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Beske RP, Obling LER, Meyer MAS, Møller JE, Kjaergaard J, Johansson PI, Hassager C. Metabolic effects of high-dose glucocorticoid following out-of-hospital cardiac arrest. Intensive Care Med Exp 2025; 13:46. [PMID: 40285920 PMCID: PMC12033126 DOI: 10.1186/s40635-025-00754-8] [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: 01/13/2025] [Accepted: 04/07/2025] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND AND AIM Patients resuscitated after out-of-hospital cardiac arrest (OHCA) face high morbidity and mortality rates, primarily due to ischemia-reperfusion injury, a complex metabolic disorder that triggers a significant systemic inflammatory response. Glucocorticoids mitigate inflammation but also impact the cells beyond the immune response. This study aims to identify glucocorticoid effects on plasma metabolites. METHODS This explorative sub-study is part of a two-center, blinded, randomized controlled trial (NCT04624776) examining the effects of high-dose glucocorticoid on comatose patients resuscitated from OHCA of presumed cardiac origin. Following resuscitation, patients received 250 mg of methylprednisolone or a placebo in the prehospital setting. Blood samples were collected upon hospital admission and 48 h later. Sixty metabolites were quantified in the plasma using mass spectrometry and compared between groups. RESULTS In the modified intention-to-treat population, 68 patients received methylprednisolone, and 69 received placebo [median age was 66 years (IQR: 56-74) and 83% were men]. Blood samples were available for 130 patients, 121 (88%) at admission and 117 patients (94% of patients alive) after 48 h. Although a nominal difference was observed at admission, no significant metabolic effects were found after correcting for multiple testing. After 48 h, the placebo group had 83.4% (95% CI 16.9-187.6%) higher prostaglandin E2 and higher levels of linolenic acid and arachidonic acid. The methylprednisolone group had higher levels of tryptophan (47.6%; 95% CI 27.9-70.2%), arginine, and propionylcarnitine (C3). CONCLUSIONS In this exploratory study, early administration of 250 mg of methylprednisolone after resuscitation appeared to drive sustained metabolic effects over 48 h. Specifically, methylprednisolone led to reductions in ω-6 fatty acids and increases in several amino acids, with a notable rise in tryptophan.
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Affiliation(s)
- Rasmus Paulin Beske
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark.
- Center for Endotheliomics, CAG, Department of Clinical Immunology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
| | - Laust Emil Roelsgaard Obling
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark
| | - Martin Abild Stengaard Meyer
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark
| | - Jacob Eifer Møller
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark
- Department of Cardiology, Odense University Hospital, Odense, Denmark
| | - Jesper Kjaergaard
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark
| | - Pär Ingemar Johansson
- Center for Endotheliomics, CAG, Department of Clinical Immunology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Christian Hassager
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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Ramirez-Falcon M, Suarez-Pajes E, Flores C. Defining the Differential Corticosteroid Response Basis from Multiple Omics Approaches. Int J Mol Sci 2024; 25:13611. [PMID: 39769372 PMCID: PMC11679800 DOI: 10.3390/ijms252413611] [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: 11/16/2024] [Revised: 12/16/2024] [Accepted: 12/17/2024] [Indexed: 01/11/2025] Open
Abstract
Since their discovery, corticosteroids have been widely used in the treatment of several diseases, including asthma, acute lymphoblastic leukemia, chronic obstructive pulmonary disease, and many other conditions. However, it has been noted that some patients develop undesired side effects or even fail to respond to treatment. The reasons behind this have not yet been fully elucidated. This poses a significant challenge to effective treatment that needs to be addressed urgently. Recent genomic, transcriptomic, and other omics-based approximations have begun to shed light into the genetic factors influencing interindividual variability in corticosteroid efficacy and its side effects. Here, we comprehensively revise the recent literature on corticosteroid response in various critical and chronic diseases, with a focus on omics approaches, and highlight existing knowledge gaps where further investigation is urgently needed.
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Affiliation(s)
- Melody Ramirez-Falcon
- Research Unit, Hospital Universitario Ntra. Sra. de Candelaria, Instituto de Investigación Sanitaria de Canarias, 38010 Santa Cruz de Tenerife, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Eva Suarez-Pajes
- Research Unit, Hospital Universitario Ntra. Sra. de Candelaria, Instituto de Investigación Sanitaria de Canarias, 38010 Santa Cruz de Tenerife, Spain
| | - Carlos Flores
- Research Unit, Hospital Universitario Ntra. Sra. de Candelaria, Instituto de Investigación Sanitaria de Canarias, 38010 Santa Cruz de Tenerife, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Genomics Division, Instituto Tecnológico y de Energías Renovables, Granadilla de Abona, 38600 Santa Cruz de Tenerife, Spain
- Facultad de Ciencias de la Salud, Universidad Fernando Pessoa Canarias, 35450 Las Palmas de Gran Canaria, Spain
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Akman TC, Kadioglu Y, Senol O, Erkayman B, Aydin İC. Understanding the side effects of chronic silodosin administration via untargeted metabolomics approach. ANNALES PHARMACEUTIQUES FRANÇAISES 2024; 82:1150-1162. [PMID: 39127320 DOI: 10.1016/j.pharma.2024.08.002] [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: 01/27/2024] [Revised: 05/17/2024] [Accepted: 08/06/2024] [Indexed: 08/12/2024]
Abstract
BACKGROUND Precision medicine, which looks for high efficacy and low toxicity in therapies, has increased in popularity with omics technology. This work aims to discover novel and low-toxicity therapy options by examining the complex relationship between silodosin-induced side effects and the metabolomic profiles associated with its administration. MATERIALS AND METHODS The plasma samples of the control group and silodosin-treated rats were analyzed by LC-Q-TOF-MS/MS. Employing XCMS and MetaboAnalyst software, MS/MS data processed to detect compounds and investigate metabolic pathways. MATLAB 2019b was used for data categorization and multivariate analysis. A thorough comparison of METLIN and HMDB databases revealed 41m/z values with significant differences between the drug-treated and control groups (p <0.01 and fold analysis≥1.5). RESULTS According to multivariate data analysis, 17-β-estradiol, taurocholic acid, L-kynurenine, N-formylkynurenine, D-glutamine, L-arginine, prostaglandin H2, prostaglandine G2, 15-keto-prostaglandin E2, calcidiol, thromboxane A2, 5'-methylthioadenosine, L-methionine and S-adenosylmethionine levels changed significantly compared to the control group. Differences in the metabolisms of glycerophospholipid, tyrosine, phenylalanine, arachidonic acid, cysteine and methionine, and biosynthesis of phenylalanine, tyrosine, and tryptophan, and aminoacyl-tRNA have been successfully demonstrated by metabolic pathway analysis. According to this study, vitamin D, D-glutamine, and L-arginine supplements can be recommended to prevent side effects such as fatigue, intraoperative floppy iris syndrome, blurred vision, and dizziness in the treatment of silodosin. Silodosin treatment negatively affected the immune system by affecting the kynurenine and tryptophan metabolism pathways. CONCLUSIONS The study is a guide for silodosin treatments that offer low side effects and high therapeutic effect within the scope of precision medicine.
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Affiliation(s)
- Tugrul Cagri Akman
- Department of Analytical Chemistry, Faculty of Pharmacy, Erzincan Binali Yildirim University, Erzincan 24100, Turkey.
| | - Yucel Kadioglu
- Department of Analytical Chemistry, Faculty of Pharmacy, Atatürk University, Erzurum, Turkey
| | - Onur Senol
- Department of Analytical Chemistry, Faculty of Pharmacy, Atatürk University, Erzurum, Turkey
| | - Beyzagul Erkayman
- Department of Pharmacology, Faculty of Pharmacy, Atatürk University, Erzurum, Turkey
| | - İsmail Cagri Aydin
- Department of Pharmacology, Faculty of Pharmacy, Erzincan Binali Yildirim University, Erzincan 24100, Turkey
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Löding S, Antti H, Sjöberg RL, Melin B, Björkblom B. Blood based metabolic markers of glioma from pre-diagnosis to surgery. Sci Rep 2024; 14:20680. [PMID: 39237693 PMCID: PMC11377417 DOI: 10.1038/s41598-024-71375-6] [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: 05/24/2024] [Accepted: 08/26/2024] [Indexed: 09/07/2024] Open
Abstract
Gliomas are highly complex and metabolically active brain tumors associated with poor prognosis. Recent reports have found altered levels of blood metabolites during early tumor development, suggesting that tumor development could be detected several years before clinical manifestation. In this study, we performed metabolite analyses of blood samples collected from healthy controls and future glioma patients, up to eight years before glioma diagnosis, and on the day of glioma surgery. We discovered that metabolites related to early glioma development were associated with an increased energy turnover, as highlighted by elevated levels of TCA-related metabolites such as fumarate, malate, lactate and pyruvate in pre-diagnostic cases. We also found that metabolites related to glioma progression at surgery were primarily high levels of amino acids and metabolites of amino acid catabolism, with elevated levels of 11 amino acids and two branched-chain alpha-ketoacids, ketoleucine and ketoisoleucine. High amino acid turnover in glioma tumor tissue is currently utilized for PET imaging, diagnosis and delineation of tumor margins. By examining blood-based metabolic progression patterns towards disease onset, we demonstrate that this high amino acid turnover is also detectable in a simple blood sample. These findings provide additional insight of metabolic alterations during glioma development and progression.
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Affiliation(s)
- Sebastian Löding
- Department of Chemistry, Umeå University, Linnaeus väg 10, 901 87, Umeå, Sweden.
| | - Henrik Antti
- Department of Chemistry, Umeå University, Linnaeus väg 10, 901 87, Umeå, Sweden
| | - Rickard L Sjöberg
- Department of Clinical Science, Neurosciences, Umeå University, 901 85, Umeå, Sweden
| | - Beatrice Melin
- Department of Diagnostics and Intervention, Oncology, Umeå University, 901 87, Umeå, Sweden
| | - Benny Björkblom
- Department of Chemistry, Umeå University, Linnaeus väg 10, 901 87, Umeå, Sweden.
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Kimble LP, Khosroshahi A, Brewster GS, Dunbar SB, Ryan D, Carlson N, Eldridge R, Houser M, Corwin E. Associations between TCA cycle plasma metabolites and fatigue in black females with systemic lupus erythematosus: An untargeted metabolomics pilot study. Lupus 2024; 33:948-961. [PMID: 38885489 PMCID: PMC11296915 DOI: 10.1177/09612033241260334] [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: 06/20/2024]
Abstract
OBJECTIVE In this pilot study, we used untargeted metabolomics to identify biochemical mechanisms or biomarkers potentially underlying SLE-related fatigue. METHODS Metabolon conducted untargeted metabolomic plasma profiling using ultrahigh performance liquid chromatography/tandem mass spectrometry on plasma samples of 23 Black females with systemic lupus erythematosus (SLE) and 21 no SLE controls. Fatigue phenotypes of general fatigue, physical fatigue, mental fatigue, reduced activity, and reduced motivation were measured with the reliable and valid Multidimensional Fatigue Inventory (MFI). RESULTS A total of 290 metabolites were significantly different between the SLE and no SLE groups, encompassing metabolites related to glycolysis, TCA cycle activity, heme catabolism, branched chain amino acids, fatty acid metabolism, and steroids. Within the SLE group, controlling for age and co-morbidities, TCA cycle metabolites of alpha-ketoglutarate (AKG) and succinate were statistically significantly associated (p < .05) with physical and general fatigue. CONCLUSION While pervasive perturbations in the entire TCA cycle have been implicated as a potential mechanism for fatigue, our results suggest individual metabolites of AKG and succinate may be potential biomarkers or targets of intervention for fatigue symptom management in SLE. Additionally, perturbations in heme metabolism in the SLE group provide additional insights into mechanisms that promote systemic inflammation.
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Affiliation(s)
| | | | | | | | | | | | - Ron Eldridge
- School of Nursing, Emory University, Atlanta, GA, USA
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Manning JE, Harris E, Mathieson H, Sorensen L, Luqmani R, McGettrick HM, Morgan AW, Young SP, Mackie SL. Polymyalgia rheumatica shows metabolomic alterations that are further altered by glucocorticoid treatment: Identification of metabolic correlates of fatigue. J Autoimmun 2024; 147:103260. [PMID: 38797046 DOI: 10.1016/j.jaut.2024.103260] [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: 01/10/2024] [Revised: 04/17/2024] [Accepted: 05/21/2024] [Indexed: 05/29/2024]
Abstract
OBJECTIVE In polymyalgia rheumatica (PMR), glucocorticoids (GCs) relieve pain and stiffness, but fatigue may persist. We aimed to explore the effect of disease, GCs and PMR symptoms in the metabolite signatures of peripheral blood from patients with PMR or the related disease, giant cell arteritis (GCA). METHODS Nuclear magnetic resonance spectroscopy was performed on serum from 40 patients with untreated PMR, 84 with new-onset confirmed GCA, and 53 with suspected GCA who later were clinically confirmed non-GCA, and 39 age-matched controls. Further samples from PMR patients were taken one and six months into glucocorticoid therapy to explore relationship of metabolites to persistent fatigue. 100 metabolites were identified using Chenomx and statistical analysis performed in SIMCA-P to examine the relationship between metabolic profiles and, disease, GC treatment or symptoms. RESULTS The metabolite signature of patients with PMR and GCA differed from that of age-matched non-inflammatory controls (R2 > 0.7). There was a smaller separation between patients with clinically confirmed GCA and those with suspected GCA who later were clinically confirmed non-GCA (R2 = 0.135). In PMR, metabolite signatures were further altered with glucocorticoid treatment (R2 = 0.42) but did not return to that seen in controls. Metabolites correlated with CRP, pain, stiffness, and fatigue (R2 ≥ 0.39). CRP, pain, and stiffness declined with treatment and were associated with 3-hydroxybutyrate and acetoacetate, but fatigue did not. Metabolites differentiated patients with high and low fatigue both before and after treatment (R2 > 0.9). Low serum glutamine was predictive of high fatigue at both time points (0.79-fold change). CONCLUSION PMR and GCA alter the metabolite signature. In PMR, this is further altered by glucocorticoid therapy. Treatment-induced metabolite changes were linked to measures of inflammation (CRP, pain and stiffness), but not to fatigue. Furthermore, metabolite signatures distinguished patients with high or low fatigue.
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Affiliation(s)
- Julia E Manning
- Institute for Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15-2TT, UK.
| | - Emma Harris
- School of Medicine, University of Leeds, Leeds, LS7 4SA, UK and School of Human and Health Sciences, University of Huddersfield, Huddersfield, UK.
| | - Hannah Mathieson
- School of Medicine, University of Leeds, Leeds, LS7 4SA, UK and Leeds NIHR Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
| | - Louise Sorensen
- School of Medicine, University of Leeds, Leeds, LS7 4SA, UK.
| | - Raashid Luqmani
- NIHR Musculoskeletal Biomedical Research Unit, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK.
| | - Helen M McGettrick
- Institute for Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15-2TT, UK.
| | - Ann W Morgan
- School of Medicine, University of Leeds, Leeds, School of Human and Health Sciences, University of Huddersfield, Huddersfield, And Leeds NIHR Medtech and in Vitro Diagnostics Co-operative, Leeds Teaching Hospitals NHS Trust, Leeds, LS7 4SA, UK.
| | - Stephen P Young
- Institute for Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15-2TT, UK.
| | - Sarah L Mackie
- School of Medicine, University of Leeds, Leeds, LS7 4SA, UK and School of Human and Health Sciences, University of Huddersfield, Huddersfield, UK.
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Deng Y, Zheng H, Li B, Huang F, Qiu Y, Yang Y, Sheng W, Peng C, Tian X, Wang W, Yu H. Nanomedicines targeting activated immune cells and effector cells for rheumatoid arthritis treatment. J Control Release 2024; 371:498-515. [PMID: 38849090 DOI: 10.1016/j.jconrel.2024.06.010] [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: 02/27/2024] [Revised: 06/01/2024] [Accepted: 06/03/2024] [Indexed: 06/09/2024]
Abstract
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by synovial inflammation and inflammatory cellular infiltration. Functional cells in the RA microenvironment (RAM) are composed of activated immune cells and effector cells. Activated immune cells, including macrophages, neutrophils, and T cells, can induce RA. Effector cells, including synoviocytes, osteoclasts, and chondrocytes, receiving inflammatory stimuli, exacerbate RA. These functional cells, often associated with the upregulation of surface-specific receptor proteins and significant homing effects, can secrete pro-inflammatory factors and interfere with each other, thereby jointly promoting the progression of RA. Recently, some nanomedicines have alleviated RA by targeting and modulating functional cells with ligand modifications, while other nanoparticles whose surfaces are camouflaged by membranes or extracellular vesicles (EVs) of these functional cells target and attack the lesion site for RA treatment. When ligand-modified nanomaterials target specific functional cells to treat RA, the functional cells are subjected to attack, much like the intended targets. When functional cell membranes or EVs are modified onto nanomaterials to deliver drugs for RA treatment, functional cells become the attackers, similar to arrows. This study summarized how diversified functional cells serve as targets or arrows by engineered nanoparticles to treat RA. Moreover, the key challenges in preparing nanomaterials and their stability, long-term efficacy, safety, and future clinical patient compliance have been discussed here.
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Affiliation(s)
- Yasi Deng
- TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Materia Medica Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Hao Zheng
- TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Materia Medica Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Bin Li
- TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Materia Medica Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Feibing Huang
- TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Materia Medica Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Yun Qiu
- TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Materia Medica Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Yupei Yang
- TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Materia Medica Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Wenbing Sheng
- TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Materia Medica Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Caiyun Peng
- TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Materia Medica Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Xing Tian
- TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Materia Medica Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Wei Wang
- TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Materia Medica Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China.
| | - Huanghe Yu
- TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Materia Medica Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China.
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Pan B, Chen C, Zhao Y, Cai J, Fu S, Liu J. SIRT3: A Potential Target of Different Types of Osteoporosis. Cell Biochem Biophys 2024; 82:489-500. [PMID: 38512537 DOI: 10.1007/s12013-024-01254-4] [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: 02/19/2024] [Accepted: 03/13/2024] [Indexed: 03/23/2024]
Abstract
Osteoporosis (OP) is a common age-related disease. OP is mainly a decrease in bone density and mass caused by the destruction of bone microstructure, which leads to an increase in bone fragility. SIRT3 is a mitochondrial deacetylase that plays critical roles in mitochondrial homeostasis, metabolic regulation, gene transcription, stress response, and gene stability. Studies have shown that the higher expression levels of SIRT3 are associated with decreased levels of oxidative stress in the body and may play important roles in the prevention of age-related diseases. SIRTs can enhance the osteogenic potential and osteoblastic activity of bone marrow mesenchymal stromal cells not only by enhancing PGC-1α, FOXO3, SOD2, and oxidative phosphorylation, but also by anti-aging and reducing mitochondrial autophagy. SIRT3 is able to upregulate antioxidant enzymes to exert an inhibitory effect on osteoclasts, however, it has been shown that the inflammatory cascade response can in turn increase SIRT3 and inhibit osteoclast differentiation through the AMPK-PGC-1β pathway. SIRT3 plays an important role in different types of osteoporosis by affecting osteoblasts, osteoclasts, and bone marrow mesenchymal cells. In this review, we discuss the classification and physiological functions of SIRTs, the effects of SIRT3 on OCs osteoblasts, and BMSCs, and the roles and mechanisms of SIRT3 in different types of OP, such as diabetic OP, glucocorticoid-induced OP, postmenopausal OP, and senile OP.
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Affiliation(s)
- Binjing Pan
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Chongyang Chen
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Yangting Zhao
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Jing Cai
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Songbo Fu
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of Endocrinology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Jingfang Liu
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China.
- Department of Endocrinology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China.
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Hora J, Rambhia N, Mani I. Drug repurposing for personalized medicine. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2024; 207:107-122. [PMID: 38942534 DOI: 10.1016/bs.pmbts.2024.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/30/2024]
Abstract
Personalized medicine has emerged as a revolutionary approach to healthcare in the 21st century. By understanding a patient's unique genetic and biological characteristics, it aims to tailor treatments specifically to the individual. This approach takes into account factors such as an individual's lifestyle, genetic makeup, and environmental factors to provide targeted therapies that have the potential to be more effective and lower the risk of side reactions or ineffective treatments. It is a paradigm shift from the traditional "one size fits all" approach in medicine, where patients with similar symptoms or diagnoses receive the same standard treatments regardless of their differences. It leads to improved clinical outcomes and more efficient use of healthcare resources. Drug repurposing is a strategy that uses existing drugs for new indications and aims to take advantage of the known safety profiles, pharmacokinetics, and mechanisms of action of these drugs to accelerate the development process. Precision medicine may undergo a revolutionary change as a result, enabling the rapid development of novel treatment plans utilizing drugs that traditional methods would not otherwise link to. In this chapter, we have focused on a few strategies wherein drug repurposing has shown great success for precision medicine. The approach is particularly useful in oncology as there are many variations induced in the genetic material of cancer patients, so tailored treatment approaches go a long way. We have discussed the cases of breast cancer, glioblastoma and hepatocellular carcinoma. Other than that, we have also looked at drug repurposing approaches in anxiety disorders and COVID-19.
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Affiliation(s)
- Jahnvi Hora
- Manipal School of Life Science, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Nishita Rambhia
- Manipal School of Life Science, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Indra Mani
- Department of Microbiology, Gargi College, University of Delhi, New Delhi, India.
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Rojo-Sánchez A, Carmona-Martes A, Díaz-Olmos Y, Santamaría-Torres M, Cala MP, Orozco-Acosta E, Aroca-Martínez G, Pacheco-Londoño L, Navarro-Quiroz E, Pacheco-Lugo LA. Urinary metabolomic profiling of a cohort of Colombian patients with systemic lupus erythematosus. Sci Rep 2024; 14:9555. [PMID: 38664528 PMCID: PMC11045835 DOI: 10.1038/s41598-024-60217-0] [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: 12/22/2023] [Accepted: 04/19/2024] [Indexed: 04/28/2024] Open
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune and multisystem disease with a high public health impact. Lupus nephritis (LN), commonly known as renal involvement in SLE, is associated with a poorer prognosis and increased rates of morbidity and mortality in patients with SLE. Identifying new urinary biomarkers that can be used for LN prognosis or diagnosis is essential and is part of current active research. In this study, we applied an untargeted metabolomics approach involving liquid and gas chromatography coupled with mass spectrometry to urine samples collected from 17 individuals with SLE and no kidney damage, 23 individuals with LN, and 10 clinically healthy controls (HCs) to identify differential metabolic profiles for SLE and LN. The data analysis revealed a differentially abundant metabolite expression profile for each study group, and those metabolites may act as potential differential biomarkers of SLE and LN. The differential metabolic pathways found between the LN and SLE patients with no kidney involvement included primary bile acid biosynthesis, branched-chain amino acid synthesis and degradation, pantothenate and coenzyme A biosynthesis, lysine degradation, and tryptophan metabolism. Receiver operating characteristic curve analysis revealed that monopalmitin, glycolic acid, and glutamic acid allowed for the differentiation of individuals with SLE and no kidney involvement and individuals with LN considering high confidence levels. While the results offer promise, it is important to recognize the significant influence of medications and other external factors on metabolomics studies. This impact has the potential to obscure differences in metabolic profiles, presenting a considerable challenge in the identification of disease biomarkers. Therefore, experimental validation should be conducted with a larger sample size to explore the diagnostic potential of the metabolites found as well as to examine how treatment and disease activity influence the identified chemical compounds. This will be crucial for refining the accuracy and effectiveness of using urine metabolomics for diagnosing and monitoring lupus and lupus nephritis.
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Affiliation(s)
- Alejandra Rojo-Sánchez
- Life Sciences Research Center, School of Basic and Biomedical Sciences, Universidad Simón Bolívar, Barranquilla, Colombia
| | - Ada Carmona-Martes
- Life Sciences Research Center, School of Basic and Biomedical Sciences, Universidad Simón Bolívar, Barranquilla, Colombia
| | - Yirys Díaz-Olmos
- Health Sciences Division, Medicine Program, Universidad del Norte, Barranquilla, Colombia
| | - Mary Santamaría-Torres
- Metabolomics Core Facility-MetCore, Vice-Presidency for Research, Universidad de los Andes, Bogotá, Colombia
| | - Mónica P Cala
- Metabolomics Core Facility-MetCore, Vice-Presidency for Research, Universidad de los Andes, Bogotá, Colombia
| | - Erick Orozco-Acosta
- Life Sciences Research Center, School of Basic and Biomedical Sciences, Universidad Simón Bolívar, Barranquilla, Colombia
| | - Gustavo Aroca-Martínez
- Life Sciences Research Center, School of Basic and Biomedical Sciences, Universidad Simón Bolívar, Barranquilla, Colombia
- Clínica de la Costa, Barranquilla, Colombia
| | - Leonardo Pacheco-Londoño
- Life Sciences Research Center, School of Basic and Biomedical Sciences, Universidad Simón Bolívar, Barranquilla, Colombia
| | - Elkin Navarro-Quiroz
- Life Sciences Research Center, School of Basic and Biomedical Sciences, Universidad Simón Bolívar, Barranquilla, Colombia
| | - Lisandro A Pacheco-Lugo
- Life Sciences Research Center, School of Basic and Biomedical Sciences, Universidad Simón Bolívar, Barranquilla, Colombia.
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11
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Eladwy RA, Alsherbiny MA, Chang D, Fares M, Li CG, Bhuyan DJ. The postbiotic sodium butyrate synergizes the antiproliferative effects of dexamethasone against the AGS gastric adenocarcinoma cells. Front Nutr 2024; 11:1372982. [PMID: 38533461 PMCID: PMC10963608 DOI: 10.3389/fnut.2024.1372982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 02/26/2024] [Indexed: 03/28/2024] Open
Abstract
A growing body of literature underlines the fundamental role of gut microbiota in the occurrence, treatment, and prognosis of cancer. In particular, the activity of gut microbial metabolites (also known as postbiotics) against different cancer types has been recently reported in several studies. However, their in-depth molecular mechanisms of action and potential interactions with standard chemotherapeutic drugs remain to be fully understood. This research investigates the antiproliferative activities of postbiotics- short-chain fatty acid (SCFA) salts, specifically magnesium acetate (MgA), sodium propionate (NaP), and sodium butyrate (NaB), against the AGS gastric adenocarcinoma cells. Furthermore, the potential synergistic interactions between the most active SCFA salt-NaB and the standard drug dexamethasone (Dex) were explored using the combination index model. The molecular mechanisms of the synergy were investigated using reactive oxygen species (ROS), flow cytometry and biochemometric and liquid chromatography-mass spectrometry (LC-MS)-driven proteomics analyses. NaB exhibited the most significant inhibitory effect (p < 0.05) among the tested SCFA salts against the AGS gastric cancer cells. Additionally, Dex and NaB exhibited strong synergy at a 2:8 ratio (40 μg/mL Dex + 2,400 μg/mL NaB) with significantly greater inhibitory activity (p < 0.05) compared to the mono treatments against the AGS gastric cancer cells. MgA and NaP reduced ROS production, while NaB exhibited pro-oxidative properties. Dex displayed antioxidative effects, and the combination of Dex and NaB (2,8) demonstrated a unique pattern, potentially counteracting the pro-oxidative effects of NaB, highlighting an interaction. Dex and NaB individually and in combination (Dex:NaB 40:2400 μg/mL) induced significant changes in cell populations, suggesting a shift toward apoptosis (p < 0.0001). Analysis of dysregulated proteins in the AGS cells treated with the synergistic combination revealed notable downregulation of the oncogene TNS4, suggesting a potential mechanism for the observed antiproliferative effects. These findings propose the potential implementation of NaB as an adjuvant therapy with Dex. Further investigations into additional combination therapies, in-depth studies of the molecular mechanisms, and in vivo research will provide deeper insights into the use of these postbiotics in cancer, particularly in gastric malignancies.
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Affiliation(s)
- Radwa A Eladwy
- NICM Health Research Institute, Western Sydney University, Penrith, NSW, Australia
- Department of Pharmacology, Faculty of Pharmacy, Egyptian Russian University, Badr City, Egypt
| | | | - Dennis Chang
- NICM Health Research Institute, Western Sydney University, Penrith, NSW, Australia
| | - Mohamed Fares
- School of Pharmacy, The University of Sydney, Sydney, NSW, Australia
| | - Chun-Guang Li
- NICM Health Research Institute, Western Sydney University, Penrith, NSW, Australia
| | - Deep Jyoti Bhuyan
- NICM Health Research Institute, Western Sydney University, Penrith, NSW, Australia
- School of Science, Western Sydney University, Penrith, NSW, Australia
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12
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Tapryal N, Chakraborty A, Saha K, Islam A, Pan L, Hosoki K, Sayed IM, Duran JM, Alcantara J, Castillo V, Tindle C, Sarker AH, Wakamiya M, Cardenas VJ, Sharma G, Crotty Alexander LE, Sur S, Sahoo D, Ghosh G, Das S, Ghosh P, Boldogh I, Hazra TK. The DNA glycosylase NEIL2 is protective during SARS-CoV-2 infection. Nat Commun 2023; 14:8169. [PMID: 38071370 PMCID: PMC10710473 DOI: 10.1038/s41467-023-43938-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 11/24/2023] [Indexed: 12/18/2023] Open
Abstract
SARS-CoV-2 infection-induced aggravation of host innate immune response not only causes tissue damage and multiorgan failure in COVID-19 patients but also induces host genome damage and activates DNA damage response pathways. To test whether the compromised DNA repair capacity of individuals modulates the severity of COVID-19 infection, we analyze DNA repair gene expression in publicly available patient datasets and observe a lower level of the DNA glycosylase NEIL2 in the lungs of severely infected COVID-19 patients. This observation of lower NEIL2 levels is further validated in infected patients, hamsters and ACE2 receptor-expressing human A549 (A549-ACE2) cells. Furthermore, delivery of recombinant NEIL2 in A549-ACE2 cells shows decreased expression of proinflammatory genes and viral E-gene, as well as lowers the yield of viral progeny compared to mock-treated cells. Mechanistically, NEIL2 cooperatively binds to the 5'-UTR of SARS-CoV-2 genomic RNA to block viral protein synthesis. Collectively, these data strongly suggest that the maintenance of basal NEIL2 levels is critical for the protective response of hosts to viral infection and disease.
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Affiliation(s)
- Nisha Tapryal
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, 77555, USA
| | - Anirban Chakraborty
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, 77555, USA
| | - Kaushik Saha
- Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, 92037, USA
- Department of Biological Sciences, School of Engineering and Sciences, SRM University-AP, Guntur District, Andhra Pradesh, 522240, India
| | - Azharul Islam
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, 77555, USA
| | - Lang Pan
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, 77555, USA
| | - Koa Hosoki
- Department of Medicine, Immunology Allergy and Rheumatology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Ibrahim M Sayed
- Department of Pathology, University of California, San Diego, CA, 92093, USA
- Department of Biomedical and Nutritional Science, University of Massachusetts-Lowell, Lowell, MA, 01854, USA
| | - Jason M Duran
- Department of Internal Medicine, Division of Cardiology, UC San Diego Medical Center, La Jolla, CA, 92037, USA
| | - Joshua Alcantara
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, 92093, USA
| | - Vanessa Castillo
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, 92093, USA
| | - Courtney Tindle
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, 92093, USA
| | - Altaf H Sarker
- Department of Cancer and DNA Damage Responses, Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA
| | - Maki Wakamiya
- Department of Neurology, University of Texas Medical Branch, Galveston, TX, 77555, USA
| | - Victor J Cardenas
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, 77555, USA
| | - Gulshan Sharma
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, 77555, USA
| | | | - Sanjiv Sur
- Department of Medicine, Immunology Allergy and Rheumatology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Debashis Sahoo
- Department of Pediatrics, University of California San Diego, La Jolla, CA, 92093, USA.
- Department of Computer Science and Engineering, Jacob's School of Engineering, University of California San Diego, La Jolla, CA, 92093, USA.
| | - Gourisankar Ghosh
- Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, 92037, USA.
| | - Soumita Das
- Department of Pathology, University of California, San Diego, CA, 92093, USA.
- Department of Biomedical and Nutritional Science, University of Massachusetts-Lowell, Lowell, MA, 01854, USA.
| | - Pradipta Ghosh
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
- Department of Medicine, University of California, San Diego, CA, 92093, USA.
| | - Istvan Boldogh
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, 77555, USA.
| | - Tapas K Hazra
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, 77555, USA.
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13
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Madama D, Carrageta DF, Guerra-Carvalho B, Botelho MF, Oliveira PF, Cordeiro CR, Alves MG, Abrantes AM. Impact of Different Treatment Regimens and Timeframes in the Plasmatic Metabolic Profiling of Patients with Lung Adenocarcinoma. Metabolites 2023; 13:1180. [PMID: 38132862 PMCID: PMC10744969 DOI: 10.3390/metabo13121180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 11/20/2023] [Accepted: 11/24/2023] [Indexed: 12/23/2023] Open
Abstract
In recent years, the treatment of advanced non-small cell lung cancer (NSCLC) has suffered a variety of alterations. Chemotherapy (CTX), immunotherapy (IT) and tyrosine kinase inhibitors (TKI) have shown remarkable results. However, not all patients with NSCLC respond to these drug treatments or receive durable benefits. In this framework, metabolomics has been applied to improve the diagnosis, treatment, and prognosis of lung cancer and particularly lung adenocarcinoma (AdC). In our study, metabolomics was used to analyze plasma samples from 18 patients with AdC treated with CTX or IT via 1H-NMR spectroscopy. Relevant clinical information was gathered, and several biochemical parameters were also evaluated throughout the treatments. During the follow-up of patients undergoing CTX or IT, imaging control is recommended in order to assess the effectiveness of the therapy. This evaluation is usually performed every three treatments. Based on this procedure, all the samples were collected before the beginning of the treatment and after three and six treatments. The identified and quantified metabolites in the analyzed plasma samples were the following: isoleucine, valine, alanine, acetate, lactate, glucose, tyrosine, and formate. Multivariate/univariate statistical analyses were performed. Our data are in accordance with previous published results, suggesting that the plasma glucose levels of patients under CTX become higher throughout the course of treatment, which we hypothesize could be related to the tumor response to the therapy. It was also found that alanine levels become lower during treatment with CTX regimens, a fact that could be associated with frailty. NMR spectra of long responders' profiles also showed similar results. Based on the results of the study, metabolomics can represent a potential option for future studies, in order to facilitate patient selection and the monitoring of therapy efficacy in treated patients with AdC. Further studies are needed to improve the prospective identification of predictive markers, particularly glucose and alanine levels, as well as confer guidance to NSCLC treatment and patient stratification, thus avoiding ineffective therapeutic strategies.
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Affiliation(s)
- Daniela Madama
- Clinical Academic Centre of Coimbra (CACC), Department of Pulmonology, Faculty of Medicine, University Hospitals of Coimbra, University of Coimbra, 3004-504 Coimbra, Portugal
| | - David F. Carrageta
- Clinical and Experimental Endocrinology, UMIB—Unit for Multidisciplinary Research in Biomedicine, ICBAS—School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal (M.G.A.)
- Laboratory for Integrative and Translational Research in Population Health (ITR), University of Porto, 4050-600 Porto, Portugal
| | - Bárbara Guerra-Carvalho
- Clinical and Experimental Endocrinology, UMIB—Unit for Multidisciplinary Research in Biomedicine, ICBAS—School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal (M.G.A.)
- Laboratory for Integrative and Translational Research in Population Health (ITR), University of Porto, 4050-600 Porto, Portugal
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal;
| | - Maria F. Botelho
- Clinical Academic Centre of Coimbra (CACC), Centre for Innovative Biomedicine and Biotechnology (CIBB), Coimbra Institute for Clinical and Biomedical Research (iCBR), Biophysics Institute of Faculty of Medicine of University of Coimbra, Area of Environmental Genetics and Oncobiology (CIMAGO), 3000-548 Coimbra, Portugal
| | - Pedro F. Oliveira
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal;
| | - Carlos R. Cordeiro
- Clinical Academic Centre of Coimbra (CACC), Department of Pulmonology, Faculty of Medicine, University Hospitals of Coimbra, University of Coimbra, 3004-504 Coimbra, Portugal
| | - Marco G. Alves
- Clinical and Experimental Endocrinology, UMIB—Unit for Multidisciplinary Research in Biomedicine, ICBAS—School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal (M.G.A.)
| | - Ana M. Abrantes
- Clinical Academic Centre of Coimbra (CACC), Centre for Innovative Biomedicine and Biotechnology (CIBB), Coimbra Institute for Clinical and Biomedical Research (iCBR), Biophysics Institute of Faculty of Medicine of University of Coimbra, Area of Environmental Genetics and Oncobiology (CIMAGO), 3000-548 Coimbra, Portugal
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14
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Kim H, Park KT, Jo H, Shin Y, Chung G, Ko SG, Jin YH, Kim W. The effect of ginger extract on cisplatin-induced acute anorexia in rats. Front Pharmacol 2023; 14:1267254. [PMID: 38026983 PMCID: PMC10665510 DOI: 10.3389/fphar.2023.1267254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 10/30/2023] [Indexed: 12/01/2023] Open
Abstract
Cisplatin is a platinum-based chemotherapeutic agent widely used to treat various cancers. However, several side effects have been reported in treated patients. Among these, acute anorexia is one of the most severe secondary effects. In this study, a single oral administration of 100 or 500 mg/kg ginger extract (GE) significantly alleviated the cisplatin-induced decrease in food intake in rats. However, these body weight and water intake decreases were reversed in the 100 mg/kg group rats. To elucidate the underlying mechanism of action, serotonin (5-HT) and 5-HT2C, 3A, and 4 receptors in the nodose ganglion of the vagus nerve were investigated. The results showed that cisplatin-induced increases in serotonin levels in both the blood and nodose ganglion tissues were significantly decreased by100 and 500 mg/kg of GE administration. On 5-HT receptors, 5-HT3A and 4, but not 2C receptors, were affected by cisplatin, and GE 100 and 500 mg/kg succeeded in downregulating the evoked upregulated gene of these receptors. Protein expression of 5-HT3A and 4 receptors were also reduced in the 100 mg/kg group. Furthermore, the injection of 5-HT3A, and 4 receptors antagonists (palonostron, 0.1 mg/kg, i.p.; piboserod, 1 mg/kg, i.p., respectively) in cisplatin treated rats prevented the decrease in food intake. Using high-performance liquid chromatography (HPLC) analysis, [6]-gingerol and [6]-shogaol were identified and quantified as the major components of GE, comprising 4.12% and 2.15% of the GE, respectively. Although [6]-gingerol or [6]-shogaol alone failed to alleviate the evoked anorexia, when treated together, the effect was significant on the cisplatin-induced decrease in food intake. These results show that GE can be considered a treatment option to alleviate cisplatin-induced anorexia.
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Affiliation(s)
- Hyeonah Kim
- Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Keun-Tae Park
- Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Heejoon Jo
- Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Yuchan Shin
- Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Geehoon Chung
- Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Seong-Gyu Ko
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Young-Ho Jin
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Woojin Kim
- Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
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15
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Martín-Masot R, Jiménez-Muñoz M, Herrador-López M, Navas-López VM, Obis E, Jové M, Pamplona R, Nestares T. Metabolomic Profiling in Children with Celiac Disease: Beyond the Gluten-Free Diet. Nutrients 2023; 15:2871. [PMID: 37447198 DOI: 10.3390/nu15132871] [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: 05/24/2023] [Revised: 06/20/2023] [Accepted: 06/22/2023] [Indexed: 07/15/2023] Open
Abstract
Celiac disease (CD) is included in the group of complex or multifactorial diseases, i.e., those caused by the interaction of genetic and environmental factors. Despite a growing understanding of the pathophysiological mechanisms of the disease, diagnosis is still often delayed and there are no effective biomarkers for early diagnosis. The only current treatment, a gluten-free diet (GFD), can alleviate symptoms and restore intestinal villi, but its cellular effects remain poorly understood. To gain a comprehensive understanding of CD's progression, it is crucial to advance knowledge across various scientific disciplines and explore what transpires after disease onset. Metabolomics studies hold particular significance in unravelling the complexities of multifactorial and multisystemic disorders, where environmental factors play a significant role in disease manifestation and progression. By analyzing metabolites, we can gain insights into the reasons behind CD's occurrence, as well as better comprehend the impact of treatment initiation on patients. In this review, we present a collection of articles that showcase the latest breakthroughs in the field of metabolomics in pediatric CD, with the aim of trying to identify CD biomarkers for both early diagnosis and treatment monitoring. These advancements shed light on the potential of metabolomic analysis in enhancing our understanding of the disease and improving diagnostic and therapeutic strategies. More studies need to be designed to cover metabolic profiles in subjects at risk of developing the disease, as well as those analyzing biomarkers for follow-up treatment with a GFD.
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Affiliation(s)
- Rafael Martín-Masot
- Pediatric Gastroenterology and Nutrition Unit, Hospital Regional Universitario de Malaga, 29010 Málaga, Spain
- Institute of Nutrition and Food Technology "José MataixVerdú" (INYTA), Biomedical Research Centre (CIBM), University of Granada, 18071 Granada, Spain
| | - María Jiménez-Muñoz
- Pediatric Gastroenterology and Nutrition Unit, Hospital Regional Universitario de Malaga, 29010 Málaga, Spain
| | - Marta Herrador-López
- Pediatric Gastroenterology and Nutrition Unit, Hospital Regional Universitario de Malaga, 29010 Málaga, Spain
| | - Víctor Manuel Navas-López
- Pediatric Gastroenterology and Nutrition Unit, Hospital Regional Universitario de Malaga, 29010 Málaga, Spain
| | - Elia Obis
- Department of Experimental Medicine, Lleida Biomedical Research Institute (IRBLleida), University of Lleida (UdL), 25198 Lleida, Spain
| | - Mariona Jové
- Department of Experimental Medicine, Lleida Biomedical Research Institute (IRBLleida), University of Lleida (UdL), 25198 Lleida, Spain
| | - Reinald Pamplona
- Department of Experimental Medicine, Lleida Biomedical Research Institute (IRBLleida), University of Lleida (UdL), 25198 Lleida, Spain
| | - Teresa Nestares
- Institute of Nutrition and Food Technology "José MataixVerdú" (INYTA), Biomedical Research Centre (CIBM), University of Granada, 18071 Granada, Spain
- Department of Physiology, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain
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16
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Choi YJ, Han H, Lee JH, Lee J, Kim CY, Byun MK, Cho JH, Park HJ. Particulate matter 10-induced airway inflammation and fibrosis can be regulated by chitinase-1 suppression. Respir Res 2023; 24:85. [PMID: 36934237 PMCID: PMC10024831 DOI: 10.1186/s12931-023-02392-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 03/09/2023] [Indexed: 03/20/2023] Open
Abstract
BACKGROUND Particulate matter10 (PM10) can induce airway inflammation and fibrosis. Recently, chitinase-1 has been shown to play key roles in inflammation and fibrosis. We aimed to investigate the effects of chitinase-1 inhibitor in PM10-treated murine mice models. METHODS In female BALB/c mice, PM10 was intranasally administered six times over 3 weeks, and ovalbumin (OVA) was intraperitoneally injected and then intranasally administered. Chitinase-1 inhibitor (CPX) 6 times over 3 weeks or dexamethasone 3 times in the last week were intraperitoneally administered. Two days after the last challenges, mice were euthanized. Messenger RNA sequencing using lung homogenates was conducted to evaluate signaling pathways. RESULTS PM10 and/or OVA-induced airway inflammation and fibrosis murine models were established. CPX and dexamethasone ameliorated PM10 or PM10/OVA-induced airway hyper-responsiveness, airway inflammation, and fibrosis. CPX and dexamethasone also reduced levels of various inflammatory markers in lung homogenates. PM10 and OVA also induced changes in mRNA expression across an extreme range of genes. CPX and dexamethasone decreased levels of mRNA expression especially associated with inflammation and immune regulation. They also significantly regulated asthma and asthma-related pathways, including the JACK-STAT signaling pathway. CONCLUSIONS Chitinase-1 suppression by CPX can regulate PM10- and OVA-induced and aggravated airway inflammation and fibrosis via an asthma-related signaling pathway.
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Affiliation(s)
- Yong Jun Choi
- grid.459553.b0000 0004 0647 8021Division of Pulmonology, Department of Internal Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, 211, Eonju-Ro, Gangnam-Gu, Seoul, 06273 Korea
| | - Heejae Han
- grid.459553.b0000 0004 0647 8021Division of Pulmonology, Department of Internal Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, 211, Eonju-Ro, Gangnam-Gu, Seoul, 06273 Korea
| | - Jae-Hyun Lee
- grid.459553.b0000 0004 0647 8021Division of Pulmonology, Department of Internal Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, 211, Eonju-Ro, Gangnam-Gu, Seoul, 06273 Korea
| | - Jaeuk Lee
- grid.459553.b0000 0004 0647 8021Division of Pulmonology, Department of Internal Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, 211, Eonju-Ro, Gangnam-Gu, Seoul, 06273 Korea
| | - Chi Young Kim
- grid.459553.b0000 0004 0647 8021Division of Pulmonology, Department of Internal Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, 211, Eonju-Ro, Gangnam-Gu, Seoul, 06273 Korea
| | - Min Kwang Byun
- grid.459553.b0000 0004 0647 8021Division of Pulmonology, Department of Internal Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, 211, Eonju-Ro, Gangnam-Gu, Seoul, 06273 Korea
| | - Jae Hwa Cho
- grid.459553.b0000 0004 0647 8021Division of Pulmonology, Department of Internal Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, 211, Eonju-Ro, Gangnam-Gu, Seoul, 06273 Korea
| | - Hye Jung Park
- grid.459553.b0000 0004 0647 8021Division of Pulmonology, Department of Internal Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, 211, Eonju-Ro, Gangnam-Gu, Seoul, 06273 Korea
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17
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Akman TC, Kadioglu Y, Senol O, Erkayman B. A metabolomics study: Could plasma metabolites be a guide for the prevention of tamsulosin side effects? ANNALES PHARMACEUTIQUES FRANÇAISES 2023; 81:220-232. [PMID: 36126750 DOI: 10.1016/j.pharma.2022.09.004] [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: 03/01/2022] [Revised: 08/26/2022] [Accepted: 09/13/2022] [Indexed: 11/16/2022]
Abstract
BACKGROUND The understanding of precision medicine, which aims for high efficacy and low toxicity in treatments, has gained more importance with omics technologies. In this study, it was aimed to reach new suggestions for low-toxicity treatment by clarifying the relationship between tamsulosin side effects and metabolome profiles. MATERIALS AND METHODS Plasma samples of control and tamsulosin-treated rats were analyzed by LC-Q-TOF/MS/MS. MS/MS data was processed in XCMS software for the identification of metabolite and metabolic pathway analysis. Data were classified with MATLAB 2019b for multivariate data analysis. 34m/z values were found to be significantly different between the drug and control groups (P≤0.01 and fold analysis≥1.5) and identified by comparing METLIN and HMDB databases. RESULTS According to multivariate data analysis, α-Linolenic Acid, Thiamine, Retinoic acid, 1.25-Dihydroxyvitamin D3-26.23-Lactone, L-Glutamine, L-Serine, Retinaldehyde, Sphingosine 1-phosphate, L-Lysine, 23S.25-Dihydroxyvitamin D3, Sphinganine, L-Cysteine, Uridine 5'-diphosphate, Calcidiol, L-Tryptophan, L-Alanine levels changed significantly compared to the control group. Differences in the metabolisms of Retinol, Sphingolipid, Alanine-Aspartate-Glutamate, Glutathione, Fatty Acid, Tryptophan, and biosynthesis of Aminoacyl-tRNA, and Unsaturated Fatty Acid have been successfully demonstrated by metabolic pathway analysis. According to our study, vitamin A and D supplements can be recommended to prevent side effects such as asthenia, rhinitis, nasal congestion, dizziness and IFIS in the treatment of tamsulosin. Alteration of aminoacyl-tRNA biosynthesis and sphingolipid metabolism pathways during tamsulosin treatment is effective in the occurrence of nasal congestion. CONCLUSIONS Our study provides important information for tamsulosin therapy with high efficacy and low side effects in precision medicine.
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Affiliation(s)
- T C Akman
- Department of Analytical Chemistry, Faculty of Pharmacy, Erzincan Binali Yildirim University, 24100 Erzincan, Turkey.
| | - Y Kadioglu
- Department of Analytical Chemistry, Faculty of Pharmacy, Atatürk University, Erzurum, Turkey.
| | - O Senol
- Department of Analytical Chemistry, Faculty of Pharmacy, Atatürk University, Erzurum, Turkey.
| | - B Erkayman
- Department of Pharmacology, Faculty of Pharmacy, Atatürk University, Erzurum, Turkey.
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18
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Blanco-Nistal MM, Fernández-Fernández JA. Glucocorticoid Effect in Cancer Patients. Methods Mol Biol 2023; 2704:339-352. [PMID: 37642855 DOI: 10.1007/978-1-0716-3385-4_21] [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] [Indexed: 08/31/2023]
Abstract
The use of glucocorticoids is very varied in the context of cancer patients and includes the treatment of symptoms related to cancer, but also the management of the most common side effects of antitumor treatments or adverse events related to the immune system. There is a quantity of experimental evidence demonstrating that cancer cells are immunogenic. However, the effective activation of anticancer T cell responses closely depends on an efficient antigen presentation carried out by professional antigen-presenting cells such as dendritic cells (DCs). The classic strategies to improve the medical management of inflammation are aimed at exacerbating the host's immune response. Although successful in treating a number of diseases, these drugs have limited efficacy and variable responses can lead to unpredictable results. The ideal therapy should reduce inflammation without inducing immunosuppression and remains a challenge for healthcare personnel.
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Spick M, Campbell A, Baricevic-Jones I, von Gerichten J, Lewis HM, Frampas CF, Longman K, Stewart A, Dunn-Walters D, Skene DJ, Geifman N, Whetton AD, Bailey MJ. Multi-Omics Reveals Mechanisms of Partial Modulation of COVID-19 Dysregulation by Glucocorticoid Treatment. Int J Mol Sci 2022; 23:12079. [PMID: 36292938 PMCID: PMC9602480 DOI: 10.3390/ijms232012079] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/22/2022] [Accepted: 10/07/2022] [Indexed: 12/15/2022] Open
Abstract
Treatments for COVID-19 infections have improved dramatically since the beginning of the pandemic, and glucocorticoids have been a key tool in improving mortality rates. The UK's National Institute for Health and Care Excellence guidance is for treatment to be targeted only at those requiring oxygen supplementation, however, and the interactions between glucocorticoids and COVID-19 are not completely understood. In this work, a multi-omic analysis of 98 inpatient-recruited participants was performed by quantitative metabolomics (using targeted liquid chromatography-mass spectrometry) and data-independent acquisition proteomics. Both 'omics datasets were analysed for statistically significant features and pathways differentiating participants whose treatment regimens did or did not include glucocorticoids. Metabolomic differences in glucocorticoid-treated patients included the modulation of cortisol and bile acid concentrations in serum, but no alleviation of serum dyslipidemia or increased amino acid concentrations (including tyrosine and arginine) in the glucocorticoid-treated cohort relative to the untreated cohort. Proteomic pathway analysis indicated neutrophil and platelet degranulation as influenced by glucocorticoid treatment. These results are in keeping with the key role of platelet-associated pathways and neutrophils in COVID-19 pathogenesis and provide opportunity for further understanding of glucocorticoid action. The findings also, however, highlight that glucocorticoids are not fully effective across the wide range of 'omics dysregulation caused by COVID-19 infections.
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Affiliation(s)
- Matt Spick
- Faculty of Engineering and Physical Sciences, University of Surrey, Guildford GU2 7XH, UK
| | - Amy Campbell
- Stoller Biomarker Discovery Centre, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9NQ, UK
| | - Ivona Baricevic-Jones
- Stoller Biomarker Discovery Centre, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9NQ, UK
| | - Johanna von Gerichten
- Faculty of Engineering and Physical Sciences, University of Surrey, Guildford GU2 7XH, UK
- Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK
| | - Holly-May Lewis
- Faculty of Engineering and Physical Sciences, University of Surrey, Guildford GU2 7XH, UK
| | - Cecile F. Frampas
- Faculty of Engineering and Physical Sciences, University of Surrey, Guildford GU2 7XH, UK
- Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK
| | - Katie Longman
- Faculty of Engineering and Physical Sciences, University of Surrey, Guildford GU2 7XH, UK
| | - Alexander Stewart
- Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK
| | - Deborah Dunn-Walters
- Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK
| | - Debra J. Skene
- Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK
| | - Nophar Geifman
- School of Health Sciences, University of Surrey, Guildford GU2 7XH, UK
| | - Anthony D. Whetton
- School of Veterinary Medicine, School of Biosciences and Medicine, University of Surrey, Guildford GU2 7XH, UK
| | - Melanie J. Bailey
- Faculty of Engineering and Physical Sciences, University of Surrey, Guildford GU2 7XH, UK
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20
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Daley-Yates P, Keppler B, Baines A, Bardsley G, Fingleton J. Metabolomic changes related to airway inflammation, asthma pathogenesis and systemic activity following inhaled fluticasone furoate/vilanterol: a randomized controlled trial. Respir Res 2022; 23:258. [PMID: 36127726 PMCID: PMC9487108 DOI: 10.1186/s12931-022-02164-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 09/02/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Fluticasone furoate/vilanterol trifenatate (FF/VI) is an inhaled therapy for the treatment of asthma, with a prolonged duration of anti-inflammatory and bronchodilatory action. This study investigated the global metabolomic and lipidomic profile following treatment with FF/VI or placebo and assessed whether changes correlated with exhaled nitric oxide levels as a measure of airway inflammation. METHODS This was a single-center, randomized, double-blind, placebo-controlled, two-period, crossover, repeat-dose study. Adults with asthma (forced expiratory volume in 1 s ≥ 60% predicted; fraction of exhaled nitric oxide [FeNO] > 40 parts per billion) received once-daily FF/VI 100 µg/25 µg or placebo for 14 days, followed by a 21-day washout period. Serum samples were taken at pre-dose (T1), and 15 and 21 days (T2 and T3, respectively) post dose in each period. The metabolomic and lipidomic profiles were analyzed by liquid chromatography with tandem mass spectrometry and polar liquid chromatography platforms, and ions were matched to a library of standards for metabolite identification and quantification. FeNO values at each timepoint were evaluated for correlations with the biochemical data. RESULTS Of 27 randomized participants (mean age 24.5 years, 63% male), 26 provided serum samples for metabolomic analysis. A total of 1969 metabolites were identified, 1634 of which corresponded to a named structure in a reference library. Treatment-related changes in the metabolome were generally subtle, with a modest increase in metabolite perturbations across timepoints. The percentage of metabolites with significant changes (p < 0.05 for all) (increases↑/decreases↓) versus placebo were: 2.1% (1.1%↑/1.0%↓), 6.7% (0.46%↑/6.2%↓) and 11.8% (0.86%↑/10.9%↓) at T1, T2 and T3, respectively. Treatment with FF/VI reduced FeNO levels by 60%, whereas the systemic intermediates involved in NO biosynthesis remained unaffected. Evidence of systemic anti-inflammatory activity was seen in complex lipid pathways, suggesting reduced phospholipase-A2 activity, but without downstream impact on free fatty acids or inflammatory mediators. Consistent with the pathogenesis of asthma, there was evidence of higher fatty acid β-oxidation and lower glycolysis in the placebo arm; this pattern was reversed in the treatment arm. CONCLUSIONS Despite the prolonged airway anti-inflammatory action of FF/VI, this was accompanied by only subtle systemic metabolomic and lipidomic changes. Trial registration Prospectively registered on ClinicalTrials.gov registry number NCT02712047.
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Affiliation(s)
- Peter Daley-Yates
- Respiratory Clinical Development, GSK Research and Development, Stockley Park West, 1-3 Ironbridge Road, Uxbridge, Middlesex, UB11 1BT, UK.
| | - Brian Keppler
- Metabolon Inc., 617 Davis Drive, Suite 100, Morrisville, NC, 27560, USA
| | - Amanda Baines
- Medicines Development Centre, GSK Research and Development, Stevenage, UK
| | - George Bardsley
- Tauranga Hospital, 829 Cameron Road, Tauranga South, Tauranga, 3112, New Zealand
| | - James Fingleton
- Medical Research Institute of New Zealand, Wellington, New Zealand
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21
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Quentin V, Singh M, Nguyen LS. A review of potential mechanisms and uses of SGLT2 inhibitors in ischemia-reperfusion phenomena. World J Diabetes 2022; 13:683-695. [PMID: 36188147 PMCID: PMC9521445 DOI: 10.4239/wjd.v13.i9.683] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/13/2022] [Accepted: 08/16/2022] [Indexed: 02/05/2023] Open
Abstract
Recently added to the therapeutic arsenal against chronic heart failure as a first intention drug, the antidiabetic drug-class sodium-glucose cotransporter-2 inhibitors (SGLT2i) showed efficacy in decreasing overall mortality, hospitalization, and sudden death in patients of this very population, in whom chronic or acute ischemia count among the first cause. Remarkably, this benefit was observed independently from diabetic status, and benefited both preserved and altered ventricular ejection fraction. This feature, observed in several large randomized controlled trials, suggests additional effects from SGLT2i beyond isolated glycemia control. Indeed, both in-vitro and animal models suggest that inhibiting the Na+/H+ exchanger (NHE) may be key to preventing ischemia/ reperfusion injuries, and by extension may hold a similar role in ischemic damage control and ischemic preconditioning. Yet, several other mechanisms may be explored which may help better target those who may benefit most from SGLT2i molecules. Because of a large therapeutic margin with few adverse events, ease of prescription and potential pharmacological efficacity, SGLT2i could be candidate for wider indications. In this review, we aim to summarize all evidence which link SGLT2i and ischemia/reperfusion injuries modulation, by first listing known mechanisms, including metabolic switch, prevention of lethal arrythmias and others, which portend the latter, and second, hypothesize how the former may interact with these mechanisms.
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Affiliation(s)
- Victor Quentin
- Intensive Care Medicine, CMC Ambroise Paré, Neuilly-sur-Seine 92200, France
| | - Manveer Singh
- Intensive Care Medicine, CMC Ambroise Paré, Neuilly-sur-Seine 92200, France
| | - Lee S Nguyen
- Research and Innovation, CMC Ambroise Paré, Neuilly-sur-Seine 92200, France
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22
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Zhang Y, Gan L, Tang J, Liu D, Chen G, Xu B. Metabolic profiling reveals new serum signatures to discriminate lupus nephritis from systemic lupus erythematosus. Front Immunol 2022; 13:967371. [PMID: 36059469 PMCID: PMC9437530 DOI: 10.3389/fimmu.2022.967371] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 08/04/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundLupus nephritis (LN) occurs in 50% of patients with systemic lupus erythematosus (SLE), causing considerable morbidity and even mortality. Previous studies had shown the potential of metabolic profiling in the diagnosis of SLE or LN. However, few metabonomics studies have attempted to distinguish SLE from LN based on metabolic changes. The current study was designed to find new candidate serum signatures that could differentiate LN from SLE patients using a non-targeted metabonomics method based on ultra high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS).MethodMetabolic profiling of sera obtained from 21 healthy controls, 52 SLE patients and 43 LN patients. We used SPSS 25.0 for statistical analysis. Principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA) and metabolic pathway analysis were used to analyze the metabolic data.ResultsUpon comparison of SLE and LN groups, 28 differential metabolites were detected, the majority of which were lipids and amino acids. Glycerolphospholipid metabolism, pentose and glucuronate interconversions and porphyrin and chlorophyll metabolism were obviously enriched in LN patients versus those with SLE. Among the 28 characteristic metabolites, five key serum metabolites including SM d34:2, DG (18:3(9Z,12Z,15Z)/20:5(5Z,8Z,11Z,14Z,17Z)/0:0), nervonic acid, Cer-NS d27:4, and PC (18:3(6Z,9Z,12Z)/18:3(6Z,9Z,12Z) performed higher diagnostic performance in discriminating LN from SLE (all AUC > 0.75). Moreover, combined analysis of neuritic acid, C1q, and CysC (AUC = 0.916) produced the best combined diagnosis.ConclusionThis study identified five serum metabolites that are potential indicators for the differential diagnosis of SLE and LN. Glycerolphospholipid metabolism may play an important role in the development of SLE to LN. The metabolites we screened can provide more references for the diagnosis of LN and more support for the pathophysiological study of SLE progressed to LN.
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Affiliation(s)
- Yamei Zhang
- Department of Clinical Laboratory, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Lingling Gan
- Department of Clinical Laboratory, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Jie Tang
- Department of Clinical Laboratory, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Dan Liu
- Department of Pathology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Gang Chen
- Department of Clinical Laboratory, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Bei Xu
- Department of Clinical Laboratory, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
- *Correspondence: Gang Chen, ; Bei Xu,
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23
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Seo HR, Han HJ, Lee Y, Noh YW, Cho SJ, Kim JH. Human Pluripotent Stem Cell-Derived Alveolar Organoid with Macrophages. Int J Mol Sci 2022; 23:ijms23169211. [PMID: 36012471 PMCID: PMC9409017 DOI: 10.3390/ijms23169211] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/07/2022] [Accepted: 08/10/2022] [Indexed: 11/25/2022] Open
Abstract
Alveolar organoids (AOs), derived from human pluripotent stem cells (hPSCs) exhibit lung-specific functions. Therefore, the application of AOs in pulmonary disease modeling is a promising tool for understanding disease pathogenesis. However, the lack of immune cells in organoids limits the use of human AOs as models of inflammatory diseases. In this study, we generated AOs containing a functional macrophage derived from hPSCs based on human fetal lung development using biomimetic strategies. We optimized culture conditions to maintain the iMACs (induced hPSC-derived macrophages) AOs for up to 14 days. In lipopolysaccharide (LPS)-induced inflammatory conditions, IL-1β, MCP-1 and TNF-α levels were significantly increased in iMAC-AOs, which were not detected in AOs. In addition, chemotactic factor IL-8, which is produced by mononuclear phagocytic cells, was induced by LPS treatment in iMACs-AOs. iMACs-AOs can be used to understand pulmonary infectious diseases and is a useful tool in identifying the mechanism of action of therapeutic drugs in humans. Our study highlights the importance of immune cell presentation in AOs for modeling inflammatory pulmonary diseases.
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Affiliation(s)
- Ha-Rim Seo
- Division of Drug Evaluation, New Drug Development Center, Osong Medical Innovation Foundation, Cheongju-si 28160, Korea
| | - Hyeong-Jun Han
- Division of Intractable Diseases, Department of Chronic Diseases Convergence Research, Korea National Institute of Health, Cheongju-si 28159, Korea
- Korea National Stem Cell Bank, Cheongju-si 28159, Korea
| | - Youngsun Lee
- Division of Intractable Diseases, Department of Chronic Diseases Convergence Research, Korea National Institute of Health, Cheongju-si 28159, Korea
- Korea National Stem Cell Bank, Cheongju-si 28159, Korea
| | - Young-Woock Noh
- Division of Drug Evaluation, New Drug Development Center, Osong Medical Innovation Foundation, Cheongju-si 28160, Korea
| | - Seung-Ju Cho
- Division of Drug Evaluation, New Drug Development Center, Osong Medical Innovation Foundation, Cheongju-si 28160, Korea
- Correspondence: (S.-J.C.); (J.-H.K.)
| | - Jung-Hyun Kim
- Division of Intractable Diseases, Department of Chronic Diseases Convergence Research, Korea National Institute of Health, Cheongju-si 28159, Korea
- Korea National Stem Cell Bank, Cheongju-si 28159, Korea
- Correspondence: (S.-J.C.); (J.-H.K.)
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24
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Mihailovici R, Croitoriu A, Nedeff F, Nedeff V, Ochiuz L, Vasincu D, Popa O, Agop M, Moraru A, Costin D, Costuleanu M, Verestiuc L. Drug-Loaded Polymeric Particulated Systems for Ophthalmic Drugs Release. Molecules 2022; 27:molecules27144512. [PMID: 35889383 PMCID: PMC9323211 DOI: 10.3390/molecules27144512] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 07/11/2022] [Accepted: 07/12/2022] [Indexed: 02/05/2023] Open
Abstract
Drug delivery to the anterior or posterior segments of the eye is a major challenge due to the protection barriers and removal mechanisms associated with the unique anatomical and physiological nature of the ocular system. The paper presents the preparation and characterization of drug-loaded polymeric particulated systems based on pre-emulsion coated with biodegradable polymers. Low molecular weight biopolymers (chitosan, sodium hyaluronate and heparin sodium) were selected due to their ability to attach polymer chains to the surface of the growing system. The particulated systems with dimensions of 190–270 nm and a zeta potential varying from −37 mV to +24 mV depending on the biopolymer charges have been obtained. Current studies show that particles release drugs (dexamethasone/pilocarpine/bevacizumab) in a safe and effective manner, maintaining therapeutic concentration for a longer period of time. An extensive modeling study was performed in order to evaluate the drug release profile from the prepared systems. In a multifractal paradigm of motion, nonlinear behaviors of a drug delivery system are analyzed in the fractal theory of motion, in order to correlate the drug structure with polymer. Then, the functionality of a SL(2R) type ”hidden symmetry” implies, through a Riccati type gauge, different ”synchronization modes” (period doubling, damped oscillations, quasi-periodicity and intermittency) during the drug release process. Among these, a special mode of Kink type, better reflects the empirical data. The fractal study indicated more complex interactions between the angiogenesis inhibitor Bevacizumab and polymeric structure.
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Affiliation(s)
- Ruxandra Mihailovici
- Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania; (R.M.); (A.C.); (D.C.); (M.C.)
| | - Alexandra Croitoriu
- Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania; (R.M.); (A.C.); (D.C.); (M.C.)
- Faculty of Medical Bioengineering, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania;
| | - Florin Nedeff
- Department of Industrial Systems Engineering and Management, Faculty of Engineering, “Vasile Alecsandri” University of Bacau, 600115 Bacau, Romania
- Correspondence: (F.N.); (M.A.); (A.M.)
| | - Valentin Nedeff
- Department of Environmental Engineering and Mechanical Engineering, Faculty of Engineering, “Vasile Alecsandri” University of Bacau, 600115 Bacau, Romania;
| | - Lacramioara Ochiuz
- Department of Pharmaceutical and Biotechnological Drug Industry, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania;
| | - Decebal Vasincu
- Department of Natural, Bioactive and Biocompatible Polymers, Petru Poni Institute of Macromolecular Chemistry, Aleea Grigore Ghica Voda 41A, 700487 Iasi, Romania;
| | - Ovidiu Popa
- Department of Emergency Medicine, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania;
| | - Maricel Agop
- Department of Physics, “Gh. Asachi” Technical University of Iasi, 700050 Iasi, Romania
- Romanian Scientists Academy, 050094 Bucharest, Romania
- Correspondence: (F.N.); (M.A.); (A.M.)
| | - Andreea Moraru
- Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania; (R.M.); (A.C.); (D.C.); (M.C.)
- Correspondence: (F.N.); (M.A.); (A.M.)
| | - Danut Costin
- Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania; (R.M.); (A.C.); (D.C.); (M.C.)
| | - Marcel Costuleanu
- Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania; (R.M.); (A.C.); (D.C.); (M.C.)
| | - Liliana Verestiuc
- Faculty of Medical Bioengineering, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania;
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25
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Circadian patterns of heart rate, respiratory rate and skin temperature in hospitalized COVID-19 patients. PLoS One 2022; 17:e0268065. [PMID: 35797369 PMCID: PMC9262173 DOI: 10.1371/journal.pone.0268065] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 04/22/2022] [Indexed: 12/15/2022] Open
Abstract
Rationale
Vital signs follow circadian patterns in both healthy volunteers and critically ill patients, which seem to be influenced by disease severity in the latter. In this study we explored the existence of circadian patterns in heart rate, respiratory rate and skin temperature of hospitalized COVID-19 patients, and aimed to explore differences in circadian rhythm amplitude during patient deterioration.
Methods
We performed a retrospective study of COVID-19 patients admitted to the general ward of a tertiary hospital between April 2020 and March 2021. Patients were continuously monitored using a wireless sensor and fingertip pulse oximeter. Data was divided into three cohorts: patients who recovered, patients who developed respiratory insufficiency and patients who died. For each cohort, a population mean cosinor model was fitted to detect rhythmicity. To assess changes in amplitude, a mixed-effect cosinor model was fitted.
Results
A total of 429 patients were monitored. Rhythmicity was observed in heartrate for the recovery cohort (p<0.001), respiratory insufficiency cohort (p<0.001 and mortality cohort (p = 0.002). Respiratory rate showed rhythmicity in the recovery cohort (p<0.001), but not in the other cohorts (p = 0.18 and p = 0.51). Skin temperature also showed rhythmicity in the recovery cohort (p<0.001), but not in the other cohorts (p = 0.22 and p = 0.12). For respiratory insufficiency, only the amplitude of heart rate circadian pattern increased slightly the day before (1.2 (99%CI 0.16–2.2, p = 0.002)). In the mortality cohort, the amplitude of heart rate decreased (-1.5 (99%CI -2.6- -0.42, p<0.001)) and respiratory rate amplitude increased (0.72 (99%CI 0.27–1.3, p = 0.002) the days before death.
Conclusion
A circadian rhythm is present in heart rate of COVID-19 patients admitted to the general ward. For respiratory rate and skin temperature, rhythmicity was only found in patients who recover, but not in patients developing respiratory insufficiency or death. We found no consistent changes in circadian rhythm amplitude accompanying patient deterioration.
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26
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Burtscher J, Niedermeier M, Hüfner K, van den Burg E, Kopp M, Stoop R, Burtscher M, Gatterer H, Millet GP. The interplay of hypoxic and mental stress: Implications for anxiety and depressive disorders. Neurosci Biobehav Rev 2022; 138:104718. [PMID: 35661753 DOI: 10.1016/j.neubiorev.2022.104718] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/26/2022] [Accepted: 05/27/2022] [Indexed: 12/14/2022]
Abstract
Adequate oxygen supply is essential for the human brain to meet its high energy demands. Therefore, elaborate molecular and systemic mechanism are in place to enable adaptation to low oxygen availability. Anxiety and depressive disorders are characterized by alterations in brain oxygen metabolism and of its components, such as mitochondria or hypoxia inducible factor (HIF)-pathways. Conversely, sensitivity and tolerance to hypoxia may depend on parameters of mental stress and the severity of anxiety and depressive disorders. Here we discuss relevant mechanisms of adaptations to hypoxia, as well as their involvement in mental stress and the etiopathogenesis of anxiety and depressive disorders. We suggest that mechanisms of adaptations to hypoxia (including metabolic responses, inflammation, and the activation of chemosensitive brain regions) modulate and are modulated by stress-related pathways and associated psychiatric diseases. While severe chronic hypoxia or dysfunctional hypoxia adaptations can contribute to the pathogenesis of anxiety and depressive disorders, harnessing controlled responses to hypoxia to increase cellular and psychological resilience emerges as a novel treatment strategy for these diseases.
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Affiliation(s)
- Johannes Burtscher
- Institute of Sport Sciences, University of Lausanne, Lausanne, Switzerland; Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland.
| | - Martin Niedermeier
- Department of Sport Science, University of Innsbruck, Innsbruck, Austria
| | - Katharina Hüfner
- Department of Psychiatry, Psychotherapy, Psychosomatics and Medical Psychology, University Clinic for Psychiatry II, Innsbruck Medical University, Innsbruck, Austria
| | - Erwin van den Burg
- Department of Psychiatry, Center of Psychiatric Neuroscience (CNP), University Hospital of Lausanne (CHUV), Prilly, Lausanne, Switzerland
| | - Martin Kopp
- Department of Sport Science, University of Innsbruck, Innsbruck, Austria
| | - Ron Stoop
- Department of Psychiatry, Center of Psychiatric Neuroscience (CNP), University Hospital of Lausanne (CHUV), Prilly, Lausanne, Switzerland
| | - Martin Burtscher
- Department of Sport Science, University of Innsbruck, Innsbruck, Austria
| | - Hannes Gatterer
- Institute of Mountain Emergency Medicine, Eurac Research, Bolzano, Italy
| | - Grégoire P Millet
- Institute of Sport Sciences, University of Lausanne, Lausanne, Switzerland; Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
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27
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Hazra T, Tapryal N, Chakraborty A, Rayavara K, Wakamiya M, Islam A, Pan L, Hsu J, Tat V, Maruyama J, Hosoki K, Sayed I, Alcantara J, Castillo V, Tindle C, Sarker A, Cardenas V, Sharma G, Alexander LC, Sur S, Ghosh G, Paessler S, Sahoo D, Ghosh P, Das S, Boldogh I, Tseng CT. The DNA glycosylase NEIL2 plays a vital role in combating SARS-CoV-2 infection. RESEARCH SQUARE 2022:rs.3.rs-1690354. [PMID: 35665009 PMCID: PMC9164514 DOI: 10.21203/rs.3.rs-1690354/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Compromised DNA repair capacity of individuals could play a critical role in the severity of SARS-CoV-2 infection-induced COVID-19. We therefore analyzed the expression of DNA repair genes in publicly available transcriptomic datasets of COVID-19 patients and found that the level of NEIL2, an oxidized base specific mammalian DNA glycosylase, is particularly low in the lungs of COVID-19 patients displaying severe symptoms. Downregulation of pulmonary NEIL2 in CoV-2-permissive animals and postmortem COVID-19 patients validated these results. To investigate the potential roles of NEIL2 in CoV-2 pathogenesis, we infected Neil2-null (Neil2-/-) mice with a mouse-adapted CoV-2 strain and found that Neil2-/- mice suffered more severe viral infection concomitant with increased expression of proinflammatory genes, which resulted in an enhanced mortality rate of 80%, up from 20% for the age matched Neil2+/+ cohorts. We also found that infected animals accumulated a significant amount of damage in their lung DNA. Surprisingly, recombinant NEIL2 delivered into permissive A549-ACE2 cells significantly decreased viral replication. Toward better understanding the mechanistic basis of how NEIL2 plays such a protective role against CoV-2 infection, we determined that NEIL2 specifically binds to the 5'-UTR of SARS-CoV-2 genomic RNA and blocks protein synthesis. Together, our data suggest that NEIL2 plays a previously unidentified role in regulating CoV-2-induced pathogenesis, via inhibiting viral replication and preventing exacerbated proinflammatory responses, and also via its well-established role of repairing host genome damage.
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Affiliation(s)
- Tapas Hazra
- The University of Texas Medical Branch at Galveston
| | | | | | | | | | | | - Lang Pan
- The University of Texas Medical Branch at Galveston
| | - Jason Hsu
- The University of Texas Medical Branch
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28
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Jang WY, Lee HP, Kim SA, Huang L, Yoon JH, Shin CY, Mitra A, Kim HG, Cho JY. Angiopteris cochinchinensis de Vriese Ameliorates LPS-Induced Acute Lung Injury via Src Inhibition. PLANTS 2022; 11:plants11101306. [PMID: 35631731 PMCID: PMC9143704 DOI: 10.3390/plants11101306] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Revised: 05/02/2022] [Accepted: 05/10/2022] [Indexed: 11/16/2022]
Abstract
Growing demand for treatment options against acute lung injury (ALI) emphasizes studies on plant extracts harboring anti-inflammatory effects. According to GC-MS analysis, Angiopteris cochinchinensis de Vriese consists of various flavonoids with anti-inflammatory activities. Thus, in this study, the anti-inflammatory effects of an extract of Angiopteris cochinchinensis de Vriese (Ac-EE) were assessed using RAW264.6 murine macrophages and a lipopolysaccharide (LPS)-induced ALI model. Ac-EE reduced the nitric oxide production in murine macrophages increased by LPS induction. Moreover, protective effects of Ac-EE on lung tissue were demonstrated by shrinkage of edema and lung injury. Reduced neutrophil infiltration and formation of hyaline membranes were also detected in lung tissues after H&E staining. Semiquantitative RT-PCR, quantitative real-time PCR, and ELISA showed that Ac-EE inhibits the production of proinflammatory mediators, including iNOS and COX-2, and cytokines, such as TNF-α, IL-1β, and IL-6. An Ac-EE-mediated anti-inflammatory response was derived from inhibiting the NF-κB signaling pathway, which was evaluated by luciferase reporter assay and Western blotting analysis. A cellular thermal shift assay revealed that the prime target of Ac-EE in alleviating inflammation was Src. With its direct binding with Src, Angiopteris cochinchinensis de Vriese significantly mitigates lung injury, showing possibilities of its potential as an effective botanical drug.
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Affiliation(s)
- Won Young Jang
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Korea; (W.Y.J.); (H.P.L.); (S.A.K.)
| | - Hwa Pyoung Lee
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Korea; (W.Y.J.); (H.P.L.); (S.A.K.)
| | - Seung A Kim
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Korea; (W.Y.J.); (H.P.L.); (S.A.K.)
| | - Lei Huang
- Department of Biocosmetics, Sungkyunkwan University, Suwon 16419, Korea; (L.H.); (J.H.Y.); (C.Y.S.)
| | - Ji Hye Yoon
- Department of Biocosmetics, Sungkyunkwan University, Suwon 16419, Korea; (L.H.); (J.H.Y.); (C.Y.S.)
| | - Chae Yun Shin
- Department of Biocosmetics, Sungkyunkwan University, Suwon 16419, Korea; (L.H.); (J.H.Y.); (C.Y.S.)
| | - Ankita Mitra
- Department of Integrative Biotechnology and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, Korea;
| | - Han Gyung Kim
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Korea; (W.Y.J.); (H.P.L.); (S.A.K.)
- Correspondence: (H.G.K.); (J.Y.C.); Tel.: +82-31-290-7878 (H.G.K.); +82-31-290-7868 (J.Y.C.)
| | - Jae Youl Cho
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Korea; (W.Y.J.); (H.P.L.); (S.A.K.)
- Correspondence: (H.G.K.); (J.Y.C.); Tel.: +82-31-290-7878 (H.G.K.); +82-31-290-7868 (J.Y.C.)
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29
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Gabarre P, Loens C, Tamzali Y, Barrou B, Jaisser F, Tourret J. Immunosuppressive therapy after solid organ transplantation and the gut microbiota: Bidirectional interactions with clinical consequences. Am J Transplant 2022; 22:1014-1030. [PMID: 34510717 DOI: 10.1111/ajt.16836] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 08/23/2021] [Accepted: 09/02/2021] [Indexed: 01/25/2023]
Abstract
Our understanding of the involvement of the gut microbiota (GM) in human health has expanded exponentially over the last few decades, particularly in the fields of metabolism, inflammation, and immunology. Immunosuppressive treatment (IST) prescribed to solid organ transplant (SOT) recipients produces GM changes that affect these different processes. This review aims at describing the current knowledge of how IST changes the GM. Overall, SOT followed by IST results in persistent changes in the GM, with a consistent increase in proteobacteria including opportunistic pathobionts. In mice, Tacrolimus induces dysbiosis and metabolic disorders, and alters the intestinal barrier. The transfer of the GM from Tacrolimus-treated hosts confers immunosuppressive properties, suggesting a contributory role for the GM in this drug's efficacy. Steroids induce dysbiosis and intestinal barrier alterations, and also seem to depend partly on the GM for their immunosuppressive and metabolic effects. Mycophenolate Mofetil, frequently responsible for digestive side effects such as diarrhea and colitis, is associated with pro-inflammatory dysbiosis and increased endotoxemia. Alemtuzumab, m-TOR inhibitors, and belatacept have shown more marginal impact on the GM. Most of these observations are descriptive. Future studies should explore the underlying mechanism of IST-induced dysbiosis in order to better understand their efficacy and safety characteristics.
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Affiliation(s)
- Paul Gabarre
- Centre de Recherche des Cordeliers, Team "Diabetes, metabolic diseases and comorbidities", Sorbonne Université, Université de Paris, INSERM, Paris, France
| | - Christopher Loens
- Centre de Recherche des Cordeliers, Team "Diabetes, metabolic diseases and comorbidities", Sorbonne Université, Université de Paris, INSERM, Paris, France
| | - Yanis Tamzali
- Centre de Recherche des Cordeliers, Team "Diabetes, metabolic diseases and comorbidities", Sorbonne Université, Université de Paris, INSERM, Paris, France
| | - Benoit Barrou
- Assistance Publique - Hôpitaux Paris APHP, Medical and Surgical Unit of Kidney Transplantation Unit, Pitié-Salpêtrière Hospital, Sorbonne Université, Paris, France
| | - Frédéric Jaisser
- Centre de Recherche des Cordeliers, Team "Diabetes, metabolic diseases and comorbidities", Sorbonne Université, Université de Paris, INSERM, Paris, France
| | - Jérôme Tourret
- Centre de Recherche des Cordeliers, Team "Diabetes, metabolic diseases and comorbidities", Sorbonne Université, Université de Paris, INSERM, Paris, France.,Assistance Publique - Hôpitaux Paris APHP, Medical and Surgical Unit of Kidney Transplantation Unit, Pitié-Salpêtrière Hospital, Sorbonne Université, Paris, France
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30
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Spehlmann ME, Rangrez AY, Dhotre DP, Schmiedel N, Chavan N, Bang C, Müller OJ, Shouche YS, Franke A, Frank D, Frey N. Heart Failure Severity Closely Correlates with Intestinal Dysbiosis and Subsequent Metabolomic Alterations. Biomedicines 2022; 10:biomedicines10040809. [PMID: 35453559 PMCID: PMC9033061 DOI: 10.3390/biomedicines10040809] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/23/2022] [Accepted: 03/26/2022] [Indexed: 02/01/2023] Open
Abstract
Growing evidence suggests an altered gut microbiome in patients with heart failure (HF). However, the exact interrelationship between microbiota, HF, and its consequences on the metabolome are still unknown. We thus aimed here to decipher the association between the severity and progression of HF and the gut microbiome composition and circulating metabolites. Using a mouse model of transverse aortic constriction (TAC), gut bacterial diversity was found to be significantly lower in mice as early as day 7 post-TAC compared to Sham controls (p = 0.03), with a gradual progressive decrease in alpha-diversity on days 7, 14, and 42 (p = 0.014, p = 0.0016, p = 0.0021) compared to day 0, which coincided with compensated hypertrophy, maladaptive hypertrophy, and overtly failing hearts, respectively. Strikingly, segregated analysis based on the severity of the cardiac dysfunction (EF < 40% vs. EF 40−55%) manifested marked differences in the abundance and the grouping of several taxa. Multivariate analysis of plasma metabolites and bacterial diversity produced a strong correlation of metabolic alterations, such as reduced short-chain fatty acids and an increase in primary bile acids, with a differential abundance of distinct bacteria in HF. In conclusion, we showed that HF begets HF, likely via a vicious cycle of an altered microbiome and metabolic products.
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Affiliation(s)
- Martina E. Spehlmann
- Department of Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine, University Hospital of Schleswig-Holstein, Rosalind-Franklin Str. 12, 24105 Kiel, Germany; (M.E.S.); (N.S.); (O.J.M.); (D.F.)
- German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, 24105 Kiel, Germany
| | - Ashraf Y. Rangrez
- Department of Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine, University Hospital of Schleswig-Holstein, Rosalind-Franklin Str. 12, 24105 Kiel, Germany; (M.E.S.); (N.S.); (O.J.M.); (D.F.)
- Department of Internal Medicine III, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, 69120 Heidelberg, Germany
- Correspondence: (A.Y.R.); (N.F.)
| | - Dhiraj P. Dhotre
- National Centre for Cell Science, Pune 411021, India; (D.P.D.); (N.C.); (Y.S.S.)
| | - Nesrin Schmiedel
- Department of Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine, University Hospital of Schleswig-Holstein, Rosalind-Franklin Str. 12, 24105 Kiel, Germany; (M.E.S.); (N.S.); (O.J.M.); (D.F.)
- German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, 24105 Kiel, Germany
| | - Nikita Chavan
- National Centre for Cell Science, Pune 411021, India; (D.P.D.); (N.C.); (Y.S.S.)
| | - Corinna Bang
- Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Rosalind-Franklin-Strasse 12, 24105 Kiel, Germany; (C.B.); (A.F.)
| | - Oliver J. Müller
- Department of Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine, University Hospital of Schleswig-Holstein, Rosalind-Franklin Str. 12, 24105 Kiel, Germany; (M.E.S.); (N.S.); (O.J.M.); (D.F.)
- German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, 24105 Kiel, Germany
| | - Yogesh S. Shouche
- National Centre for Cell Science, Pune 411021, India; (D.P.D.); (N.C.); (Y.S.S.)
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Rosalind-Franklin-Strasse 12, 24105 Kiel, Germany; (C.B.); (A.F.)
| | - Derk Frank
- Department of Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine, University Hospital of Schleswig-Holstein, Rosalind-Franklin Str. 12, 24105 Kiel, Germany; (M.E.S.); (N.S.); (O.J.M.); (D.F.)
- German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, 24105 Kiel, Germany
| | - Norbert Frey
- Department of Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine, University Hospital of Schleswig-Holstein, Rosalind-Franklin Str. 12, 24105 Kiel, Germany; (M.E.S.); (N.S.); (O.J.M.); (D.F.)
- Department of Internal Medicine III, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, 69120 Heidelberg, Germany
- Correspondence: (A.Y.R.); (N.F.)
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31
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Dwivedi S, Choudhary P, Gupta A, Singh S. The cross-talk between mucormycosis, steroids and diabetes mellitus amidst the global contagion of COVID-19. Crit Rev Microbiol 2022; 49:318-333. [PMID: 35324372 DOI: 10.1080/1040841x.2022.2052795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Mucormycosis is an opportunistic fungal disease that targets individuals having an impaired immune system due to a wide array of risk factors including HIV-AIDS, immunosuppressive therapy, diabetes mellitus, etc. The current explosive outbreak of coronavirus disease 2019 (COVID-19) has become the latest threat to such patients who are already susceptible to secondary infections. Physiological outcomes of COVID-19 end up in a cascade of grave alterations to the immunological profile and irreparable harm to their respiratory passage, heart and kidneys. Corticosteroidal treatment facilitates faster recovery and alleviates the adverse pathological effects of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). But clinical reports lend this approach a darker perspective especially if these patients have pre-existing diabetes mellitus. The mucormycotic fungal genera belonging to the order Mucorales not only survive but thrive under the comorbidity of COVID-19 and diabetes, often staying undetected until they have inflicted irreversible damage. Steroidal usage has been noted to be a common thread in the sudden spurt in secondary fungal infections among COVID-19 cases. Once considered a rare occurrence, mucormycosis has now acquired a notoriously lethal status in mainstream medical hierarchy. We set out to investigate whether corticosteroidal therapy against COVID-19 emboldens the development of mucormycosis. We also assess the conditions brought forth by steroidal usage and uncontrolled progression of diabetes in COVID-19 cases and their effect on the susceptibility towards mucormycosis.
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Affiliation(s)
- Shrey Dwivedi
- Department of Applied Science, Indian Institute of Information Technology, Allahabad, India
| | - Princy Choudhary
- Department of Applied Science, Indian Institute of Information Technology, Allahabad, India
| | - Ayushi Gupta
- Department of Applied Science, Indian Institute of Information Technology, Allahabad, India
| | - Sangeeta Singh
- Department of Applied Science, Indian Institute of Information Technology, Allahabad, India
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32
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Li Q, Chen H, Li Z, Zhang F, Chen L. Glucocorticoid caused lactic acid accumulation and damage in human chondrocytes via ROS-mediated inhibition of Monocarboxylate Transporter 4. Bone 2022; 155:116299. [PMID: 34915176 DOI: 10.1016/j.bone.2021.116299] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 11/23/2021] [Accepted: 12/09/2021] [Indexed: 12/26/2022]
Abstract
Osteoarthritis (OA) is a common joint disease lacking effective treatments. Dexamethasone (Dex) is often used to relieve joint pain. However, the adverse effects of Dex on cartilage can't be ignored. This study aimed to investigate the effect of Dex on articular cartilage and its mechanism by in vitro and in vivo experiments. The results showed that intra-articular injection with Dex damaged the matrix synthesis of cartilage. In vitro, Dex induced human chondrocytes mitochondrial dysfunction and increased reactive oxygen species (ROS) level, while down-regulated or unchanged key glycolysis genes, but increased lactic acid (LA) concentration. It was showed that high concentrations of LA induced chondrocytes apoptosis. Mechanistically, monocarboxylate transporter 4 (MCT4) was inhibited by Dex and had a significant negative correlation with ROS level. Further results showed that the trimethyl-histone H3-K4 (H3K4me3) level of MCT4 was reduced by Dex, and the ROS scavenger N-Acetyl-L-cysteine (NAC) and α-ketoglutarate (α-KG) alleviated the Dex-induced obstruction of matrix synthesis and high level of ROS by up-regulating the H3K4me3 level of MCT4 and its expression. In conclusion, Dex exhibited harm to cartilage, shown as mitochondrial dysfunction and increased ROS. The latter further caused LA accumulation in chondrocytes via decreasing the H3K4me3 level of MCT4 and its expression, which may account for the long-term side effects of Dex on chondrocytes. And α-KG may be used as an auxiliary drug to weaken the toxic effect of Dex on cartilage.
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Affiliation(s)
- Qingxian Li
- Division of Joint Surgery and Sports Medicine, Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Haitao Chen
- Division of Joint Surgery and Sports Medicine, Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Zhenyu Li
- Division of Joint Surgery and Sports Medicine, Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Fan Zhang
- Division of Joint Surgery and Sports Medicine, Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Liaobin Chen
- Division of Joint Surgery and Sports Medicine, Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
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33
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Zheng X, Li C, Gao X. Overexpression of miR‑375 reverses the effects of dexamethasone on the viability, migration, invasion and apoptosis of human airway epithelial cells by targeting DUSP6. Int J Mol Med 2022; 49:26. [PMID: 35014672 PMCID: PMC8788922 DOI: 10.3892/ijmm.2022.5081] [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: 05/28/2020] [Accepted: 11/03/2021] [Indexed: 11/09/2022] Open
Abstract
Airway epithelial cell (AEC) dysfunction has been proven to be involved in the pathogenesis of asthma, which may be induced by the use of dexamethasone (Dex). The altered expression of microRNAs (miRNAs/miRs) has been found in asthma. However, the detailed mechanisms responsible for the effects of miR-375 on Dex-induced AEC dysfunction remain elusive. Thus, the present study aimed to elucidate these mechanisms. Following treatment with Dex for 0, 6, 12 and 24 h, AEC viability, migration, invasion and apoptosis were examined using Cell Counting Kit-8 (CCK-8), wound healing and Transwell assays, and flow cytometry, respectively. The expression levels of miR-375, dual specificity phosphatase 6 (DUSP6) and apoptosis-related proteins (Bcl-2, Bax, cleaved caspase-3) were measured using reverse transcription-quantitative polymerase chain reaction and western blot analysis. The target genes and potential binding sites of miR-375 and DUSP6 were predicted using TargetScan and confirmed using dual-luciferase reporter assay. The viability, migration, invasion and apoptosis of Dex-treated AECs were further assessed with or without miR-375 and DUSP6. In the AECs (9HTE cells), Dex treatment suppressed cell viability and miR-375 expression, whereas it promoted cell apoptosis and the expression of DUSP6, the target gene of miR-375. The overexpression of miR-375 reversed the effects of Dex treatment on miR-375 expression, cell viability, migration and invasion, and apoptosis-related protein expression; in turn, these effects were reversed by the overexpression of DUSP6, with the exception of miR-375 expression. On the whole, the present study demonstrates that the overexpression of miR-375 counteracts the effects of Dex treatment on AEC viability, migration, invasion and apoptosis by targeting DUSP6. Thus, it was suggested that the downregulated expression of miR-375 may be a therapeutic target for AEC dysfunction.
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Affiliation(s)
- Xiaojing Zheng
- Department of Pediatrics, Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261031, P.R. China
| | - Chunlian Li
- Department of Pediatrics, Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261031, P.R. China
| | - Xiang Gao
- Department of Cardiology, Fangzi District People's Hospital, Weifang, Shandong 261206, P.R. China
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34
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Yeo T, Probert F, Sealey M, Saldana L, Geraldes R, Höeckner S, Schiffer E, Claridge TDW, Leppert D, DeLuca G, Kuhle J, Palace J, Anthony DC. Objective biomarkers for clinical relapse in multiple sclerosis: a metabolomics approach. Brain Commun 2021; 3:fcab240. [PMID: 34755110 PMCID: PMC8568847 DOI: 10.1093/braincomms/fcab240] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 09/01/2021] [Accepted: 09/21/2021] [Indexed: 11/14/2022] Open
Abstract
Accurate determination of relapses in multiple sclerosis is important for diagnosis, classification of clinical course and therapeutic decision making. The identification of biofluid markers for multiple sclerosis relapses would add to our current diagnostic armamentarium and increase our understanding of the biology underlying the clinical expression of inflammation in multiple sclerosis. However, there is presently no biofluid marker capable of objectively determining multiple sclerosis relapses although some, in particular neurofilament-light chain, have shown promise. In this study, we sought to determine if metabolic perturbations are present during multiple sclerosis relapses, and, if so, identify candidate metabolite biomarkers and evaluate their discriminatory abilities at both group and individual levels, in comparison with neurofilament-light chain. High-resolution global and targeted 1H nuclear magnetic resonance metabolomics as well as neurofilament-light chain measurements were performed on the serum in four groups of relapsing-remitting multiple sclerosis patients, stratified by time since relapse onset: (i) in relapse (R); (ii) last relapse (LR) ≥ 1 month (M) to < 6 M ago; (iii) LR ≥ 6 M to < 24 M ago; and (iv) LR ≥ 24 M ago. Two hundred and one relapsing-remitting multiple sclerosis patients were recruited: R (n = 38), LR 1–6 M (n = 28), LR 6–24 M (n = 34), LR ≥ 24 M (n = 101). Using supervised multivariate analysis, we found that the global metabolomics profile of R patients was significantly perturbed compared to LR ≥ 24 M patients. Identified discriminatory metabolites were then quantified using targeted metabolomics. Lysine and asparagine (higher in R), as well as, isoleucine and leucine (lower in R), were shortlisted as potential metabolite biomarkers. ANOVA of these metabolites revealed significant differences across the four patient groups, with a clear trend with time since relapse onset. Multivariable receiver operating characteristics analysis of these four metabolites in discriminating R versus LR ≥ 24 M showed an area under the curve of 0.758, while the area under the curve for serum neurofilament-light chain was 0.575. Within individual patients with paired relapse–remission samples, all four metabolites were significantly different in relapse versus remission, with the direction of change consistent with that observed at group level, while neurofilament-light chain was not discriminatory. The perturbations in the identified metabolites point towards energy deficiency and immune activation in multiple sclerosis relapses, and the measurement of these metabolites, either singly or in combination, are useful as biomarkers to differentiate relapse from remission at both group and individual levels.
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Affiliation(s)
- Tianrong Yeo
- Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK.,Department of Neurology, National Neuroscience Institute, Singapore 308433, Singapore.,Duke-NUS Medical School, Singapore 169857, Singapore
| | - Fay Probert
- Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK
| | - Megan Sealey
- Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK
| | - Luisa Saldana
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
| | - Ruth Geraldes
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
| | | | | | - Timothy D W Claridge
- Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK
| | - David Leppert
- Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), Departments of Biomedicine and Clinical Research, University Hospital Basel and University of Basel, Basel CH-4031, Switzerland
| | - Gabriele DeLuca
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
| | - Jens Kuhle
- Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), Departments of Biomedicine and Clinical Research, University Hospital Basel and University of Basel, Basel CH-4031, Switzerland
| | - Jacqueline Palace
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
| | - Daniel C Anthony
- Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK
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Sabri S, Bourron O, Phan F, Nguyen LS. Interactions between diabetes and COVID-19: A narrative review. World J Diabetes 2021; 12:1674-1692. [PMID: 34754370 PMCID: PMC8554367 DOI: 10.4239/wjd.v12.i10.1674] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/29/2021] [Accepted: 08/31/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetes, whether due to pancreatic beta cells insufficiency or peripheral resistance to insulin, has been suggested as a risk factor of developing severe acute respiratory disease coronavirus-2 (SARS-CoV-2) infections. Indeed, diabetes has been associated with a higher risk of infections and higher risk of developing severe forms of coronavirus disease 2019 (COVID-19) related pneumonia. Diabetic patients often present associated comorbidities such as obesity, hypertension and cardiovascular diseases, and complications of diabetes, including chronic kidney disease, vasculopathy and relative immune dysfunction, all of which make them more susceptible to infectious complications. Moreover, they often present low-grade inflammation with increased circulating interleukin levels, endothelial susceptibility to inflammation and dysfunction, and finally, hyperglycemia, which increases this risk. Additionally, corticosteroids, which count among the few medications which showed benefit on survival and mechanical ventilation requirement in COVID-19 pneumonia in large randomized controlled trials, are associated to new onsets of diabetes, and metabolic disorders in patients with previous history of diabetes. Finally, SARS-CoV-2 via the alternate effects of the renin-angiotensin system, mediated by the angiotensin-converting-enzyme 2, was also associated with insulin resistance in key tissues involved in glucose homeostasis, such as liver, skeletal muscles, and adipose tissue; and also, with impaired insulin secretion by pancreatic β-cells. In this work, we reviewed all elements which may help understand how diabetes affects patients with COVID-19, how treatments affect outcomes in patients with COVID-19, how they may cause new onsets of diabetes, and finally review how SARS-CoV-2 may inherently be a risk factor of developing diabetes, through immune-mediated diabetogenic mechanisms.
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Affiliation(s)
- Sophia Sabri
- Intensive Care Medicine, CMC Ambroise Paré, Neuilly-Sur-Seine 92200, France
| | - Olivier Bourron
- Sorbonne Université Médecine; Assistance publique Hôpitaux de Paris (APHP), Service de Diabétologie, Hôpital Pitié-Salpêtrière; INSERM UMRS_1138, Centre de recherche des Cordeliers; Institute of CArdiometabolisme and Nutrition (ICAN), Paris 75013, France
| | - Franck Phan
- Sorbonne Université Médecine; Assistance publique Hôpitaux de Paris (APHP), Service de Diabétologie, Hôpital Pitié-Salpêtrière; INSERM UMRS_1138, Centre de recherche des Cordeliers; Institute of CArdiometabolisme and Nutrition (ICAN), Paris 75013, France
| | - Lee S Nguyen
- Research and Innovation, RICAP, CMC Ambroise Paré, Neuilly-Sur-Seine 92200, France
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36
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Barko PC, Williams DA. Untargeted analysis of the serum metabolome in cats with exocrine pancreatic insufficiency. PLoS One 2021; 16:e0257856. [PMID: 34591942 PMCID: PMC8483406 DOI: 10.1371/journal.pone.0257856] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 09/12/2021] [Indexed: 11/18/2022] Open
Abstract
Exocrine pancreatic insufficiency (EPI) causes chronic digestive dysfunction in cats, but its pathogenesis and pathophysiology are poorly understood. Untargeted metabolomics is a promising analytic methodology that can reveal novel metabolic features and biomarkers of clinical disease syndromes. The purpose of this preliminary study was to use untargeted analysis of the serum metabolome to discover novel aspects of the pathobiology of EPI in cats. Serum samples were collected from 5 cats with EPI and 8 healthy controls. The diagnosis of EPI was confirmed by measurement of subnormal serum feline trypsin-like immunoreactivity (fTLI). Untargeted quantification of serum metabolite utilized ultra-high-performance liquid chromatography-tandem mass spectroscopy. Cats with EPI had significantly increased serum quantities of long-chain fatty acids, polyunsaturated fatty acids, mevalonate pathway intermediates, and endocannabinoids compared with healthy controls. Diacylglycerols, phosphatidylethanolamines, amino acid derivatives, and microbial metabolites were significantly decreased in cats with EPI compared to healthy controls. Diacyclglycerols and amino acid metabolites were positively correlated, and sphingolipids and long-chain fatty acids were negatively correlated with serum fTLI, respectively. These results suggest that EPI in cats is associated with increased lipolysis of peripheral adipose stores, dysfunction of the mevalonate pathway, and altered amino acid metabolism. Differences in microbial metabolites indicate that feline EPI is also associated with enteric microbial dysbiosis. Targeted studies of the metabolome of cats with EPI are warranted to further elucidate the mechanisms of these metabolic derangements and their influence on the pathogenesis and pathophysiology of EPI in cats.
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Affiliation(s)
- Patrick C. Barko
- Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
- * E-mail:
| | - David A. Williams
- Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
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Song MK, Kim YJ, Kim SH, Yeo SG, Kim YJ. Environmental enrichment modulates silent information regulator 1 (SIRT1) activity to attenuate central presbycusis in a rat model of normal aging. Exp Gerontol 2021; 155:111552. [PMID: 34530105 DOI: 10.1016/j.exger.2021.111552] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 08/21/2021] [Accepted: 08/31/2021] [Indexed: 11/15/2022]
Abstract
Age-related hearing loss (ARHL) is sensory impairment in the elderly. This study aimed to identify a critical molecular mechanism that can maintain young phenotypes. We focused on the effect of exposure to environmental enrichment (EE) for 12 weeks in the central auditory pathway and limbic system of aged rats. The effects of EE were compared with the effects of dexamethasone administration. We found that in 74-week-old rats hearing function was significantly reduced and the number of neuronal specific nuclear protein (NeuN)-positive cells was decreased by 10-15% in the auditory cortex, amygdala, and hippocampus. EE exposure did not significantly affect the number of neurons, but DX administration significantly decreased their numbers in the amygdala compared with untreated aged rats. Both treatments reduced inducible nitric oxide synthase (iNOS) expression in the auditory pathway and limbic system. Exposure to EE significantly increased silent information regulator 1 (SIRT1) expression and activity, and nicotinamide phosphoribosyltransferase (NAMPT) concentration. In this study, the exposure to EE resulted in attenuated age-related hearing loss accompanied by reduction of iNOS expression and increase SIRT1 activity and NAMPT level. These data showed that EE may be a potential therapeutic to prevent ARHL.
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Affiliation(s)
- Min Kyung Song
- Department of Nursing, Graduate School, Kyung Hee University, Seoul, Republic of Korea
| | - Yoon Ju Kim
- Department of Nursing, Graduate School, Kyung Hee University, Seoul, Republic of Korea
| | - Sang Hoon Kim
- Department of Otorhinolaryngology, School of Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Seung Geun Yeo
- Department of Otorhinolaryngology, School of Medicine, Kyung Hee University, Seoul, Republic of Korea.
| | - Youn-Jung Kim
- College of Nursing Science, Kyung Hee University·East-West Nursing Research Institute, Seoul, Republic of Korea.
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38
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Li QY, An ZY, Pan ZH, Qi RY. Rationale and design of REGULATE: an observational study protocol for relationship between plasma metabolome and the efficacy of systemic glucocorticoid in acute exacerbation of chronic obstructive pulmonary disease. BMC Pulm Med 2021; 21:250. [PMID: 34320980 PMCID: PMC8317418 DOI: 10.1186/s12890-021-01614-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 07/21/2021] [Indexed: 12/03/2022] Open
Abstract
Background Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) significantly increases the mortality of patients with COPD. Guidelines have recommended systemic glucocorticoid as a regular treatment. Recently, evidence has shown that systemic glucocorticoid cannot be a benefit to all of the patients with AECOPD. Thus, the problem that how the clinicians can screen the patients who can benefit from systemic glucocorticoid needs to be solved urgently. This study is aimed to detect the metabolic biomarkers and metabolic pathways that are related to the efficacy of systemic glucocorticoid and contribute to the precise treatment of COPD. Methods and design In this study, we will utilize ultraperformance liquid chromatography/mass spectrometry (LC–MS) and gas chromatography/mass spectrometry (GC–MS) methods for the analysis of the metabolites in AECOPD patients and compare the metabolites profiles between patients with systemic glucocorticoid treatment success group and treatment failure group. We aim to detect the metabolic biomarkers and metabolic pathways that are related to the efficacy of systemic glucocorticoid and contribute to the precise treatment of COPD. Discussion Previous studies have found that plasma metabolome changed significantly after dexamethasone treatment in healthy participants. Furthermore, inter-person variability was high and remained uninfluenced by treatment, suggesting the potential of metabolomics for predicting the efficacy and side effects of systemic glucocorticoid. Therefore, we hypothesized that metabolome changes in patients with AECOPD may be associated with the efficacy of systemic glucocorticoid. Trial registration Clinicaltrials.gov registration number NCT04710849. Registered 15 January 2021, https://clinicaltrials.gov/ct2/show/NCT04710849.
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Affiliation(s)
- Qiu-Yu Li
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, 100191, People's Republic of China.
| | - Zhuo-Yu An
- Peking University Institute of Hematology, Peking University People's Hospital, Beijing, 100191, People's Republic of China
| | - Zi-Han Pan
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, 100191, People's Republic of China
| | - Rui-Ying Qi
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, 100191, People's Republic of China
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Vohra M, Sharma AR, Satyamoorthy K, Rai PS. Pharmacogenomic considerations for repurposing of dexamethasone as a potential drug against SARS-CoV-2 infection. Per Med 2021; 18:389-398. [PMID: 34086487 PMCID: PMC8186476 DOI: 10.2217/pme-2020-0183] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 04/27/2021] [Indexed: 12/15/2022]
Abstract
Immunomodulatory and analgesic effects of dexamethasone are clinically well established, and this synthetic corticosteroid acts as an agonist of glucocorticoid receptors. Early results of the RECOVERY Trial from the United Kingdom and others suggest certain benefits of dexamethasone against COVID-19 chronic patients. The efforts have been acknowledged by World Health Organization with an interim guideline to use in patients with a severe and critical illness. The inherent genetic variations in genes such as CYP3A5, NR3C1, NR3C2, etc., involved in the pharmacokinetic and pharmacodynamic processes may influence dexamethasone's effects as an anti-inflammatory drug. Besides, the drug may influence transcriptome or metabolic changes in the individuals. In the present review, we summarize the reported genetic variations that impact dexamethasone response and discuss dexamethasone-induced changes in transcriptome and metabolome that may influence potential treatment outcome against COVID-19.
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Affiliation(s)
- Manik Vohra
- Department of Biotechnology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Anu Radha Sharma
- Department of Biotechnology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Kapaettu Satyamoorthy
- Department of Cell & Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Padmalatha S Rai
- Department of Biotechnology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
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40
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Han NR, Ko SG, Moon PD, Park HJ. Chloroquine attenuates thymic stromal lymphopoietin production via suppressing caspase-1 signaling in mast cells. Biomed Pharmacother 2021; 141:111835. [PMID: 34146852 DOI: 10.1016/j.biopha.2021.111835] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 05/21/2021] [Accepted: 06/14/2021] [Indexed: 01/14/2023] Open
Abstract
Thymic stromal lymphopoietin (TSLP) produced by mast cells is involved in allergic inflammation pathogenesis. Chloroquine (CQ) is known to be an anti-malarial drug; however, additional protective functions of CQ have been discovered. This study aims to clarify an anti-inflammatory effect of CQ through modulating TSLP levels using an in vitro model of phorbol myristate acetate (PMA) + A23187-activated human mast cell line (HMC-1) and an in vivo model of PMA-irritated ear edema. CQ treatment reduced the production and mRNA expression levels of TSLP in activated HMC-1 cells. CQ down-regulated caspase-1 (CASP1), MAPKs, and NF-κB levels enhanced by stimulation with PMA + A23187. Moreover, ear thickness in ear edema was suppressed following CQ treatment. CQ decreased CASP1 and NF-κB levels in the ear tissue. TSLP levels in the ear tissue and serum were reduced following CQ treatment. Collectively, the above findings elucidate that CQ inhibits the pro-inflammatory mechanisms of TSLP via the down-regulation of distinct intracellular signaling cascade in mast cells. Therefore, CQ may have protective roles against TSLP-mediated inflammatory disorders.
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Affiliation(s)
- Na-Ra Han
- College of Korean Medicine, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
| | - Seong-Gyu Ko
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; Department of Preventive Medicine, College of Korean Medicine, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
| | - Phil-Dong Moon
- Center for Converging Humanities, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
| | - Hi-Joon Park
- Department of Anatomy & Information Sciences, College of Korean Medicine, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
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41
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Ali A, Lim J, Kim EH, Lee JH, Seong S, Kim W. Anti-Inflammatory Effects of Heat-Processed Artemisia capillaris Thunberg by Regulating I κB α/NF- κB Complex and 15-PGDH in Mouse Macrophage Cells. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2021; 2021:5320314. [PMID: 34194517 PMCID: PMC8203361 DOI: 10.1155/2021/5320314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 05/26/2021] [Indexed: 11/18/2022]
Abstract
Growing evidence suggests that dietary nutrients in herbs and plants are beneficial in improving inflammatory disorders. Artemisia capillaris Thunberg (AC) is a traditional herbal medicine widely used in East Asia to treat pain, hepatotoxicity, and inflammatory disorders. Heat processing is a unique pharmaceutical method used in traditional herbal medicine to enhance the pharmacological effects and safety of medicinal plants. This study demonstrates the anti-inflammatory effects of heat-processed AC (HPAC) in lipopolysaccharide- (LPS-) treated mouse macrophage cells. HPAC reduced LPS-induced inflammatory mediators such as IL-6, IL-1β, TNF-α, NO, and PGE2 in RAW 264.7 cells. Interestingly, 15-PGDH appears to play a pivotal role rather than COX-2 and mPGES-1 when HPAC regulated PGE2 levels. Meanwhile, HPAC showed anti-inflammatory effects by blocking IκBα phosphorylation and NF-κB nuclear translocalization. Also, we found that HO-1 upregulation was mediated by the mitogen-activated protein kinase (MAPK) pathways in HPAC-treated RAW 264.7 cells. And, in RAW 264.7 cells challenged with LPS, HPAC restored HO-1 expression, leading to NF-κB inhibition. Through further experiments using specific MAPK inhibitors, we found that, in response to LPS, the phosphorylated IκBα and activated NF-κB were attenuated by p38 MAPK/HO-1 pathway. Therefore, HPAC targeting both the IκBα/NF-κB complex and 15-PGDH may be considered as a potential novel anti-inflammatory agent derived from a natural source.
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Affiliation(s)
- Akhtar Ali
- Cnh Center for Cancer Research, Gangnam-gu, Seoul 06154, Republic of Korea
| | - Junsik Lim
- Division of Pharmacology, College of Korean Medicine, Semyung University, Jecheon 27136, Republic of Korea
| | - En Hyung Kim
- Department of Dermatology, Bundang Jesaeng General Hospital, Seongnam, Gyeonggi 13590, Republic of Korea
| | - Jong-Hyun Lee
- Department of Natural Medicine, College of Pharmacy, Dongduk Women's University, Seongbuk-gu, Seoul 02748, Republic of Korea
| | - Shin Seong
- Soram Korean Medicine Hospital, Gangnam-gu, Seoul 06154, Republic of Korea
| | - Wonnam Kim
- Cnh Center for Cancer Research, Gangnam-gu, Seoul 06154, Republic of Korea
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42
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Tapryal N, Shahabi S, Chakraborty A, Hosoki K, Wakamiya M, Sarkar G, Sharma G, Cardenas VJ, Boldogh I, Sur S, Ghosh G, Hazra TK. Intrapulmonary administration of purified NEIL2 abrogates NF-κB-mediated inflammation. J Biol Chem 2021; 296:100723. [PMID: 33932404 PMCID: PMC8164026 DOI: 10.1016/j.jbc.2021.100723] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 04/22/2021] [Accepted: 04/27/2021] [Indexed: 02/07/2023] Open
Abstract
Aberrant or constitutive activation of nuclear factor kappa B (NF-κB) contributes to various human inflammatory diseases and malignancies via the upregulation of genes involved in cell proliferation, survival, angiogenesis, inflammation, and metastasis. Thus, inhibition of NF-κB signaling has potential for therapeutic applications in cancer and inflammatory diseases. We reported previously that Nei-like DNA glycosylase 2 (NEIL2), a mammalian DNA glycosylase, is involved in the preferential repair of oxidized DNA bases from the transcriptionally active sequences via the transcription-coupled base excision repair pathway. We have further shown that Neil2-null mice are highly sensitive to tumor necrosis factor α (TNFα)- and lipopolysaccharide-induced inflammation. Both TNFα and lipopolysaccharide are potent activators of NF-κB. However, the underlying mechanism of NEIL2's role in the NF-κB-mediated inflammation remains elusive. Here, we have documented a noncanonical function of NEIL2 and demonstrated that the expression of genes, such as Cxcl1, Cxcl2, Cxcl10, Il6, and Tnfα, involved in inflammation and immune cell migration was significantly higher in both mock- and TNFα-treated Neil2-null mice compared with that in the WT mice. NEIL2 blocks NF-κB's binding to target gene promoters by directly interacting with the Rel homology region of RelA and represses proinflammatory gene expression as determined by co-immunoprecipitation, chromatin immunoprecipitation, and electrophoretic mobility-shift assays. Remarkably, intrapulmonary administration of purified NEIL2 via a noninvasive nasal route significantly abrogated binding of NF-κB to cognate DNA, leading to decreased expression of proinflammatory genes and neutrophil recruitment in Neil2-null as well as WT mouse lungs. Our findings thus highlight the potential of NEIL2 as a biologic for inflammation-associated human diseases.
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Affiliation(s)
- Nisha Tapryal
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA
| | - Shandy Shahabi
- Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA
| | - Anirban Chakraborty
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA
| | - Koa Hosoki
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA,Department of Medicine, Immunology, Allergy and Rheumatology, Baylor College of Medicine, Houston, Texas, USA
| | - Maki Wakamiya
- Departments of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Gobinda Sarkar
- Department of Orthopedics, Mayo Clinic and Foundation, Rochester, Minnesota, USA,Department of Experimental Pathology, Mayo Clinic and Foundation, Rochester, Minnesota, USA
| | - Gulshan Sharma
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA
| | - Victor J. Cardenas
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA
| | - Istvan Boldogh
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Sanjiv Sur
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA,Department of Medicine, Immunology, Allergy and Rheumatology, Baylor College of Medicine, Houston, Texas, USA
| | - Gourisankar Ghosh
- Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA
| | - Tapas K. Hazra
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA,For correspondence: Tapas K. Hazra
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Chantzichristos D, Svensson PA, Garner T, Glad CA, Walker BR, Bergthorsdottir R, Ragnarsson O, Trimpou P, Stimson RH, Borresen SW, Feldt-Rasmussen U, Jansson PA, Skrtic S, Stevens A, Johannsson G. Identification of human glucocorticoid response markers using integrated multi-omic analysis from a randomized crossover trial. eLife 2021; 10:62236. [PMID: 33821793 PMCID: PMC8024021 DOI: 10.7554/elife.62236] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 02/25/2021] [Indexed: 12/17/2022] Open
Abstract
Background: Glucocorticoids are among the most commonly prescribed drugs, but there is no biomarker that can quantify their action. The aim of the study was to identify and validate circulating biomarkers of glucocorticoid action. Methods: In a randomized, crossover, single-blind, discovery study, 10 subjects with primary adrenal insufficiency (and no other endocrinopathies) were admitted at the in-patient clinic and studied during physiological glucocorticoid exposure and withdrawal. A randomization plan before the first intervention was used. Besides mild physical and/or mental fatigue and salt craving, no serious adverse events were observed. The transcriptome in peripheral blood mononuclear cells and adipose tissue, plasma miRNAomic, and serum metabolomics were compared between the interventions using integrated multi-omic analysis. Results: We identified a transcriptomic profile derived from two tissues and a multi-omic cluster, both predictive of glucocorticoid exposure. A microRNA (miR-122-5p) that was correlated with genes and metabolites regulated by glucocorticoid exposure was identified (p=0.009) and replicated in independent studies with varying glucocorticoid exposure (0.01 ≤ p≤0.05). Conclusions: We have generated results that construct the basis for successful discovery of biomarker(s) to measure effects of glucocorticoids, allowing strategies to individualize and optimize glucocorticoid therapy, and shedding light on disease etiology related to unphysiological glucocorticoid exposure, such as in cardiovascular disease and obesity. Funding: The Swedish Research Council (Grant 2015-02561 and 2019-01112); The Swedish federal government under the LUA/ALF agreement (Grant ALFGBG-719531); The Swedish Endocrinology Association; The Gothenburg Medical Society; Wellcome Trust; The Medical Research Council, UK; The Chief Scientist Office, UK; The Eva Madura’s Foundation; The Research Foundation of Copenhagen University Hospital; and The Danish Rheumatism Association. Clinical trial number: NCT02152553. Several diseases, including asthma, arthritis, some skin conditions, and cancer, are treated with medications called glucocorticoids, which are synthetic versions of human hormones. These drugs are also used to treat people with a condition call adrenal insufficiency who do not produce enough of an important hormone called cortisol. Use of glucocorticoids is very common, the proportion of people in a given country taking them can range from 0.5% to 21% of the population depending on the duration of the treatment. But, like any medication, glucocorticoids have both benefits and risks: people who take glucocorticoids for a long time have an increased risk of diabetes, obesity, cardiovascular disease, and death. Because of the risks associated with taking glucocorticoids, it is very important for physicians to tailor the dose to each patient’s needs. Doing this can be tricky, because the levels of glucocorticoids in a patient’s blood are not a good indicator of the medication’s activity in the body. A test that can accurately measure the glucocorticoid activity could help physicians personalize treatment and reduce harmful side effects. As a first step towards developing such a test, Chantzichristos et al. identified a potential way to measure glucocorticoid activity in patient’s blood. In the experiments, blood samples were collected from ten patients with adrenal insufficiency both when they were on no medication, and when they were taking a glucocorticoid to replace their missing hormones. Next, the blood samples were analyzed to determine which genes were turned on and off in each patient with and without the medication. They also compared small molecules in the blood called metabolites and tiny pieces of genetic material called microRNAs that turn genes on and off. The experiments revealed networks of genes, metabolites, and microRNAs that are associated with glucocorticoid activity, and one microRNA called miR-122-5p stood out as a potential way to measure glucocorticoid activity. To verify this microRNA’s usefulness, Chantzichristos et al. looked at levels of miR-122-5p in people participating in three other studies and confirmed that it was a good indicator of the glucocorticoid activity. More research is needed to confirm Chantzichristos et al.’s findings and to develop a test that can be used by physicians to measure glucocorticoid activity. The microRNA identified, miR-122-5p, has been previously linked to diabetes, so studying it further may also help scientists understand how taking glucocorticoids may increase the risk of developing diabetes and related diseases.
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Affiliation(s)
- Dimitrios Chantzichristos
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Endocrinology, Diabetology and Metabolism, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Per-Arne Svensson
- Department of Molecular and Clinical Medicine, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Institute of Health and Care Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Terence Garner
- Division of Developmental Biology & Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Camilla Am Glad
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Endocrinology, Diabetology and Metabolism, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Brian R Walker
- Clinical and Translational Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.,BHF/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
| | - Ragnhildur Bergthorsdottir
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Endocrinology, Diabetology and Metabolism, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Oskar Ragnarsson
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Endocrinology, Diabetology and Metabolism, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Penelope Trimpou
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Endocrinology, Diabetology and Metabolism, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Roland H Stimson
- BHF/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
| | - Stina W Borresen
- Department of Medical Endocrinology and Metabolism, Copenhagen University Hospital, Copenhagen, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Ulla Feldt-Rasmussen
- Department of Medical Endocrinology and Metabolism, Copenhagen University Hospital, Copenhagen, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Per-Anders Jansson
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Stanko Skrtic
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Innovation Strategies and External Liaison, Pharmaceutical Technologies and Development, Gothenburg, Sweden
| | - Adam Stevens
- Division of Developmental Biology & Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Gudmundur Johannsson
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Endocrinology, Diabetology and Metabolism, Sahlgrenska University Hospital, Gothenburg, Sweden
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Jaszczyk A, Juszczak GR. Glucocorticoids, metabolism and brain activity. Neurosci Biobehav Rev 2021; 126:113-145. [PMID: 33727030 DOI: 10.1016/j.neubiorev.2021.03.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 03/04/2021] [Accepted: 03/07/2021] [Indexed: 12/17/2022]
Abstract
The review integrates different experimental approaches including biochemistry, c-Fos expression, microdialysis (glutamate, GABA, noradrenaline and serotonin), electrophysiology and fMRI to better understand the effect of elevated level of glucocorticoids on the brain activity and metabolism. The available data indicate that glucocorticoids alter the dynamics of neuronal activity leading to context-specific changes including both excitation and inhibition and these effects are expected to support the task-related responses. Glucocorticoids also lead to diversification of available sources of energy due to elevated levels of glucose, lactate, pyruvate, mannose and hydroxybutyrate (ketone bodies), which can be used to fuel brain, and facilitate storage and utilization of brain carbohydrate reserves formed by glycogen. However, the mismatch between carbohydrate supply and utilization that is most likely to occur in situations not requiring energy-consuming activities lead to metabolic stress due to elevated brain levels of glucose. Excessive doses of glucocorticoids also impair the production of energy (ATP) and mitochondrial oxidation. Therefore, glucocorticoids have both adaptive and maladaptive effects consistently with the concept of allostatic load and overload.
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Affiliation(s)
- Aneta Jaszczyk
- Department of Animal Behavior and Welfare, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05-552 Jastrzebiec, 36a Postepu str., Poland
| | - Grzegorz R Juszczak
- Department of Animal Behavior and Welfare, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05-552 Jastrzebiec, 36a Postepu str., Poland.
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Xu J, Su G, Huang X, Chang R, Chen Z, Ye Z, Cao Q, Kijlstra A, Yang P. Metabolomic Analysis of Aqueous Humor Identifies Aberrant Amino Acid and Fatty Acid Metabolism in Vogt-Koyanagi-Harada and Behcet's Disease. Front Immunol 2021; 12:587393. [PMID: 33732231 PMCID: PMC7959366 DOI: 10.3389/fimmu.2021.587393] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 01/08/2021] [Indexed: 11/13/2022] Open
Abstract
To investigate aqueous metabolic profiles in Vogt-Koyanagi-Harada (VKH) and Behcet's disease (BD), we applied ultra-high-performance liquid chromatography equipped with quadrupole time-of flight mass spectrometry in aqueous humor samples collected from these patients and controls. Metabolite levels in these three groups were analyzed by univariate logistic regression. The differential metabolites were subjected to subsequent pathway analysis by MetaboAnalyst. The results showed that both partial-least squares discrimination analysis and hierarchical clustering analysis showed specific aqueous metabolite profiles when comparing VKH, BD, and controls. There were 28 differential metabolites in VKH compared to controls and 29 differential metabolites in BD compared to controls. Amino acids and fatty acids were the two most abundant categories of differential metabolites. Furthermore, pathway enrichment analysis identified several perturbed pathways, including pantothenate and CoA biosynthesis when comparing VKH with the control group, and D-arginine and D-ornithine metabolism and phenylalanine metabolism when comparing BD with the control group. Aminoacyl-tRNA biosynthesis was altered in both VKH and BD when compared to controls. Our findings suggest that amino acids metabolism as well as two fatty acids, palmitic acid and oleic acid, may be involved in the pathogenesis of BD and VKH.
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Affiliation(s)
- Jing Xu
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing, China
| | - Guannan Su
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing, China
| | - Xinyue Huang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing, China
| | - Rui Chang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing, China
| | - Zhijun Chen
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing, China
| | - Zi Ye
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing, China
| | - Qingfeng Cao
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing, China
| | - Aize Kijlstra
- University Eye Clinic Maastricht, Maastricht, Netherlands
| | - Peizeng Yang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing, China
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Blood metabolomics in infants enrolled in a dose escalation pilot trial of budesonide in surfactant. Pediatr Res 2021; 90:784-794. [PMID: 33469180 PMCID: PMC7814527 DOI: 10.1038/s41390-020-01343-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 12/04/2020] [Accepted: 12/09/2020] [Indexed: 01/30/2023]
Abstract
BACKGROUND The pathogenesis of BPD includes inflammation and oxidative stress in the immature lung. Corticosteroids improve respiratory status and outcome, but the optimal treatment regimen for benefit with low systemic effects is uncertain. METHODS In a pilot dose escalation trial, we administered ≤5 daily doses of budesonide in surfactant to 24 intubated premature infants (Steroid And Surfactant in ELGANs (SASSIE)). Untargeted metabolomics was performed on dried blood spots using UPLC-MS/MS. Tracheal aspirate IL-8 concentration was determined as a measure of lung inflammation. RESULTS Metabolomics data for 829 biochemicals were obtained on 121 blood samples over 96 h from 23 infants receiving 0.025, 0.05, or 0.1 mg budesonide/kg. Ninety metabolites were increased or decreased in a time- and dose-dependent manner at q ≤ 0.1 with overrepresentation in lipid and amino acid super pathways. Different dose response patterns occurred, with negative regulation associated with highest sensitivity to budesonide. Baseline levels of 22 regulated biochemicals correlated with lung inflammation (IL-8), with highest significance for sphingosine and thiamin. CONCLUSIONS Numerous metabolic pathways are regulated in a dose-dependent manner by glucocorticoids, which apparently act via distinct mechanisms that impact dose sensitivity. The findings identify candidate blood biochemicals as biomarkers of lung inflammation and systemic responses to corticosteroids. IMPACT Treatment of premature infants in respiratory failure with 0.1 mg/kg intra-tracheal budesonide in surfactant alters levels of ~11% of detected blood biochemicals in discrete time- and dose-dependent patterns. A subset of glucocorticoid-regulated biochemicals is associated with lung inflammatory status as assessed by lung fluid cytokine concentration. Lower doses of budesonide in surfactant than currently used may provide adequate anti-inflammatory responses in the lung with fewer systemic effects, improving the benefit:risk ratio.
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Wang L, Li Q, Yan H, Jiao G, Wang H, Chi H, Zhou H, Chen L, Shan Y, Chen Y. Resveratrol Protects Osteoblasts Against Dexamethasone-Induced Cytotoxicity Through Activation of AMP-Activated Protein Kinase. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:4451-4463. [PMID: 33122889 PMCID: PMC7591001 DOI: 10.2147/dddt.s266502] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Accepted: 09/23/2020] [Indexed: 12/16/2022]
Abstract
Purpose Glucocorticoids are used for the treatment of inflammatory diseases, but glucocorticoid treatment is associated with bone damage. Resveratrol is a phytoalexin found in many plants, and we investigated its protective role on dexamethasone-induced dysfunction in MC3T3-E1 cells and primary osteoblasts. Materials and Methods MC3T3-E1 cells and primary osteoblasts were treated with dexamethasone in the presence/absence of different doses of resveratrol for 24 or 48 h. Then, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium (MTT) and lactate dehydrogenase (LDH) assays were used to evaluate cell viability. Apoptosis was analyzed by a flow cytometry. An alkaline phosphatase (ALP) activity assay and Alizarin Red S staining were used to study osteoblast differentiation. Expression of osteoblast-related genes was measured by real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The AMP-activated protein kinase (AMPK) signaling pathway and mitochondrial expression of superoxide dismutase were evaluated by Western blotting. Intracellular reactive oxygen species (ROS), adenosine triphosphate (ATP) content, mitochondrial-complex activity, and mitochondrial DNA content were measured to evaluate mitochondrial function. Results Resveratrol induced the proliferation and inhibited apoptosis of osteoblasts in the presence of dexamethasone. Resveratrol increased the ALP activity and mineralization of osteoblasts. Resveratrol also attenuated dexamethasone-induced inhibition of mRNA expression of osteogenesis maker genes, including bone morphogenetic protein-2, osteoprotegerin, runt-related transcription factor-2, and bone Gla protein. Resveratrol alleviated dexamethasone-induced mitochondrial dysfunction. Resveratrol strongly stimulated expression of peroxisome proliferator–activated receptor-γ coactivator 1α and sirtuin-3 genes, as well as their downstream target gene superoxide dismutase-2. Resveratrol induced phosphorylation of AMPK and acetyl-CoA carboxylase (ACC). Blockade of AMPK signaling using compound C reversed the protective effects of resveratrol against dexamethasone. Conclusion Resveratrol showed protective effects against dexamethasone-induced dysfunction of osteoblasts by activating AMPK signaling.
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Affiliation(s)
- Liang Wang
- Department of Orthopedics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.,Shandong University Spine and Spine Cord Disease Research Center, Shandong University, Jinan, Shandong, People's Republic of China.,Department of Internal Medicine, Shandong Medical College, Linyi, Shandong, People's Republic of China
| | - Qiushi Li
- Department of Orthopedics, Linyi People's Hospital, Linyi, Shandong, People's Republic of China
| | - Haibo Yan
- Department of Internal Medicine, Shandong Medical College, Linyi, Shandong, People's Republic of China
| | - Guangjun Jiao
- Department of Orthopedics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People's Republic of China
| | - Hongliang Wang
- Department of Orthopedics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People's Republic of China
| | - Hai Chi
- Department of Traumatic Orthopedics, Shandong Provincial ENT Hospital (Affiliated to Shandong University), Jinan, Shandong, People's Republic of China
| | - Hongming Zhou
- Department of Orthopedics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.,Department of Emergency Trauma Surgery, Linyi Central Hospital, Linyi, Shandong, People's Republic of China
| | - Lu Chen
- Department of Orthopedics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People's Republic of China
| | - Yu Shan
- Department of Orthopedics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People's Republic of China
| | - Yunzhen Chen
- Department of Orthopedics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.,Shandong University Spine and Spine Cord Disease Research Center, Shandong University, Jinan, Shandong, People's Republic of China
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48
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Insights into glucocorticoid responses derived from omics studies. Pharmacol Ther 2020; 218:107674. [PMID: 32910934 DOI: 10.1016/j.pharmthera.2020.107674] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 08/20/2020] [Indexed: 12/26/2022]
Abstract
Glucocorticoid drugs are commonly used in the treatment of several conditions, including autoimmune diseases, asthma and cancer. Despite their widespread use and knowledge of biological pathways via which they act, much remains to be learned about the cell type-specific mechanisms of glucocorticoid action and the reasons why patients respond differently to them. In recent years, human and in vitro studies have addressed these questions with genomics, transcriptomics and other omics approaches. Here, we summarize key insights derived from omics studies of glucocorticoid response, and we identify existing knowledge gaps related to mechanisms of glucocorticoid action that future studies can address.
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Zhang T, Mohan C. Caution in studying and interpreting the lupus metabolome. Arthritis Res Ther 2020; 22:172. [PMID: 32680552 PMCID: PMC7367412 DOI: 10.1186/s13075-020-02264-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 07/07/2020] [Indexed: 02/06/2023] Open
Abstract
Several metabolomics studies have shed substantial light on the pathophysiological pathways underlying multiple diseases including systemic lupus erythematosus (SLE). This review takes stock of our current understanding of this field. We compare, collate, and investigate the metabolites in SLE patients and healthy volunteers, as gleaned from published metabolomics studies on SLE. In the surveyed primary reports, serum or plasma samples from SLE patients and healthy controls were assayed using mass spectrometry or nuclear magnetic resonance spectroscopy, and metabolites differentiating SLE from controls were identified. Collectively, the circulating metabolome in SLE is characterized by reduced energy substrates from glycolysis, Krebs cycle, fatty acid β oxidation, and glucogenic and ketogenic amino acid metabolism; enhanced activity of the urea cycle; decreased long-chain fatty acids; increased medium-chain and free fatty acids; and augmented peroxidation and inflammation. However, these findings should be interpreted with caution because several of the same metabolic pathways are also significantly influenced by the medications commonly used in SLE patients, common co-morbidities, and other factors including smoking and diet. In particular, whereas the metabolic alterations relating to inflammation, oxidative stress, lipid peroxidation, and glutathione generation do not appear to be steroid-dependent, the other metabolic changes may in part be influenced by steroids. To conclude, metabolomics studies of SLE and other rheumatic diseases ought to factor in the potential contributions of confounders such as medications, co-morbidities, smoking, and diet.
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Affiliation(s)
- Ting Zhang
- Department of biomedical engineering, University of Houston, Houston, TX, 77204, USA
| | - Chandra Mohan
- Department of biomedical engineering, University of Houston, Houston, TX, 77204, USA.
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50
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Müller OJ, Heckmann MB, Ding L, Rapti K, Rangrez AY, Gerken T, Christiansen N, Rennefahrt UEE, Witt H, González Maldonado S, Ternes P, Schwab DM, Ruf T, Hille S, Remes A, Jungmann A, Weis TM, Kreußer JS, Gröne HJ, Backs J, Schatz P, Katus HA, Frey N. Comprehensive plasma and tissue profiling reveals systemic metabolic alterations in cardiac hypertrophy and failure. Cardiovasc Res 2020; 115:1296-1305. [PMID: 30418544 DOI: 10.1093/cvr/cvy274] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 04/23/2018] [Accepted: 11/08/2018] [Indexed: 01/30/2023] Open
Abstract
AIMS Heart failure is characterized by structural and metabolic cardiac remodelling. The aim of the present study is to expand our understanding of the complex metabolic alterations in the transition from pathological hypertrophy to heart failure and exploit the results from a translational perspective. METHODS AND RESULTS Mice were subjected to transverse aortic constriction (TAC) or sham surgery and sacrificed 2 weeks, 4 weeks, or 6 weeks after the procedure. Samples from plasma, liver, skeletal muscle, and heart were collected and analysed using metabolomics. Cardiac samples were also analysed by transcriptional profiling. Progressive alterations of key cardiac metabolic pathways and gene expression patterns indicated impaired mitochondrial function and a metabolic switch during transition to heart failure. Similar to the heart, liver, and skeletal muscle revealed significant metabolic alterations such as depletion of essential fatty acids and glycerolipids in late stages of heart failure. Circulating metabolites, particularly fatty acids, reflected cardiac metabolic defects, and deteriorating heart function. For example, inverse correlation was found between plasma and the heart levels of triacylglycerol (C18:1, C18:2, C18:3), and sphingomyelin (d18:1, C23:0) already at an early stage of heart failure. Interestingly, combining metabolic and transcriptional data from cardiac tissue revealed that decreased carnitine shuttling and transportation preceded mitochondrial dysfunction. We, thus, studied the therapeutic potential of OCTN2 (Organic Cation/Carnitine Transporter 2), an important factor for carnitine transportation. Cardiac overexpression of OCTN2 using an adeno-associated viral vector significantly improved ejection fraction and reduced interstitial fibrosis in mice subjected to TAC. CONCLUSION Comprehensive plasma and tissue profiling reveals systemic metabolic alterations in heart failure, which can be used for identification of novel biomarkers and potential therapeutic targets.
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Affiliation(s)
- Oliver J Müller
- Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, Heidelberg, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Germany
| | - Markus B Heckmann
- Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, Heidelberg, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Germany
| | - Lin Ding
- Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, Heidelberg, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Germany
| | - Kleopatra Rapti
- Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, Heidelberg, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Germany
| | - Ashraf Y Rangrez
- Department of Internal Medicine III, University of Kiel, Arnold-Heller-Str. 3, Kiel, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Germany
| | - Thomas Gerken
- Metanomics Health GmbH, Tegeler Weg 33, Berlin, Germany
| | | | | | - Henning Witt
- Metanomics GmbH, Tegeler Weg 33, Berlin, Germany
| | | | | | - Dominic M Schwab
- Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, Heidelberg, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Germany
| | - Theresa Ruf
- Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, Heidelberg, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Germany
| | - Susanne Hille
- Department of Internal Medicine III, University of Kiel, Arnold-Heller-Str. 3, Kiel, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Germany
| | - Anca Remes
- Department of Internal Medicine III, University of Kiel, Arnold-Heller-Str. 3, Kiel, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Germany
| | - Andreas Jungmann
- Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, Heidelberg, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Germany
| | - Tanja M Weis
- Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, Heidelberg, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Germany
| | - Julia S Kreußer
- Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, Heidelberg, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Germany.,Department of Molecular Cardiology and Epigenetics, University of Heidelberg, Im Neuenheimer Feld 669, Heidelberg, Germany
| | - Hermann-Josef Gröne
- Department of Cellular and Molecular Pathology, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg, Germany
| | - Johannes Backs
- DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Germany.,Department of Molecular Cardiology and Epigenetics, University of Heidelberg, Im Neuenheimer Feld 669, Heidelberg, Germany
| | | | - Hugo A Katus
- Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, Heidelberg, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Germany
| | - Norbert Frey
- Department of Internal Medicine III, University of Kiel, Arnold-Heller-Str. 3, Kiel, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Germany
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