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Akan G, Balcı MC, Tuncel G, Karaca M, Kazan HH, Özketen AÇ, Özgen Ö, Gökçay GF, Atalar F. Development and validation of a carnitine cycle and transport disorders (CCD) panel: an ONT-compatible multi-gene diagnostic kit for newborn and selective screening. Orphanet J Rare Dis 2025; 20:250. [PMID: 40420233 DOI: 10.1186/s13023-025-03775-4] [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: 12/14/2024] [Accepted: 05/05/2025] [Indexed: 05/28/2025] Open
Abstract
Carnitine transport and cycle disorders (CCD) are a group of metabolic disorders characterized by either carnitine depletion or dysfunction in the carnitine cycle, a critical process for the transport of fatty acids into the mitochondria and their subsequent β-oxidation. Clinically, CCD can manifest with a wide range of symptoms, including hypoketotic hypoglycemia, which may be accompanied by signs of liver dysfunction, hepatic steatosis, myopathy and cardiomyopathy. Biochemical diagnosis typically involves measuring carnitine and acylcarnitine levels in blood, alongside organic acid profiling in urine. However, due to phenotypic overlaps with other metabolic disorders, precise molecular diagnosis is essential for accurate disease classification and subtype determination. The present study aimed to develop and clinically validate a novel CCD panel, specifically designed for Oxford Nanopore Technologies (ONT) platform compatibility. The panel targeted four key CCD related genes (CPT-1, CPT-2, SLC22A5 and SLC25A20). An amplification-based library preparation method pooling 21 primers specific to the CCD-related genes into two tubes was optimized. The panel was then applied to screen 20 patients previously diagnosed with CCD via second-generation sequencing platform. Comparative analysis of results from both platforms revealed a 100% concordance in detecting pathogenic, likely pathogenic, and variants of unknown significance associated with CCD. In silico analysis was also performed to predict the pathogenic potential of the variants of unknown significance. Here we report the development and clinical validation of a multi-gene diagnostic panel for ONT platform. The results demonstrated the feasibility of ONT-based genetic testing for CCD and set the stage for the development of similar diagnostic panels for other genetic disorders, offering a streamlined and putatively cost-effective alternative to current sequencing methodologies.
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Affiliation(s)
- Gökçe Akan
- DESAM Institute, Near East University, Mersin 10, Türkiye
| | - Mehmet Cihan Balcı
- Division of Pediatric Nutrition and Metabolism, Istanbul Medical Faculty, Istanbul University, Istanbul, Türkiye
| | - Gülten Tuncel
- DESAM Institute, Near East University, Mersin 10, Türkiye
| | - Meryem Karaca
- Division of Pediatric Nutrition and Metabolism, Istanbul Medical Faculty, Istanbul University, Istanbul, Türkiye
| | - Hasan Hüseyin Kazan
- Department of Medical Biology, Gulhane Faculty of Medicine, University of Health Sciences, Ankara, Türkiye
| | | | - Özge Özgen
- Rare Diseases Research Laboratory, Istanbul Medical Faculty, Istanbul University, Istanbul, Türkiye
| | - Gülden Fatma Gökçay
- Division of Pediatric Nutrition and Metabolism, Istanbul Medical Faculty, Istanbul University, Istanbul, Türkiye
- Rare Diseases Research Laboratory, Istanbul Medical Faculty, Istanbul University, Istanbul, Türkiye
- Department of Rare Diseases, Child Health Institute, Istanbul University, Istanbul, Türkiye
| | - Fatmahan Atalar
- Rare Diseases Research Laboratory, Istanbul Medical Faculty, Istanbul University, Istanbul, Türkiye.
- Department of Rare Diseases, Child Health Institute, Istanbul University, Istanbul, Türkiye.
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Senko D, Efimova O, Osetrova M, Anikanov N, Boyko M, Sharaev M, Morozova A, Zorkina Y, Kislov M, Kostyuk G, Stekolshchikova E, Khaitovich P. White matter lipidome alterations in the schizophrenia brain. SCHIZOPHRENIA (HEIDELBERG, GERMANY) 2024; 10:123. [PMID: 39725684 DOI: 10.1038/s41537-024-00542-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 11/25/2024] [Indexed: 12/28/2024]
Abstract
Numerous brain imaging studies have reported white matter alterations in schizophrenia, but the lipidome analysis of the corresponding tissue remains incomplete. In this study, we investigated the lipidome composition of six subcortical white matter regions corresponding to major axonal tracks in both control subjects and schizophrenia patients. All six regions exhibited a consistent pattern of quantitative lipidome alterations in schizophrenia, involving myelin-forming and mitochondria associated lipid classes. While alteration levels of myelin-forming lipids, particularly sphingolipids, aligned with the extent of the myelin changes reported in structural brain imaging studies, a significant decrease of mitochondria in the white matter, indicated by the lipidome alterations, was not previously investigated. To verify this effect, we performed lipidome analysis in a larger set of individuals and in the mitochondria-enriched membrane fraction, as well as directly quantified mitochondrial content. Our results suggest a substantial reduction of the mitochondrial quotient accompanied by the imbalance in myelin lipids in schizophrenia white matter.
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Affiliation(s)
- Dmitry Senko
- Skolkovo Institute of Science and Technology, Moscow, Russia.
| | - Olga Efimova
- Skolkovo Institute of Science and Technology, Moscow, Russia
| | - Maria Osetrova
- Skolkovo Institute of Science and Technology, Moscow, Russia
- Mental Health Clinic No.1 Named After N. A. Alexeev of Moscow Healthcare Department, Moscow, Russia
| | | | - Maria Boyko
- Skolkovo Institute of Science and Technology, Moscow, Russia
- BIMAI-lab, Sharjah, UAE
| | - Maksim Sharaev
- Skolkovo Institute of Science and Technology, Moscow, Russia
- Mental Health Clinic No.1 Named After N. A. Alexeev of Moscow Healthcare Department, Moscow, Russia
- BIMAI-lab, Sharjah, UAE
| | - Anna Morozova
- Mental Health Clinic No.1 Named After N. A. Alexeev of Moscow Healthcare Department, Moscow, Russia
- Serbsky National Medical Research Centre of Psychiatry and Narcology, Moscow, Russia
| | - Yana Zorkina
- Mental Health Clinic No.1 Named After N. A. Alexeev of Moscow Healthcare Department, Moscow, Russia
- Serbsky National Medical Research Centre of Psychiatry and Narcology, Moscow, Russia
| | - Maksim Kislov
- Pirogov Russian National Research Medical University, Moscow, Russia
| | - Georgiy Kostyuk
- Mental Health Clinic No.1 Named After N. A. Alexeev of Moscow Healthcare Department, Moscow, Russia
- Lomonosov Moscow State University, Moscow, Russia
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Xue J, Wu D, Bao Y, Wu Y, Zhang X, Chen L. The Abnormal Proliferation of Midbrain Dopamine Cells From Human Pluripotent Stem Cells Is Induced by Exposure to the Tumor Microenvironment. CNS Neurosci Ther 2024; 30:e70117. [PMID: 39563017 PMCID: PMC11576488 DOI: 10.1111/cns.70117] [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: 02/03/2024] [Revised: 10/16/2024] [Accepted: 10/21/2024] [Indexed: 11/21/2024] Open
Abstract
AIMS Tumorigenicity is a significant concern in stem cell-based therapies. However, traditional tumorigenicity tests using animal models often produce inaccurate results. Consequently, a more sensitive method for assessing tumorigenicity is required. This study aimed to enhance sensitivity by exposing functional progenitors derived from human pluripotent stem cells (hPSCs) to the tumor microenvironment (TME) in vitro before transplantation, potentially making them more prone to abnormal proliferation or tumorigenicity. METHODS Midbrain dopamine (mDA) cells derived from hPSCs were exposed to the TME by coculturing with medulloblastoma. The cellular characteristics of these cocultured mDA cells were evaluated both in vitro and in vivo, and the mechanisms underlying the observed alterations were investigated. RESULTS Our findings demonstrated increased proliferation of cocultured mDA cells both in vitro and in vivo. Moreover, these proliferating cells showed a higher expression of Ki67 and SOX1, suggesting abnormal proliferation. The observed abnormal proliferation in cocultured mDA cells was attributed to the hyperactivation of proliferation-related genes, the JAK/STAT3 pathway, and cytokine stimulation. CONCLUSION This study indicates that exposing functional progenitors to the TME in vitro before transplantation can induce abnormal proliferation, thereby increasing the sensitivity of tumorigenicity tests.
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Affiliation(s)
- Jun Xue
- Department of Neurosurgery, Huashan Hospital, MOE Frontiers Center for Brain ScienceFudan UniversityShanghaiChina
- National Center for Neurological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Huashan HospitalFudan UniversityShanghaiChina
| | - Dongyan Wu
- Institute of Neurology, Huashan Hospital, Shanghai Medical CollegeFudan UniversityShanghaiChina
- National Clinical Research Center for Aging and Medicine, Huashan HospitalFudan UniversityShanghaiChina
| | - Yuting Bao
- Department of Neurosurgery, Huashan Hospital, MOE Frontiers Center for Brain ScienceFudan UniversityShanghaiChina
- National Center for Neurological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Huashan HospitalFudan UniversityShanghaiChina
| | - Yifan Wu
- Department of Neurosurgery, Huashan Hospital, MOE Frontiers Center for Brain ScienceFudan UniversityShanghaiChina
- National Center for Neurological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Huashan HospitalFudan UniversityShanghaiChina
| | - Xin Zhang
- Department of Neurosurgery, Huashan Hospital, MOE Frontiers Center for Brain ScienceFudan UniversityShanghaiChina
- National Center for Neurological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Huashan HospitalFudan UniversityShanghaiChina
| | - Liang Chen
- Department of Neurosurgery, Huashan Hospital, MOE Frontiers Center for Brain ScienceFudan UniversityShanghaiChina
- National Center for Neurological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Huashan HospitalFudan UniversityShanghaiChina
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Wang Y, Chen Y, Ma X, Guan J, Gao Y, Hong X, Fu P, Zhou F. Apo E protein and related markers show the prognosis of stress urinary incontinence rats treated with modified Buzhong Yiqi Decoction. Int J Biol Macromol 2024; 280:135996. [PMID: 39326601 DOI: 10.1016/j.ijbiomac.2024.135996] [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: 08/03/2024] [Revised: 09/12/2024] [Accepted: 09/23/2024] [Indexed: 09/28/2024]
Abstract
Stress urinary incontinence (SUI) is a common disease that seriously affects the quality of life of patients. In recent years, studies have shown that apolipoprotein E (ApoE) plays a role in neuroprotection and repair, but its specific role in SUI remains unclear. The aim of this study was to investigate the effect of macromolecular protein ApoE related markers on the prognosis of rats with SUI treated by modified Buzhong Yiqi Decoction (MBZYQD), in order to provide a new target for the treatment of SUI. Healthy rats were selected to establish a SUI model and divided into groups. The levels of ApoE related metabolites in blood of rats were detected by Metabolomics analysis and Lipidomics analysis. The urine leakage point pressure (LPP) were compared in each group, and the therapeutic effect of MBZYQD was evaluated. Compared with the model group, the LPP of rats in MBZYQD supplemented group was significantly higher. Compared with the control group, the LPP of MBZYQD was not statistically significant before and after treatment. The macromolecular protein ApoE may plays a key role in the treatment of SUI by MBZYQD, which can improve symptoms by regulating lipid metabolism repair.
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Affiliation(s)
- Yuhan Wang
- Hangzhou TCM Hospital of Zhejiang Chinese Medical University (Hangzhou Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Yijie Chen
- Center for Reproductive Medicine, Department of Reproductive Endocrinology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China
| | - Xiaofang Ma
- Center for Reproductive Medicine, Department of Reproductive Endocrinology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China
| | - Jili Guan
- Center for Reproductive Medicine, Department of Reproductive Endocrinology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China
| | - Yang Gao
- Center for Reproductive Medicine, Department of Reproductive Endocrinology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China
| | - Xuezi Hong
- School of Clinical Medicine, Hangzhou Normal University, Hangzhou, China
| | - Ping Fu
- Hangzhou TCM Hospital of Zhejiang Chinese Medical University (Hangzhou Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - FeiFei Zhou
- Center for Reproductive Medicine, Department of Reproductive Endocrinology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China.
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Bustamante-Rangel M, Rodríguez-Gonzalo E, Pérez-Pavón JL. Simultaneous determination of semi-essential nutrients taurine, l-carnitine and choline in infant formulas and adult/pediatric nutritional formulas by hydrophilic interaction liquid chromatography-electrospray ionization-tandem mass spectrometry. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2024; 104:8553-8560. [PMID: 39392653 DOI: 10.1002/jsfa.13682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 04/12/2024] [Accepted: 06/10/2024] [Indexed: 10/12/2024]
Abstract
BACKGROUND The nutritional intake of formula-fed newborns is often limited to a single source, so it must be supplemented with essential nutrients for the growth and proper development of infants. Taurine, l-carnitine, and choline are considered conditionally essential nutrients especially in newborns and infants. RESULTS In this work, a simple routine hydrophilic interaction liquid chromatography-electrospray ionization-tandem mass spectrometry (HILIC-ESI-MS/MS) method was developed and validated for the simultaneous determination of these semi-essential nutrients in infant and adult/pediatric milk formulas. The extraction recoveries were between 90% and 114%. Precision of the method offered relative standard deviation below 5% and 7% for intra-day and inter-day precision, respectively. The proposed method was successfully applied to quantification of taurine, l-carnitine, and choline in milk formula. The contents found were in good agreement with those provided on the product label for almost all samples. CONCLUSION In view of these results, it can be concluded that the developed method can be a useful approach for the simultaneous determination of taurine, l-carnitine and choline in powdered milk samples, so it can be useful in the routine quality control of this kind of samples. © 2024 The Author(s). Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
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Affiliation(s)
- Myriam Bustamante-Rangel
- Department of Analytical Chemistry, Nutrition and Food Science, Faculty of Chemical Sciences, University of Salamanca, Salamanca, Spain
| | - Encarnación Rodríguez-Gonzalo
- Department of Analytical Chemistry, Nutrition and Food Science, Faculty of Chemical Sciences, University of Salamanca, Salamanca, Spain
| | - José Luis Pérez-Pavón
- Department of Analytical Chemistry, Nutrition and Food Science, Faculty of Chemical Sciences, University of Salamanca, Salamanca, Spain
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Meng C, Ma Y, Fu N, Li J, Sun B, Li Z, Wang Q, Liu P. The supplementation of L-carnitine in critically ill patients with sepsis: a systematic review and meta-analysis of randomized controlled trials. Eur J Med Res 2024; 29:488. [PMID: 39367436 PMCID: PMC11453008 DOI: 10.1186/s40001-024-02087-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 09/28/2024] [Indexed: 10/06/2024] Open
Abstract
OBJECTIVES The evidence suggests that L-carnitine may reduce mortality in critically ill patients with sepsis. However, the conclusions of different studies are inconsistent. A meta-analysis was conducted to evaluate the effect of L-carnitine compliance on mortality in patients with sepsis. METHODS A search of the PubMed, Embase, and Cochrane Library databases was conducted on 1 June 2024. The risk ratio (RR) was pooled with a 95% confidence interval (CI) for dichotomous data. The publications were subjected to a review in accordance with the guidelines set forth in the Cochrane Handbook and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). This study has been registered with INPLASY (number INPLASY202460086). RESULTS A total of 356 patients were included in four randomized controlled trials. The results indicated that L-carnitine supplementation was not associated with 28-day mortality in sepsis patients (RR: 0.65; 95% CI 0.33-1.28; I2 = 70%; P = 0.21). And there was no significant effect on 12-month mortality (RR: 0.72; 95% CI 0.47-1.11; I2 = 0%; P = 0.14) compared to placebo. CONCLUSIONS The use of L-carnitine was not found to be significantly correlated with 28-day or 12-month mortality in patients with sepsis.
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Affiliation(s)
- Chang Meng
- Department of Emergency, Emergency General Hospital, XiBaHe South Road 29, Chaoyang District, Beijing, 100028, People's Republic of China
| | - Yudan Ma
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Fuxing Road 28, Haidian District, Beijing, 100039, People's Republic of China
| | - Ning Fu
- Department of Cardiology, Hebei Yanda Hospital, Langfang, 065201, People's Republic of China
| | - Jie Li
- Department of Emergency, Emergency General Hospital, XiBaHe South Road 29, Chaoyang District, Beijing, 100028, People's Republic of China
| | - Biao Sun
- Department of Emergency, Emergency General Hospital, XiBaHe South Road 29, Chaoyang District, Beijing, 100028, People's Republic of China
| | - Zhichao Li
- Department of Emergency, Emergency General Hospital, XiBaHe South Road 29, Chaoyang District, Beijing, 100028, People's Republic of China
| | - Qing Wang
- Department of Emergency, Emergency General Hospital, XiBaHe South Road 29, Chaoyang District, Beijing, 100028, People's Republic of China.
| | - Peng Liu
- Department of Cardiology, Ordos Central Hospital, Ordos School of Clinical Medicine, Inner Mongolia Medical University, 23 Yijin Huoluo West Street, Dongsheng District, Inner Mongolia, Ordos, 017000, People's Republic of China.
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Zhang X, Chen Y, Yang H, Ding H, Cai P, Ge Y, Zheng H, Sun X, Yang Y, Li X, Lin T. Plasma Metabolomics Indicates Potential Biomarkers and Abnormal Metabolic Pathways in Female Melasma Patients. Ann Dermatol 2024; 36:300-309. [PMID: 39343757 PMCID: PMC11439978 DOI: 10.5021/ad.23.141] [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: 11/21/2023] [Revised: 02/18/2024] [Accepted: 02/18/2024] [Indexed: 10/01/2024] Open
Abstract
BACKGROUND Melasma is a common and chronic pigmentary disorder with complex pathogenesis, and the relationship between melasma and metabolic syndrome remains elusive. Thus, metabolomics might contribute to the early detection of potential metabolic abnormalities in individuals with melasma. OBJECTIVE The present study aims to analyze changes in plasma metabolites of female melasma patients and identify disease markers as well as explore potential therapeutic targets. METHODS Plasma samples from 20 female patients with melasma and 21 healthy female controls that were comparable in terms of age and body mass index were collected for untargeted metabolomics investigations. Ultra-high performance liquid chromatography-mass spectrometry was used to analyze metabolites in the plasma. Metabolic pathway analyses were employed to identify significantly differentially expressed metabolites in melasma patients. Receiver operating characteristic curves were constructed, and correlation analyses were performed using the modified Melasma Area and Severity Index and oxidative stress levels. RESULTS In contrast to healthy subjects, melasma patients showed significant alterations in 125 plasma metabolites, including amino acids, lipids, and carbohydrate-related metabolites. KEGG pathway analysis suggested that primary pathways associated with the development of melasma include tryptophan metabolism, as well as the biosynthesis of phenylalanine, tyrosine, and tryptophan. Importantly, based on receiver operating characteristic curves and correlation analyses, several metabolites were identified as robust biomarkers for melasma. CONCLUSION Collectively, this study identified significant changes in plasma metabolites in melasma patients, providing new insights into the pathogenesis of melasma and opening novel therapeutic avenues.
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Affiliation(s)
- Xiaoli Zhang
- Department of Cosmetic Laser Surgery, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Yi Chen
- Pharmacal Research Laboratory, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Hedan Yang
- Department of Cosmetic Laser Surgery, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Hui Ding
- Department of Cosmetic Laser Surgery, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Pingping Cai
- Department of Cosmetic Laser Surgery, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Yiping Ge
- Department of Cosmetic Laser Surgery, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Huiying Zheng
- Department of Cosmetic Laser Surgery, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Xiaojie Sun
- Department of Cosmetic Laser Surgery, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Yin Yang
- Department of Cosmetic Laser Surgery, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China.
| | - Xinyu Li
- Pharmacal Research Laboratory, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China.
| | - Tong Lin
- Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China.
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Prajapat SK, Maharana KC, Singh S. Mitochondrial dysfunction in the pathogenesis of endothelial dysfunction. Mol Cell Biochem 2024; 479:1999-2016. [PMID: 37642880 DOI: 10.1007/s11010-023-04835-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 08/14/2023] [Indexed: 08/31/2023]
Abstract
Cardiovascular diseases (CVDs) are a matter of concern worldwide, and mitochondrial dysfunction is one of the major contributing factors. Vascular endothelial dysfunction has a major role in the development of atherosclerosis because of the abnormal chemokine secretion, inflammatory mediators, enhancement of LDL oxidation, cytokine elevation, and smooth muscle cell proliferation. Endothelial cells transfer oxygen from the pulmonary circulatory system to the tissue surrounding the blood vessels, and a majority of oxygen is transferred to the myocardium by endothelial cells, which utilise a small amount of oxygen to generate ATP. Free radicals of oxide are produced by mitochondria, which are responsible for cellular oxygen uptake. Increased mitochondrial ROS generation and reduction in agonist-stimulated eNOS activation and nitric oxide bioavailability were directly linked to the observed change in mitochondrial dynamics, resulting in various CVDs and endothelial dysfunction. Presently, the manuscript mainly focuses on endothelial dysfunction, providing a deep understanding of the various features of mitochondrial mechanisms that are used to modulate endothelial dysfunction. We talk about recent findings and approaches that may make it possible to detect mitochondrial dysfunction as a potential biomarker for risk assessment and diagnosis of endothelial dysfunction. In the end, we cover several targets that may reduce mitochondrial dysfunction through both direct and indirect processes and assess the impact of several different classes of drugs in the context of endothelial dysfunction.
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Affiliation(s)
- Suresh Kumar Prajapat
- National Institute of Pharmaceutical Education and Research, Export Promotion Industrial Park (EPIP) Zandaha Road, Hajipur, Bihar, India
| | - Krushna Ch Maharana
- National Institute of Pharmaceutical Education and Research, Export Promotion Industrial Park (EPIP) Zandaha Road, Hajipur, Bihar, India
| | - Sanjiv Singh
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Export Promotions Industrial Park (EPIP), Industrial Area, Dist: Vaishali, Hajipur, Bihar, 844102, India.
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Lietzke AC, Bealer E, Crumley K, King J, Stendahl AM, Zhu J, Pearson GL, Levi-D'Ancona E, Henry-Kanarek B, Reck EC, Arnipalli M, Sidarala V, Walker EM, Pennathur S, Madsen JGS, Shea LD, Soleimanpour SA. Limitations in mitochondrial programming restrain the differentiation and maturation of human stem cell-derived β cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.26.605318. [PMID: 39211191 PMCID: PMC11361182 DOI: 10.1101/2024.07.26.605318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Pluripotent stem cell (SC)-derived islets offer hope as a renewable source for β cell replacement for type 1 diabetes (T1D), yet functional and metabolic immaturity may limit their long-term therapeutic potential. Here, we show that limitations in mitochondrial transcriptional programming impede the formation and maturation of SC-derived β (SC-β) cells. Utilizing transcriptomic profiling, assessments of chromatin accessibility, mitochondrial phenotyping, and lipidomics analyses, we observed that SC-β cells exhibit reduced oxidative and mitochondrial fatty acid metabolism compared to primary human islets that are related to limitations in key mitochondrial transcriptional networks. Surprisingly, we found that reductions in glucose- stimulated mitochondrial respiration in SC-islets were not associated with alterations in mitochondrial mass, structure, or genome integrity. In contrast, SC-islets show limited expression of targets of PPARIZ and PPARγ, which regulate mitochondrial programming, yet whose functions in β cell differentiation are unknown. Importantly, treatment with WY14643, a potent PPARIZ agonist, induced expression of mitochondrial targets, improved insulin secretion, and increased the formation and maturation of SC-β cells both in vitro and following transplantation. Thus, mitochondrial programming promotes the differentiation and maturation of SC-β cells and may be a promising target to improve β cell replacement efforts for T1D.
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Yu D, Wan H, Tong C, Guang L, Chen G, Su J, Zhang L, Wang Y, Xiao Z, Zhai J, Yan L, Ma W, Liang K, Liu T, Wang Y, Peng Z, Luo L, Yu R, Li W, Qi H, Wang H, Shyh-Chang N. A multi-tissue metabolome atlas of primate pregnancy. Cell 2024; 187:764-781.e14. [PMID: 38306985 DOI: 10.1016/j.cell.2023.11.043] [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: 11/08/2022] [Revised: 08/08/2023] [Accepted: 11/29/2023] [Indexed: 02/04/2024]
Abstract
Pregnancy induces dramatic metabolic changes in females; yet, the intricacies of this metabolic reprogramming remain poorly understood, especially in primates. Using cynomolgus monkeys, we constructed a comprehensive multi-tissue metabolome atlas, analyzing 273 samples from 23 maternal tissues during pregnancy. We discovered a decline in metabolic coupling between tissues as pregnancy progressed. Core metabolic pathways that were rewired during primate pregnancy included steroidogenesis, fatty acid metabolism, and arachidonic acid metabolism. Our atlas revealed 91 pregnancy-adaptive metabolites changing consistently across 23 tissues, whose roles we verified in human cell models and patient samples. Corticosterone and palmitoyl-carnitine regulated placental maturation and maternal tissue progenitors, respectively, with implications for maternal preeclampsia, diabetes, cardiac hypertrophy, and muscle and liver regeneration. Moreover, we found that corticosterone deficiency induced preeclampsia-like inflammation, indicating the atlas's potential clinical value. Overall, our multi-tissue metabolome atlas serves as a framework for elucidating the role of metabolic regulation in female health during pregnancy.
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Affiliation(s)
- Dainan Yu
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Haifeng Wan
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Chao Tong
- State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Lu Guang
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Gang Chen
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Jiali Su
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Lan Zhang
- State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Yue Wang
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Zhenyu Xiao
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Jinglei Zhai
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Long Yan
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Wenwu Ma
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Kun Liang
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Taoyan Liu
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Yuefan Wang
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Zehang Peng
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Lanfang Luo
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Ruoxuan Yu
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Wei Li
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China.
| | - Hongbo Qi
- Department of Obstetrics and Gynecology, Women and Children's Hospital of Chongqing Medical University, Chongqing 401120, China.
| | - Hongmei Wang
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China.
| | - Ng Shyh-Chang
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China.
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11
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Gowtham L, Halder N, Angmo D, Singh SB, Jayasundar R, Dada T, Velpandian T. Untargeted metabolomics in the aqueous humor reveals the involvement of TAAR pathway in glaucoma. Exp Eye Res 2023; 234:109592. [PMID: 37474016 DOI: 10.1016/j.exer.2023.109592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 07/07/2023] [Accepted: 07/18/2023] [Indexed: 07/22/2023]
Abstract
Understanding the metabolic dysfunctions and underlying complex pathological mechanisms of neurodegeneration in glaucoma could help discover disease pathways, identify novel biomarkers, and rationalize newer therapeutics. Therefore, we aimed to investigate the local metabolomic alterations in the aqueous humor and plasma of primary glaucomatous patients. This study cohort comprised primary open-angle glaucoma (POAG), primary angle-closure glaucoma (PACG), and cataract control groups. Aqueous humor and plasma samples were collected from patients undergoing trabeculectomy or cataract surgery and subjected to high-resolution mass spectrometry (HRMS) analysis. Spectral information was processed, and the acquired data were subjected to uni-variate as well as multi-variate statistical analyses using MetaboAnalyst ver5.0. To further understand the localized metabolic abnormalities in glaucoma, metabolites affected in aqueous humor were distinguished from metabolites altered in plasma in this study. Nine and twelve metabolites were found to be significantly altered (p < 0.05, variable importance of projection >1 and log2 fold change ≥0.58/≤ -0.58) in the aqueous humor of PACG and POAG patients, respectively. The galactose and amino acid metabolic pathways were locally affected in the PACG and POAG groups, respectively. Based on the observation of the previous findings, gene expression profiles of trace amine-associated receptor-1 (TAAR-1) were studied in rat ocular tissues. The pharmacodynamics of TAAR-1 were explored in rabbits using topical administration of its agonist, β-phenyl-ethylamine (β-PEA). TAAR-1 was expressed in the rat's iris-ciliary body, optic nerve, lens, and cornea. β-PEA elicited a mydriatic response in rabbit eyes, without altering intraocular pressure. Targeted analysis of β-PEA levels in the aqueous humor of POAG patients showed an insignificant elevation. This study provides new insights regarding alterations in both localized and systemic metabolites in primary glaucomatous patients. This study also demonstrated the propensity of β-PEA to cause an adrenergic response through the TAAR-1 pathway.
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Affiliation(s)
- Lakshminarayanan Gowtham
- Department of Ocular Pharmacology and Pharmacy Division, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| | - Nabanita Halder
- Department of Ocular Pharmacology and Pharmacy Division, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| | - Dewang Angmo
- Department of Ophthalmology, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| | | | - Rama Jayasundar
- Department of NMR, All India Institute of Medical Sciences, New Delhi, India
| | - Tanuj Dada
- Department of Ophthalmology, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| | - Thirumurthy Velpandian
- Department of Ocular Pharmacology and Pharmacy Division, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India.
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12
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Targeted metabolomics detects a putatively diagnostic signature in plasma and dried blood spots from head and neck paraganglioma patients. Oncogenesis 2023; 12:10. [PMID: 36841802 PMCID: PMC9968333 DOI: 10.1038/s41389-023-00456-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 02/10/2023] [Accepted: 02/14/2023] [Indexed: 02/27/2023] Open
Abstract
Head and neck paragangliomas (HNPGLs), rare chemoresistant tumors curable only with surgery, are strongly influenced by genetic predisposition, hence patients and relatives require lifetime follow-up with MRI and/or PET-CT because of de novo disease risk. This entails exposure to electromagnetic/ionizing radiation, costs, and organizational challenges, because patients and relatives are scattered far from reference centers. Simplified first-line screening strategies are needed. We employed flow injection analysis tandem mass spectrometry, as used in newborn metabolic screening, to compare the plasma metabolic profile of HNPGL patients (59 samples, 56 cases) and healthy controls (24 samples, 24 cases). Principal Component Analysis (PCA) and Partial Least Discriminant Analysis (PLS-DA) highlighted a distinctive HNPGL signature, likely reflecting the anaplerotic conversion of the TCA cycle to glutaminolysis and catabolism of branched amino acids, DNA damage and deoxyadenosine (dAdo) accumulation, impairment of fatty acid oxidation, switch towards the Warburg effect and proinflammatory lysophosphatidylcholines (LPCs) signaling. Statistical analysis of the metabolites that most impacted on PLS-DA was extended to 10 acoustic neuroma and 2 cholesteatoma patients, confirming significant differences relative to the HNPGL plasma metabolomic profile. The best confusion matrix from the ROC curve built on 2 metabolites, dAdo and C26:0-LPC, provided specificity of 94.29% and sensitivity of 89.29%, with positive and negative predictive values of 96.2% and 84.6%, respectively. Analysis of dAdo and C26:0-LPC levels in dried venous and capillary blood confirmed that dAdo, likely deriving from 2'-deoxy-ATP accumulated in HNPGL cells following endogenous genotoxic damage, efficiently discriminated HNPGL patients from healthy controls and acoustic neuroma/cholesteatoma patients on easily manageable dried blood spots.
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13
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Li JM, Zhang Z, Kong A, Lai W, Xu W, Cao X, Zhao M, Li J, Shentu J, Guo X, Mai K, Ai Q. Dietary l-carnitine regulates liver lipid metabolism via simultaneously activating fatty acid β-oxidation and suppressing endoplasmic reticulum stress in large yellow croaker fed with high-fat diets. Br J Nutr 2023; 129:29-40. [PMID: 35473947 DOI: 10.1017/s0007114522000101] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Dietary l-carnitine (LC) is a nutritional factor that reduces liver lipid content. However, whether dietary LC can improve lipid metabolism via simultaneous activation of mitochondrial fatty acid (FA) β-oxidation and suppression of endoplasmic reticulum (ER) stress is still unknown. Large yellow croaker were fed with a high-fat diet (HFD) supplemented with dietary LC at 0, 1·2 or 2·4 ‰ for 10 weeks. The results indicated that a HFD supplemented with LC reduced the liver total lipid and TAG content and improved serum lipid profiles. LC supplementation administered to this fish increased the liver antioxidant capacity by decreasing serum and liver malondialdehyde levels and enhancing the liver antioxidant capacity, which then relieved the liver damage. Dietary LC increased the ATP dynamic process and mitochondrial number, decreased mitochondrial DNA damage and enhanced the protein expression of mitochondrial β-oxidation, biogenesis and mitophagy. Furthermore, dietary LC supplementation increased the expression of genes and proteins related to peroxisomal β-oxidation and biogenesis. Interestingly, feeding fish with LC-enriched diets decreased the protein levels indicative of ER stress, such as glucose-regulated protein 78, p-eukaryotic translational initiation factor 2a and activating transcription factor 6. Dietary LC supplementation downregulated mRNA expression relative to FA synthesis, reduced liver lipid and relieved liver damage through regulating β-oxidation and biogenesis of mitochondria and peroxisomes, as well as the ER stress pathway in fish fed with HFD. The present study provides the first evidence that dietary LC can improve lipid metabolism via simultaneously promoting FA β-oxidation capability and suppressing the ER stress pathway in fish.
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Affiliation(s)
- Jia-Min Li
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture and Rural Affairs, and The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, 5 Yushan Road, Qingdao, Shandong266003, People's Republic of China
| | - Zhou Zhang
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture and Rural Affairs, and The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, 5 Yushan Road, Qingdao, Shandong266003, People's Republic of China
| | - Adong Kong
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture and Rural Affairs, and The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, 5 Yushan Road, Qingdao, Shandong266003, People's Republic of China
| | - Wencong Lai
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture and Rural Affairs, and The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, 5 Yushan Road, Qingdao, Shandong266003, People's Republic of China
| | - Wenxuan Xu
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture and Rural Affairs, and The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, 5 Yushan Road, Qingdao, Shandong266003, People's Republic of China
| | - Xiufei Cao
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture and Rural Affairs, and The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, 5 Yushan Road, Qingdao, Shandong266003, People's Republic of China
| | - Manxi Zhao
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture and Rural Affairs, and The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, 5 Yushan Road, Qingdao, Shandong266003, People's Republic of China
| | - Jinbao Li
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture and Rural Affairs, and The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, 5 Yushan Road, Qingdao, Shandong266003, People's Republic of China
| | - Jikang Shentu
- Ningbo Academy of Ocean and Fishery, Ningbo, Zhejiang315012, People's Republic of China
| | - Xiaohua Guo
- Shandong Meijia Group Co. LTD, 1 Haibin Road, Rizhao, Shandong266003, People's Republic of China
| | - Kangsen Mai
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture and Rural Affairs, and The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, 5 Yushan Road, Qingdao, Shandong266003, People's Republic of China
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, 1 Wenhai Road, Qingdao, Shandong266237, People's Republic of China
| | - Qinghui Ai
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture and Rural Affairs, and The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, 5 Yushan Road, Qingdao, Shandong266003, People's Republic of China
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, 1 Wenhai Road, Qingdao, Shandong266237, People's Republic of China
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14
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Liu X, Tian X, Qinghong S, Sun H, Jing L, Tang X, Guo Z, Liu Y, Wang Y, Ma J, Na R, He C, Song W, Sun W. Characterization of LC-MS based urine metabolomics in healthy children and adults. PeerJ 2022; 10:e13545. [PMID: 35762019 PMCID: PMC9233480 DOI: 10.7717/peerj.13545] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 05/16/2022] [Indexed: 01/17/2023] Open
Abstract
Previous studies reported that sex and age could influence urine metabolomics, which should be considered in biomarker discovery. As a consequence, for the baseline of urine metabolomics characteristics, it becomes critical to avoid confounding effects in clinical cohort studies. In this study, we provided a comprehensive lifespan characterization of urine metabolomics in a cohort of 348 healthy children and 315 adults, aged 1 to 78 years, using liquid chromatography coupled with high resolution mass spectrometry. Our results suggest that sex-dependent urine metabolites are much greater in adults than in children. The pantothenate and CoA biosynthesis and alanine metabolism pathways were enriched in early life. Androgen and estrogen metabolism showed high activity during adolescence and youth stages. Pyrimidine metabolism was enriched in the geriatric stage. Based on the above analysis, metabolomic characteristics of each age stage were provided. This work could help us understand the baseline of urine metabolism characteristics and contribute to further studies of clinical disease biomarker discovery.
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Affiliation(s)
- Xiaoyan Liu
- Proteomics Research Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Xiaoyi Tian
- Department of Clinical Laboratory, National Center for Children’s Health, Beijing Children’s Hospital, Capital Medical University, Beijing, China,Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University & Capital Medical University, Beijing, China
| | - Shi Qinghong
- China-Japan Union Hospital of Jilin University, Jilin, China
| | - Haidan Sun
- Proteomics Research Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Li Jing
- Proteomics Research Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Xiaoyue Tang
- Proteomics Research Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Zhengguang Guo
- Proteomics Research Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Ying Liu
- Department of Clinical Laboratory, National Center for Children’s Health, Beijing Children’s Hospital, Capital Medical University, Beijing, China
| | - Yan Wang
- Department of Clinical Laboratory, National Center for Children’s Health, Beijing Children’s Hospital, Capital Medical University, Beijing, China
| | - Jie Ma
- Department of Clinical Laboratory, National Center for Children’s Health, Beijing Children’s Hospital, Capital Medical University, Beijing, China
| | - Ren Na
- Department of Clinical Laboratory, National Center for Children’s Health, Beijing Children’s Hospital, Capital Medical University, Beijing, China
| | - Chengyan He
- China-Japan Union Hospital of Jilin University, Jilin, China
| | - Wenqi Song
- Department of Clinical Laboratory, National Center for Children’s Health, Beijing Children’s Hospital, Capital Medical University, Beijing, China,Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University & Capital Medical University, Beijing, China
| | - Wei Sun
- Proteomics Research Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
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15
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Giudice D, Console L, Arduini A, Indiveri C. Overproduction, Purification, and Stability of the Functionally Active Human Carnitine Acetyl Transferase. Mol Biotechnol 2022; 64:1431-1440. [PMID: 35727434 PMCID: PMC9573857 DOI: 10.1007/s12033-022-00522-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 06/07/2022] [Indexed: 12/30/2022]
Abstract
Human Carnitine Acetyl Transferase (hCAT) reversibly catalyzes the transfer of the acetyl-moiety from acetyl-CoA to L-carnitine, modulating the acetyl-CoA/CoA ratio in mitochondria. Derangement of acetyl-CoA/CoA ratio leads to metabolic alterations that could result in the onset or worsening of pathological states. Due to the importance of CAT as a pharmacological target and to the European directive for reducing animal experimentation, we have pointed out a procedure to produce a recombinant, pure, and functional hCAT using the E. coli expression system. The cDNA encoding for the hCAT was cloned into the pH6EX3 vector. This construct was used to transform the E. coli Rosetta strain. The optimal conditions for the overexpression of the fully active hCAT include induction with a low concentration of IPTG (0.01 mM) and a low growth temperature (25 °C). The recombinant protein was purified from bacterial homogenate by affinity chromatography. The pure hCAT is very stable in an aqueous solution, retaining full activity for at least two months if stored at − 20 °C. These results could be helpful for a broad set of functional studies on hCAT, including drug-design applications.
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Affiliation(s)
- Deborah Giudice
- Department of Biology, Ecology and Earth Sciences (DiBEST), Laboratory of Biochemistry, Molecular Biotechnology and Molecular Biology, University of Calabria, Via P. Bucci 4c, 87036, Arcavacata di Rende, Italy
| | - Lara Console
- Department of Biology, Ecology and Earth Sciences (DiBEST), Laboratory of Biochemistry, Molecular Biotechnology and Molecular Biology, University of Calabria, Via P. Bucci 4c, 87036, Arcavacata di Rende, Italy.,Unical Cure S.R.L, Via P. Bucci 4d, 87036, Arcavacata di Rende, Italy
| | - Arduino Arduini
- Unical Cure S.R.L, Via P. Bucci 4d, 87036, Arcavacata di Rende, Italy
| | - Cesare Indiveri
- Department of Biology, Ecology and Earth Sciences (DiBEST), Laboratory of Biochemistry, Molecular Biotechnology and Molecular Biology, University of Calabria, Via P. Bucci 4c, 87036, Arcavacata di Rende, Italy. .,Unical Cure S.R.L, Via P. Bucci 4d, 87036, Arcavacata di Rende, Italy. .,Institute of Biomembranes, Bioenergetics and Molecular Biotechnology (IBIOM), National Research Council (CNR), Via Amendola 122/O, 70126, Bari, Italy.
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16
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Zhang N, Jia X, Fan S, Wu B, Wang S, OuYang B. NMR Characterization of Long-Chain Fatty Acylcarnitine Binding to the Mitochondrial Carnitine/Acylcarnitine Carrier. Int J Mol Sci 2022; 23:ijms23094608. [PMID: 35563000 PMCID: PMC9103206 DOI: 10.3390/ijms23094608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 04/10/2022] [Accepted: 04/14/2022] [Indexed: 02/01/2023] Open
Abstract
The mitochondrial carnitine/acylcarnitine carrier (CAC) transports short-, medium- and long-carbon chain acylcarnitines across the mitochondrial inner membrane in exchange for carnitine. How CAC recognizes the substrates with various fatty acyl groups, especially long-chain fatty acyl groups, remains unclear. Here, using nuclear magnetic resonance (NMR) technology, we have shown that the CAC protein reconstituted into a micelle system exhibits a typical six transmembrane structure of the mitochondrial carrier family. The chemical shift perturbation patterns of different fatty acylcarnitines suggested that the segment A76–G81 in CAC specifically responds to the long-chain fatty acylcarnitine. Molecular dynamics (MD) simulations of palmitoyl-L-carnitine inside the CAC channel showed the respective interaction and motion of the long-chain acylcarnitine in CAC at the cytosol-open state and matrix-open state. Our data provided a molecular-based understanding of CAC structure and transport mechanism.
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Affiliation(s)
- Ningning Zhang
- State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China;
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xiaopu Jia
- School of Pharmacy, Tianjin Medical University, Tianjin 300070, China; (X.J.); (S.F.)
| | - Shuai Fan
- School of Pharmacy, Tianjin Medical University, Tianjin 300070, China; (X.J.); (S.F.)
| | - Bin Wu
- National Facility for Protein Science in Shanghai, ZhangJiang Laboratory, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201203, China;
| | - Shuqing Wang
- School of Pharmacy, Tianjin Medical University, Tianjin 300070, China; (X.J.); (S.F.)
- Correspondence: (S.W.); (B.O.); Tel.: +86-021-54920143 (B.O.)
| | - Bo OuYang
- State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China;
- University of Chinese Academy of Sciences, Beijing 100049, China
- Correspondence: (S.W.); (B.O.); Tel.: +86-021-54920143 (B.O.)
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17
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Liao D, Liu X, Yuan X, Feng P, Ouyang Z, Liu Y, Li C. Clinical evidence of the effects of carnitine supplementation on body weight, glycemic control and serum lipids in women with polycystic ovary syndrome: a systematic review and meta-analysis. Gynecol Endocrinol 2022; 38:110-115. [PMID: 34633275 DOI: 10.1080/09513590.2021.1988559] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age. Several clinical trials have investigated the influence of carnitine on metabolic variables in PCOS, but have yielded conflicting results. This study aimed to summarize the clinical evidence of the effects of carnitine on weight management, glycemic and serum lipids controls in women with PCOS by conducting a meta-analysis of randomized control trials (RCTs). PubMed, Embase, Web of Sciences, Scopus, and the CENTRAL database were searched from inception to March 2021 for eligible articles. Study selection and assessment of quality were conducted independently by two investigators. Effect sizes for each outcome were reported with the weighted mean differences (WMDs) and 95% confidence intervals (CIs). The statistical heterogeneity of the included clinical trials was tested using the I2 statistic. Six studies with 672 PCOS participants were included for meta-analysis. Our results revealed that carnitine supplements significantly decreased total cholesterol, low-density lipoprotein-cholesterol, triglycerides, body weight, body mass index, hip circumference, and waist circumference (All p < .05). In addition, carnitine intervention also improved the levels of high-density lipoprotein cholesterol. However, no significant changes were seen in glucose homeostasis parameters. These results were stable after sensitivity analysis, and no significant publication biases were detected. Based on current evidence, carnitine supplementation in women with PCOS had beneficial effects on weight loss and lipid profiles. Further large-scale, well-designed RCTs are required to confirm these results.
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Affiliation(s)
- Dan Liao
- Department of Gynaecology, SSL Central Hospital of Dongguan, Dongguan Third People's Hospital, Affiliated Dongguan Shilong People's Hospital of Southern Medical University, Dongguan, Guangdong, China
| | - Xiaomei Liu
- Department of Gynaecology, SSL Central Hospital of Dongguan, Dongguan Third People's Hospital, Affiliated Dongguan Shilong People's Hospital of Southern Medical University, Dongguan, Guangdong, China
| | - Xiuying Yuan
- Department of Gynaecology, SSL Central Hospital of Dongguan, Dongguan Third People's Hospital, Affiliated Dongguan Shilong People's Hospital of Southern Medical University, Dongguan, Guangdong, China
| | - Poling Feng
- Department of Gynaecology, SSL Central Hospital of Dongguan, Dongguan Third People's Hospital, Affiliated Dongguan Shilong People's Hospital of Southern Medical University, Dongguan, Guangdong, China
| | - Zhiwei Ouyang
- Department of Gynaecology, SSL Central Hospital of Dongguan, Dongguan Third People's Hospital, Affiliated Dongguan Shilong People's Hospital of Southern Medical University, Dongguan, Guangdong, China
| | - Yanyan Liu
- Department of Gynaecology, SSL Central Hospital of Dongguan, Dongguan Third People's Hospital, Affiliated Dongguan Shilong People's Hospital of Southern Medical University, Dongguan, Guangdong, China
| | - Cuifen Li
- Department of Gynaecology, SSL Central Hospital of Dongguan, Dongguan Third People's Hospital, Affiliated Dongguan Shilong People's Hospital of Southern Medical University, Dongguan, Guangdong, China
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Ravindranath A, Sarma MS. Mitochondrial hepatopathy: Anticipated difficulties in management of fatty acid oxidation defects and urea cycle defects. World J Hepatol 2022; 14:180-194. [PMID: 35126847 PMCID: PMC8790400 DOI: 10.4254/wjh.v14.i1.180] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 08/19/2021] [Accepted: 12/02/2021] [Indexed: 02/06/2023] Open
Abstract
Fatty acid oxidation defects (FAOD) and urea cycle defects (UCD) are among the most common metabolic liver diseases. Management of these disorders is dotted with challenges as the strategies differ based on the type and severity of the defect. In those with FAOD the cornerstone of management is avoiding hypoglycemia which in turn prevents the triggering of fatty acid oxidation. In this review, we discuss the role of carnitine supplementation, dietary interventions, newer therapies like triheptanoin, long-term treatment and approach to positive newborn screening. In UCD the general goal is to avoid excessive protein intake and indigenous protein breakdown. However, one size does not fit all and striking the right balance between avoiding hyperammonemia and preventing deficiencies of essential nutrients is a formidable task. Practical issues during the acute presentation including differential diagnosis of hyperammonemia, dietary dilemmas, the role of liver transplantation, management of the asymptomatic individual and monitoring are described in detail. A multi-disciplinary team consisting of hepatologists, metabolic specialists and dieticians is required for optimum management and improvement in quality of life for these patients.
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Affiliation(s)
- Aathira Ravindranath
- Division of Pediatric Gastroenterology, Institute of Gastrointestinal Sciences, Apollo BGS Hospitals, Mysore 570023, Karnataka, India
| | - Moinak Sen Sarma
- Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
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Takahashi A. The pathophysiology of leg cramping during dialysis and the use of carnitine in its treatment. Physiol Rep 2021; 9:e15114. [PMID: 34762357 PMCID: PMC8582296 DOI: 10.14814/phy2.15114] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 10/16/2021] [Accepted: 10/22/2021] [Indexed: 11/24/2022] Open
Abstract
Leg cramping is a common side effect of hemodialysis, and this is frequently treated by the administration of carnitine, but this is not effective in every patient. Alkalosis is a key component of the etiology of leg cramping during hemodialysis sessions. This is mediated through the binding of calcium ions to serum albumin, which causes hypocalcemia, and an increase in the release of calcium ions from the sarcoplasmic reticulum. Normally the calcium pump on the sarcoplasmic reticulum consumes ATP and quickly reuptakes the released calcium ions, which rapidly stops excessive muscle contractions. Thus, carnitine deficiency results in prolonged muscle contraction because of ATP depletion. However, during ATP production, carnitine is only involved up to the stage of acyl-CoA transport into mitochondria, and for the efficient generation of ATP, the subsequent metabolism of acyl-CoA is also important. For example, β-oxidation and the tricarboxylic acid cycle may be affected by a deficiency of water-soluble vitamins and the electron transport chain requires coenzyme Q10, but statins inhibit its production. The resulting accumulation of excess long-chain acyl-CoA in mitochondria inhibits enzymes involved in energy production. Thus, carnitine administration may be used more effectively if clinicians are aware of its specific physiologic roles.
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20
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Lambie M, Bonomini M, Davies SJ, Accili D, Arduini A, Zammit V. Insulin resistance in cardiovascular disease, uremia, and peritoneal dialysis. Trends Endocrinol Metab 2021; 32:721-730. [PMID: 34266706 PMCID: PMC8893168 DOI: 10.1016/j.tem.2021.06.001] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 06/03/2021] [Accepted: 06/15/2021] [Indexed: 02/09/2023]
Abstract
Diabetic nephropathy is highly correlated with the occurrence of other complications of type 1 diabetes (T1D) and type 2 diabetes (T2D) mellitus; for example, hypertension with cardiovascular disease (CVD) being the most frequent cause of death in patients with end-stage renal disease and undergoing renal dialysis. Hyperglycemia and insulin resistance (IR) are responsible for the micro- and macrovascular complications of diabetes through different mechanisms. In particular, IR plays a key role in the etiology of atherosclerosis in both diabetic and non-diabetic patients. IR - exacerbated by organ-level selectivity - is more important than glycemic control per se in determining cardiovascular outcomes. This may be exacerbated by the fact that IR is organ and pathway specific due to the only selective loss of sensitivity to insulin action of specific pathways/processes. Therefore, it is counterintuitive that the use of peritoneal dialysis (PD) in (frequently) diabetic renal disease patients should involve their exposure to high daily doses of glucose peritoneally. In view of the controversy about the causal association between glucose load and CVD in PD patients, we discuss the role that selective IR may play in the progression of CVD in diabetic renal end-stage patients. In discussing these associations, we propose that reducing glucose exposure in PD solutions may be beneficial especially if coupled with strategies that address IR directly, and the avoidance of excessive use of insulin treatment in T2D.
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Affiliation(s)
- Mark Lambie
- Faculty of Medicine and Health Sciences, Keele University, Keele ST5 5BG, UK
| | - Mario Bonomini
- Department of Medicine, G. d'Annunzio University, Chieti 66100, Italy
| | - Simon J Davies
- Faculty of Medicine and Health Sciences, Keele University, Keele ST5 5BG, UK
| | - Domenico Accili
- Columbia University College of Physicians and Surgeons, Department of Medicine, New York, NY 10032, USA
| | | | - Victor Zammit
- Translational & Experimental Medicine, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK.
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21
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How to Improve the Biocompatibility of Peritoneal Dialysis Solutions (without Jeopardizing the Patient's Health). Int J Mol Sci 2021; 22:ijms22157955. [PMID: 34360717 PMCID: PMC8347640 DOI: 10.3390/ijms22157955] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/21/2021] [Accepted: 07/24/2021] [Indexed: 12/23/2022] Open
Abstract
Peritoneal dialysis (PD) is an important, if underprescribed, modality for the treatment of patients with end-stage kidney disease. Among the barriers to its wider use are the deleterious effects of currently commercially available glucose-based PD solutions on the morphological integrity and function of the peritoneal membrane due to fibrosis. This is primarily driven by hyperglycaemia due to its effects, through multiple cytokine and transcription factor signalling-and their metabolic sequelae-on the synthesis of collagen and other extracellular membrane components. In this review, we outline these interactions and explore how novel PD solution formulations are aimed at utilizing this knowledge to minimise the complications associated with fibrosis, while maintaining adequate rates of ultrafiltration across the peritoneal membrane and preservation of patient urinary volumes. We discuss the development of a new generation of reduced-glucose PD solutions that employ a variety of osmotically active constituents and highlight the biochemical rationale underlying optimization of oxidative metabolism within the peritoneal membrane. They are aimed at achieving optimal clinical outcomes and improving the whole-body metabolic profile of patients, particularly those who are glucose-intolerant, insulin-resistant, or diabetic, and for whom daily exposure to high doses of glucose is contraindicated.
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22
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Ghaffari MH, Alaedin MT, Sadri H, Hofs I, Koch C, Sauerwein H. Longitudinal changes in fatty acid metabolism and in the mitochondrial protein import system in overconditioned and normal conditioned cows: A transcriptional study using microfluidic quantitative PCR. J Dairy Sci 2021; 104:10338-10354. [PMID: 34147221 DOI: 10.3168/jds.2021-20237] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 05/03/2021] [Indexed: 12/22/2022]
Abstract
This study investigated the effect of body condition around calving on the hepatic mRNA expression of genes involved in fatty acid (FA) metabolism and mitochondrial protein import system of dairy cows during the transition period. Fifteen weeks before their anticipated calving date, 38 multiparous Holstein cows were selected based on their current and previous body condition scores (BCS) and allocated to either a high or a normal BCS group (19 cows each). They received different diets to reach targeted differences in BCS and backfat thickness (BFT) until dry-off. At dry-off, normal BCS (NBCS) cows had a BCS <3.5 and BFT <1.2 cm, and the high BCS (HBCS) cows had a BCS >3.75 and BFT >1.4 cm. The expression of targeted genes in the liver was assayed by reverse-transcription quantitative real-time PCR using microfluidics integrated fluidic circuit chips on a subset of 5 cows from each group. Liver biopsies were collected at d -49, +3, +21, and +84 relative to parturition. The mRNA abundance of 47 genes related to lipid metabolism including carnitine metabolism, FA uptake and transport, lipoprotein export, carnitine metabolism, mitochondrial and proximal FA oxidation, ketogenesis, AMP-activated protein kinase/mammalian target of rapamycin pathway, and mitochondrial protein import system was assessed in liver tissue. The mRNA abundances of FA binding protein (FABP)6 (in both groups), and FABP1 and solute carrier family 22 member 5 (SLC22A5) in HBCS were upregulated (>1.5-fold change, FC) in early lactation (at d +3 and +21 postpartum) compared with antepartum (d -49), indicating promoted FA uptake and intracellular transport in the liver due to the metabolic adaptations of elevated lipo-mobilization after parturition. The upregulation of SLC22A5 and SLC25A20 after parturition was more pronounced in HBCS than in NBCS cows, suggesting a need for increasing the capacity of FA uptake, and FA transport into the hepatocyte. The increased mRNA abundance of carnitine palmitoyltransferase 1A, after parturition and to a greater extent in HBCS (FC = 4.1) versus NBCS (FC = 2.1) indicates a physiological increase in the capacity of long-chain fatty acyl-CoA entry into the liver mitochondria compared with antepartum (ap; d -49 relative to calving). The greater hepatic mRNA abundance of genes encoding enzymes involved in mitochondrial FA oxidation in HBCS than in NBCS points to an increased rate of mitochondrial β-oxidation. The hepatic mRNA abundance of 3-hydroxy-3-methylglutaryl-CoA synthase 2 and 3-hydroxy-3-methylglutaryl-CoA were upregulated after parturition (d +21/d +3 pp) to a greater extent in HBCS than in NBCS cows, indicating that excess acetyl-CoA generated via β-oxidation was increasingly used for ketogenesis. We observed for the first time that the mRNA abundance of genes involved in the translocase of the inner membrane (TIM) complex (TIM22 and TIM23) in the hepatic mitochondrial protein import system were undergoing distinct changes during the transition from late pregnancy to early lactation in dairy cows. Even though sample size in this study was relatively small, the results support that overconditioning around calving may contribute to mitochondrial FA overload and greater ketogenesis at the level of transcription in the liver of early lactation cows.
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Affiliation(s)
- Morteza H Ghaffari
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany.
| | - Mohamad Taher Alaedin
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany
| | - Hassan Sadri
- Department of Clinical Science, Faculty of Veterinary Medicine, University of Tabriz, 516616471 Tabriz, Iran
| | - Inga Hofs
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany
| | - Christian Koch
- Educational and Research Center for Animal Husbandry, Hofgut Neumuehle, 67728 Muenchweiler an der Alsenz, Germany
| | - Helga Sauerwein
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany
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23
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Carnitine Responsive Migraine Headache Syndrome: Case Report and Review of the Literature. Curr Pain Headache Rep 2021; 25:26. [PMID: 33755806 DOI: 10.1007/s11916-021-00936-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/19/2021] [Indexed: 12/30/2022]
Abstract
PURPOSE OF REVIEW To review carnitine's role in migraine and headache, present a case of a patient with intractable chronic migraine refractory to medications but exquisitely responsive to mitochondrial cofactors with a particularly prompt response to L-carnitine supplementation with dose response, and suggest scenarios where L-carnitine could be considered for prophylactic treatment in migraine and intractable headache with migraine features. RECENT FINDINGS Multiple treatments modalities are used to treat migraine, including nutraceutical therapies. Mitochondrial supplements are often used to treat migraine, based on controlled trials. One of the nutraceutical therapies used in neurological and non-neurological conditions is L-carnitine. A few studies have examined the effect of carnitine in patients with migraine. We present a case of a patient with chronic migraine-like headaches found to have carnitine deficiency whose headaches greatly improved with carnitine supplementation. This case suggests that secondary carnitine deficiency may cause chronic migraine. Energy deficiency states occur with migraine, and replenishment of energy substrates has demonstrated some improvement in migraine. Recent studies suggest that L-carnitine with other mitochondrial cofactors may be migraine preventives. The exact link between carnitine and migraine is unknown. Perhaps carnitine deficiency should be in the differential for refractory migraine. Supplementation with L-carnitine merits exploration as a nutraceutical treatment of chronic migraine. Our case suggests that there may be a dose-dependent response to L-carnitine.
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24
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Potential Role of L-Carnitine in Autism Spectrum Disorder. J Clin Med 2021; 10:jcm10061202. [PMID: 33805796 PMCID: PMC8000371 DOI: 10.3390/jcm10061202] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/12/2021] [Accepted: 03/12/2021] [Indexed: 12/17/2022] Open
Abstract
L-carnitine plays an important role in the functioning of the central nervous system, and especially in the mitochondrial metabolism of fatty acids. Altered carnitine metabolism, abnormal fatty acid metabolism in patients with autism spectrum disorder (ASD) has been documented. ASD is a complex heterogeneous neurodevelopmental condition that is usually diagnosed in early childhood. Patients with ASD require careful classification as this heterogeneous clinical category may include patients with an intellectual disability or high functioning, epilepsy, language impairments, or associated Mendelian genetic conditions. L-carnitine participates in the long-chain oxidation of fatty acids in the brain, stimulates acetylcholine synthesis (donor of the acyl groups), stimulates expression of growth-associated protein-43, prevents cell apoptosis and neuron damage and stimulates neurotransmission. Determination of L-carnitine in serum/plasma and analysis of acylcarnitines in a dried blood spot may be useful in ASD diagnosis and treatment. Changes in the acylcarnitine profiles may indicate potential mitochondrial dysfunctions and abnormal fatty acid metabolism in ASD children. L-carnitine deficiency or deregulation of L-carnitine metabolism in ASD is accompanied by disturbances of other metabolic pathways, e.g., Krebs cycle, the activity of respiratory chain complexes, indicative of mitochondrial dysfunction. Supplementation of L-carnitine may be beneficial to alleviate behavioral and cognitive symptoms in ASD patients.
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25
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Tang HY, Wang CH, Ho HY, Lin JF, Lo CJ, Huang CY, Cheng ML. Characteristic of Metabolic Status in Heart Failure and Its Impact in Outcome Perspective. Metabolites 2020; 10:E437. [PMID: 33138215 PMCID: PMC7692076 DOI: 10.3390/metabo10110437] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 10/20/2020] [Accepted: 10/28/2020] [Indexed: 12/30/2022] Open
Abstract
Metabolic alterations have been documented in peripheral tissues in heart failure (HF). Outcomes might be improved by early identification of risk. However, the prognostic information offered is still far from enough. We hypothesized that plasma metabolic profiling potentially provides risk stratification for HF patients. Of 61 patients hospitalized due to acute decompensated HF, 31 developed HF-related events in one year after discharge (Event group), and the other 30 patients did not (Non-event group). The plasma collected during hospital admission was analyzed by an ultra-high performance liquid chromatography time-of-flight mass spectrometry (UPLC-TOFMS)-based metabolomic approach. The orthogonal projection to latent structure discriminant analysis (OPLS-DA) reveals that the metabolomics profile is able to distinguish between events in HF. Levels of 19 metabolites including acylcarnitines, lysophospholipids, dimethylxanthine, dimethyluric acid, tryptophan, phenylacetylglutamine, and hypoxanthine are significantly different between patients with and without event (p < 0.05). Established risk prediction models of event patients by using receiver operating characteristics analysis reveal that the combination of tetradecenoylcarnitine, dimethylxanthine, phenylacetylglutamine, and hypoxanthine has better discrimination than B-type natriuretic peptide (BNP) (AUC 0.871 and 0.602, respectively). These findings suggest that metabolomics-derived metabolic profiling have the potential of identifying patients with high risk of HF-related events and provide insights related to HF outcome.
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Affiliation(s)
- Hsiang-Yu Tang
- Metabolomics Core Laboratory, Healthy Aging Research Center, Chang Gung University, Taoyuan City 33302, Taiwan; (H.-Y.T.); (J.-F.L.); (C.-J.L.); (C.-Y.H.)
| | - Chao-Hung Wang
- Heart Failure Research Center, Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung City 20401, Taiwan;
| | - Hung-Yao Ho
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan;
- Clinical Metabolomics Core Laboratory, Chang Gung Memorial Hospital, Taoyuan City 33302, Taiwan
| | - Jui-Fen Lin
- Metabolomics Core Laboratory, Healthy Aging Research Center, Chang Gung University, Taoyuan City 33302, Taiwan; (H.-Y.T.); (J.-F.L.); (C.-J.L.); (C.-Y.H.)
| | - Chi-Jen Lo
- Metabolomics Core Laboratory, Healthy Aging Research Center, Chang Gung University, Taoyuan City 33302, Taiwan; (H.-Y.T.); (J.-F.L.); (C.-J.L.); (C.-Y.H.)
| | - Cheng-Yu Huang
- Metabolomics Core Laboratory, Healthy Aging Research Center, Chang Gung University, Taoyuan City 33302, Taiwan; (H.-Y.T.); (J.-F.L.); (C.-J.L.); (C.-Y.H.)
| | - Mei-Ling Cheng
- Metabolomics Core Laboratory, Healthy Aging Research Center, Chang Gung University, Taoyuan City 33302, Taiwan; (H.-Y.T.); (J.-F.L.); (C.-J.L.); (C.-Y.H.)
- Clinical Metabolomics Core Laboratory, Chang Gung Memorial Hospital, Taoyuan City 33302, Taiwan
- Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan
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26
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Post A, Said MY, Gomes-Neto AW, Minović I, Groothof D, Swarte JC, Boer T, Kema IP, Heiner-Fokkema MR, Franssen CFM, Bakker SJL. Urinary 3-hydroxyisovaleryl carnitine excretion, protein energy malnutrition and risk of all-cause mortality in kidney transplant recipients: Results from the TransplantLines cohort studies. Clin Nutr 2020; 40:2109-2120. [PMID: 33071013 DOI: 10.1016/j.clnu.2020.09.035] [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: 03/14/2020] [Revised: 08/17/2020] [Accepted: 09/28/2020] [Indexed: 10/23/2022]
Abstract
BACKGROUND Leucine is an essential amino acid and a potent stimulator of muscle protein synthesis. Since muscle wasting is a major risk factor for mortality in kidney transplant recipients (KTR), dietary leucine intake might be linked to long-term mortality. Urinary 3-hydroxyisovaleryl carnitine (3-HIC) excretion, a functional marker of marginal biotin deficiency, may also serve as a marker for dietary leucine intake. OBJECTIVE In this study we aimed to investigate the cross-sectional determinants of urinary 3-HIC excretion and to prospectively investigate the association of urinary 3-HIC excretion with all-cause mortality in KTR. DESIGN Urinary 3-HIC excretion and plasma biotin were measured in a longitudinal cohort of 694 stable KTR. Cross-sectional and prospective analyses were performed using ordinary least squares linear regression analyses and Cox regression analyses, respectively. RESULTS In KTR (57% male, 53 ± 13 years, estimated glomerular filtration rate 45 ± 19 mL/min/1.73 m2), urinary 3-HIC excretion (0.80 [0.57-1.16] μmol/24 h) was significantly associated with plasma biotin (std. β = -0.17; P < 0.001). Subsequent adjustment for potential covariates revealed urinary creatinine excretion (std. β = 0.24; P < 0.001) and urinary urea excretion (std. β = 0.53; P < 0.001) as the primary determinant of urinary 3-HIC excretion. Whereas plasma biotin explained only 1% of the variance in urinary 3-HIC excretion, urinary urea excretion explained >45%. During median follow-up for 5.4 [4.8-6.1] years, 150 (22%) patients died. Log2-transformed urinary 3-HIC excretion was inversely associated with all-cause mortality (HR: 0.52 [0.43-0.63]; P < 0.001). This association was independent of potential confounders. CONCLUSIONS Urinary 3-HIC excretion more strongly serves as a marker of leucine intake than of biotin status. A higher urinary 3-HIC excretion is associated with a lower risk of all-cause mortality. Future studies are warranted to explore the underlying mechanism. TRIAL REGISTRATION ID NCT02811835. TRIAL REGISTRATION URL: https://clinicaltrials.gov/ct2/show/NCT02811835.
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Affiliation(s)
- Adrian Post
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, 9713 GZ, Groningen, the Netherlands.
| | - M Yusof Said
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, 9713 GZ, Groningen, the Netherlands.
| | - Antonio W Gomes-Neto
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, 9713 GZ, Groningen, the Netherlands.
| | - Isidor Minović
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
| | - Dion Groothof
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, 9713 GZ, Groningen, the Netherlands.
| | - J Casper Swarte
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, 9713 GZ, Groningen, the Netherlands.
| | - Theo Boer
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
| | - Ido P Kema
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
| | - M Rebecca Heiner-Fokkema
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
| | - Casper F M Franssen
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, 9713 GZ, Groningen, the Netherlands.
| | - Stephan J L Bakker
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, 9713 GZ, Groningen, the Netherlands.
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Pagano G, Pallardó FV, Lyakhovich A, Tiano L, Fittipaldi MR, Toscanesi M, Trifuoggi M. Aging-Related Disorders and Mitochondrial Dysfunction: A Critical Review for Prospect Mitoprotective Strategies Based on Mitochondrial Nutrient Mixtures. Int J Mol Sci 2020; 21:ijms21197060. [PMID: 32992778 PMCID: PMC7582285 DOI: 10.3390/ijms21197060] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/20/2020] [Accepted: 09/22/2020] [Indexed: 12/16/2022] Open
Abstract
A number of aging-related disorders (ARD) have been related to oxidative stress (OS) and mitochondrial dysfunction (MDF) in a well-established body of literature. Most studies focused on cardiovascular disorders (CVD), type 2 diabetes (T2D), and neurodegenerative disorders. Counteracting OS and MDF has been envisaged to improve the clinical management of ARD, and major roles have been assigned to three mitochondrial cofactors, also termed mitochondrial nutrients (MNs), i.e., α-lipoic acid (ALA), Coenzyme Q10 (CoQ10), and carnitine (CARN). These cofactors exert essential–and distinct—roles in mitochondrial machineries, along with strong antioxidant properties. Clinical trials have mostly relied on the use of only one MN to ARD-affected patients as, e.g., in the case of CoQ10 in CVD, or of ALA in T2D, possibly with the addition of other antioxidants. Only a few clinical and pre-clinical studies reported on the administration of two MNs, with beneficial outcomes, while no available studies reported on the combined administration of three MNs. Based on the literature also from pre-clinical studies, the present review is to recommend the design of clinical trials based on combinations of the three MNs.
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Affiliation(s)
- Giovanni Pagano
- Department of Chemical Sciences, Federico II Naples University, I-80126 Naples, Italy; (M.T.); (M.T.)
- Correspondence:
| | - Federico V. Pallardó
- Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia-INCLIVA, CIBERER, E-46010 Valencia, Spain;
| | - Alex Lyakhovich
- Vall d’Hebron Institut de Recerca, E-08035 Barcelona, Catalunya, Spain;
- Institute of Molecular Biology and Biophysics of the “Federal Research Center of Fundamental and Translational Medicine”, Novosibirsk 630117, Russia
| | - Luca Tiano
- Department of Life and Environmental Sciences, Polytechnical University of Marche, I-60100 Ancona, Italy;
| | - Maria Rosa Fittipaldi
- Internal Medicine Unit, San Francesco d’Assisi Hospital, I-84020 Oliveto Citra (SA), Italy;
| | - Maria Toscanesi
- Department of Chemical Sciences, Federico II Naples University, I-80126 Naples, Italy; (M.T.); (M.T.)
| | - Marco Trifuoggi
- Department of Chemical Sciences, Federico II Naples University, I-80126 Naples, Italy; (M.T.); (M.T.)
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28
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Kim S, Jang WJ, Yu H, Kim J, Lee SK, Jeong CH, Lee S. Revealing Metabolic Perturbation Following Heavy Methamphetamine Abuse by Human Hair Metabolomics and Network Analysis. Int J Mol Sci 2020; 21:E6041. [PMID: 32839415 PMCID: PMC7503996 DOI: 10.3390/ijms21176041] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 08/14/2020] [Accepted: 08/17/2020] [Indexed: 12/13/2022] Open
Abstract
Methamphetamine (MA) is a highly addictive central nervous system stimulant. Drug addiction is not a static condition but rather a chronically relapsing disorder. Hair is a valuable and stable specimen for chronic toxicological monitoring as it retains toxicants and metabolites. The primary focus of this study was to discover the metabolic effects encompassing diverse pathological symptoms of MA addiction. Therefore, metabolic alterations were investigated in human hair following heavy MA abuse using both targeted and untargeted mass spectrometry and through integrated network analysis. The statistical analyses (t-test, variable importance on projection score, and receiver-operator characteristic curve) demonstrated that 32 metabolites (in targeted metabolomics) as well as 417 and 224 ion features (in positive and negative ionization modes of untargeted metabolomics, respectively) were critically dysregulated. The network analysis showed that the biosynthesis or metabolism of lipids, such as glycosphingolipids, sphingolipids, glycerophospholipids, and ether lipids, as well as the metabolism of amino acids (glycine, serine and threonine; cysteine and methionine) is affected by heavy MA abuse. These findings reveal crucial metabolic effects caused by MA addiction, with emphasis on the value of human hair as a diagnostic specimen for determining drug addiction, and will aid in identifying robust diagnostic markers and therapeutic targets.
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Affiliation(s)
- Suji Kim
- College of Pharmacy, Keimyung University, 1095 Dalgubeoldaero, Dalseo-gu, Daegu 42601, Korea; (S.K.); (W.-J.J.); (H.Y.)
| | - Won-Jun Jang
- College of Pharmacy, Keimyung University, 1095 Dalgubeoldaero, Dalseo-gu, Daegu 42601, Korea; (S.K.); (W.-J.J.); (H.Y.)
| | - Hyerim Yu
- College of Pharmacy, Keimyung University, 1095 Dalgubeoldaero, Dalseo-gu, Daegu 42601, Korea; (S.K.); (W.-J.J.); (H.Y.)
| | - Jihyun Kim
- National Forensic Service, 10, Ipchun-ro, Wonju, Gangwon-do 26460, Korea; (J.K.); (S.-K.L.)
| | - Sang-Ki Lee
- National Forensic Service, 10, Ipchun-ro, Wonju, Gangwon-do 26460, Korea; (J.K.); (S.-K.L.)
| | - Chul-Ho Jeong
- College of Pharmacy, Keimyung University, 1095 Dalgubeoldaero, Dalseo-gu, Daegu 42601, Korea; (S.K.); (W.-J.J.); (H.Y.)
| | - Sooyeun Lee
- College of Pharmacy, Keimyung University, 1095 Dalgubeoldaero, Dalseo-gu, Daegu 42601, Korea; (S.K.); (W.-J.J.); (H.Y.)
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Structure-based virtual screening to identify novel carnitine acetyltransferase activators. J Mol Graph Model 2020; 100:107692. [PMID: 32759041 DOI: 10.1016/j.jmgm.2020.107692] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 06/28/2020] [Accepted: 07/06/2020] [Indexed: 12/22/2022]
Abstract
Carnitine acetyltransferase (CAT) is an attractive therapeutic target against fibrosis. We have identified few CAT activators through structure-based virtual screening followed by molecular dynamics simulations for assessment of the binding mode. A set of 10,000 drug-like molecules properly filtered from an initial chemical library of 13 M commercially available compounds were docked into the active site. Virtual hits were selected for in vitro experimental testing to validate the computational findings and the stability of the predicted complexes was evaluated by molecular dynamics simulations. Applied protocol led to the identification of three hit compounds showing promising activity, which can serve as potential scaffolds for further structural optimization. This is the first report of successful discovery of CAT activators through the use of structure-based virtual screening.
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The osmo-metabolic approach: a novel and tantalizing glucose-sparing strategy in peritoneal dialysis. J Nephrol 2020; 34:503-519. [PMID: 32767274 PMCID: PMC8036224 DOI: 10.1007/s40620-020-00804-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Accepted: 07/09/2020] [Indexed: 02/07/2023]
Abstract
Peritoneal dialysis (PD) is a viable but under-prescribed treatment for uremic patients. Concerns about its use include the bio-incompatibility of PD fluids, due to their potential for altering the functional and anatomical integrity of the peritoneal membrane. Many of these effects are thought to be due to the high glucose content of these solutions, with attendant issues of products generated during heat treatment of glucose-containing solutions. Moreover, excessive intraperitoneal absorption of glucose from the dialysate has many potential systemic metabolic effects. This article reviews the efforts to develop alternative PD solutions that obviate some of these side effects, through the replacement of part of their glucose content with other osmolytes which are at least as efficient in removing fluids as glucose, but less impactful on patient metabolism. In particular, we will summarize clinical studies on the use of alternative osmotic ingredients that are commercially available (icodextrin and amino acids) and preclinical studies on alternative solutions under development (taurine, polyglycerol, carnitine and xylitol). In addition to the expected benefit of a glucose-sparing approach, we describe an ‘osmo-metabolic’ approach in formulating novel PD solutions, in which there is the possibility of exploiting the pharmaco-metabolic properties of some of the osmolytes to attenuate the systemic side effects due to glucose. This approach has the potential to ameliorate pre-existing co-morbidities, including insulin resistance and type-2 diabetes, which have a high prevalence in the dialysis population, including in PD patients.
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31
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Kepka A, Ochocinska A, Borzym-Kluczyk M, Skorupa E, Stasiewicz-Jarocka B, Chojnowska S, Waszkiewicz N. Preventive Role of L-Carnitine and Balanced Diet in Alzheimer's Disease. Nutrients 2020; 12:E1987. [PMID: 32635400 PMCID: PMC7400709 DOI: 10.3390/nu12071987] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 06/25/2020] [Accepted: 06/29/2020] [Indexed: 02/06/2023] Open
Abstract
The prevention or alleviation of neurodegenerative diseases, including Alzheimer's disease (AD), is a challenge for contemporary health services. The aim of this study was to review the literature on the prevention or alleviation of AD by introducing an appropriate carnitine-rich diet, dietary carnitine supplements and the MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) diet, which contains elements of the Mediterranean diet and the Dietary Approaches to Stop Hypertension (DASH) diet. L-carnitine (LC) plays a crucial role in the energetic metabolism of the cell. A properly balanced diet contains a substantial amount of LC as well as essential amino acids and microelements taking part in endogenous carnitine synthesis. In healthy people, carnitine biosynthesis is sufficient to prevent the symptoms of carnitine deficiency. In persons with dysfunction of mitochondria, e.g., with AD connected with extensive degeneration of the brain structures, there are often serious disturbances in the functioning of the whole organism. The Mediterranean diet is characterized by a high consumption of fruits and vegetables, cereals, nuts, olive oil, and seeds as the major source of fats, moderate consumption of fish and poultry, low to moderate consumption of dairy products and alcohol, and low intake of red and processed meat. The introduction of foodstuffs rich in carnitine and the MIND diet or carnitine supplementation of the AD patients may improve their functioning in everyday life.
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Affiliation(s)
- Alina Kepka
- Department of Biochemistry, Radioimmunology and Experimental Medicine, The Children’s Memorial Health Institute, 04-730 Warsaw, Poland;
| | - Agnieszka Ochocinska
- Department of Biochemistry, Radioimmunology and Experimental Medicine, The Children’s Memorial Health Institute, 04-730 Warsaw, Poland;
| | - Małgorzata Borzym-Kluczyk
- Department of Pharmaceutical Biochemistry, Medical University of Bialystok, 15-089 Bialystok, Poland;
| | - Ewa Skorupa
- Department of Biochemistry, Radioimmunology and Experimental Medicine, The Children’s Memorial Health Institute, 04-730 Warsaw, Poland;
| | | | - Sylwia Chojnowska
- Faculty of Health Sciences, Lomza State University of Applied Sciences, 18-400 Lomza, Poland;
| | - Napoleon Waszkiewicz
- Department of Psychiatry, Medical University of Bialystok, 15-089 Bialystok, Poland;
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Hanai T, Shiraki M, Imai K, Suetugu A, Takai K, Shimizu M. Usefulness of Carnitine Supplementation for the Complications of Liver Cirrhosis. Nutrients 2020; 12:nu12071915. [PMID: 32610446 PMCID: PMC7401279 DOI: 10.3390/nu12071915] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 06/22/2020] [Accepted: 06/23/2020] [Indexed: 02/07/2023] Open
Abstract
Carnitine is a vitamin-like substance that regulates lipid metabolism and energy production. Carnitine homeostasis is mainly regulated by dietary intake and biosynthesis in the organs, including the skeletal muscle and the liver. Therefore, liver cirrhotic patients with reduced food intake, malnutrition, biosynthetic disorder, and poor storage capacity of carnitine in the skeletal muscle and liver are more likely to experience carnitine deficiency. In particular, liver cirrhotic patients with sarcopenia are at a high risk for developing carnitine deficiency. Carnitine deficiency impairs the important metabolic processes of the liver, such as gluconeogenesis, fatty acid metabolism, albumin biosynthesis, and ammonia detoxification by the urea cycle, and causes hypoalbuminemia and hyperammonemia. Carnitine deficiency should be suspected in liver cirrhotic patients with severe malaise, hepatic encephalopathy, sarcopenia, muscle cramps, and so on. Importantly, the blood carnitine level does not always decrease in patients with liver cirrhosis, and it sometimes exceeds the normal level. Therefore, patients with liver cirrhosis should be treated as if they are in a state of relative carnitine deficiency at the liver, skeletal muscle, and mitochondrial levels, even if the blood carnitine level is not decreased. Recent clinical trials have revealed the effectiveness of carnitine supplementation for the complications of liver cirrhosis, such as hepatic encephalopathy, sarcopenia, and muscle cramps. In conclusion, carnitine deficiency is not always rare in liver cirrhosis, and it requires constant attention in the daily medical care of this disease. Carnitine supplementation might be an important strategy for improving the quality of life of patients with liver cirrhosis.
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Affiliation(s)
- Tatsunori Hanai
- Correspondence: ; Tel.: +81-(58)-230-6308; Fax: +81-(58)-230-6310
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Vamecq J, Papegay B, Nuyens V, Boogaerts J, Leo O, Kruys V. Mitochondrial dysfunction, AMPK activation and peroxisomal metabolism: A coherent scenario for non-canonical 3-methylglutaconic acidurias. Biochimie 2019; 168:53-82. [PMID: 31626852 DOI: 10.1016/j.biochi.2019.10.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 10/10/2019] [Indexed: 12/13/2022]
Abstract
The occurrence of 3-methylglutaconic aciduria (3-MGA) is a well understood phenomenon in leucine oxidation and ketogenesis disorders (primary 3-MGAs). In contrast, its genesis in non-canonical (secondary) 3-MGAs, a growing-up group of disorders encompassing more than a dozen of inherited metabolic diseases, is a mystery still remaining unresolved for three decades. To puzzle out this anthologic problem of metabolism, three clues were considered: (i) the variety of disorders suggests a common cellular target at the cross-road of metabolic and signaling pathways, (ii) the response to leucine loading test only discriminative for primary but not secondary 3-MGAs suggests these latter are disorders of extramitochondrial HMG-CoA metabolism as also attested by their failure to increase 3-hydroxyisovalerate, a mitochondrial metabolite accumulating only in primary 3-MGAs, (iii) the peroxisome is an extramitochondrial site possessing its own pool and displaying metabolism of HMG-CoA, suggesting its possible involvement in producing extramitochondrial 3-methylglutaconate (3-MG). Following these clues provides a unifying common basis to non-canonical 3-MGAs: constitutive mitochondrial dysfunction induces AMPK activation which, by inhibiting early steps in cholesterol and fatty acid syntheses, pipelines cytoplasmic acetyl-CoA to peroxisomes where a rise in HMG-CoA followed by local dehydration and hydrolysis may lead to 3-MGA yield. Additional contributors are considered, notably for 3-MGAs associated with hyperammonemia, and to a lesser extent in CLPB deficiency. Metabolic and signaling itineraries followed by the proposed scenario are essentially sketched, being provided with compelling evidence from the literature coming in their support.
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Affiliation(s)
- Joseph Vamecq
- Inserm, CHU Lille, Univ Lille, Department of Biochemistry and Molecular Biology, Laboratory of Hormonology, Metabolism-Nutrition & Oncology (HMNO), Center of Biology and Pathology (CBP) Pierre-Marie Degand, CHRU Lille, EA 7364 RADEME, University of North France, Lille, France.
| | - Bérengère Papegay
- Laboratory of Experimental Medicine (ULB unit 222), University Hospital Center, Charleroi, (CHU Charleroi), Belgium
| | - Vincent Nuyens
- Laboratory of Experimental Medicine (ULB unit 222), University Hospital Center, Charleroi, (CHU Charleroi), Belgium
| | - Jean Boogaerts
- Laboratory of Experimental Medicine (ULB unit 222), University Hospital Center, Charleroi, (CHU Charleroi), Belgium
| | - Oberdan Leo
- Laboratory of Immunobiology, Department of Molecular Biology, ULB Immunology Research Center (UIRC), Free University of Brussels (ULB), Gosselies, Belgium
| | - Véronique Kruys
- Laboratory of Molecular Biology of the Gene, Department of Molecular Biology, ULB Immunology Research Center (UIRC), Free University of Brussels (ULB), Gosselies, Belgium
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Bonomini M, Di Liberato L, Zammit V, Arduini A. Current Opinion on Usage of L-Carnitine in End-Stage Renal Disease Patients on Peritoneal Dialysis. Molecules 2019; 24:molecules24193449. [PMID: 31547545 PMCID: PMC6803867 DOI: 10.3390/molecules24193449] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 09/18/2019] [Accepted: 09/18/2019] [Indexed: 12/20/2022] Open
Abstract
The advantages of peritoneal dialysis (PD) over hemodialysis (HD) are well-documented. Notwithstanding, only a small proportion of patients with end-stage renal disease (ESRD) are managed with PD. This may be related to the high glucose load that PD solutions in current use have on the patient. The effects of such excess glucose include the relatively early limitation of the ultrafiltration capacity of the peritoneal membrane, and the metabolic effects associated with hyperglycemia, e.g., decreased insulin sensitivity. This article describes the advantages that may be realized by the glucose-sparing effects of substituting part of the glucose load with other osmotically active metabolites, particularly L-carnitine. The latter is anticipated to have metabolic advantages of its own, especially as in PD patients, high plasma concentrations can be achieved in the absence of renal clearance. Besides its better biocompatibility, L-carnitine demonstrates anti-anemia action due to its effects on erythropoiesis, and positive effects on the longevity and deformability of erythrocytes. Observations from our trials on the use of carnitine-enriched PD solutions have demonstrated the effectiveness of L-carnitine as an efficient osmolyte in PD, and its favorable effect on the insulin sensitivity of the patients. The significance of these findings for future developments in the use of PD in the management of patients with ESRD is discussed.
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Affiliation(s)
- Mario Bonomini
- Department of Medicine, Section of Nephrology and Dialysis, G. d'Annunzio University, SS. Annunziata Hospital, 66100 Chieti, Italy.
| | - Lorenzo Di Liberato
- Department of Medicine, Section of Nephrology and Dialysis, G. d'Annunzio University, SS. Annunziata Hospital, 66100 Chieti, Italy
| | - Victor Zammit
- Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
| | - Arduino Arduini
- Department of Research and Development, CoreQuest Sagl, Tecnopolo, 6934 Bioggio, Switzerland
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Functional differences between l- and d-carnitine in metabolic regulation evaluated using a low-carnitine Nile tilapia model. Br J Nutr 2019; 122:625-638. [PMID: 32124711 DOI: 10.1017/s000711451900148x] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
l-Carnitine is essential for mitochondrial β-oxidation and has been used as a lipid-lowering feed additive in humans and farmed animals. d-Carnitine is an optical isomer of l-carnitine and dl-carnitine has been widely used in animal feeds. However, the functional differences between l- and d-carnitine are difficult to study because of the endogenous l-carnitine background. In the present study, we developed a low-carnitine Nile tilapia model by treating fish with a carnitine synthesis inhibitor, and used this model to investigate the functional differences between l- and d-carnitine in nutrient metabolism in fish. l- or d-carnitine (0·4 g/kg diet) was fed to the low-carnitine tilapia for 6 weeks. l-Carnitine feeding increased the acyl-carnitine concentration from 3522 to 10 822 ng/g and alleviated the lipid deposition from 15·89 to 11·97 % in the liver of low-carnitine tilapia. However, as compared with l-carnitine group, d-carnitine feeding reduced the acyl-carnitine concentration from 10 822 to 5482 ng/g, and increased lipid deposition from 11·97 to 20·21 % and the mRNA expression of the genes involved in β-oxidation and detoxification in the liver. d-Carnitine feeding also induced hepatic inflammation, oxidative stress and apoptosis. A metabolomic investigation further showed that d-carnitine feeding increased glycolysis, protein metabolism and activity of the tricarboxylic acid cycle and oxidative phosphorylation. Thus, l-carnitine can be physiologically utilised in fish, whereas d-carnitine is metabolised as a xenobiotic and induces lipotoxicity. d-Carnitine-fed fish demonstrates increases in peroxisomal β-oxidation, glycolysis and amino acid degradation to maintain energy homeostasis. Therefore, d-carnitine is not recommended for use in farmed animals.
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El Mously S, Abdel Ghaffar H, Magdy R, Hamza S, Mansour M. Carnitine deficiency in epileptic children treated with a diversity of anti-epileptic regimens. THE EGYPTIAN JOURNAL OF NEUROLOGY, PSYCHIATRY AND NEUROSURGERY 2018; 54:37. [PMID: 30546248 PMCID: PMC6267633 DOI: 10.1186/s41983-018-0033-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 10/19/2018] [Indexed: 12/30/2022] Open
Abstract
Background Carnitine deficiency is relatively common in epileptic patients. The risk factors reported include the combination of valproic acid with other antiepileptic drugs (AEDs), young age, multiple neurologic disabilities, non-ambulatory status, and being underweight. Objectives To study the level of carnitine deficiency and its associated risk factors among a group of children with idiopathic epilepsy treated with different AEDs. Patients and methods Fifty children with idiopathic epilepsy and 40 age-matched controls were enrolled. For all, serum carnitine level was measured by enzyme-linked immune sorbent assay (ELISA). Results The mean carnitine level was lower in cases compared to controls (p = 0.04). Patients receiving monotherapy treatment had a high percentage of carnitine deficiency compared to controls (p = 0.04). Patients receiving valproate with other AEDs had a lower level of carnitine compared to controls (p = 0.03). The age of the patients, the duration of treatment, and the doses of different AEDs were not risk factors for carnitine deficiency. Conclusions Carnitine deficiency is common in our population, and the use of valproate with other AEDs is considered the most important risk factor for it in epileptic children.
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Affiliation(s)
| | | | - Remon Magdy
- Faculty of Medicine, Fayoum University, Fayoum City, 63611 Egypt
| | - Somaia Hamza
- Faculty of Medicine, Fayoum University, Fayoum City, 63611 Egypt
| | - Mohamed Mansour
- Faculty of Medicine, Fayoum University, Fayoum City, 63611 Egypt
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37
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Guerrero RB, Salazar D, Tanpaiboon P. Laboratory diagnostic approaches in metabolic disorders. ANNALS OF TRANSLATIONAL MEDICINE 2018; 6:470. [PMID: 30740401 PMCID: PMC6331366 DOI: 10.21037/atm.2018.11.05] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 10/17/2018] [Indexed: 12/30/2022]
Abstract
The diagnosis of inborn errors of metabolism (IEM) takes many forms. Due to the implementation and advances in newborn screening (NBS), the diagnosis of many IEM has become relatively easy utilizing laboratory biomarkers. For the majority of IEM, early diagnosis prevents the onset of severe clinical symptoms, thus reducing morbidity and mortality. However, due to molecular, biochemical, and clinical variability of IEM, not all disorders included in NBS programs will be detected and diagnosed by screening alone. This article provides a general overview and simplified guidelines for the diagnosis of IEM in patients with and without an acute metabolic decompensation, with early or late onset of clinical symptoms. The proper use of routine laboratory results in the initial patient assessment is also discussed, which can help guide efficient ordering of specialized laboratory tests to confirm a potential diagnosis and initiate treatment as soon as possible.
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Affiliation(s)
- Ruben Bonilla Guerrero
- Formerly Quest Diagnostics, Inc., Ruben Bonilla Guerrero, Rancho Santa Margarita, CA, USA
| | - Denise Salazar
- Quest Diagnostics, Inc., Denise Salazar and Pranoot Tanpaiboon, San Juan Capistrano, CA, USA
| | - Pranoot Tanpaiboon
- Quest Diagnostics, Inc., Denise Salazar and Pranoot Tanpaiboon, San Juan Capistrano, CA, USA
- Genetics and Metabolism, Children’s National Rare Disease Institute, Washington, DC, USA
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38
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Li Z, Zhang Y, Hu T, Likhodii S, Sun G, Zhai G, Fan Z, Xuan C, Zhang W. Differential metabolomics analysis allows characterization of diversity of metabolite networks between males and females. PLoS One 2018; 13:e0207775. [PMID: 30500833 PMCID: PMC6267973 DOI: 10.1371/journal.pone.0207775] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Accepted: 11/06/2018] [Indexed: 12/30/2022] Open
Abstract
Females and males are known to have different abilities to cope with stress and disease. This study was designed to investigate the effect of sex on properties of a complex interlinked network constructed of central biochemical metabolites. The study involved the blood collection and analysis of a large set of blood metabolic markers from a total of 236 healthy participants, which included 140 females and 96 males. Metabolic profiling yielded concentrations of 168 metabolites for each subject. A differential correlation network analysis approach was developed for this study that allowed detection and characterization of interconnection differences in metabolites in males and females. Through topological analysis of the differential network that depicted metabolite differences in the sexes, we identified metabolites with high centralities in this network. These key metabolites were identified as 10 phosphatidylcholines (PCaaC34:4, PCaaC36:6, PCaaC34:3, PCaaC42:2, PCaeC38:1, PCaeC38:2, PCaaC40:1, PCaeC34:1, PC aa C32:1 and PC aa C40:6) and 4 acylcarnitines (C3-OH, C7-DC, C3 and C0). Identification of these metabolites may help further studies of sex-specific differences in the metabolome that may underlie different responses to stress and disease in males and females.
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Affiliation(s)
- Zimin Li
- School of Pharmaceutical Sciences, Jilin University, Changchun, China
- Department of pharmacy, Daqing people's hospital, Daqing, China
| | - Yuxi Zhang
- School of Pharmaceutical Sciences, Jilin University, Changchun, China
- Department of pharmacy, Daqing oil-field general hospital, Daqing, China
| | - Ting Hu
- Department of Computer Science, Memorial University, St John’s, NL, Canada
| | - Sergei Likhodii
- Provincial Toxicology Centre, Provincial Health Services Authority, Vancouver, British Columbia, Canada
| | - Guang Sun
- Discipline of Medicine, Faculty of Medicine, Memorial University, St. John’s, NL, Canada
| | - Guangju Zhai
- Discipline of Genetics, Faculty of Medicine, Memorial University, St. John’s, NL, Canada
| | - Zhaozhi Fan
- Department of Mathematics and Statistics, Memorial University, St. John’s, NL, Canada
| | - Chunji Xuan
- Northeast Asian Studies College, Jilin University, Changchun, China
| | - Weidong Zhang
- School of Pharmaceutical Sciences, Jilin University, Changchun, China
- Discipline of Genetics, Faculty of Medicine, Memorial University, St. John’s, NL, Canada
- * E-mail:
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Yang J, Tan X, Zhao Y. Chiral recognition of the carnitine enantiomers using rhodamine B as a resonance Rayleigh scattering probe. Chirality 2018; 30:1173-1181. [DOI: 10.1002/chir.23004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 04/26/2018] [Accepted: 06/07/2018] [Indexed: 12/30/2022]
Affiliation(s)
- Jidong Yang
- School of Environment and Chemical Engineering; Chongqing Three Gorges University; Chongqing People's Republic of China
- School of Chemistry and Chemical Engineering; Southwest University; Chongqing People's Republic of China
| | - Xuanping Tan
- School of Environment and Chemical Engineering; Chongqing Three Gorges University; Chongqing People's Republic of China
| | - Yanmei Zhao
- School of Environment and Chemical Engineering; Chongqing Three Gorges University; Chongqing People's Republic of China
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40
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Wesselink E, Koekkoek WAC, Grefte S, Witkamp RF, van Zanten ARH. Feeding mitochondria: Potential role of nutritional components to improve critical illness convalescence. Clin Nutr 2018; 38:982-995. [PMID: 30201141 DOI: 10.1016/j.clnu.2018.08.032] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 08/03/2018] [Accepted: 08/25/2018] [Indexed: 12/30/2022]
Abstract
Persistent physical impairment is frequently encountered after critical illness. Recent data point towards mitochondrial dysfunction as an important determinant of this phenomenon. This narrative review provides a comprehensive overview of the present knowledge of mitochondrial function during and after critical illness and the role and potential therapeutic applications of specific micronutrients to restore mitochondrial function. Increased lactate levels and decreased mitochondrial ATP-production are common findings during critical illness and considered to be associated with decreased activity of muscle mitochondrial complexes in the electron transfer system. Adequate nutrient levels are essential for mitochondrial function as several specific micronutrients play crucial roles in energy metabolism and ATP-production. We have addressed the role of B vitamins, ascorbic acid, α-tocopherol, selenium, zinc, coenzyme Q10, caffeine, melatonin, carnitine, nitrate, lipoic acid and taurine in mitochondrial function. B vitamins and lipoic acid are essential in the tricarboxylic acid cycle, while selenium, α-tocopherol, Coenzyme Q10, caffeine, and melatonin are suggested to boost the electron transfer system function. Carnitine is essential for fatty acid beta-oxidation. Selenium is involved in mitochondrial biogenesis. Notwithstanding the documented importance of several nutritional components for optimal mitochondrial function, at present, there are no studies providing directions for optimal requirements during or after critical illness although deficiencies of these specific micronutrients involved in mitochondrial metabolism are common. Considering the interplay between these specific micronutrients, future research should pay more attention to their combined supply to provide guidance for use in clinical practise. REVISION NUMBER: YCLNU-D-17-01092R2.
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Affiliation(s)
- E Wesselink
- Division of Human Nutrition and Health, Wageningen University, Stippeneng 4, 6708 WE, Wageningen, The Netherlands.
| | - W A C Koekkoek
- Department of Intensive Care Medicine, Gelderse Vallei Hospital, Willy Brandtlaan 10, 6716, Ede, The Netherlands.
| | - S Grefte
- Human and Animal Physiology, Wageningen University, De Elst 1, 6708 DW, Wageningen, The Netherlands.
| | - R F Witkamp
- Division of Human Nutrition and Health, Wageningen University, Stippeneng 4, 6708 WE, Wageningen, The Netherlands.
| | - A R H van Zanten
- Department of Intensive Care Medicine, Gelderse Vallei Hospital, Willy Brandtlaan 10, 6716, Ede, The Netherlands.
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Andrianova MS, Kuznetsov EV, Grudtsov VP, Kuznetsov AE. CMOS-compatible biosensor for L-carnitine detection. Biosens Bioelectron 2018; 119:48-54. [PMID: 30098466 DOI: 10.1016/j.bios.2018.07.044] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 07/11/2018] [Accepted: 07/22/2018] [Indexed: 02/07/2023]
Abstract
A CMOS-compatible ISFET with a Ta2O5 sensitive surface was developed. The structure was optimized for achieving high sensitivity using a subthreshold operation mode and by reducing the influence of the capacitances on the value of subthreshold swing. The developed ISFET was used as a basis for a biosensor for L-carnitine detection. To this end, carnitine acetyltransferase was immobilized on the ISFET sensitive surface. The immobilized enzyme was active (0.082 U/g model plate). The complete microsystem, consisting of a packaged chip, an immobilized enzyme and a microfluidic channel, detected L-carnitine at a range of 0.2-100 μM with a LOD of 0.2 μM. The biosensor response was linear in the range of 0.2-50 μM of L-carnitine with sensitivity 18.0 ± 1.7 mV/μM. An experiment with artificial urine containing 1.3 μM L-carnitine showed that the proposed biosensor could be used on a real sample. Therefore, a new sensor specially optimized for biosensing CMOS-compatible ISFET structures and direct determination of L-carnitine with immobilized carnitine acetyltransferase was developed.
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Affiliation(s)
- M S Andrianova
- Scientific-Manufacturing Complex Technological Centre, 124498, Shokina square, h. 1, bld. 7, Zelenograd, Moscow, Russia.
| | - E V Kuznetsov
- Scientific-Manufacturing Complex Technological Centre, 124498, Shokina square, h. 1, bld. 7, Zelenograd, Moscow, Russia
| | - V P Grudtsov
- Scientific-Manufacturing Complex Technological Centre, 124498, Shokina square, h. 1, bld. 7, Zelenograd, Moscow, Russia
| | - A E Kuznetsov
- Scientific-Manufacturing Complex Technological Centre, 124498, Shokina square, h. 1, bld. 7, Zelenograd, Moscow, Russia
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Li JM, Li LY, Qin X, Degrace P, Demizieux L, Limbu SM, Wang X, Zhang ML, Li DL, Du ZY. Inhibited Carnitine Synthesis Causes Systemic Alteration of Nutrient Metabolism in Zebrafish. Front Physiol 2018; 9:509. [PMID: 29867554 PMCID: PMC5954090 DOI: 10.3389/fphys.2018.00509] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Accepted: 04/20/2018] [Indexed: 12/30/2022] Open
Abstract
Impaired mitochondrial fatty acid β-oxidation has been correlated with many metabolic syndromes, and the metabolic characteristics of the mammalian models of mitochondrial dysfunction have also been intensively studied. However, the effects of the impaired mitochondrial fatty acid β-oxidation on systemic metabolism in teleost have never been investigated. In the present study, we established a low-carnitine zebrafish model by feeding fish with mildronate as a specific carnitine synthesis inhibitor [0.05% body weight (BW)/d] for 7 weeks, and the systemically changed nutrient metabolism, including carnitine and triglyceride (TG) concentrations, fatty acid (FA) β-oxidation capability, and other molecular and biochemical assays of lipid, glucose, and protein metabolism, were measured. The results indicated that mildronate markedly decreased hepatic carnitine concentrations while it had no effect in muscle. Liver TG concentrations increased by more than 50% in mildronate-treated fish. Mildronate decreased the efficiency of liver mitochondrial β-oxidation, increased the hepatic mRNA expression of genes related to FA β-oxidation and lipolysis, and decreased the expression of lipogenesis genes. Mildronate decreased whole body glycogen content, increased glucose metabolism rate, and upregulated the expression of glucose uptake and glycolysis genes. Mildronate also increased whole body protein content and hepatic mRNA expression of mechanistic target of rapamycin (mtor), and decreased the expression of a protein catabolism-related gene. Liver, rather than muscle, was the primary organ targeted by mildronate. In short, mildronate-induced hepatic inhibited carnitine synthesis in zebrafish caused decreased mitochondrial FA β-oxidation efficiency, greater lipid accumulation, and altered glucose and protein metabolism. This reveals the key roles of mitochondrial fatty acid β-oxidation in nutrient metabolism in fish, and this low-carnitine zebrafish model could also be used as a novel fish model for future metabolism studies.
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Affiliation(s)
- Jia-Min Li
- Laboratory of Aquaculture Nutrition and Environmental Health, School of Life Sciences, East China Normal University, Shanghai, China
| | - Ling-Yu Li
- Laboratory of Aquaculture Nutrition and Environmental Health, School of Life Sciences, East China Normal University, Shanghai, China
| | - Xuan Qin
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Pascal Degrace
- Team Pathophysiology of Dyslipidemia, Faculty of Sciences Gabriel, INSERM UMR1231 "Lipides, Nutrition, Cancer," Université Bourgogne Franche-Comté, Dijon, France
| | - Laurent Demizieux
- Team Pathophysiology of Dyslipidemia, Faculty of Sciences Gabriel, INSERM UMR1231 "Lipides, Nutrition, Cancer," Université Bourgogne Franche-Comté, Dijon, France
| | - Samwel M Limbu
- Laboratory of Aquaculture Nutrition and Environmental Health, School of Life Sciences, East China Normal University, Shanghai, China.,Department of Aquatic Sciences and Fisheries Technology, University of Dar es Salaam, Dar es Salaam, Tanzania
| | - Xin Wang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Mei-Ling Zhang
- Laboratory of Aquaculture Nutrition and Environmental Health, School of Life Sciences, East China Normal University, Shanghai, China
| | - Dong-Liang Li
- Laboratory of Aquaculture Nutrition and Environmental Health, School of Life Sciences, East China Normal University, Shanghai, China
| | - Zhen-Yu Du
- Laboratory of Aquaculture Nutrition and Environmental Health, School of Life Sciences, East China Normal University, Shanghai, China
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Dehdari Vais R, Yadegari H, Sattarahmady N, Heli H. An anodized nanostructure of Ni/Cu alloy synthesized in ethaline for electrocatalytic oxidation and amperometric determination of l-carnitine. J Electroanal Chem (Lausanne) 2018. [DOI: 10.1016/j.jelechem.2018.03.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Cytosolic carnitine acetyltransferase as a source of cytosolic acetyl-CoA: a possible mechanism for regulation of cardiac energy metabolism. Biochem J 2018; 475:959-976. [PMID: 29438065 DOI: 10.1042/bcj20170823] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 02/05/2018] [Accepted: 02/05/2018] [Indexed: 12/30/2022]
Abstract
The role of carnitine acetyltransferase (CrAT) in regulating cardiac energy metabolism is poorly understood. CrAT modulates mitochondrial acetyl-CoA/CoA (coenzyme A) ratios, thus regulating pyruvate dehydrogenase activity and glucose oxidation. Here, we propose that cardiac CrAT also provides cytosolic acetyl-CoA for the production of malonyl-CoA, a potent inhibitor of fatty acid oxidation. We show that in the murine cardiomyocyte cytosol, reverse CrAT activity (RCrAT, producing acetyl-CoA) is higher compared with the liver, which primarily uses ATP-citrate lyase to produce cytosolic acetyl-CoA for lipogenesis. The heart displayed a lower RCrAT Km for CoA compared with the liver. Furthermore, cytosolic RCrAT accounted for 4.6 ± 0.7% of total activity in heart tissue and 12.7 ± 0.2% in H9C2 cells, while highly purified heart cytosolic fractions showed significant CrAT protein levels. To investigate the relationship between CrAT and acetyl-CoA carboxylase (ACC), the cytosolic enzyme catalyzing malonyl-CoA production from acetyl-CoA, we studied ACC2-knockout mouse hearts which showed decreased CrAT protein levels and activity, associated with increased palmitate oxidation and acetyl-CoA/CoA ratio compared with controls. Conversely, feeding mice a high-fat diet for 10 weeks increased cardiac CrAT protein levels and activity, associated with a reduced acetyl-CoA/CoA ratio and glucose oxidation. These data support the presence of a cytosolic CrAT with a low Km for CoA, favoring the formation of cytosolic acetyl-CoA, providing an additional source to the classical ATP-citrate lyase pathway, and that there is an inverse relation between CrAT and the ratio of acetyl-CoA/CoA as evident in conditions affecting the regulation of cardiac energy metabolism.
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Strand E, Rebnord EW, Flygel MR, Lysne V, Svingen GFT, Tell GS, Løland KH, Berge RK, Svardal A, Nygård O, Pedersen ER. Serum Carnitine Metabolites and Incident Type 2 Diabetes Mellitus in Patients With Suspected Stable Angina Pectoris. J Clin Endocrinol Metab 2018; 103:1033-1041. [PMID: 29325058 DOI: 10.1210/jc.2017-02139] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Accepted: 01/04/2018] [Indexed: 02/13/2023]
Abstract
CONTEXT Carnitine and its metabolites are centrally involved in fatty acid metabolism. Although elevated circulating concentrations have been observed in obesity and insulin resistance, prospective studies examining whether these metabolites are associated with incident type 2 diabetes mellitus (T2D) are sparse. OBJECTIVE We performed a comprehensive evaluation of metabolites along the carnitine pathway relative to incident T2D. DESIGN A total of 2519 patients (73.1% men) with coronary artery disease, but without T2D, were followed for median 7.7 years until the end of 2009, during which 173 (6.9%) new cases of T2D were identified. Serum levels of free carnitine, its precursors trimethyllysine (TML) and γ-butyrobetaine, and the esters acetyl-, propionyl-, (iso)valeryl-, octanoyl-, and palmitoylcarnitine were measured by liquid chromatography/tandem mass spectrometry. Risk associations were explored by logistic regression and reported per (log-transformed) standard deviation increment. RESULTS Median age at inclusion was 62 years and median body mass index (BMI) 26.0 kg/m2. In models adjusted for age, sex, fasting status, BMI, estimated glomerular filtration rate, glycated hemoglobin A1c, triglyceride and high-density lipoprotein cholesterol levels, and study center, serum levels of TML and palmitoylcarnitine associated positively [odds ratio (95% confidence interval), 1.22 (1.04 to 1.43) and 1.24 (1.04 to 1.49), respectively], whereas γ-butyrobetaine associated negatively [odds ratio (95% confidence interval) 0.81 (0.66 to 0.98)] with T2D risk. CONCLUSION Serum levels of TML, γ-butyrobetaine, and the long-chained palmitoylcarnitine predict long-term risk of T2D independently of traditional risk factors, possibly reflecting dysfunctional fatty acid metabolism in patients susceptible to T2D development.
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Affiliation(s)
- Elin Strand
- Department of Clinical Science, University of Bergen, Haukeland University Hospital, Bergen, Norway
| | - Eirik W Rebnord
- Department of Clinical Science, University of Bergen, Haukeland University Hospital, Bergen, Norway
- KG Jebsen Center for Diabetes Research, University of Bergen, Children and Youth Hospital, Bergen, Norway
- Department of Heart Disease, Haukeland University Hospital, Bergen, Norway
| | - Malin R Flygel
- Department of Heart Disease, Haukeland University Hospital, Bergen, Norway
| | - Vegard Lysne
- Department of Clinical Science, University of Bergen, Haukeland University Hospital, Bergen, Norway
| | - Gard F T Svingen
- Department of Heart Disease, Haukeland University Hospital, Bergen, Norway
| | - Grethe S Tell
- Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway
| | - Kjetil H Løland
- Department of Heart Disease, Haukeland University Hospital, Bergen, Norway
| | - Rolf K Berge
- Department of Clinical Science, University of Bergen, Haukeland University Hospital, Bergen, Norway
- Department of Heart Disease, Haukeland University Hospital, Bergen, Norway
| | - Asbjørn Svardal
- Department of Clinical Science, University of Bergen, Haukeland University Hospital, Bergen, Norway
| | - Ottar Nygård
- Department of Clinical Science, University of Bergen, Haukeland University Hospital, Bergen, Norway
- KG Jebsen Center for Diabetes Research, University of Bergen, Children and Youth Hospital, Bergen, Norway
- Department of Heart Disease, Haukeland University Hospital, Bergen, Norway
| | - Eva R Pedersen
- Department of Clinical Science, University of Bergen, Haukeland University Hospital, Bergen, Norway
- KG Jebsen Center for Diabetes Research, University of Bergen, Children and Youth Hospital, Bergen, Norway
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Zakharenko LP, Petrovsky DV, Putilov AA. Treatments with thousands therapeutic doses of meldonium failed to alter the Drosophila’s circadian clocks but negatively affected the germination of Pisum’s seeds. BIOL RHYTHM RES 2018. [DOI: 10.1080/09291016.2018.1429552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Lyudmila P. Zakharenko
- Department of Insect Genetics, Institute of Cytology and Genetics of the Siberian Branch, the Russian Academy of Sciences, Novosibirsk, Russia
- Faculty of Natural Science, Novosibirsk State University, Novosibirsk, Russia
| | - Dmitriy V. Petrovsky
- Department of Insect Genetics, Institute of Cytology and Genetics of the Siberian Branch, the Russian Academy of Sciences, Novosibirsk, Russia
| | - Arcady A. Putilov
- Research Group for Biomedical Systems Modeling, Research Institute for Molecular Biology and Biophysics, Novosibirsk, Russia
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Jang WJ, Choi B, Song SH, Lee N, Kim DJ, Lee S, Jeong CH. Multi-omics analysis reveals that ornithine decarboxylase contributes to erlotinib resistance in pancreatic cancer cells. Oncotarget 2017; 8:92727-92742. [PMID: 29190951 PMCID: PMC5696217 DOI: 10.18632/oncotarget.21572] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2017] [Accepted: 09/04/2017] [Indexed: 12/30/2022] Open
Abstract
Molecular and metabolic alterations in cancer cells are one of the leading causes of acquired resistance to chemotherapeutics. In this study, we explored an experimental strategy to identify which of these alterations can induce erlotinib resistance in human pancreatic cancer. Using genetically matched erlotinib-sensitive (BxPC-3) and erlotinib-resistant (BxPC-3ER) pancreatic cancer cells, we conducted a multi-omics analysis of metabolomes and transcriptomes in these cells. Untargeted and targeted metabolomic analyses revealed significant changes in metabolic pathways involved in the regulation of polyamines, amino acids, and fatty acids. Further transcriptomic analysis identified that ornithine decarboxylase (ODC) and its major metabolite, putrescine, contribute to the acquisition of erlotinib resistance in BxPC-3ER cells. Notably, either pharmacological or genetic blockage of ODC was able to restore erlotinib sensitivity, and this could be rescued by treatment with exogenous putrescine in erlotinib-resistant BxPC-3ER cells. Moreover, using a panel of cancer cells we demonstrated that ODC expression levels in cancer cells are inversely correlated with sensitivity to chemotherapeutics. Taken together, our findings will begin to uncover mechanisms of acquired drug resistance and ultimately help to identify potential therapeutic markers in cancer.
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Affiliation(s)
- Won-Jun Jang
- College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea
| | - Boyeon Choi
- College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea
| | - Sang-Hoon Song
- College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea
| | - Naeun Lee
- College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea
| | - Dong-Joon Kim
- China-US (Henan) Hormel Cancer Institute, Zhengzhou 450008, China
| | - Sooyeun Lee
- College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea
| | - Chul-Ho Jeong
- College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea
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Altered Carnitine Homeostasis in Children With Increased Pulmonary Blood Flow Due to Ventricular Septal Defects. Pediatr Crit Care Med 2017; 18:931-934. [PMID: 28723882 PMCID: PMC5628126 DOI: 10.1097/pcc.0000000000001275] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVES Congenital heart disease with increased pulmonary blood flow results in progressive pulmonary vascular endothelial dysfunction and associated increased perioperative morbidity. Using our ovine model of congenital heart disease with increased pulmonary blood flow, we have previously demonstrated progressive endothelial dysfunction associated with disruption in carnitine homeostasis, mitochondrial dysfunction, decreased nitric oxide signaling, and enhanced reactive oxygen species generation. However, potential alterations in these parameters in patients with congenital heart disease have not been investigated. The objective of this study was to test the hypothesis that children with increased pulmonary blood flow will have evidence of altered carnitine homeostasis, mitochondrial dysfunction, decreased nitric oxide levels, and increased reactive oxygen species generation. DESIGN A prospective single-center cohort study. SETTING A tertiary care cardiac ICU/PICU. PATIENTS Arterial blood samples from 18 patients with congenital heart disease associated with increased pulmonary blood flow (ventricular septal defect), 20 with congenital heart disease without increased pulmonary blood flow (tetralogy of Fallot), and 10 without heart disease (controls) were obtained. INTERVENTIONS Plasma levels of total carnitine, free carnitine, acylcarnitine, and lactate-to-pyruvate ratios, an indicator of mitochondrial function, were determined and compared. In addition, levels of superoxide and hydrogen peroxide were determined and compared in patients with ventricular septal defect and controls. Statistical analysis was performed using an unpaired t test and analysis of variance. MEASUREMENTS AND MAIN RESULTS Baseline acylcarnitine levels (25.7 ± 13 vs 12.7 ± 8.3; p < 0.05), the acylcarnitine-to-free carnitine ratio (0.8 ± 0.1 vs 0.3 ± 0.05; p < 0.05), and the lactate-to-pyruvate ratio were higher in ventricular septal defect (27.5 ± 3.8 vs 11.1 ± 4.1, p < 0.05) than tetralogy of Fallot; there were no differences between tetralogy of Fallot and control. Superoxide and H2O2 levels were also higher in ventricular septal defect compared with controls, and NOx levels were lower in ventricular septal defect patients compared with tetralogy of Fallot and controls (p < 0.05). CONCLUSIONS These data suggest that increased pulmonary blood flow from ventricular septal defect results in altered carnitine and mitochondrial homeostasis, decreased nitric oxide signaling, and increased reactive oxygen species production. These data are consistent with our animal data demonstrating that altered carnitine homeostasis results in mitochondrial dysfunction, increased reactive oxygen species production, and decreased bioavailable nitric oxide. Since disruption of carnitine metabolism may contribute to endothelial dysfunction, carnitine supplementation may attenuate endothelial dysfunction associated with increased pulmonary blood flow and warrants further investigation.
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Alwashih MA, Stimson RH, Andrew R, Walker BR, Watson DG. Acute interaction between hydrocortisone and insulin alters the plasma metabolome in humans. Sci Rep 2017; 7:11488. [PMID: 28904371 PMCID: PMC5597623 DOI: 10.1038/s41598-017-10200-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Accepted: 08/07/2017] [Indexed: 12/30/2022] Open
Abstract
With the aim of identifying biomarkers of glucocorticoid action and their relationship with biomarkers of insulin action, metabolomic profiling was carried out in plasma samples from twenty healthy men who were administered either a low or medium dose insulin infusion (n = 10 each group). In addition, all subjects were given metyrapone (to inhibit adrenal cortisol secretion) + /− hydrocortisone (HC) in a randomised crossover design to produce low, medium and high glucocorticoid levels. The clearest effects of insulin were to reduce plasma levels of the branched chain amino acids (BCAs) leucine/isoleucine and their deaminated metabolites, and lowered free fatty acids and acylcarnitines. The highest dose of hydrocortisone increased plasma BCAs in both insulin groups but increased free fatty acids only in the high insulin group, however hydrocortisone did not affect the levels of acyl carnitines in either group. The clearest interaction between HC and insulin was that hydrocortisone produced an elevation in levels of BCAs and their metabolites which were lowered by insulin. The direct modulation of BCAs by glucocorticoids and insulin may provide the basis for improved in vivo monitoring of glucocorticoid and insulin action.
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Affiliation(s)
- Mohammad A Alwashih
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, G4 0RE, UK.,General Directorate of Medical Services, Ministry of Interior, Riyadh, 13321, Saudi Arabia
| | - Roland H Stimson
- BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Scotland, UK
| | - Ruth Andrew
- BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Scotland, UK
| | - Brian R Walker
- BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Scotland, UK
| | - David G Watson
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, G4 0RE, UK.
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50
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Mock DM. Biotin: From Nutrition to Therapeutics. J Nutr 2017; 147:1487-1492. [PMID: 28701385 PMCID: PMC5525106 DOI: 10.3945/jn.116.238956] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 03/01/2017] [Accepted: 06/08/2017] [Indexed: 12/30/2022] Open
Abstract
Although frank symptomatic biotin deficiency is rare, some evidence suggests that marginal biotin deficiency occurs spontaneously in a substantial proportion of women during normal human pregnancy and might confer an increased risk of birth defects. Herein I review 1) advances in assessing biotin status, including the relation between acylcarnitine excretion and biotin status; 2) recent studies of biotin status in pregnancy; 3) advances in understanding the role of biotin in gene expression and the potential roles of biotinylated proteins that are neither histones nor carboxylases; and 4) novel large-dose biotin supplementation as therapy for multiple sclerosis. The review concludes with a summary of recent studies that have reported potentially dangerous erroneous results in individuals consuming large amounts of biotin for measurements of various plasma hormones for common clinical assays that use streptavidin-biotin technology.
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Affiliation(s)
- Donald M Mock
- University of Arkansas for Medical Sciences, Departments of Biochemistry and Molecular Biology and Pediatrics, Little Rock, AR
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