrials.gov (NCT03986892) on June 5, 2019.
Collapse
Affiliation(s)
- Luisa Prechtl
- School of Cardiovascular and Metabolic Health, University of Glasgow, 126 University Place, Glasgow, G12 8TA, Scotland
| | - Justin Carrard
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Grosse Allee 6, 4052, Basel, Switzerland.
| | - Hector Gallart-Ayala
- Metabolomics Platform, Faculty of Biology and Medicine, University of Lausanne, Quartier UNIL-CHUV-Rue du Bugnon 19, 1005, Lausanne, Switzerland
| | - Rébecca Borreggine
- Metabolomics Platform, Faculty of Biology and Medicine, University of Lausanne, Quartier UNIL-CHUV-Rue du Bugnon 19, 1005, Lausanne, Switzerland
| | - Tony Teav
- Metabolomics Platform, Faculty of Biology and Medicine, University of Lausanne, Quartier UNIL-CHUV-Rue du Bugnon 19, 1005, Lausanne, Switzerland
| | - Karsten Königstein
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Grosse Allee 6, 4052, Basel, Switzerland
| | - Jonathan Wagner
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Grosse Allee 6, 4052, Basel, Switzerland
| | - Raphael Knaier
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Grosse Allee 6, 4052, Basel, Switzerland
| | - Denis Infanger
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Grosse Allee 6, 4052, Basel, Switzerland
| | - Lukas Streese
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Grosse Allee 6, 4052, Basel, Switzerland
| | - Timo Hinrichs
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Grosse Allee 6, 4052, Basel, Switzerland
| | - Henner Hanssen
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Grosse Allee 6, 4052, Basel, Switzerland
| | - Julijana Ivanisevic
- Metabolomics Platform, Faculty of Biology and Medicine, University of Lausanne, Quartier UNIL-CHUV-Rue du Bugnon 19, 1005, Lausanne, Switzerland.
| | - Arno Schmidt-Trucksäss
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Grosse Allee 6, 4052, Basel, Switzerland
| |
Collapse
|
19
|
Zhang J, Jiang X, Pang B, Li D, Kang L, Zhou T, Wang B, Zheng L, Zhou CM, Zhang L. Association between tryptophan concentrations and the risk of developing cardiovascular diseases: a systematic review and meta-analysis. Nutr Metab (Lond) 2024; 21:82. [PMID: 39407297 PMCID: PMC11476920 DOI: 10.1186/s12986-024-00857-1] [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] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 10/04/2024] [Indexed: 10/20/2024] Open
Abstract
BACKGROUND Metabolic regulation of various amino acids have been proven to be effective in preventing cardiovascular disease (CVD). The impact of tryptophan, an essential amino acid, on the risk of developing CVD has not been fully elucidated. AIMS The aim of this meta-analysis was to systematically review evidence of the effects of tryptophan on CVD risk. METHODS The PubMed, Embase, Web of Science, Cochrane Library, and China National Knowledge Infrastructure (CNKI) databases were searched to collect relevant trials from inception to August 2024. The means and hazard ratios (HRs) were extracted and pooled. Subgroup analysis was performed to identify pooled effect estimates, and sensitivity analysis was conducted to assess the robustness of the pooled estimates. RESULTS Data were collected from 34,370 people under follow-up for CVD events in 13 studies, including cohort studies and case-control studies. They were categorized into three groups on the basis of sample type and indicators: the plasma tryptophan level group, the plasma tryptophan CVD hazard group, and the urinary tryptophan CVD hazard group. The CVD included in this study were coronary artery disease, heart failure, and peripheral artery disease. Twelve studies on plasma tryptophan were meta-analyzed. The plasma tryptophan levels in CVD patients were generally lower than those in individuals without CVD (SMD = -8.57, 95%CI (-15.77, -1.37), P = 0.02). Decreased circulating tryptophan levels are associated with cardiovascular disease risk (HR = 0.85, 95%CI (0.78, 0.92), P < 0.00001). CONCLUSIONS Decreased circulating tryptophan levels are associated with an increased risk of CVD events. Intervention in circulating tryptophan levels may be indicated to help prevent CVD.
Collapse
Affiliation(s)
- Jing Zhang
- Department of General Surgery, Department of Vascular Surgery, The First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xia Jiang
- Hebei Key Laboratory of Colorectal Cancer Precision Diagnosis and Treatment, The First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Bo Pang
- Hebei Key Laboratory of Colorectal Cancer Precision Diagnosis and Treatment, The First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Dongyun Li
- Hebei Key Laboratory of Colorectal Cancer Precision Diagnosis and Treatment, The First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Longfei Kang
- Hebei Key Laboratory of Colorectal Cancer Precision Diagnosis and Treatment, The First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Tengda Zhou
- Department of General Surgery, Department of Vascular Surgery, The First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Boyu Wang
- Department of General Surgery, Department of Vascular Surgery, The First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Lihua Zheng
- Department of General Surgery, Department of Vascular Surgery, The First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Chuan-Min Zhou
- Hebei Key Laboratory of Colorectal Cancer Precision Diagnosis and Treatment, The First Hospital of Hebei Medical University, Shijiazhuang, China.
| | - Lei Zhang
- Department of General Surgery, Department of Vascular Surgery, The First Hospital of Hebei Medical University, Shijiazhuang, China.
| |
Collapse
|
20
|
Yang X, Yang R, Zhang T, Tan DJ, Pan R, Chen Z, Wu D, Chen C, Xu Y, Zhang L, Li X, Shu Q, Hu L. Genotypic and phenotypic spectrum of maple syrup urine disease in Zhejiang of China. QJM 2024; 117:717-727. [PMID: 38837343 PMCID: PMC11604211 DOI: 10.1093/qjmed/hcae104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 04/23/2024] [Indexed: 06/07/2024] Open
Abstract
BACKGROUND Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder originating from defects in the branched-chain α-ketoacid dehydrogenase (BCKDH) complex encoded by BCKDHA, BCKDHB and DBT. This condition presents a spectrum of symptoms and potentially fatal outcomes. Although numerous mutations in the BCKDH complex genes associated with MSUD have been identified, the relationship between specific genotypes remains to be fully elucidated. AIM Our objective was to predict the pathogenicity of these genetic mutations and establish potential links between genotypic alterations and the clinical phenotypes of MSUD. DESIGN Retrospective population-based cohort. METHODS We analyzed 20 MSUD patients from the Children's Hospital at Zhejiang University School of Medicine (Hangzhou, China), recorded from January 2010 to December 2023. Patients' blood samples were collected by heel-stick through neonatal screening, and amino acid profiles were measured by tandem mass spectrometry. In silico methods were employed to assess the pathogenicity, stability and biophysical properties. Various computation tools were utilized for assessment, namely PredictSNP, MAGPIE, iStable, Align GVGD, ConSurf and SNP effect. RESULTS We detected 25 distinct mutations, including 12 novel mutations. The BCKDHB gene was the most commonly affected (53.3%) compared to the BCKDHA gene (20.0%) and DBT gene (26.7%). In silico webservers predicted all novel mutations were disease-causing. CONCLUSIONS This study highlights the genetic complexity of MSUD and underscores the importance of early detection and intervention. Integrating neonatal screening with advanced sequencing methodologies is pivotal in ensuring precise diagnosis and effective management of MSUD, thereby significantly improving the prognosis for individuals afflicted with this condition.
Collapse
Affiliation(s)
- X Yang
- Department of Genetics and Metabolism, Children’s Hospital of Zhejiang University, School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - R Yang
- Department of Genetics and Metabolism, Children’s Hospital of Zhejiang University, School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - T Zhang
- Department of Genetics and Metabolism, Children’s Hospital of Zhejiang University, School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - D J Tan
- Department of Genetics and Metabolism, Children’s Hospital of Zhejiang University, School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - R Pan
- Department of Genetics and Metabolism, Children’s Hospital of Zhejiang University, School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Z Chen
- Department of Genetics and Metabolism, Children’s Hospital of Zhejiang University, School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - D Wu
- Department of Genetics and Metabolism, Children’s Hospital of Zhejiang University, School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - C Chen
- Department of Genetics and Metabolism, Children’s Hospital of Zhejiang University, School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Y Xu
- Department of Genetics and Metabolism, Children’s Hospital of Zhejiang University, School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - L Zhang
- Department of Radiology, Children’s Hospital of Zhejiang University, School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - X Li
- Department of Genetics and Metabolism, Children’s Hospital of Zhejiang University, School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Q Shu
- Department of Genetics and Metabolism, Children’s Hospital of Zhejiang University, School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - L Hu
- Department of Genetics and Metabolism, Children’s Hospital of Zhejiang University, School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| |
Collapse
|
21
|
Li Q, Pang B, Dang E, Wang G. Endothelial Dysfunction in Psoriasis: An Integrative Review. J Invest Dermatol 2024; 144:1935-1942. [PMID: 38493385 DOI: 10.1016/j.jid.2024.02.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 02/07/2024] [Accepted: 02/20/2024] [Indexed: 03/18/2024]
Abstract
Vascular endothelial cells (ECs), the inner layer of blood vessels, were previously considered to be a passive lining that facilitates cellular and molecular exchange. However, recent studies have revealed that ECs can respond to various stimuli and actively regulate vascular function and skin inflammation. Specific subtypes of ECs are known to have significant roles in a diverse range of physiological and pathological processes in the skin. This review suggests that EC dysfunction is both causal and consequential in the pathogenesis of psoriasis. Further investigations into dysregulated pathways in EC dysfunction may provide new insights for the treatment of psoriasis.
Collapse
Affiliation(s)
- Qingyang Li
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People Republic of China
| | - Bingyu Pang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People Republic of China
| | - Erle Dang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People Republic of China
| | - Gang Wang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People Republic of China.
| |
Collapse
|
22
|
Yao H, Jiang W, Liao X, Wang D, Zhu H. Regulatory mechanisms of amino acids in ferroptosis. Life Sci 2024; 351:122803. [PMID: 38857653 DOI: 10.1016/j.lfs.2024.122803] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 05/19/2024] [Accepted: 06/04/2024] [Indexed: 06/12/2024]
Abstract
Ferroptosis, an iron-dependent non-apoptotic regulated cell death process, is associated with the pathogenesis of various diseases. Amino acids, which are indispensable substrates of vital activities, significantly regulate ferroptosis. Amino acid metabolism is involved in maintaining iron and lipid homeostasis and redox balance. The regulatory effects of amino acids on ferroptosis are complex. An amino acid may exert contrasting effects on ferroptosis depending on the context. This review systematically and comprehensively summarized the distinct roles of amino acids in regulating ferroptosis and highlighted the emerging opportunities to develop clinical therapeutic strategies targeting amino acid-mediated ferroptosis.
Collapse
Affiliation(s)
- Heying Yao
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang 212001, China
| | - Wei Jiang
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang 212001, China
| | - Xiang Liao
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang 212001, China
| | - Dongqing Wang
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang 212001, China; Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China.
| | - Haitao Zhu
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang 212001, China; Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China.
| |
Collapse
|
23
|
Feng M, Qiao L, Yu Q, Liu M, Zhang J, Wen S, Li X, Teng V, Yan L, Zhang C, Li S, Guo Y, Lu P. Blood chromium and lung function among Chinese young adults: A comprehensive analysis based on epidemiology and metabolomics. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 281:116594. [PMID: 38941662 DOI: 10.1016/j.ecoenv.2024.116594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 06/10/2024] [Accepted: 06/12/2024] [Indexed: 06/30/2024]
Abstract
Chromium (Cr) exposure is associated with various respiratory system diseases, but there are limited studies investigating its impact on lung function in young adults. The Cr exposure-related metabolomic changes are not well elucidated. This study recruited 608 students from a university in Shandong Province, China in 2019. We used cohort design fitted with linear mixed-effects models to assess the association between blood Cr concentration and lung function. In addition, we performed metabolomic and lipidomic analyses of baseline serum samples (N = 582) using liquid chromatography-mass spectrometry. Two-step statistical analysis (analysis of variance and mixed-linear effect model) was used to evaluate the effect of blood Cr exposure on metabolites. We found that blood Cr was associated with decreased lung function in young adults. Each 2-fold increase in blood Cr concentrations was significantly associated with decreased FEV1 and FVC by 35.26 mL (95 % CI: -60.75, -9.78) and 38.56 mL (95 % CI: -66.60, -10.51), respectively. In the metabolomics analysis, blood Cr exposure was significantly associated with 14 key metabolites. The changed metabolites were mainly enriched in six pathways including lipid metabolism, amino acid metabolism, and cofactor vitamin metabolism. Blood Cr may affect lung function through oxidative stress and inflammation related pathways.
Collapse
Affiliation(s)
- Mingyu Feng
- Binzhou Medical University, Yantai, Shandong, China
| | - Lingyan Qiao
- Binzhou Medical University, Yantai, Shandong, China
| | - Qingxia Yu
- Binzhou Medical University, Yantai, Shandong, China
| | - Meiling Liu
- YanTaiShan Hospital, YanTai, Shandong, China
| | - Jia Zhang
- Binzhou Medical University, Yantai, Shandong, China
| | - Shuo Wen
- Binzhou Medical University, Yantai, Shandong, China
| | - Xinyuan Li
- Binzhou Medical University, Yantai, Shandong, China
| | - Victor Teng
- Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Victoria, Melbourne, Australia
| | - Lailai Yan
- Department of Laboratorial Science and Technology, School of Public Health, Peking University, Beijing, China
| | | | - Shanshan Li
- Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Victoria, Melbourne, Australia
| | - Yuming Guo
- Binzhou Medical University, Yantai, Shandong, China; Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Victoria, Melbourne, Australia.
| | - Peng Lu
- Binzhou Medical University, Yantai, Shandong, China.
| |
Collapse
|
24
|
Lee CY, Wu SW, Yang JJ, Chen WY, Chen CJ, Chen HH, Lee YC, Su CH, Kuan YH. Vascular endothelial dysfunction induced by 3-bromofluoranthene via MAPK-mediated-NFκB pro-inflammatory pathway and intracellular ROS generation. Arch Toxicol 2024; 98:2247-2259. [PMID: 38635053 PMCID: PMC11169047 DOI: 10.1007/s00204-024-03751-0] [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: 01/04/2024] [Accepted: 03/21/2024] [Indexed: 04/19/2024]
Abstract
3-Bromofluoranthene (3-BrFlu) is the secondary metabolite of fluoranthene, which is classified as a polycyclic aromatic hydrocarbon, through bromination and exists in the fine particulate matter of air pollutants. Endothelial dysfunction plays a critical role in the pathogenesis of cardiovascular and vascular diseases. Little is known about the molecular mechanism of 3-BrFlu on endothelial dysfunction in vivo and in vitro assay. In the present study, 3-BrFlu included concentration-dependent changes in ectopic angiogenesis of the sub-intestinal vein and dilation of the dorsal aorta in zebrafish. Disruption of vascular endothelial integrity and up-regulation of vascular endothelial permeability were also induced by 3-BrFlu in a concentration-dependent manner through pro-inflammatory responses in vascular endothelial cells, namely, SVEC4-10 cells. Generation of pro-inflammatory mediator PGE2 was induced by 3-BrFlu through COX2 expression. Expression of COX2 and generation of pro-inflammatory cytokines, including TNFα and IL-6, were induced by 3-BrFlu through phosphorylation of NF-κB p65, which was mediated by phosphorylation of MAPK, including p38 MAPK, ERK and JNK. Furthermore, generation of intracellular ROS was induced by 3-BrFlu, which is associated with the down-regulated activities of the antioxidant enzyme (AOE), including SOD and catalase. We also found that 3-BrFlu up-regulated expression of the AOE and HO-1 induced by 3-BrFlu through Nrf-2 expression. However, the 3-BrFlu-induced upregulation of AOE and HO-1 expression could not be revised the responses of vascular endothelial dysfunction. In conclusion, 3-BrFlu is a hazardous substance that results in vascular endothelial dysfunction through the MAPK-mediated-NFκB pro-inflammatory pathway and intracellular ROS generation.
Collapse
Affiliation(s)
- Chien-Ying Lee
- Department of Pharmacology, School of Medicine, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Rd., Taichung, 402, Taiwan, ROC
- Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Sheng-Wen Wu
- Division of Nephrology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
- Department of Internal Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Jiann-Jou Yang
- Department of BioMedical Sciences, Chung Shan Medical University, Taichung, Taiwan
| | - Wen-Ying Chen
- Department of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Chun-Jung Chen
- Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Hsin-Hung Chen
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Asia University Hospital, Taichung, Taiwan
- School of Medicine, Institute of Medicine and Public Health, Chung Shan Medical University, Taichung, Taiwan
- Chung Sheng Clinic, Nantou, Taiwan
| | - Yi-Chia Lee
- Department of Pharmacology, School of Medicine, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Rd., Taichung, 402, Taiwan, ROC
- Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chun-Hung Su
- Department of Internal Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Yu-Hsiang Kuan
- Department of Pharmacology, School of Medicine, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Rd., Taichung, 402, Taiwan, ROC.
- Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan.
| |
Collapse
|
25
|
Hirata A, Harada S, Iida M, Kurihara A, Fukai K, Kuwabara K, Kato S, Matsumoto M, Sata M, Miyagawa N, Toki R, Edagawa S, Sugiyama D, Sato A, Hirayama A, Sugimoto M, Soga T, Tomita M, Okamura T, Takebayashi T. Association of Nonalcoholic Fatty Liver Disease with Arterial Stiffness and its Metabolomic Profiling in Japanese Community-Dwellers. J Atheroscler Thromb 2024; 31:1031-1047. [PMID: 38311416 PMCID: PMC11224684 DOI: 10.5551/jat.64616] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 11/28/2023] [Indexed: 02/10/2024] Open
Abstract
AIMS Nonalcoholic fatty liver disease (NAFLD) is known to be associated with atherosclerosis. This study focused on upstream changes in the process by which NAFLD leads to atherosclerosis. The study aimed to confirm the association between NAFLD and the cardio-ankle vascular index (CAVI), an indicator of subclinical atherosclerosis, and explore metabolites involved in both by assessing 94 plasma polar metabolites. METHODS A total of 928 Japanese community-dwellers (306 men and 622 women) were included in this study. The association between NAFLD and CAVI was examined using a multivariable regression model adjusted for confounders. Metabolites commonly associated with NAFLD and CAVI were investigated using linear mixed-effects models in which batch numbers of metabolite measurements were used as a random-effects variable, and false discovery rate-adjusted p-values were calculated. To determine the extent to which these metabolites mediated the association between NAFLD and CAVI, mediation analysis was conducted. RESULTS NAFLD was positively associated with CAVI (coefficients [95% Confidence intervals (CI)]=0.23 [0.09-0.37]; p=0.001). A total of 10 metabolites were involved in NAFLD and CAVI, namely, branched-chain amino acids (BCAAs; valine, leucine, and isoleucine), aromatic amino acids (AAAs; tyrosine and tryptophan), alanine, proline, glutamic acid, glycerophosphorylcholine, and 4-methyl-2-oxopentanoate. Mediation analysis showed that BCAAs mediated more than 20% of the total effect in the association between NAFLD and CAVI. CONCLUSIONS NAFLD was associated with a marker of atherosclerosis, and several metabolites related to insulin resistance, including BCAAs and AAAs, could be involved in the process by which NAFLD leads to atherosclerosis.
Collapse
Affiliation(s)
- Aya Hirata
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
| | - Sei Harada
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
- Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - Miho Iida
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
| | - Ayako Kurihara
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
| | - Kota Fukai
- Department of Preventive Medicine, Tokai University School of Medicine, Kanagawa, Japan
| | - Kazuyo Kuwabara
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
| | - Suzuka Kato
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
| | - Minako Matsumoto
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
| | - Mizuki Sata
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
| | - Naoko Miyagawa
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
| | - Ryota Toki
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
| | - Shun Edagawa
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
| | - Daisuke Sugiyama
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
- Faculty of Nursing and Medical Care, Keio University, Kanagawa, Japan
| | - Asako Sato
- Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - Akiyoshi Hirayama
- Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - Masahiro Sugimoto
- Institute for Advanced Biosciences, Keio University, Yamagata, Japan
- Institute of Medical Science, Tokyo Medical University, Tokyo, Japan
| | - Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, Yamagata, Japan
- Faculty of Environment and Information Studies, Keio University, Kanagawa, Japan
| | - Masaru Tomita
- Institute for Advanced Biosciences, Keio University, Yamagata, Japan
- Faculty of Environment and Information Studies, Keio University, Kanagawa, Japan
| | - Tomonori Okamura
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
| | - Toru Takebayashi
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
- Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| |
Collapse
|
26
|
Meng X, Ren K, Liu X, Lyu C, Jung HW, Zhang Y, Zhang S. Efficacy of Rhamnus utilis Decne. Aqueous extract in mice with acute alcoholic liver injury and metabolomic study. Heliyon 2024; 10:e32523. [PMID: 38952369 PMCID: PMC11215275 DOI: 10.1016/j.heliyon.2024.e32523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 06/04/2024] [Accepted: 06/05/2024] [Indexed: 07/03/2024] Open
Abstract
Rhamnus utilis Decne. (Family Rhamnaceae Juss.) leaf is commonly prepared as a anti-inflammatory herbal medicine and used for tea production. To investigate the mechanism of Rhamnus utilis Decne. aqueous extract (RDAE) against acute alcoholic liver disease (ALD) in mice. The ALD mouse (Male ICR) model was induced via intragastric administration of 52 % alcohol. Mice in each group were treated by gavage once daily with the RDAE (1.12, 2.25, 4.500 g/kg). The expression of proteins involved in the MAPKs/NF-κB/COX-2-iNOS pathway was measured by western blotting. Non-targeted metabolomics was used to determine metabolic profiles and critical pathways, while targeted metabolomics validated key amino acid metabolites. After administration of RDAE, the body mass of mice was significantly increased. The liver index was significantly decreased. Meanwhile, the serum levels of AST, ALT, TG, TC, MDA, TNF-α, IL-1β and IL-6 were significantly decreased (P < 0.05, P < 0.01), but GSH level was inversely increased (P < 0.05). Metabolomic analysis revealed nine major pathways involved in the therapeutic effect of RDAE, including fructose and mannose metabolism. The levels of 7 amino acids including leucine, proline and alanine/sarcosine were significantly upregulated. Additionally, protein levels of p-NF-κB (p65)/NF-κB (p65), p-ERK1/2/ERK1/2, p-JNK/JNK, p-p38/p38, COX-2 and iNOS were significantly decreased (P < 0.01, P < 0.05). RDAE is used to treat acute ALD by improving lipid metabolism, inhibiting the expression of pro-inflammatory cytokines and regulating MAPKs/NF-κB/COX-2-iNOS signalling pathway. These findings provide valuable insights for acute ALD therapy based on traditional Chinese medicine (TCM).
Collapse
Affiliation(s)
- Xianglong Meng
- College of Chinese Materia Medica and Food Engineering, Shanxi University of Chinese Medicine, Jinzhong, 030619, Shanxi, China
- Shanxi Key Laboratory of Traditional Herbal Medicines Processing, Jinzhong, 030619, Shanxi, China
| | - Kele Ren
- College of Chinese Materia Medica and Food Engineering, Shanxi University of Chinese Medicine, Jinzhong, 030619, Shanxi, China
- Shanxi Key Laboratory of Traditional Herbal Medicines Processing, Jinzhong, 030619, Shanxi, China
| | - Xiaoqin Liu
- College of Chinese Materia Medica and Food Engineering, Shanxi University of Chinese Medicine, Jinzhong, 030619, Shanxi, China
- Shanxi Key Laboratory of Traditional Herbal Medicines Processing, Jinzhong, 030619, Shanxi, China
- College of Pharmacy, Shandong Modern University, Jinan, 250104, China
| | - Chenzi Lyu
- Department of Herbology, College of Korean Medicine, Dongguk University, Gyeongju, 38066, South Korea
| | - Hyo Won Jung
- Department of Herbology, College of Korean Medicine, Dongguk University, Gyeongju, 38066, South Korea
| | - Yilong Zhang
- Shanxi Pengyakang Biotechnology Co., Ltd, Lyuliang, 033000, Shanxi, China
| | - Shuosheng Zhang
- College of Chinese Materia Medica and Food Engineering, Shanxi University of Chinese Medicine, Jinzhong, 030619, Shanxi, China
- Shanxi Key Laboratory of Traditional Herbal Medicines Processing, Jinzhong, 030619, Shanxi, China
| |
Collapse
|
27
|
Tanase DM, Valasciuc E, Costea CF, Scripcariu DV, Ouatu A, Hurjui LL, Tarniceriu CC, Floria DE, Ciocoiu M, Baroi LG, Floria M. Duality of Branched-Chain Amino Acids in Chronic Cardiovascular Disease: Potential Biomarkers versus Active Pathophysiological Promoters. Nutrients 2024; 16:1972. [PMID: 38931325 PMCID: PMC11206939 DOI: 10.3390/nu16121972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Revised: 06/13/2024] [Accepted: 06/18/2024] [Indexed: 06/28/2024] Open
Abstract
Branched-chain amino acids (BCAAs), comprising leucine (Leu), isoleucine (Ile), and valine (Val), are essential nutrients vital for protein synthesis and metabolic regulation via specialized signaling networks. Their association with cardiovascular diseases (CVDs) has become a focal point of scientific debate, with emerging evidence suggesting both beneficial and detrimental roles. This review aims to dissect the multifaceted relationship between BCAAs and cardiovascular health, exploring the molecular mechanisms and clinical implications. Elevated BCAA levels have also been linked to insulin resistance (IR), type 2 diabetes mellitus (T2DM), inflammation, and dyslipidemia, which are well-established risk factors for CVD. Central to these processes are key pathways such as mammalian target of rapamycin (mTOR) signaling, nuclear factor kappa-light-chain-enhancer of activate B cells (NF-κB)-mediated inflammation, and oxidative stress. Additionally, the interplay between BCAA metabolism and gut microbiota, particularly the production of metabolites like trimethylamine-N-oxide (TMAO), adds another layer of complexity. Contrarily, some studies propose that BCAAs may have cardioprotective effects under certain conditions, contributing to muscle maintenance and metabolic health. This review critically evaluates the evidence, addressing the biological basis and signal transduction mechanism, and also discusses the potential for BCAAs to act as biomarkers versus active mediators of cardiovascular pathology. By presenting a balanced analysis, this review seeks to clarify the contentious roles of BCAAs in CVD, providing a foundation for future research and therapeutic strategies required because of the rising prevalence, incidence, and total burden of CVDs.
Collapse
Affiliation(s)
- Daniela Maria Tanase
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (D.M.T.); (A.O.); (D.E.F.); (M.F.)
- Internal Medicine Clinic, “St. Spiridon” County Clinical Emergency Hospital, Iasi 700111, Romania
| | - Emilia Valasciuc
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (D.M.T.); (A.O.); (D.E.F.); (M.F.)
- Internal Medicine Clinic, “St. Spiridon” County Clinical Emergency Hospital, Iasi 700111, Romania
| | - Claudia Florida Costea
- Department of Ophthalmology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
- 2nd Ophthalmology Clinic, “Prof. Dr. Nicolae Oblu” Emergency Clinical Hospital, 700309 Iași, Romania
| | - Dragos Viorel Scripcariu
- Department of General Surgery, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
- Regional Institute of Oncology, 700483 Iasi, Romania
| | - Anca Ouatu
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (D.M.T.); (A.O.); (D.E.F.); (M.F.)
- Internal Medicine Clinic, “St. Spiridon” County Clinical Emergency Hospital, Iasi 700111, Romania
| | - Loredana Liliana Hurjui
- Department of Morpho-Functional Sciences II, Physiology Discipline, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
- Hematology Laboratory, “St. Spiridon” County Clinical Emergency Hospital, 700111 Iasi, Romania
| | - Claudia Cristina Tarniceriu
- Department of Morpho-Functional Sciences I, Discipline of Anatomy, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
- Hematology Clinic, “Sf. Spiridon” County Clinical Emergency Hospital, 700111 Iasi, Romania
| | - Diana Elena Floria
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (D.M.T.); (A.O.); (D.E.F.); (M.F.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” County Clinical Emergency Hospital, 700111 Iasi, Romania
| | - Manuela Ciocoiu
- Department of Pathophysiology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
| | - Livia Genoveva Baroi
- Department of Surgery, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
- Department of Vascular Surgery, “St. Spiridon” County Clinical Emergency Hospital, 700111 Iasi, Romania
| | - Mariana Floria
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (D.M.T.); (A.O.); (D.E.F.); (M.F.)
- Internal Medicine Clinic, “St. Spiridon” County Clinical Emergency Hospital, Iasi 700111, Romania
| |
Collapse
|
28
|
Chen H, Zhang L, Li Y, Meng X, Chi Y, Liu M. Gut Microbiota and Its Metabolites: The Emerging Bridge Between Coronary Artery Disease and Anxiety and Depression? Aging Dis 2024; 16:1265-1284. [PMID: 39012662 PMCID: PMC12096936 DOI: 10.14336/ad.2024.0538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 06/19/2024] [Indexed: 07/17/2024] Open
Abstract
The increasing studies indicated that cardiovascular diseases, such as coronary artery disease (CAD), usually induce and exacerbate psychological problems, including anxiety and depression. These psychological issues are admitted as independent risk factors of heart disease as well. The interaction between CAD and anxiety and depression deteriorates the development and prognosis of CAD, which severely threatens the quality of life of patients. Although the existing mechanisms revealed the pathological relationship between CAD and anxiety and depression, there are few studies investigating the correlation between CAD and anxiety and depression from the aspect of gut microbiota (GM) and its metabolites. Therefore, in this review, we summarized whether GM and its metabolites are the emergent bridge between CAD and anxiety and depression. The results showed that there are four kinds of jointly up-regulated bacteria (i.e., Staphylococcus, Escherichia coli, Helicobacter pylori, and Shigella) and five kinds of jointly down-regulated bacteria (i.e., Prevotella, Lactobacillus, Faecalibacterium prausnitzii, Collinsella, and Bifidobacterium) in CAD as well as anxiety and depression. In addition, in CAD and anxiety and depression, the dysbiosis of the former four kinds of bacterium frequently leads to the outburst of inflammatory response, and the dysbiosis of the latter five kinds of bacterium is usually related to the metabolic abnormality of short-chain fatty acids, bile acids, and branched-chain amino acids. Therefore, we believe that GM and its metabolites act as the emergent bridge between CAD and anxiety and depression. The findings of this review provide novel insights and approaches for the clinical treatment of patients with both CAD and anxiety and depression.
Collapse
Affiliation(s)
- Haiyang Chen
- Department of Psycho-cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| | - Lijun Zhang
- Department of Psycho-cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| | - Yanwei Li
- Department of Psycho-cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
- School of Clinical Medicine, Henan University, Kaifeng, China.
| | - Xiangxi Meng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.
| | - Yunpeng Chi
- Department of Psycho-cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| | - Meiyan Liu
- Department of Psycho-cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| |
Collapse
|
29
|
Dziedzic M, Józefczuk E, Guzik TJ, Siedlinski M. Interplay Between Plasma Glycine and Branched-Chain Amino Acids Contributes to the Development of Hypertension and Coronary Heart Disease. Hypertension 2024; 81:1320-1331. [PMID: 38587181 PMCID: PMC11095885 DOI: 10.1161/hypertensionaha.123.22649] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 03/28/2024] [Indexed: 04/09/2024]
Abstract
BACKGROUND Higher levels of plasma glycine are linked to a reduced risk, while increased levels of total branched-chain amino acids (tBCAAs) are associated with a higher risk of essential hypertension and coronary heart disease (CHD). As these metabolic components are interconnected, analyzing the tBCAAs/glycine ratio may help to understand their interplay in the pathogenesis of cardiovascular disease. METHODS The Cox regression approach was combined with the development of novel genetic tools for assessments of associations between plasma metabolomic data (glycine, tBCAAs, and tBCAAs/glycine ratio) from the UK Biobank and the development of hypertension and CHD. Genome-wide association study was performed on 186 523 White UK Biobank participants to identify new independent genetic instruments for the 2-sample Mendelian randomization analyses. P-gain statistic >10 identified instruments associated with tBCAAs/glycine ratio significantly stronger compared with individual amino acids. Outcomes of genome-wide association study on hypertension and CHD were derived from the UK Biobank (nonoverlapping sample), FinnGen, and CARDIoGRAMplusC4D. RESULTS The tBCAAs/glycine ratio was prospectively associated with a higher risk of developing hypertension and CHD (hazard ratio quintile Q5 versus Q1, 1.196 [95% CI, 1.109-1.289] and 1.226 [95% CI, 1.160-1.296], respectively). Mendelian randomization analysis demonstrated that tBCAAs/glycine ratio (P-gain >10) was a risk factor for hypertension (meta-analyzed inverse-variance weighted causal estimate 0.45 log odds ratio/SD (95% CI, 0.26-0.64) and CHD (0.48 [95% CI, 0.29-0.67]) with an absolute effect significantly larger compared with the effect of glycine (-0.06 [95% CI, -0.1 to -0.03] and -0.08 [95% CI, -0.11 to -0.05], respectively) or tBCAAs (0.22 [95% CI, 0.09-0.34] and 0.12 [95% CI, 0.01-0.24], respectively). CONCLUSIONS The total BCAAs/glycine ratio is a key element of the metabolic signature contributing to hypertension and CHD, which may reflect biological pathways shared by glycine and tBCAAs.
Collapse
Affiliation(s)
- Mateusz Dziedzic
- Department of Internal Medicine (M.D., E.J., T.J.G., M.S.), Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Ewelina Józefczuk
- Department of Internal Medicine (M.D., E.J., T.J.G., M.S.), Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
- Center for Medical Genomics OMICRON (T.J.G., M.S.), Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Tomasz J. Guzik
- Department of Internal Medicine (M.D., E.J., T.J.G., M.S.), Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
- Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, United Kingdom (T.J.G., M.S.)
| | - Mateusz Siedlinski
- Department of Internal Medicine (M.D., E.J., T.J.G., M.S.), Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
- Center for Medical Genomics OMICRON (T.J.G., M.S.), Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
- Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, United Kingdom (T.J.G., M.S.)
| |
Collapse
|
30
|
Han X, Hong Q, Peng F, Zhang Y, Wu L, Wang X, Zheng Y, Chen X. Hippo pathway activated by circulating reactive oxygen species mediates cardiac diastolic dysfunction after acute kidney injury. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167184. [PMID: 38648903 DOI: 10.1016/j.bbadis.2024.167184] [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: 01/04/2024] [Revised: 04/15/2024] [Accepted: 04/16/2024] [Indexed: 04/25/2024]
Abstract
Acute kidney injury (AKI) can cause distal cardiac dysfunction; however, the underlying mechanism is unknown. Oxidative stress is proved prominent in AKI-induced cardiac dysfunction, and a possible bridge role of oxidative-stress products in cardio-renal interaction has been reported. Therefore, this study aimed to investigate the critical role of circulating reactive oxygen species (ROS) in mediating cardiac dysfunction after bilateral renal ischemia-reperfusion injury (IRI). We observed the diastolic dysfunction in the mice following renal IRI, accompanied by reduced ATP levels, oxidative stress, and branched-chain amino acids (BCAA) accumulation in the heart. Notably, ROS levels showed a sequential increase in the kidneys, circulation, and heart. Treatment with tempol, an ROS scavenger, significantly restored cardiac diastolic function in the renal IRI mice, corroborating the bridge role of circulating ROS. Accumulating evidence has identified oxidative stress as upstream of Mst1/Hippo in cardiac injury, which could regulate the expression of downstream genes related to mitochondrial quality control, leading to lower ATP, higher ROS and metabolic disorder. To verify this, we examined the activation of the Mst1/Hippo pathway in the heart of renal IRI mice, which was alleviated by tempol treatment as well. In vitro, analysis revealed that Mst1-knockdown cardiomyocytes could be activated by hydrogen peroxide (H2O2). Analysis of Mst1-overexpression cardiomyocytes confirmed the critical role of the Mst1/Hippo pathway in oxidative stress and BCAA dysmetabolism. Therefore, our results indicated that circulating ROS following renal IRI activates the Mst1/Hippo pathway of myocardium, leading to cardiac oxidative stress and diastolic dysfunction. This finding provides new insights for the clinical exploration of improved treatment options for cardiorenal syndrome.
Collapse
Affiliation(s)
- Xiao Han
- Department of Nephrology, First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Chinese PLA Institute of Nephrology, National Key Laboratory of Kidney Diseases, National Clinical Research Center for Chronic Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing 100853, China
| | - Quan Hong
- Department of Nephrology, First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Chinese PLA Institute of Nephrology, National Key Laboratory of Kidney Diseases, National Clinical Research Center for Chronic Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing 100853, China
| | - Fei Peng
- Department of Nephrology, First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Chinese PLA Institute of Nephrology, National Key Laboratory of Kidney Diseases, National Clinical Research Center for Chronic Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing 100853, China
| | - Yan Zhang
- Department of Nephrology, First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Chinese PLA Institute of Nephrology, National Key Laboratory of Kidney Diseases, National Clinical Research Center for Chronic Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing 100853, China
| | - Lingling Wu
- Department of Nephrology, First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Chinese PLA Institute of Nephrology, National Key Laboratory of Kidney Diseases, National Clinical Research Center for Chronic Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing 100853, China
| | - Xu Wang
- Department of Nephrology, First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Chinese PLA Institute of Nephrology, National Key Laboratory of Kidney Diseases, National Clinical Research Center for Chronic Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing 100853, China
| | - Ying Zheng
- Department of Nephrology, First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Chinese PLA Institute of Nephrology, National Key Laboratory of Kidney Diseases, National Clinical Research Center for Chronic Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing 100853, China.
| | - Xiangmei Chen
- Department of Nephrology, First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Chinese PLA Institute of Nephrology, National Key Laboratory of Kidney Diseases, National Clinical Research Center for Chronic Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing 100853, China.
| |
Collapse
|
31
|
Dong C, Liu Z, Zhu C, Zhang Y, Yang X, Xu X, Guan Q, Xia Y. Contribution of serum elements to blood pressure during pregnancy by impacting gut microbiota: A prospective cohort study. JOURNAL OF HAZARDOUS MATERIALS 2024; 465:133383. [PMID: 38160557 DOI: 10.1016/j.jhazmat.2023.133383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 12/07/2023] [Accepted: 12/25/2023] [Indexed: 01/03/2024]
Abstract
Exposure to environmental elements can alter gut microbiota, further affecting host health. Exploring the interrelationships among element exposure, gut microbiota and blood pressure (BP) during pregnancy, as well as the mediating roles of gut microbiota, is warranted, which holds implications for maternal and offspring health. In a prospective cohort study between 2017-2018, 733 pregnant women were included. The serum elements and gut microbiota during the second trimester were assessed, and BP was collected during the second and third trimester and before delivery. Fourteen associations were identified between serum elements and BP, including positive associations of zinc (Zn) and thallium (Tl) with systolic BP during the second trimester. Rubidium (Rb) showed a positive association with Pielou's evenness. Serum elements, such as Tl and Rb, were significantly associated with the relative abundance of bacteria and co-abundance groups (CAGs). Alpha diversity was negatively associated with BP levels and trajectories. Moreover, 15 associations between gut microbiota and BP were shown. Finally, mediation analysis confirmed that CAG2 and Pielou's evenness mediated the associations of Tl and Rb with BP, respectively. We concluded that serum elements can contribute to BP changes during pregnancy through gut microbiota, suggesting gut microbiota-targeted approach as a potential intervention.
Collapse
Affiliation(s)
- Chao Dong
- State Key Laboratory of Reproductive Medicine and Offspring Health, Institute of Toxicology, Nanjing 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing 211166, China
| | - Zhaofeng Liu
- State Key Laboratory of Reproductive Medicine and Offspring Health, Institute of Toxicology, Nanjing 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing 211166, China
| | - Chun Zhu
- Department of Child Health Care, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing 210004, China
| | - Yuepei Zhang
- State Key Laboratory of Reproductive Medicine and Offspring Health, Institute of Toxicology, Nanjing 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing 211166, China
| | - Xu Yang
- State Key Laboratory of Reproductive Medicine and Offspring Health, Institute of Toxicology, Nanjing 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing 211166, China
| | - Xiaoyu Xu
- State Key Laboratory of Reproductive Medicine and Offspring Health, Institute of Toxicology, Nanjing 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing 211166, China
| | - Quanquan Guan
- State Key Laboratory of Reproductive Medicine and Offspring Health, Institute of Toxicology, Nanjing 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing 211166, China
| | - Yankai Xia
- State Key Laboratory of Reproductive Medicine and Offspring Health, Institute of Toxicology, Nanjing 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing 211166, China.
| |
Collapse
|
32
|
Marquis KA, Merenstein C, Bushman FD. 2-Hydroxyisovalerate Is Produced During Bacterial Vaginosis and Boosts HIV Infection in Resting T Cells. AIDS Res Hum Retroviruses 2024; 40:158-170. [PMID: 37548528 PMCID: PMC10924192 DOI: 10.1089/aid.2022.0171] [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] [Indexed: 08/08/2023] Open
Abstract
Human immunodeficiency virus (HIV) infection and the ensuing acquired immunodeficiency syndrome (AIDS) disproportionally affect young women, yet understanding of the factors promoting heterosexual transmission in the female genital tract is limited. Colonization with highly diverse, Lactobacillus-deficient communities (HDCs) increases a woman's risk of acquiring HIV-1 compared with colonization with Lactobacillus-dominated low diversity communities (LDCs). The polymicrobial nature of these communities has made it challenging to elucidate the microbial mechanisms responsible for modulating HIV susceptibility. Here, we analyzed conserved changes in small-molecule metabolites present in the cervicovaginal lavage fluid collected from women colonized with HDCs and LDCs with the goal of identifying possible chemicals influencing HIV infection. As in previous studies, we found that the catabolite of the branched-chain amino acid valine, 2-hydroxyisovalerate (2-HV), was a consistent component of dysbiotic HDC microbiota. Effects of 2-HV on HIV infection were assessed. In experimental infections with HIV, treatment with 2-HV increased infections of resting CD4+ T cells. To understand bacterial production of 2-HV in more detail, we cultured purified HDC and LDC bacteria and used mass spectrometry to identify two HDC bacteria that synthesize high levels of 2-HV. In contrast, protective vaginal Lactobacilli did not produce high levels of 2-HV. A genomic analysis of genes encoding 2-HV synthetic pathways showed a correlation between high-level production of 2-HV and pathways for synthesis of the immediate precursor 2-ketoisovalerate. Thus, 2-HV is a candidate mediator linking vaginal microbiome structure and heterosexual HIV transmission in women.
Collapse
Affiliation(s)
- Kaitlin A. Marquis
- Chan Zuckerberg Biohub, University of California San Francisco, San Francisco, California, USA
| | - Carter Merenstein
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Frederic D. Bushman
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| |
Collapse
|
33
|
Alqudah A, Qnais E, Wedyan M, Awali A, Bseiso Y, Gammoh O. Amino acid profiles: exploring their diagnostic and pathophysiological significance in hypertension. Mol Biol Rep 2024; 51:200. [PMID: 38270677 DOI: 10.1007/s11033-023-09107-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 12/05/2023] [Indexed: 01/26/2024]
Abstract
Hypertension, a major contributor to cardiovascular morbidity, is closely linked to amino acid metabolism. Amino acids, particularly branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs), may play pivotal roles in the pathogenesis and potential management of hypertension. This review investigated the relationships between amino acid profiles, specifically BCAAs and AAAs, and hypertension, and examined their potential as diagnostic and therapeutic targets. An in-depth analysis was conducted on studies highlighting the associations of specific amino acids such as arginine, glycine, proline, glutamine, and the BCAAs and AAAs with hypertension. BCAAs and AAAs, alongside other amino acids like arginine, glycine, and proline, showed significant correlations with hypertension. These amino acids influence multiple pathways including nitric oxide synthesis, vascular remodeling, and neurotransmitter production, among others. Distinct amino acid profiles were discerned between hypertensive and non-hypertensive individuals. Amino acid profiling, particularly the levels of BCAAs and AAAs, offers promising avenues in the diagnostic and therapeutic strategies for hypertension. Future studies are crucial to confirm these findings and to delineate amino acid-based interventions for hypertension treatment.
Collapse
Affiliation(s)
- Abdelrahim Alqudah
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmaceutical Sciences, The Hashemite University, Zarqa, Jordan.
| | - Esam Qnais
- Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa, Jordan
| | - Mohammed Wedyan
- Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa, Jordan
| | - Ayat Awali
- Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa, Jordan
| | - Yousra Bseiso
- Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa, Jordan
| | - Omar Gammoh
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Yarmouk University, Irbid, Jordan
| |
Collapse
|
34
|
Garcia BREV, Makiyama EN, Sampaio GR, Soares-Freitas RAM, Bonvini A, Amaral AG, Bordin S, Fock RA, Rogero MM. Effects of Branched-Chain Amino Acids on the Inflammatory Response Induced by LPS in Caco-2 Cells. Metabolites 2024; 14:76. [PMID: 38276311 PMCID: PMC10821323 DOI: 10.3390/metabo14010076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 01/09/2024] [Accepted: 01/20/2024] [Indexed: 01/27/2024] Open
Abstract
Branched-chain amino acids (BCAA) are essential for maintaining intestinal mucosal integrity. However, only a few studies have explored the role of BCAA in the modulation of intestinal inflammation. In this study, we investigated in vitro effects of BCAA on the inflammatory response induced by lipopolysaccharide (LPS) (1 µg/mL) in Caco-2 cells. Caco-2 cells were assigned to six groups: control without BCAA (CTL0), normal BCAA (CTL; 0.8 mM leucine, 0.8 mM isoleucine, and 0.8 mM valine); leucine (LEU; 2 mM leucine), isoleucine (ISO; 2 mM isoleucine), valine (VAL; 2 mM valine), and high BCAA (LIV; 2 mM leucine, 2 mM isoleucine, and 2 mM valine). BCAA was added to the culture medium 24 h before LPS stimulation. Our results indicated that BCAA supplementation did not impair cell viability. The amino acids leucine and isoleucine attenuated the synthesis of IL-8 and JNK and NF-kB phosphorylation induced by LPS. Furthermore, neither BCAA supplementation nor LPS treatment modulated the activity of glutathione peroxidase or the intracellular reduced glutathione/oxidized glutathione ratio. Therefore, leucine and isoleucine exert anti-inflammatory effects in Caco-2 cells exposed to LPS by modulating JNK and NF-kB phosphorylation and IL-8 production. Further in vivo studies are required to validate these findings and gather valuable information for potential therapeutic or dietary interventions.
Collapse
Affiliation(s)
- Bruna Ruschel Ewald Vega Garcia
- Department of Nutrition, School of Public Health, University of São Paulo, São Paulo 01246-904, Brazil; (B.R.E.V.G.); (G.R.S.); (R.A.M.S.-F.)
| | - Edson Naoto Makiyama
- Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508-000, Brazil; (E.N.M.); (R.A.F.)
| | - Geni Rodrigues Sampaio
- Department of Nutrition, School of Public Health, University of São Paulo, São Paulo 01246-904, Brazil; (B.R.E.V.G.); (G.R.S.); (R.A.M.S.-F.)
| | | | - Andrea Bonvini
- Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of Sao Paulo, São Paulo 05508-000, Brazil;
| | - Andressa Godoy Amaral
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo 05508-000, Brazil; (A.G.A.); (S.B.)
| | - Silvana Bordin
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo 05508-000, Brazil; (A.G.A.); (S.B.)
| | - Ricardo Ambrósio Fock
- Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508-000, Brazil; (E.N.M.); (R.A.F.)
| | - Marcelo Macedo Rogero
- Department of Nutrition, School of Public Health, University of São Paulo, São Paulo 01246-904, Brazil; (B.R.E.V.G.); (G.R.S.); (R.A.M.S.-F.)
- Food Research Center (FoRC), CEPID-FAPESP (Research Innovation and Dissemination Centers São Paulo Research Foundation), São Paulo 05508-000, Brazil
| |
Collapse
|
35
|
Sun J, Ou Y, Liu X, Sun H, Guo Z, Qi F, Lan Y, Liu W, Sun W. LC-MS-based urine metabolomics analysis of chronic subdural hematoma for biomarker discovery. Proteomics Clin Appl 2024; 18:e2200107. [PMID: 37697649 DOI: 10.1002/prca.202200107] [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: 12/06/2022] [Revised: 06/20/2023] [Accepted: 08/24/2023] [Indexed: 09/13/2023]
Abstract
BACKGROUND Chronic subdural hematoma (CSDH) is one of the most common neurosurgical diseases with atypical manifestations. The aim of this study was to utilize urine metabolomics to explore potential biomarkers for the diagnosis and prognosis of CSDH. METHODS Seventy-seven healthy controls and ninety-two patients with CSDH were enrolled in our study. In total, 261 urine samples divided into the discovery group and validation group were analyzed by LC-MS. The statistical analysis and functional annotation were applied to discover potential biomarker panels and altered metabolic pathways. RESULTS A total of 53 differential metabolites were identified in this study. And the urinary metabolic profiles showed apparent separation between patients and controls. Further functional annotation showed that the differential metabolites were associated with lipid metabolism, fatty acid metabolism, amino acid metabolism, biotin metabolism, steroid hormone biosynthesis, and pentose and glucuronate interconversions. Moreover, one panel of Capryloylglycine, cis-5-Octenoic acid, Ethisterone, and 5,6-DiHETE showed good predictive performance in the diagnosis of CSDH, with an AUC of 0.89 in discovery group and an AUC of 0.822 in validation group. Another five metabolites (Trilobinol, 3'-Hydroxyropivacaine, Ethisterone, Arginyl-Proline, 5-alpha-Dihydrotestosterone glucuronide) showed the levels of them returned to a healthy state after surgery, showing good possibility to monitor the recovery of CSDH patients. CONCLUSION AND CLINICAL RELEVANCE The findings of the study revealed urine metabolomic differences between CSDH and controls. The potentially diagnostic and prognostic biomarker panels of urine metabolites were established, and functional analysis demonstrated deeper metabolic disorders of CSDH, which might conduce to improve early diagnose of CSDH clinically.
Collapse
Affiliation(s)
- Jiameng Sun
- Core Instrument Facility, Institute of Basic Medical Sciences, School of Basic Medicine, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Yunwei Ou
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xiaoyan Liu
- Core Instrument Facility, Institute of Basic Medical Sciences, School of Basic Medicine, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Haidan Sun
- Core Instrument Facility, Institute of Basic Medical Sciences, School of Basic Medicine, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Zhengguang Guo
- Core Instrument Facility, Institute of Basic Medical Sciences, School of Basic Medicine, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Feng Qi
- Core Instrument Facility, Institute of Basic Medical Sciences, School of Basic Medicine, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Ying Lan
- State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
| | - Weiming Liu
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Wei Sun
- Core Instrument Facility, Institute of Basic Medical Sciences, School of Basic Medicine, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| |
Collapse
|
36
|
Yu L, Huang T, Zhao J, Zhou Z, Cao Z, Chi Y, Meng S, Huang Y, Xu Y, Xia L, Jiang H, Yin Z, Wang H. Branched-chain amino acid catabolic defect in vascular smooth muscle cells drives thoracic aortic dissection via mTOR hyperactivation. Free Radic Biol Med 2024; 210:25-41. [PMID: 37956909 DOI: 10.1016/j.freeradbiomed.2023.11.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 10/30/2023] [Accepted: 11/06/2023] [Indexed: 11/21/2023]
Abstract
Metabolic reprogramming of vascular smooth muscle cell (VSMC) plays a critical role in the pathogenesis of thoracic aortic dissection (TAD). Previous researches have mainly focused on dysregulation of fatty acid or glucose metabolism, while the impact of amino acids catabolic disorder in VSMCs during the development of TAD remains elusive. Here, we identified branched-chain amino acid (BCAA) catabolic defect as a metabolic hallmark of TAD. The bioinformatics analysis and data from human aorta revealed impaired BCAA catabolism in TAD individuals. This was accompanied by upregulated branched-chain α-ketoacid dehydrogenase kinase (BCKDK) expression and BCKD E1 subunit alpha (BCKDHA) phosphorylation, enhanced vascular inflammation, and hyperactivation of mTOR signaling. Further in vivo experiments demonstrated that inhibition of BCKDK with BT2 (a BCKDK allosteric inhibitor) treatment dephosphorylated BCKDHA and re-activated BCAA catabolism, attenuated VSMCs phenotypic switching, alleviated aortic remodeling, mitochondrial reactive oxygen species (ROS) damage and vascular inflammation. Additionally, the beneficial actions of BT2 were validated in a TNF-α challenged murine VSMC cell line. Meanwhile, rapamycin conferred similar beneficial effects against VSMC phenotypic switching, cellular ROS damage as well as inflammatory response. However, co-treatment with MHY1485 (a classic mTOR activator) reversed the beneficial effects of BT2 by reactivating mTOR signaling. Taken together, the in vivo and in vitro evidence showed that impairment of BCAA catabolism resulted in aortic accumulation of BCAA and further caused VSMC phenotypic switching, mitochondrial ROS damage and inflammatory response via mTOR hyperactivation. BCKDK and mTOR signaling may serve as the potential drug targets for the prevention and treatment of TAD.
Collapse
Affiliation(s)
- Liming Yu
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning, 110016, PR China
| | - Tao Huang
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning, 110016, PR China
| | - Jikai Zhao
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning, 110016, PR China
| | - Zijun Zhou
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning, 110016, PR China
| | - Zijun Cao
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning, 110016, PR China; Graduate School, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, 110847, PR China
| | - Yanbang Chi
- Department of Obstetrics and Gynecology, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning, 110016, PR China
| | - Shan Meng
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning, 110016, PR China; Graduate School, Jinzhou Medical University, Jinzhou, Liaoning, 121001, PR China
| | - Yuting Huang
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning, 110016, PR China
| | - Yinli Xu
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning, 110016, PR China
| | - Lin Xia
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning, 110016, PR China
| | - Hui Jiang
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning, 110016, PR China
| | - Zongtao Yin
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning, 110016, PR China
| | - Huishan Wang
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning, 110016, PR China.
| |
Collapse
|
37
|
Kukułowicz J, Pietrzak-Lichwa K, Klimończyk K, Idlin N, Bajda M. The SLC6A15-SLC6A20 Neutral Amino Acid Transporter Subfamily: Functions, Diseases, and Their Therapeutic Relevance. Pharmacol Rev 2023; 76:142-193. [PMID: 37940347 DOI: 10.1124/pharmrev.123.000886] [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: 03/23/2023] [Revised: 09/07/2023] [Accepted: 11/02/2023] [Indexed: 11/10/2023] Open
Abstract
The neutral amino acid transporter subfamily that consists of six members, consecutively SLC6A15-SLC620, also called orphan transporters, represents membrane, sodium-dependent symporter proteins that belong to the family of solute carrier 6 (SLC6). Primarily, they mediate the transport of neutral amino acids from the extracellular milieu toward cell or storage vesicles utilizing an electric membrane potential as the driving force. Orphan transporters are widely distributed throughout the body, covering many systems; for instance, the central nervous, renal, or intestinal system, supplying cells into molecules used in biochemical, signaling, and building pathways afterward. They are responsible for intestinal absorption and renal reabsorption of amino acids. In the central nervous system, orphan transporters constitute a significant medium for the provision of neurotransmitter precursors. Diseases related with aforementioned transporters highlight their significance; SLC6A19 mutations are associated with metabolic Hartnup disorder, whereas altered expression of SLC6A15 has been associated with a depression/stress-related disorders. Mutations of SLC6A18-SLCA20 cause iminoglycinuria and/or hyperglycinuria. SLC6A18-SLC6A20 to reach the cellular membrane require an ancillary unit ACE2 that is a molecular target for the spike protein of the SARS-CoV-2 virus. SLC6A19 has been proposed as a molecular target for the treatment of metabolic disorders resembling gastric surgery bypass. Inhibition of SLC6A15 appears to have a promising outcome in the treatment of psychiatric disorders. SLC6A19 and SLC6A20 have been suggested as potential targets in the treatment of COVID-19. In this review, we gathered recent advances on orphan transporters, their structure, functions, related disorders, and diseases, and in particular their relevance as therapeutic targets. SIGNIFICANCE STATEMENT: The following review systematizes current knowledge about the SLC6A15-SLCA20 neutral amino acid transporter subfamily and their therapeutic relevance in the treatment of different diseases.
Collapse
Affiliation(s)
- Jędrzej Kukułowicz
- Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland
| | - Krzysztof Pietrzak-Lichwa
- Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland
| | - Klaudia Klimończyk
- Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland
| | - Nathalie Idlin
- Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland
| | - Marek Bajda
- Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland
| |
Collapse
|
38
|
Kurt Z, Cheng J, Barrere-Cain R, McQuillen CN, Saleem Z, Hsu N, Jiang N, Pan C, Franzén O, Koplev S, Wang S, Björkegren J, Lusis AJ, Blencowe M, Yang X. Shared and distinct pathways and networks genetically linked to coronary artery disease between human and mouse. eLife 2023; 12:RP88266. [PMID: 38060277 PMCID: PMC10703441 DOI: 10.7554/elife.88266] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/08/2023] Open
Abstract
Mouse models have been used extensively to study human coronary artery disease (CAD) or atherosclerosis and to test therapeutic targets. However, whether mouse and human share similar genetic factors and pathogenic mechanisms of atherosclerosis has not been thoroughly investigated in a data-driven manner. We conducted a cross-species comparison study to better understand atherosclerosis pathogenesis between species by leveraging multiomics data. Specifically, we compared genetically driven and thus CAD-causal gene networks and pathways, by using human GWAS of CAD from the CARDIoGRAMplusC4D consortium and mouse GWAS of atherosclerosis from the Hybrid Mouse Diversity Panel (HMDP) followed by integration with functional multiomics human (STARNET and GTEx) and mouse (HMDP) databases. We found that mouse and human shared >75% of CAD causal pathways. Based on network topology, we then predicted key regulatory genes for both the shared pathways and species-specific pathways, which were further validated through the use of single cell data and the latest CAD GWAS. In sum, our results should serve as a much-needed guidance for which human CAD-causal pathways can or cannot be further evaluated for novel CAD therapies using mouse models.
Collapse
Affiliation(s)
- Zeyneb Kurt
- Department of Integrative Biology and Physiology, University of California, Los AngelesLos AngelesUnited States
- The Information School at the University of SheffieldSheffieldUnited Kingdom
| | - Jenny Cheng
- Department of Integrative Biology and Physiology, University of California, Los AngelesLos AngelesUnited States
- Interdepartmental Program of Molecular, Cellular and Integrative Physiology, University of California, Los AngelesLos AngelesUnited States
| | - Rio Barrere-Cain
- Department of Integrative Biology and Physiology, University of California, Los AngelesLos AngelesUnited States
| | - Caden N McQuillen
- Department of Integrative Biology and Physiology, University of California, Los AngelesLos AngelesUnited States
| | - Zara Saleem
- Department of Integrative Biology and Physiology, University of California, Los AngelesLos AngelesUnited States
| | - Neil Hsu
- Department of Integrative Biology and Physiology, University of California, Los AngelesLos AngelesUnited States
| | - Nuoya Jiang
- Department of Integrative Biology and Physiology, University of California, Los AngelesLos AngelesUnited States
| | - Calvin Pan
- Department of Medicine, Division of Cardiology, University of California, Los AngelesLos AngelesUnited States
| | - Oscar Franzén
- Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Simon Koplev
- Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Susanna Wang
- Department of Integrative Biology and Physiology, University of California, Los AngelesLos AngelesUnited States
| | - Johan Björkegren
- Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
- Department of Medicine, (Huddinge), Karolinska InstitutetHuddingeSweden
| | - Aldons J Lusis
- Department of Medicine, Division of Cardiology, University of California, Los AngelesLos AngelesUnited States
- Departments of Human Genetics & Microbiology, Immunology, and Molecular Genetics, UCLALos AngelesUnited States
- Cardiovascular Research Laboratory, David Geffen School of Medicine, UCLALos AngelesUnited States
| | - Montgomery Blencowe
- Department of Integrative Biology and Physiology, University of California, Los AngelesLos AngelesUnited States
- Interdepartmental Program of Molecular, Cellular and Integrative Physiology, University of California, Los AngelesLos AngelesUnited States
| | - Xia Yang
- Department of Integrative Biology and Physiology, University of California, Los AngelesLos AngelesUnited States
- Interdepartmental Program of Molecular, Cellular and Integrative Physiology, University of California, Los AngelesLos AngelesUnited States
- Interdepartmental Program of Bioinformatics, University of California, Los AngelesLos AngelesUnited States
- Department of Molecular and Medical Pharmacology, University of California, Los AngelesLos AngelesUnited States
| |
Collapse
|
39
|
Martínez-Beamonte R, Sánchez-Marco J, Gómez M, Lázaro G, Barco M, Herrero-Continente T, Serrano-Megías M, Botaya D, Arnal C, Barranquero C, Surra JC, Manso-Alonso JA, Osada J, Navarro MA. Dietary proteins modulate high-density lipoprotein characteristics in a sex-specific way in Apoe-deficient mice. Nutrition 2023; 116:112211. [PMID: 37812855 DOI: 10.1016/j.nut.2023.112211] [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: 06/06/2023] [Accepted: 09/01/2023] [Indexed: 10/11/2023]
Abstract
OBJECTIVES The type and amount of dietary protein have become a topic of renewed interest, considering their involvement in several diseases. However, little attention has been devoted to the effect of avian proteins despite their wide human consumption. In a previous study, we saw that compared with soybean protein, the consumption of avian proteins, depending on sex, resulted in similar or lower atherosclerosis with a higher paraoxonase 1 activity, an antioxidant enzyme carried by high-density lipoproteins (HDL). This suggests that under these conditions, the HDL lipoproteins may undergo important changes. The aim of this research was to study the influence of soybean, chicken, and turkey proteins on the characteristics of HDL. METHODS Male and female Apoe-deficient mice were fed purified Western diets based on the AIN-93 diet, differing only in the protein source, for 12 wk. After this period, blood and liver samples were taken for analysis of HDL composition and hepatic expression of genes related to HDL metabolism (Abca1, Lcat, Pltp, Pon1, and Scarb1). Depending on sex, these genes define a different network of interactions. Females consuming the turkey protein-containing diet showed decreased atherosclerotic foci, which can be due to larger very-low-density lipoproteins (VLDLs) calculated by molar ratio triacylglycerols/VLDL cholesterol and higher expression of Lcat. In contrast, in males, a higher ratio of paraoxonase1 to apolipoprotein A1 decreased the oxidative status of the different lipoproteins, and augmented Abca1 expression was observed. CONCLUSIONS The source of protein has an effect on the development of atherosclerosis depending on sex by modifying HDL characteristics and the expression of genes involved in their properties.
Collapse
Affiliation(s)
- Roberto Martínez-Beamonte
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón, Universidad de Zaragoza, Zaragoza, Spain; Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.
| | - Javier Sánchez-Marco
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón, Universidad de Zaragoza, Zaragoza, Spain; Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain
| | - Marta Gómez
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón, Universidad de Zaragoza, Zaragoza, Spain
| | - Gonzalo Lázaro
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón, Universidad de Zaragoza, Zaragoza, Spain
| | - María Barco
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón, Universidad de Zaragoza, Zaragoza, Spain
| | - Tania Herrero-Continente
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón, Universidad de Zaragoza, Zaragoza, Spain
| | - Marta Serrano-Megías
- Departamento de Ciencias de la Salud, Universidad San Jorge, Autovía A-23 Zaragoza-Huesca Km. 299.50.830, Zaragoza, Spain
| | - David Botaya
- Aves Nobles y Derivados-Aldelis, Zaragoza, Spain
| | - Carmen Arnal
- Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain; Departamento de Patología Animal, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón, Universidad de Zaragoza, Zaragoza, Spain
| | - Cristina Barranquero
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón, Universidad de Zaragoza, Zaragoza, Spain; Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Joaquín C Surra
- Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain; Departamento de Producción Animal y Ciencia de los Alimentos, Escuela Politécnica Superior de Huesca, Instituto de Investigación Sanitaria de Aragón, Universidad de Zaragoza, Huesca, Spain
| | | | - Jesús Osada
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón, Universidad de Zaragoza, Zaragoza, Spain; Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - María A Navarro
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón, Universidad de Zaragoza, Zaragoza, Spain; Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| |
Collapse
|
40
|
Hora S, Pahwa P, Siddiqui H, Saxena A, Kashyap M, Sevak JK, Singh R, Javed M, Yadav P, Kale P, Ramakrishna G, Bajpai M, Rathore A, Maras JS, Tyagi S, Sarin SK, Trehanpati N. Metabolic alterations unravel the maternofetal immune responses with disease severity in pregnant women infected with SARS-CoV-2. J Med Virol 2023; 95:e29257. [PMID: 38054548 DOI: 10.1002/jmv.29257] [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: 05/10/2023] [Revised: 10/27/2023] [Accepted: 11/13/2023] [Indexed: 12/07/2023]
Abstract
Pregnancy being an immune compromised state, coronavirus disease of 2019 (COVID-19) disease poses high risk of premature delivery and threat to fetus. Plasma metabolome regulates immune cellular responses, therefore we aimed to analyze the change in plasma secretome, metabolome, and immune cells with disease severity in COVID-19 positive pregnant females and their cord blood. COVID-19 reverse transcriptase-polymerase chain reaction positive pregnant females (n = 112) with asymptomatic (Asy) (n = 82), mild (n = 21), or moderate (n = 9) disease, healthy pregnant (n = 18), COVID-19 positive nonpregnant females (n = 7) were included. Eighty-two cord blood from COVID-19 positive and seven healthy cord blood were also analyzed. Mother's peripheral blood and cord blood were analyzed for untargeted metabolome profiling and cytokines by using high-resolution mass spectrometry and cytokine bead array. Immune scan was performed only in mothers' blood by flow cytometry. In Asy severe acute respiratory syndrome coronavirus 2 infection, the amino acid metabolic pathways such as glycine, serine, l-lactate, and threonine metabolism were upregulated with downregulation of riboflavin and tyrosine metabolism. However, with mild-to-moderate disease, the pyruvate and nicotinamide adenine dinucleotide (NAD+ ) metabolism were mostly altered. Cord blood mimicked the mother's metabolomic profiles by showing altered valine, leucine, isoleucine, glycine, serine, threonine in Asy and NAD+ , riboflavin metabolism in mild and moderate. Additionally, with disease severity tumor necrosis factor-α, interferon (IFN)-α, IFN-γ, interleukin (IL)-6 cytokine storm, IL-9 was raised in both mothers and neonates. Pyruvate, NAD metabolism and increase in IL-9 and IFN-γ had an impact on nonclassical monocytes, exhausted T and B cells. Our results demonstrated that immune-metabolic interplay in mother and fetus is influenced with increase in IL-9 and IFN-γ regulated pyruvate, lactate tricarboxylic acid, and riboflavin metabolism with context to disease severity.
Collapse
Affiliation(s)
- Sandhya Hora
- Department of Molecular and Cellular Medicine, Laboratory of Molecular Immunology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Prabhjyoti Pahwa
- Department of Molecular and Cellular Medicine, Laboratory of Molecular Immunology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Hamda Siddiqui
- Department of Molecular and Cellular Medicine, Laboratory of Molecular Immunology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Anoushka Saxena
- Department of Molecular and Cellular Medicine, Laboratory of Molecular Immunology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Minal Kashyap
- Department of Gynecology and Obstetrics, Lok Nayak Jai Prakash Hospital, New Delhi, India
| | - Jayesh K Sevak
- Department of Molecular and Cellular Medicine, Laboratory of Molecular Immunology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ravinder Singh
- Department of Molecular and Cellular Medicine, Laboratory of Molecular Immunology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Maryam Javed
- Department of Molecular and Cellular Medicine, Laboratory of Molecular Immunology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Pushpa Yadav
- Department of Molecular and Cellular Medicine, Laboratory of Molecular Immunology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Pratibha Kale
- Department of Microbiology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Gayatri Ramakrishna
- Department of Molecular and Cellular Medicine, Laboratory of Molecular Immunology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Meenu Bajpai
- Department of Transfusion Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Asmita Rathore
- Department of Gynecology and Obstetrics, Lok Nayak Jai Prakash Hospital, New Delhi, India
| | - Jaswinder S Maras
- Department of Molecular and Cellular Medicine, Laboratory of Molecular Immunology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shakun Tyagi
- Department of Gynecology and Obstetrics, Lok Nayak Jai Prakash Hospital, New Delhi, India
| | - Shiv K Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Nirupama Trehanpati
- Department of Molecular and Cellular Medicine, Laboratory of Molecular Immunology, Institute of Liver and Biliary Sciences, New Delhi, India
| |
Collapse
|
41
|
Hu S, Lin Z, Hu MJ, Tan JS, Guo TT, Huang X, Hua L. Causal relationships of circulating amino acids with cardiovascular disease: a trans-ancestry Mendelian randomization analysis. J Transl Med 2023; 21:699. [PMID: 37805555 PMCID: PMC10559604 DOI: 10.1186/s12967-023-04580-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 09/29/2023] [Indexed: 10/09/2023] Open
Abstract
BACKGROUND Epidemiological studies demonstrated that multiple amino acids (AAs) were associated with cardiovascular diseases (CVDs), but whether these associations were causal remains unclear. This study aims to investigate the causal relationships between circulating levels of 20 AAs and 10 CVDs in European and East Asian populations by Mendelian randomization (MR). METHODS This MR study utilized single-nucleotide polymorphisms that were significantly associated with AAs as instrumental variables. Summary-level data for AAs and CVDs were obtained from public genome-wide association studies. The causal effects were primarily estimated by inverse variance weighting with multiplicative random effect method. Sensitivity analyses, including weighted median, weighted mode, and MR Egger regression, were used to test the robustness of our results. RESULTS In the European population, alanine and serine were inversely associated with angina pectoris (AP) and chronic heart failure, respectively. With each unit increase of leucine, the risk of ischemic stroke increased by 10%. Moreover, tyrosine was positively associated with AP and deep vein thrombosis. In the East Asian population, each unit increase in glycine was associated with 4.1% and 9.0% decreased risks of coronary artery disease (CAD) and myocardial infarction (MI), respectively. A unit increase in serine was associated with 13.1%, 12.6% and 15.5% decreased risks of AP, CAD and MI, respectively. Sensitivity analyses supported the robustness of our results. CONCLUSIONS This MR study demonstrated significant causal effects of circulating levels of AAs on CVDs, indicating the potential use of AAs as biomarkers or as therapeutic targets for CVD in clinical scenarios.
Collapse
Affiliation(s)
- Song Hu
- Key Laboratory of Pulmonary Vascular Medicine, State Key Laboratory of Cardiovascular Disease, Center for Respiratory and Pulmonary Vascular Diseases, Department of Cardiology, National Clinical Research Center of Cardiovascular Diseases, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China
| | - Zhennan Lin
- Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China
| | - Meng-Jin Hu
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China
| | - Jiang-Shan Tan
- Key Laboratory of Pulmonary Vascular Medicine, State Key Laboratory of Cardiovascular Disease, Center for Respiratory and Pulmonary Vascular Diseases, Department of Cardiology, National Clinical Research Center of Cardiovascular Diseases, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China
| | - Ting-Ting Guo
- Key Laboratory of Pulmonary Vascular Medicine, State Key Laboratory of Cardiovascular Disease, Center for Respiratory and Pulmonary Vascular Diseases, Department of Cardiology, National Clinical Research Center of Cardiovascular Diseases, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China
| | - Xin Huang
- Department of Cardiology, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, 100853, China
| | - Lu Hua
- Key Laboratory of Pulmonary Vascular Medicine, State Key Laboratory of Cardiovascular Disease, Center for Respiratory and Pulmonary Vascular Diseases, Department of Cardiology, National Clinical Research Center of Cardiovascular Diseases, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
- Fuwai Hospital, Chinese Academy of Medical Sciences, Shenzhen, China.
| |
Collapse
|
42
|
Jiang J, Shi H, Jiang S, Wang A, Zou X, Wang Y, Li W, Zhang Y, Sun M, Ren Q, Xu J. Nutrition in Alzheimer's disease: a review of an underappreciated pathophysiological mechanism. SCIENCE CHINA. LIFE SCIENCES 2023; 66:2257-2279. [PMID: 37058185 DOI: 10.1007/s11427-022-2276-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 02/16/2023] [Indexed: 04/15/2023]
Abstract
Alzheimer's disease (AD) is the leading cause of dementia in older individuals and is an escalating challenge to global public health. Pharmacy therapy of AD is one of the well-funded areas; however, little progress has been made due to the complex pathogenesis. Recent evidence has demonstrated that modifying risk factors and lifestyle may prevent or delay the incidence of AD by 40%, which suggests that the management should pivot from single pharmacotherapy toward a multipronged approach because AD is a complex and multifaceted disease. Recently, the gut-microbiota-brain axis has gained tremendous traction in the pathogenesis of AD through bidirectional communication with multiple neural, immune, and metabolic pathways, providing new insights into novel therapeutic strategies. Dietary nutrition is an important and profound environmental factor that influences the composition and function of the microbiota. The Nutrition for Dementia Prevention Working Group recently found that dietary nutrition can affect cognition in AD-related dementia directly or indirectly through complex interactions of behavioral, genetic, systemic, and brain factors. Thus, considering the multiple etiologies of AD, nutrition represents a multidimensional factor that has a profound effect on AD onset and development. However, mechanistically, the effect of nutrition on AD is uncertain; therefore, optimal strategies or the timing of nutritional intervention to prevent or treat AD has not been established.Thus, this review summarizes the current state of knowledge concerning nutritional disorders, AD patient and caregiver burden, and the roles of nutrition in the pathophysiology of AD. We aim to emphasize knowledge gaps to provide direction for future research and to establish optimal nutrition-based intervention strategies for AD.
Collapse
Affiliation(s)
- Jiwei Jiang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, 100070, China
| | - Hanping Shi
- Department of Gastrointestinal Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China
- Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China
- Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, 100038, China
| | - Shirui Jiang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, 100070, China
| | - Anxin Wang
- China National Clinical Research Center for Neurological Diseases, Beijing, 100070, China
| | - Xinying Zou
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, 100070, China
| | - Yanli Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, 100070, China
| | - Wenyi Li
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, 100070, China
| | - Yuan Zhang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, 100070, China
| | - Mengfan Sun
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, 100070, China
| | - Qiwei Ren
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, 100070, China
| | - Jun Xu
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
- China National Clinical Research Center for Neurological Diseases, Beijing, 100070, China.
| |
Collapse
|
43
|
Tanase DM, Gosav EM, Botoc T, Floria M, Tarniceriu CC, Maranduca MA, Haisan A, Cucu AI, Rezus C, Costea CF. Depiction of Branched-Chain Amino Acids (BCAAs) in Diabetes with a Focus on Diabetic Microvascular Complications. J Clin Med 2023; 12:6053. [PMID: 37762992 PMCID: PMC10531730 DOI: 10.3390/jcm12186053] [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: 08/21/2023] [Revised: 09/10/2023] [Accepted: 09/17/2023] [Indexed: 09/29/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) still holds the title as one of the most debilitating chronic diseases with rising prevalence and incidence, including its complications such as retinal, renal, and peripheral nerve disease. In order to develop novel molecules for diagnosis and treatment, a deep understanding of the complex molecular pathways is imperative. Currently, the existing agents for T2DM treatment target only blood glucose levels. Over the past decades, specific building blocks of proteins-branched-chain amino acids (BCAAs) including leucine, isoleucine, and valine-have gained attention because they are linked with insulin resistance, pre-diabetes, and diabetes development. In this review, we discuss the hypothetical link between BCAA metabolism, insulin resistance, T2DM, and its microvascular complications including diabetic retinopathy and diabetic nephropathy. Further research on these amino acids and their derivates may eventually pave the way to novel biomarkers or therapeutic concepts for the treatment of diabetes and its accompanied complications.
Collapse
Affiliation(s)
- Daniela Maria Tanase
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (D.M.T.); (E.M.G.)
- Internal Medicine Clinic, “St. Spiridon” County Clinical Emergency Hospital Iasi, 700111 Iasi, Romania;
| | - Evelina Maria Gosav
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (D.M.T.); (E.M.G.)
- Internal Medicine Clinic, “St. Spiridon” County Clinical Emergency Hospital Iasi, 700111 Iasi, Romania;
| | - Tina Botoc
- Department of Ophthalmology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (T.B.); (C.F.C.)
- 2nd Ophthalmology Clinic, “Prof. Dr. Nicolae Oblu” Emergency Clinical Hospital, 700309 Iasi, Romania
| | - Mariana Floria
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (D.M.T.); (E.M.G.)
- Internal Medicine Clinic, “St. Spiridon” County Clinical Emergency Hospital Iasi, 700111 Iasi, Romania;
| | - Claudia Cristina Tarniceriu
- Department of Morpho-Functional Sciences I, Discipline of Anatomy, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
- Hematology Clinic, “St. Spiridon” County Clinical Emergency Hospital, 700111 Iasi, Romania
| | - Minela Aida Maranduca
- Internal Medicine Clinic, “St. Spiridon” County Clinical Emergency Hospital Iasi, 700111 Iasi, Romania;
- Department of Morpho-Functional Sciences II, Discipline of Physiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Anca Haisan
- Department of Emergency Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
- Emergency Department, “St. Spiridon” County Clinical Emergency Hospital, 700111 Iasi, Romania
| | - Andrei Ionut Cucu
- Department of Biomedical Sciences, Faculty of Medicine and Biological Sciences, “Ștefan cel Mare” University, 720229 Suceava, Romania;
- Department of Neurosurgery, “Prof. Dr. Nicolae Oblu” Emergency Clinical Hospital, 700309 Iasi, Romania
| | - Ciprian Rezus
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (D.M.T.); (E.M.G.)
- Internal Medicine Clinic, “St. Spiridon” County Clinical Emergency Hospital Iasi, 700111 Iasi, Romania;
| | - Claudia Florida Costea
- Department of Ophthalmology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (T.B.); (C.F.C.)
- 2nd Ophthalmology Clinic, “Prof. Dr. Nicolae Oblu” Emergency Clinical Hospital, 700309 Iasi, Romania
| |
Collapse
|
44
|
Zhang S, Li S, Huang J, Ding X, Qiu Y, Luo X, Meng J, Hu Y, Zhou H, Fan H, Cao Y, Gao F, Xue Y, Zou M. Gram-Negative Bacteria and Lipopolysaccharides as Risk Factors for the Occurrence of Diabetic Foot. J Clin Endocrinol Metab 2023; 108:2604-2614. [PMID: 36974462 PMCID: PMC10505552 DOI: 10.1210/clinem/dgad178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 03/03/2023] [Accepted: 03/24/2023] [Indexed: 03/29/2023]
Abstract
CONTEXT Imbalance of the skin microbial community could impair skin immune homeostasis and thus trigger skin lesions. Dysbiosis of skin microbiome may be involved in the early pathogenesis of diabetic foot (DF). However, the potential mechanism remains unclear. OBJECTIVE To investigate the dynamic composition and function of the foot skin microbiome with risk stratification for DF and assess whether dysbiosis of the skin microbiome induces diabetic skin lesions. METHODS We enrolled 90 consecutive subjects who were divided into 5 groups based on DF risk stratification: very low, low, moderate, and high risk for ulcers and a healthy control group. Integrated analysis of 16S ribosomal RNA and metagenomic sequencing of cotton swab samples was applied to identify the foot skin microbiome composition and functions in subjects. Then a mouse model of microbiota transplantation was used to evaluate the effects of the skin microbiome on diabetic skin lesions. RESULTS The results demonstrated that, with the progression of diabetic complications, the proportion of gram-negative bacteria in plantar skin increased. At the species level, metagenome sequencing analyses showed Moraxella osloensis to be a representative core strain in the high-risk group. The major microbial metabolites affecting diabetic skin lesions were increased amino acid metabolites, and antibiotic resistance genes in microorganisms were abundant. Skin microbiota from high-risk patients induced more inflammatory cell infiltration, similar to the lipopolysaccharide (LPS)-stimulated response, which was inhibited by Toll-like receptor 4 (TLR4) antagonists. CONCLUSIONS The skin microbiome in patients with diabetes undergoes dynamic changes at taxonomic and functional levels with the progression of diabetic complications. The increase in gram-negative bacteria on the skin surface through LPS-TLR4 signal transduction could induce inflammatory response in early diabetic skin lesions.
Collapse
Affiliation(s)
- Shili Zhang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Shuxian Li
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jiali Huang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Xinyi Ding
- School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Yan Qiu
- School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Xiangrong Luo
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jianfu Meng
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - YanJun Hu
- Department of Orthopedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Hao Zhou
- Department of Hospital Infection Management, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Hongying Fan
- School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Ying Cao
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Fang Gao
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yaoming Xue
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Mengchen Zou
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| |
Collapse
|
45
|
Duarte PRA, Franco RR, Vilela DD, Caixeta DC, de Souza AV, Deconte SR, Mendes-Rodrigues C, Fidale TM, Espindola FS, Teixeira RR, Resende ES. Effects of an L-Leucine-Rich Diet on Liver and Kidneys in a Doxorubicin Toxicity Model. Life (Basel) 2023; 13:1823. [PMID: 37763227 PMCID: PMC10532802 DOI: 10.3390/life13091823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 07/24/2023] [Accepted: 08/02/2023] [Indexed: 09/29/2023] Open
Abstract
Supplements and diets containing L-leucine, a branched-chain amino acid, have been considered beneficial for controlling oxidative stress and maintaining cardiac tissue in toxicity models using doxorubicin, a drug widely used in cancer treatment. However, there is a lack of studies in the literature that assess the effects of this diet on other organs and tissues, such as the liver and kidneys. Therefore, this study aimed to evaluate the effects of a leucine-rich diet on the liver and kidneys of healthy rats submitted to the doxorubicin toxicity model by analyzing biomarkers of oxidative stress and histological parameters. The animals were divided into four groups: naive, doxorubicin, L-leucine, and doxorubicin + L-leucine, and the diet was standardized with 5% L-leucine and a dose of 7.5 mg/kg of doxorubicin. We evaluated tissue injury parameters and biomarkers of oxidative stress, including enzymes, antioxidant profile, and oxidized molecules, in the liver and kidneys. Although some studies have indicated benefits of a diet rich in L-leucine for the muscle tissue of animals that received doxorubicin, our results showed that the liver was the most affected organ by the L-leucine-rich diet since the diet reduced its antioxidant defenses and increased the deposit of collagen and fat in the hepatic tissue. In the kidneys, the main alteration was the reduction in the number of glomeruli. These results contribute to the scientific literature and encourage further studies to evaluate the effects of an L-leucine-rich diet or its supplementation, alone or combined with doxorubicin using an animal model of cancer. Therefore, our study concludes that the leucine-rich diet itself was harmful and, when co-administered with doxorubicin, was not able to maintain the antioxidant defenses and tissue structure of the evaluated organs.
Collapse
Affiliation(s)
- Poliana Rodrigues Alves Duarte
- Faculdade de Medicina, Universidade Federal de Uberlândia, Uberlândia 38400-902, MG, Brazil; (P.R.A.D.); (S.R.D.); (C.M.-R.); (T.M.F.)
| | - Rodrigo Rodrigues Franco
- Departamento de Medicina, Universidade Federal de Catalão, Catalão 75706-881, GO, Brazil;
- Instituto de Biotecnologia, Universidade Federal de Uberlândia, Uberlândia 38400-902, MG, Brazil; (D.D.V.); (D.C.C.); (A.V.d.S.)
| | - Danielle Diniz Vilela
- Instituto de Biotecnologia, Universidade Federal de Uberlândia, Uberlândia 38400-902, MG, Brazil; (D.D.V.); (D.C.C.); (A.V.d.S.)
| | - Douglas Carvalho Caixeta
- Instituto de Biotecnologia, Universidade Federal de Uberlândia, Uberlândia 38400-902, MG, Brazil; (D.D.V.); (D.C.C.); (A.V.d.S.)
| | - Adriele Vieira de Souza
- Instituto de Biotecnologia, Universidade Federal de Uberlândia, Uberlândia 38400-902, MG, Brazil; (D.D.V.); (D.C.C.); (A.V.d.S.)
| | - Simone Ramos Deconte
- Faculdade de Medicina, Universidade Federal de Uberlândia, Uberlândia 38400-902, MG, Brazil; (P.R.A.D.); (S.R.D.); (C.M.-R.); (T.M.F.)
| | - Clesnan Mendes-Rodrigues
- Faculdade de Medicina, Universidade Federal de Uberlândia, Uberlândia 38400-902, MG, Brazil; (P.R.A.D.); (S.R.D.); (C.M.-R.); (T.M.F.)
| | - Thiago Montes Fidale
- Faculdade de Medicina, Universidade Federal de Uberlândia, Uberlândia 38400-902, MG, Brazil; (P.R.A.D.); (S.R.D.); (C.M.-R.); (T.M.F.)
- Departamento de Medicina, Universidade Federal de Catalão, Catalão 75706-881, GO, Brazil;
| | - Foued Salmen Espindola
- Instituto de Biotecnologia, Universidade Federal de Uberlândia, Uberlândia 38400-902, MG, Brazil; (D.D.V.); (D.C.C.); (A.V.d.S.)
| | - Renata Roland Teixeira
- Instituto de Biotecnologia, Universidade Federal de Uberlândia, Uberlândia 38400-902, MG, Brazil; (D.D.V.); (D.C.C.); (A.V.d.S.)
| | - Elmiro Santos Resende
- Faculdade de Medicina, Universidade Federal de Uberlândia, Uberlândia 38400-902, MG, Brazil; (P.R.A.D.); (S.R.D.); (C.M.-R.); (T.M.F.)
| |
Collapse
|
46
|
Yu JY, Cao N, Rau CD, Lee RP, Yang J, Flach RJR, Petersen L, Zhu C, Pak YL, Miller RA, Liu Y, Wang Y, Li Z, Sun H, Gao C. Cell-autonomous effect of cardiomyocyte branched-chain amino acid catabolism in heart failure in mice. Acta Pharmacol Sin 2023; 44:1380-1390. [PMID: 36991098 PMCID: PMC10310802 DOI: 10.1038/s41401-023-01076-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 03/12/2023] [Indexed: 03/31/2023]
Abstract
Parallel to major changes in fatty acid and glucose metabolism, defect in branched-chain amino acid (BCAA) catabolism has also been recognized as a metabolic hallmark and potential therapeutic target for heart failure. However, BCAA catabolic enzymes are ubiquitously expressed in all cell types and a systemic BCAA catabolic defect is also manifested in metabolic disorder associated with obesity and diabetes. Therefore, it remains to be determined the cell-autonomous impact of BCAA catabolic defect in cardiomyocytes in intact hearts independent from its potential global effects. In this study, we developed two mouse models. One is cardiomyocyte and temporal-specific inactivation of the E1α subunit (BCKDHA-cKO) of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which blocks BCAA catabolism. Another model is cardiomyocyte specific inactivation of the BCKDH kinase (BCKDK-cKO), which promotes BCAA catabolism by constitutively activating BCKDH activity in adult cardiomyocytes. Functional and molecular characterizations showed E1α inactivation in cardiomyocytes was sufficient to induce loss of cardiac function, systolic chamber dilation and pathological transcriptome reprogramming. On the other hand, inactivation of BCKDK in intact heart does not have an impact on baseline cardiac function or cardiac dysfunction under pressure overload. Our results for the first time established the cardiomyocyte cell autonomous role of BCAA catabolism in cardiac physiology. These mouse lines will serve as valuable model systems to investigate the underlying mechanisms of BCAA catabolic defect induced heart failure and to provide potential insights for BCAA targeted therapy.
Collapse
Affiliation(s)
- Jia-Yu Yu
- Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University of Medicine, Shanghai, 200025, China
| | - Nancy Cao
- School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - Christoph D Rau
- Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Ro-Po Lee
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Jieping Yang
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | | | - Lauren Petersen
- Health Science Center, University of Utah, Salt Lake City, UT, USA
| | - Cansheng Zhu
- Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, OH, USA
| | - Yea-Lyn Pak
- Department of Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | | | - Yunxia Liu
- Signature Research Program in Cardiovascular and Metabolic Diseases, DukeNUS School of Medicine and National Heart Center of Singapore, Singapore, Singapore
| | - Yibin Wang
- Signature Research Program in Cardiovascular and Metabolic Diseases, DukeNUS School of Medicine and National Heart Center of Singapore, Singapore, Singapore
| | - Zhaoping Li
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Haipeng Sun
- Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University of Medicine, Shanghai, 200025, China
| | - Chen Gao
- Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, OH, USA.
| |
Collapse
|
47
|
Lee J, Orzabal MR, Naik VD, Ramadoss J. Impact of e-cigarette vaping aerosol exposure in pregnancy on mTOR signaling in rat fetal hippocampus. Front Neurosci 2023; 17:1217127. [PMID: 37449268 PMCID: PMC10337480 DOI: 10.3389/fnins.2023.1217127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 06/15/2023] [Indexed: 07/18/2023] Open
Abstract
Electronic cigarette (e-cig) use during pregnancy has become a major health concern in recent years and many view them as less harmful and may help quit or reduce combustible cigarettes. Implementing a state-of-the-art engineered vaping system, comprising an atomizer similar to those sold in vape shops, we aimed to utilize a translational e-cig inhalation delivery method to provide crucial information on the impact of prenatal e-cig aerosols on the developing brain hippocampal mTOR system in a rat model system. Gestational e-cig vaping significantly increased P-mTOR levels (p < 0.05) in the rat fetal hippocampi in the nicotine group (comprising of VG/PG + nicotine) compared to the control and the juice (comprising of VG/PG) groups. Total mTOR expression was not different among groups. Immunofluorescence imaging demonstrated P-mTOR was detected exclusively in the granule cells of the dentate gyrus of the fetal hippocampus. E-cig did not alter DEPTOR, but RAPTOR and RICTOR were higher (p < 0.05) in the Nicotine group. Gestational e-cig vaping with nicotine increased (p < 0.05) the activity and expression of 4EBP1, p70S6K, but decreased (p < 0.05) P-PKCα in the fetal hippocampi. In summary, dysregulation of mTORC1 and the related mTORC2, their activity, and downstream proteins together may play a critical role in e-cig-vaping-induced neurobiological phenotypes during development.
Collapse
Affiliation(s)
- Jehoon Lee
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, United States
| | - Marcus R. Orzabal
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, United States
| | - Vishal D. Naik
- Department of Obstetrics and Gynecology, C.S. Mott Center for Human Growth and Development, School of Medicine, Wayne State University, Detroit, MI, United States
| | - Jayanth Ramadoss
- Department of Obstetrics and Gynecology, C.S. Mott Center for Human Growth and Development, School of Medicine, Wayne State University, Detroit, MI, United States
- Department of Physiology, School of Medicine, Wayne State University, Detroit, MI, United States
| |
Collapse
|
48
|
Turkoglu O, Alhousseini A, Sajja S, Idler J, Stuart S, Ashrafi N, Yilmaz A, Wharton K, Graham SF, Bahado-Singh RO. Fetal effects of mild maternal COVID-19 infection: metabolomic profiling of cord blood. Metabolomics 2023; 19:41. [PMID: 37060499 PMCID: PMC10105349 DOI: 10.1007/s11306-023-01988-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Accepted: 03/05/2023] [Indexed: 04/16/2023]
Abstract
INTRODUCTION The impact of maternal coronavirus disease 2019 (COVID-19) infection on fetal health remains to be precisely characterized. OBJECTIVES Using metabolomic profiling of newborn umbilical cord blood, we aimed to investigate the potential fetal biological consequences of maternal COVID-19 infection. METHODS Cord blood plasma samples from 23 mild COVID-19 cases (mother infected/newborn negative) and 23 gestational age-matched controls were analyzed using nuclear magnetic spectroscopy and liquid chromatography coupled with mass spectrometry. Metabolite set enrichment analysis (MSEA) was used to evaluate altered biochemical pathways due to COVID-19 intrauterine exposure. Logistic regression models were developed using metabolites to predict intrauterine exposure. RESULTS Significant concentration differences between groups (p-value < 0.05) were observed in 19 metabolites. Elevated levels of glucocorticoids, pyruvate, lactate, purine metabolites, phenylalanine, and branched-chain amino acids of valine and isoleucine were discovered in cases while ceramide subclasses were decreased. The top metabolite model including cortisol and ceramide (d18:1/23:0) achieved an Area under the Receiver Operating Characteristics curve (95% CI) = 0.841 (0.725-0.957) for detecting fetal exposure to maternal COVID-19 infection. MSEA highlighted steroidogenesis, pyruvate metabolism, gluconeogenesis, and the Warburg effect as the major perturbed metabolic pathways (p-value < 0.05). These changes indicate fetal increased oxidative metabolism, hyperinsulinemia, and inflammatory response. CONCLUSION We present fetal biochemical changes related to intrauterine inflammation and altered energy metabolism in cases of mild maternal COVID-19 infection despite the absence of viral infection. Elucidation of the long-term consequences of these findings is imperative considering the large number of exposures in the population.
Collapse
Affiliation(s)
- Onur Turkoglu
- Department of Obstetrics and Gynecology, Corewell Health, Oakland University William Beaumont School of Medicine, 3535 W. 13 Mile Rd, Royal Oak, MI, 48073, USA.
| | - Ali Alhousseini
- Department of Maternal-Fetal Medicine, Sparrow Hospital, Michigan State University, Lansing, MI, 48912, USA
| | - Sonia Sajja
- Department of Obstetrics and Gynecology, Corewell Health, Oakland University William Beaumont School of Medicine, 3535 W. 13 Mile Rd, Royal Oak, MI, 48073, USA
| | - Jay Idler
- Department of Obstetrics and Gynecology, Corewell Health, Oakland University William Beaumont School of Medicine, 3535 W. 13 Mile Rd, Royal Oak, MI, 48073, USA
| | - Sean Stuart
- Department of Obstetrics and Gynecology, Corewell Health, Oakland University William Beaumont School of Medicine, 3535 W. 13 Mile Rd, Royal Oak, MI, 48073, USA
| | - Nadia Ashrafi
- Metabolomics Department, Beaumont Research Institute, Corewell Health, William Beaumont University Hospital, Royal Oak, MI, 48073, USA
| | - Ali Yilmaz
- Metabolomics Department, Beaumont Research Institute, Corewell Health, William Beaumont University Hospital, Royal Oak, MI, 48073, USA
| | - Kurt Wharton
- Department of Obstetrics and Gynecology, Corewell Health, Oakland University William Beaumont School of Medicine, 3535 W. 13 Mile Rd, Royal Oak, MI, 48073, USA
| | - Stewart F Graham
- Department of Obstetrics and Gynecology, Corewell Health, Oakland University William Beaumont School of Medicine, 3535 W. 13 Mile Rd, Royal Oak, MI, 48073, USA
- Metabolomics Department, Beaumont Research Institute, Corewell Health, William Beaumont University Hospital, Royal Oak, MI, 48073, USA
| | - Ray O Bahado-Singh
- Department of Obstetrics and Gynecology, Corewell Health, Oakland University William Beaumont School of Medicine, 3535 W. 13 Mile Rd, Royal Oak, MI, 48073, USA
| |
Collapse
|
49
|
Zhao S, Zhou L, Wang Q, Cao JH, Chen Y, Wang W, Zhu BD, Wei ZH, Li R, Li CY, Zhou GY, Tan ZJ, Zhou HP, Li CX, Gao HK, Qin XJ, Lian K. Elevated branched-chain amino acid promotes atherosclerosis progression by enhancing mitochondrial-to-nuclear H2O2-disulfide HMGB1 in macrophages. Redox Biol 2023; 62:102696. [PMID: 37058999 PMCID: PMC10130699 DOI: 10.1016/j.redox.2023.102696] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/01/2023] [Accepted: 04/03/2023] [Indexed: 04/08/2023] Open
Abstract
As the essential amino acids, branched-chain amino acid (BCAA) from diets is indispensable for health. BCAA supplementation is often recommended for patients with consumptive diseases or healthy people who exercise regularly. Latest studies and ours reported that elevated BCAA level was positively correlated with metabolic syndrome, diabetes, thrombosis and heart failure. However, the adverse effect of BCAA in atherosclerosis (AS) and its underlying mechanism remain unknown. Here, we found elevated plasma BCAA level was an independent risk factor for CHD patients by a human cohort study. By employing the HCD-fed ApoE-/- mice of AS model, ingestion of BCAA significantly increased plaque volume, instability and inflammation in AS. Elevated BCAA due to high dietary BCAA intake or BCAA catabolic defects promoted AS progression. Furthermore, BCAA catabolic defects were found in the monocytes of patients with CHD and abdominal macrophages in AS mice. Improvement of BCAA catabolism in macrophages alleviated AS burden in mice. The protein screening assay revealed HMGB1 as a potential molecular target of BCAA in activating proinflammatory macrophages. Excessive BCAA induced the formation and secretion of disulfide HMGB1 as well as subsequent inflammatory cascade of macrophages in a mitochondrial-nuclear H2O2 dependent manner. Scavenging nuclear H2O2 by overexpression of nucleus-targeting catalase (nCAT) effectively inhibited BCAA-induced inflammation in macrophages. All of the results above illustrate that elevated BCAA promotes AS progression by inducing redox-regulated HMGB1 translocation and further proinflammatory macrophage activation. Our findings provide novel insights into the role of animo acids as the daily dietary nutrients in AS development, and also suggest that restricting excessive dietary BCAA consuming and promoting BCAA catabolism may serve as promising strategies to alleviate and prevent AS and its subsequent CHD.
Collapse
|
50
|
Lohkamp KJ, van den Hoek AM, Solé-Guardia G, Lisovets M, Alves Hoffmann T, Velanaki K, Geenen B, Verweij V, Morrison MC, Kleemann R, Wiesmann M, Kiliaan AJ. The Preventive Effect of Exercise and Oral Branched-Chain Amino Acid Supplementation on Obesity-Induced Brain Changes in Ldlr−/−.Leiden Mice. Nutrients 2023; 15:nu15071716. [PMID: 37049556 PMCID: PMC10097391 DOI: 10.3390/nu15071716] [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: 02/16/2023] [Revised: 03/28/2023] [Accepted: 03/29/2023] [Indexed: 04/03/2023] Open
Abstract
Exercise and dietary interventions are promising approaches to tackle obesity and its obesogenic effects on the brain. We investigated the impact of exercise and possible synergistic effects of exercise and branched-chain amino acids (BCAA) supplementation on the brain and behavior in high-fat-diet (HFD)-induced obese Ldlr−/−.Leiden mice. Baseline measurements were performed in chow-fed Ldlr−/−.Leiden mice to assess metabolic risk factors, cognition, and brain structure using magnetic resonance imaging. Thereafter, a subgroup was sacrificed, serving as a healthy reference. The remaining mice were fed an HFD and divided into three groups: (i) no exercise, (ii) exercise, or (iii) exercise and dietary BCAA. Mice were followed for 6 months and aforementioned tests were repeated. We found that exercise alone changed cerebral blood flow, attenuated white matter loss, and reduced neuroinflammation compared to non-exercising HFD-fed mice. Contrarily, no favorable effects of exercise on the brain were found in combination with BCAA, and neuroinflammation was increased. However, cognition was slightly improved in exercising mice on BCAA. Moreover, BCAA and exercise increased the percentage of epididymal white adipose tissue and muscle weight, decreased body weight and fasting insulin levels, improved the circadian rhythm, and transiently improved grip strength. In conclusion, BCAA should be supplemented with caution, although beneficial effects on metabolism, behavior, and cognition were observed.
Collapse
Affiliation(s)
- Klara J. Lohkamp
- Department of Medical Imaging, Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behavior, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, 6525 EZ Nijmegen, The Netherlands; (K.J.L.); (G.S.-G.); (M.L.); (T.A.H.); (K.V.); (B.G.); (V.V.); (M.W.)
| | - Anita M. van den Hoek
- Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 BE Leiden, The Netherlands; (A.M.v.d.H.); (M.C.M.); (R.K.)
| | - Gemma Solé-Guardia
- Department of Medical Imaging, Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behavior, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, 6525 EZ Nijmegen, The Netherlands; (K.J.L.); (G.S.-G.); (M.L.); (T.A.H.); (K.V.); (B.G.); (V.V.); (M.W.)
| | - Maria Lisovets
- Department of Medical Imaging, Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behavior, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, 6525 EZ Nijmegen, The Netherlands; (K.J.L.); (G.S.-G.); (M.L.); (T.A.H.); (K.V.); (B.G.); (V.V.); (M.W.)
| | - Talissa Alves Hoffmann
- Department of Medical Imaging, Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behavior, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, 6525 EZ Nijmegen, The Netherlands; (K.J.L.); (G.S.-G.); (M.L.); (T.A.H.); (K.V.); (B.G.); (V.V.); (M.W.)
| | - Konstantina Velanaki
- Department of Medical Imaging, Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behavior, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, 6525 EZ Nijmegen, The Netherlands; (K.J.L.); (G.S.-G.); (M.L.); (T.A.H.); (K.V.); (B.G.); (V.V.); (M.W.)
| | - Bram Geenen
- Department of Medical Imaging, Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behavior, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, 6525 EZ Nijmegen, The Netherlands; (K.J.L.); (G.S.-G.); (M.L.); (T.A.H.); (K.V.); (B.G.); (V.V.); (M.W.)
| | - Vivienne Verweij
- Department of Medical Imaging, Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behavior, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, 6525 EZ Nijmegen, The Netherlands; (K.J.L.); (G.S.-G.); (M.L.); (T.A.H.); (K.V.); (B.G.); (V.V.); (M.W.)
| | - Martine C. Morrison
- Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 BE Leiden, The Netherlands; (A.M.v.d.H.); (M.C.M.); (R.K.)
| | - Robert Kleemann
- Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 BE Leiden, The Netherlands; (A.M.v.d.H.); (M.C.M.); (R.K.)
| | - Maximilian Wiesmann
- Department of Medical Imaging, Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behavior, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, 6525 EZ Nijmegen, The Netherlands; (K.J.L.); (G.S.-G.); (M.L.); (T.A.H.); (K.V.); (B.G.); (V.V.); (M.W.)
| | - Amanda J. Kiliaan
- Department of Medical Imaging, Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behavior, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, 6525 EZ Nijmegen, The Netherlands; (K.J.L.); (G.S.-G.); (M.L.); (T.A.H.); (K.V.); (B.G.); (V.V.); (M.W.)
- Correspondence:
| |
Collapse
|