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Ajmeriya S, Kashyap N, Gul A, Ahirwar A, Singh S, Tripathi S, Dhar R, Nayak NR, Karmakar S. Aberrant expression of solute carrier family transporters in placentas associated with pregnancy complications. Placenta 2025; 159:9-19. [PMID: 39602836 DOI: 10.1016/j.placenta.2024.11.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 11/01/2024] [Accepted: 11/20/2024] [Indexed: 11/29/2024]
Abstract
INTRODUCTION Solute carrier family transporters (SLCs), crucial for nutrient and trace element uptake in the placenta, play a significant role in fetal growth and development. Their dysregulation is associated with various pregnancy disorders. However, a comprehensive understanding of their role and regulation in placental function and pregnancy complications is still a largely unexplored area, making this study novel and significant. METHODS We performed a rigorous meta-analysis of publicly available NCBI GEO microarray and RNA-Seq datasets followed by bioinformatics analysis of differentially expressed SLCs in PE and IUGR. The identified SLCs were then validated using qPCR on PE placental samples, ensuring the reliability and validity of the findings. RESULTS Bioinformatics analysis of preeclampsia (PE) and Intrauterine Growth restriction (IUGR) datasets revealed significant associations between specific SLC transporters with disease pathology, identified by studying differentially expressed SLCs. Subsequent validation using qPCR on placental samples confirmed considerable downregulation of SLC6A8, SLC16A10, SLC25A3, and SLC29A3, highlighting their dysregulation in the pathogenesis of PE and IUGR. DISCUSSION The significant downregulation of SLC6A8, SLC16A10, SLC25A3, and SLC29A3 observed by bioinformatics analyses and validated by qPCR indicates atypical expression of these SLCs in gestational disorders. Our findings underscore the potential contribution of multiple SLC gene families to the development of placental pathologies associated with diverse pregnancy complications.
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Affiliation(s)
- Swati Ajmeriya
- Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India
| | - Neha Kashyap
- Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India
| | - Anamta Gul
- Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India
| | - Ashok Ahirwar
- Department of Laboratory Medicine, AIl India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India
| | - Sunil Singh
- Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India
| | - Smita Tripathi
- Department of Biochemistry, Lady Harding Medical College, New Delhi, 110029, India
| | - Ruby Dhar
- Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India
| | - Nihar R Nayak
- Department of Obstetrics and Gynecology, University of Missouri, Kansas City, USA
| | - Subhradip Karmakar
- Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.
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Vo DK, Trinh KTL. Emerging Biomarkers in Metabolomics: Advancements in Precision Health and Disease Diagnosis. Int J Mol Sci 2024; 25:13190. [PMID: 39684900 DOI: 10.3390/ijms252313190] [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: 11/19/2024] [Revised: 12/01/2024] [Accepted: 12/06/2024] [Indexed: 12/18/2024] Open
Abstract
Metabolomics has come to the fore as an efficient tool in the search for biomarkers that are critical for precision health approaches and improved diagnostics. This review will outline recent advances in biomarker discovery based on metabolomics, focusing on metabolomics biomarkers reported in cancer, neurodegenerative disorders, cardiovascular diseases, and metabolic health. In cancer, metabolomics provides evidence for unique oncometabolites that are important for early disease detection and monitoring of treatment responses. Metabolite profiling for conditions such as neurodegenerative and mental health disorders can offer early diagnosis and mechanisms into the disease especially in Alzheimer's and Parkinson's diseases. In addition to these, lipid biomarkers and other metabolites relating to cardiovascular and metabolic disorders are promising for patient stratification and personalized treatment. The gut microbiome and environmental exposure also feature among the influential factors in biomarker discovery because they sculpt individual metabolic profiles, impacting overall health. Further, we discuss technological advances in metabolomics, current clinical applications, and the challenges faced by metabolomics biomarker validation toward precision medicine. Finally, this review discusses future opportunities regarding the integration of metabolomics into routine healthcare to enable preventive and personalized approaches.
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Affiliation(s)
- Dang-Khoa Vo
- College of Pharmacy, Gachon University, 191 Hambakmoe-ro, Yeonsu-gu, Incheon 21936, Republic of Korea
| | - Kieu The Loan Trinh
- BioNano Applications Research Center, Gachon University, 1342 Seongnam-daero, Sujeong-gu, Seongnam-si 13120, Gyeonggi-do, Republic of Korea
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Wang X, Zhang X, Zhang J, Yang H, Liu Z, Peng D, Han L. Illustrate the metabolic regulatory mechanism of Taohong Siwu decoction in ischemic stroke by mass spectrometry imaging. Anal Bioanal Chem 2024; 416:6931-6944. [PMID: 39467910 DOI: 10.1007/s00216-024-05591-4] [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: 08/21/2024] [Revised: 09/30/2024] [Accepted: 10/04/2024] [Indexed: 10/30/2024]
Abstract
Metabolic dysregulation in the ischemic region has been increasingly recognized as a contributing factor to ischemic stroke pathogenesis. Taohong Siwu decoction (THSWD), a traditional Chinese medicine preparation used to enhance blood circulation, is frequently employed in treating ischemic stroke. However, the metabolic regulatory mechanism underlying the therapeutic effects of THSWD in ischemic stroke remains largely unexplored. In this study, we employed desorption electrospray ionization mass spectrometry imaging (DESI-MSI) to investigate the metabolic changes in the brain tissue of ischemic stroke rat model. Our investigation revealed that 30 metabolites exhibited significant dysregulation in the ischemic brain regions, specifically the cortex and striatum, following ischemic injury. Following the treatment of THSWD, almost all the dysregulated metabolites got different degrees of callback. Further pathway analysis indicated that THSWD might exert its therapeutic effects by restoring energy metabolism, improving neurotransmitter metabolism, recovering polyamine metabolism, and so on. DESI-MSI offers a favorable methodology for investigating the alterations in the spatial distribution and level within the ischemic brain region following treatment with THSWD in ischemic stroke. These findings provide a novel perspective on the underlying mechanisms of the efficacy of THSWD in ischemic stroke treatment.
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Affiliation(s)
- Xiaoqun Wang
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, Anhui, China
- MOE-Anhui Joint Collaborative Innovation Center for Quality Improvement of Anhui Genuine Chinese Medicinal Materials, Hefei, 230012, Anhui, China
| | - Xueting Zhang
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, Anhui, China
| | - Jiayu Zhang
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, Anhui, China
| | - Hanxue Yang
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, Anhui, China
| | - Zhuqing Liu
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, Anhui, China
- Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, 230012, Anhui, China
| | - Daiyin Peng
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, Anhui, China.
- MOE-Anhui Joint Collaborative Innovation Center for Quality Improvement of Anhui Genuine Chinese Medicinal Materials, Hefei, 230012, Anhui, China.
- Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, 230012, Anhui, China.
| | - Lan Han
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, Anhui, China.
- MOE-Anhui Joint Collaborative Innovation Center for Quality Improvement of Anhui Genuine Chinese Medicinal Materials, Hefei, 230012, Anhui, China.
- Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, 230012, Anhui, China.
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Lestingi A, Alagawany M, Di Cerbo A, Crescenzo G, Zizzadoro C. Spirulina (Arthrospira platensis) Used as Functional Feed Supplement or Alternative Protein Source: A Review of the Effects of Different Dietary Inclusion Levels on Production Performance, Health Status, and Meat Quality of Broiler Chickens. Life (Basel) 2024; 14:1537. [PMID: 39768246 PMCID: PMC11679488 DOI: 10.3390/life14121537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 11/13/2024] [Accepted: 11/14/2024] [Indexed: 01/11/2025] Open
Abstract
The broiler industry is pivotal in meeting the growing global demand for highly nutritious animal protein foods. Hence, there is a continuous interest in identifying novel, alternative, and even unconventional feed resources that could help sustainably support chicken meat production and quality. In this view, the microalga Spirulina (Arthrospira, formerly Spirulina, platensis), due to its unique chemical composition and some ecological advantages offered by its cultivation over traditional agriculture, has attracted great attention in the poultry sector for potential application in broiler diets, either as a functional supplement or a replacer of conventional protein sources such as soybean meal. The studies conducted so far seem to have confirmed many of the initial expectations regarding the advantages that may derive from dietary Spirulina supplementation, documenting its capacity to positively influence the intestinal and general health status of broiler chickens, leading to improved or preserved productive performance (under normal or challenging conditions, respectively), as well as to increased disease resistance and survivability. Furthermore, dietary Spirulina supplementation has been shown to induce positive changes in some important traits of broiler meat quality. However, at present, the inclusion of Spirulina in broiler diet, especially but not solely in relation to the use as an alternative protein source, presents several technical and economic limitations. To increase the overall awareness around the actual usefulness and practical usability of Spirulina as a novel natural component of the broiler diet, this review paper seeks to provide a comprehensive and integrated presentation of what is currently known about this topic, highlighting critical issues that are still pending and would require further research efforts.
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Affiliation(s)
- Antonia Lestingi
- Department of Veterinary Medicine, University of Bari Aldo Moro, 70010 Valenzano, Italy; (A.L.); (G.C.); (C.Z.)
| | - Mahmoud Alagawany
- Poultry Department, Agriculture Faculty, Zagazig University, Zagazig 44519, Egypt;
| | - Alessandro Di Cerbo
- School of Biosciences and Veterinary Medicine, University of Camerino, 62024 Matelica, Italy
| | - Giuseppe Crescenzo
- Department of Veterinary Medicine, University of Bari Aldo Moro, 70010 Valenzano, Italy; (A.L.); (G.C.); (C.Z.)
| | - Claudia Zizzadoro
- Department of Veterinary Medicine, University of Bari Aldo Moro, 70010 Valenzano, Italy; (A.L.); (G.C.); (C.Z.)
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Ahanger IA, Dar TA. Small molecule modulators of alpha-synuclein aggregation and toxicity: Pioneering an emerging arsenal against Parkinson's disease. Ageing Res Rev 2024; 101:102538. [PMID: 39389237 DOI: 10.1016/j.arr.2024.102538] [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: 06/21/2024] [Revised: 10/01/2024] [Accepted: 10/03/2024] [Indexed: 10/12/2024]
Abstract
Parkinson's disease (PD) is primarily characterized by loss of dopaminergic neurons in the substantia nigra pars compacta region of the brain and accumulation of aggregated forms of alpha-synuclein (α-Syn), an intrinsically disordered protein, in the form of Lewy Bodies and Lewy Neurites. Substantial evidences point to the aggregated/fibrillar forms of α-Syn as a central event in PD pathogenesis, underscoring the modulation of α-Syn aggregation as a promising strategy for PD treatment. Consequently, numerous anti-aggregation agents, spanning from small molecules to polymers, have been scrutinized for their potential to mitigate α-Syn aggregation and its associated toxicity. Among these, small molecule modulators like osmoprotectants, polyphenols, cellular metabolites, metals, and peptides have emerged as promising candidates with significant potential in PD management. This article offers a comprehensive overview of the effects of these small molecule modulators on the aggregation propensity and associated toxicity of α-Syn and its PD-associated mutants. It serves as a valuable resource for identifying and developing potent, non-invasive, non-toxic, and highly specific small molecule-based therapeutic arsenal for combating PD. Additionally, it raises pertinent questions aimed at guiding future research endeavours in the field of α-Syn aggregation remodelling.
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Affiliation(s)
- Ishfaq Ahmad Ahanger
- Department of Clinical Biochemistry, University of Kashmir, Srinagar, Jammu and Kashmir 190006, India.
| | - Tanveer Ali Dar
- Department of Clinical Biochemistry, University of Kashmir, Srinagar, Jammu and Kashmir 190006, India.
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Wang J, Ma H, Guo H, Chen Y, Liu Y. Clinical applications of phosphocreatine and related mechanisms. Life Sci 2024; 355:123012. [PMID: 39181314 DOI: 10.1016/j.lfs.2024.123012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 08/14/2024] [Accepted: 08/21/2024] [Indexed: 08/27/2024]
Abstract
Phosphocreatine (PCr), a naturally occurring creatine phosphorylated molecule, is a high-energy phosphate compound that is one of the most important substances involved in cell energy metabolism, and also has anti-apoptosis and anti-oxidative stress effects. It is precisely because of its role in maintaining energy homeostasis that PCr is widely used in diseases related to energy damage. In the regulation of cell signal, PCr mainly plays a role through MAPK, NF-κB, PI3K/AKT, ERK/Nrf2/HO-1 and JAK2/STAT3. In clinical applications, PCr is commonly used as a cardioprotective drug, such as ischemic heart disease, myocardial fibrosis, myocardial infarction, arrhythmia, and myocarditis. In recent years, further research on PCr has found that PCr also has a positive role in the treatment of other diseases, including diabetes-induced liver injury, kidney injury, cerebral ischemia-reperfusion injury, and neurodegenerative diseases. In this paper, the literature on PCr in three databases, Web of Sciences, SciFinder, and PubMed, was summarized and analyzed, and the research progress of PCr in recent years was reviewed, hoping to provide help for the expansion of its application in clinical therapy.
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Affiliation(s)
- Jing Wang
- School of Pharmaceutical Sciences, Liaoning University, Shenyang 110036, China
| | - Huizhong Ma
- School of Pharmaceutical Sciences, Liaoning University, Shenyang 110036, China
| | - Haohao Guo
- School of Pharmaceutical Sciences, Liaoning University, Shenyang 110036, China
| | - Yuan Chen
- School of Pharmaceutical Sciences, Liaoning University, Shenyang 110036, China
| | - Yufeng Liu
- School of Pharmaceutical Sciences, Liaoning University, Shenyang 110036, China; Natural Products Pharmaceutical Engineering Technology Research Center of Liaoning Province, Shenyang 110036, China.
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Koike S, Mitsuhashi H, Kishida A, Ogasawara Y. Elucidating the Antiglycation Effect of Creatine on Methylglyoxal-Induced Carbonyl Stress In Vitro. Int J Mol Sci 2024; 25:10880. [PMID: 39456665 PMCID: PMC11506949 DOI: 10.3390/ijms252010880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 10/04/2024] [Accepted: 10/07/2024] [Indexed: 10/28/2024] Open
Abstract
Advanced glycation end products (AGEs) with multiple structures are formed at the sites where carbonyl groups of reducing sugars bind to free amino groups of proteins through the Maillard reaction. In recent years, it has been highlighted that the accumulation of AGEs, which are generated when carbonyl compounds produced in the process of sugar metabolism react with proteins, is involved in various diseases. Creatine is a biocomponent that is homeostatically present throughout the body and is known to react nonenzymatically with α-dicarbonyl compounds. This study evaluated the antiglycation potential of creatine against methylglyoxal (MGO), a glucose metabolite that induces carbonyl stress with formation of AGEs in vitro. Further, to elucidate the mechanism of the cytoprotective action of creatine, its effect on the accumulation of carbonyl proteins in the cells and the MGO-induced cellular damage were investigated using neuroblastoma cells. The results revealed that creatine significantly inhibits protein carbonylation by directly reacting with MGO, and creatine added to the culture medium suppressed MGO-derived carbonylation of intracellular proteins and exerted a protective effect on MGO-induced cytotoxicity. These findings suggest that endogenous and supplemented creatine may contribute to the attenuation of carbonyl stress in vivo.
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Affiliation(s)
- Shin Koike
- Department of Analytical Biochemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan; (S.K.); (H.M.)
| | - Haruka Mitsuhashi
- Department of Analytical Biochemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan; (S.K.); (H.M.)
| | - Atsushi Kishida
- Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan;
| | - Yuki Ogasawara
- Department of Analytical Biochemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan; (S.K.); (H.M.)
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Wang Y, Liu S, Cao W, Lv J, Yu C, Huang T, Sun D, Liao C, Pang Y, Pang Z, Yu M, Wang H, Wu X, Liu Y, Gao W, Li L. The metabolic signature of blood lipids: a causal inference study using twins. J Lipid Res 2024; 65:100625. [PMID: 39303494 PMCID: PMC11437770 DOI: 10.1016/j.jlr.2024.100625] [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: 10/26/2023] [Revised: 08/02/2024] [Accepted: 08/16/2024] [Indexed: 09/22/2024] Open
Abstract
Dyslipidemia is one of the cardiometabolic risk factors that influences mortality globally. Unraveling the causality between blood lipids and metabolites and the complex networks connecting lipids, metabolites, and other cardiometabolic traits can help to more accurately reflect the body's metabolic disorders and even cardiometabolic diseases. We conducted targeted metabolomics of 248 metabolites in 437 twins from the Chinese National Twin Registry. Inference about Causation through Examination of FAmiliaL CONfounding (ICE FALCON) analysis was used for causal inference between metabolites and lipid parameters. Bidirectional mediation analysis was performed to explore the linkages between blood lipids, metabolites, and other seven cardiometabolic traits. We identified 44, 1, and 31 metabolites associated with triglyceride (TG), total cholesterol (TC), and high-density lipoprotein-cholesterol (HDL-C), most of which were gut microbiota-derived metabolites. There were 9, 1, and 14 metabolites that showed novel associations with TG, TC, and HDL-C, respectively. ICE FALCON analysis found that TG and HDL-C may have a predicted causal effect on 23 and six metabolites, respectively, and one metabolite may have a predicted causal effect on TG. Mediation analysis discovered 14 linkages connecting blood lipids, metabolites, and other cardiometabolic traits. Our study highlights the significance of gut microbiota-derived metabolites in lipid metabolism. Most of the identified cross-sectional associations may be due to the lipids having a predicted causal effect on metabolites, but not vice versa, nor are they due to family confounding. These findings shed new light on lipid metabolism and personalized management of cardiometabolic diseases.
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Affiliation(s)
- Yutong Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China; Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China
| | - Shunkai Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China; Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China
| | - Weihua Cao
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China; Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China
| | - Jun Lv
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China; Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China; Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing, China
| | - Canqing Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China; Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China; Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing, China
| | - Tao Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China; Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China
| | - Dianjianyi Sun
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China; Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China; Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing, China
| | - Chunxiao Liao
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China; Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China; Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing, China
| | - Yuanjie Pang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China; Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China
| | - Zengchang Pang
- Qingdao Center for Disease Control and Prevention, Qingdao, China
| | - Min Yu
- Zhejiang Center for Disease Control and Prevention, Hangzhou, China
| | - Hua Wang
- Jiangsu Center for Disease Control and Prevention, Nanjing, China
| | - Xianping Wu
- Sichuan Center for Disease Control and Prevention, Chengdu, China
| | - Yu Liu
- Heilongjiang Center for Disease Control and Prevention, Harbin, China
| | - Wenjing Gao
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China; Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China.
| | - Liming Li
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China; Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China; Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing, China.
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Rastogi S, Verma A, Trivedi R, Shukla A, Kumar D. Clinical metabolomics investigation of rheumatoid arthritis patients receiving ayurvedic whole system intervention. J Ayurveda Integr Med 2024; 15:101009. [PMID: 38972279 PMCID: PMC11264181 DOI: 10.1016/j.jaim.2024.101009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 05/27/2024] [Accepted: 06/03/2024] [Indexed: 07/09/2024] Open
Abstract
BACKGROUND Arthritis is a common clinical condition seen in Ayurveda clinics. Clinical trials have reported Ayurvedic interventions to be of benefits in many arthritic conditions including Rheumatoid Arthritis (RA). No mechanistic details however are available about how such interventions on their own or as a combination of whole system Ayurveda might be working. OBJECTIVE The study aims to evaluate simultaneously the clinical outcome of Ayurveda whole system (AWS) intervention in RA patients and identifying the serum metabolic signatures which could be useful for diagnosing the disease and monitoring treatment response. MATERIAL AND METHODS RA patients (n = 37) simultaneously diagnosed as Amavata fulfilling the specific inclusion and exclusion criteria were recruited in the study and were given Ayurveda whole system (AWS) intervention comprised of oral medicines, local therapy and dietary recommendation for 3 months. The clinical and serum metabolic changes were investigated for pre-treatment RA patients (baseline RA group, n = 37) and post-treatment RA patients (following treatment of 6-weeks (RA_F, n = 26) and three months (RA_T, n = 36). For comparative serum metabolomics analysis, 57 normal healthy control (HC) subjects were also involved and the serum metabolic profiles were measured at high-field 800 MHz NMR spectrometer. The serum metabolic profiles were compared using multivariate statistical analysis and discriminatory metabolic features were evaluated for diagnostic potential using receiver operating characteristic (ROC) curve analysis. RESULTS A significant reduction in DAS-28 ESR, AAM Score, total swollen joints, total tender joints were observed following AWS intervention. The clinical outcomes were concordant with changes in metabolic profiles of RA patients as these were also shifting towards the normal levels following the intervention. Compared to healthy control (HC) subjects, the sera of baseline RA patients were characterised by increased circulatory level of succinate, lysine, mannose, creatine, and 3-Hydroxybutyrate (3-HB) and decreased levels of alanine. The present study also evaluated the serum metabolic ratios for their discriminatory and diagnostic potential and notably, six metabolic ratios (KHR, KThR, KVR, GHR, PTR and SHR) were found significantly altered (elevated) in baseline RA patients. However, in RA patients receiving AWS treatment, these metabolic changes showed marked convergence towards the metabolic signatures of healthy controls. CONCLUSION This first of its kind study clearly shows the clinical efficacy of Ayurvedic Whole System (AWS) intervention in the management of Rheumatoid Arthritis (RA), as demonstrated by significant improvements in key clinical parameters. The intervention not only alleviated symptoms but also induced a profound metabolic shifting towards normalization; thus, underscoring the potential of AWS intervention to modulate cellular metabolism in a manner that facilitates a return to homeostasis in RA patients. However, future studies are imperative to confirm these preliminary observations and delineate the underlying mechanisms of action of intervention in cases of RA.
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Affiliation(s)
- Sanjeev Rastogi
- Ayurveda -Arthritis Treatment and Advanced Research Center (A-ATARC), Department of Kaya Chikitsa, State Ayurvedibc College and Hospital, Lucknow University, Lucknow, 226003, India.
| | - Ankita Verma
- Ayurveda -Arthritis Treatment and Advanced Research Center (A-ATARC), Department of Kaya Chikitsa, State Ayurvedibc College and Hospital, Lucknow University, Lucknow, 226003, India
| | - Rimjhim Trivedi
- Centre of Biomedical Research (CBMR), SGPGIMS Campus, Lucknow, 226014, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, 201002, India
| | - Anuj Shukla
- Ayurveda -Arthritis Treatment and Advanced Research Center (A-ATARC), Department of Kaya Chikitsa, State Ayurvedibc College and Hospital, Lucknow University, Lucknow, 226003, India
| | - Dinesh Kumar
- Centre of Biomedical Research (CBMR), SGPGIMS Campus, Lucknow, 226014, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, 201002, India.
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Correia JP, Gromicho M, Pronto-Laborinho AC, Oliveira Santos M, de Carvalho M. Creatine Kinase and Respiratory Decline in Amyotrophic Lateral Sclerosis. Brain Sci 2024; 14:661. [PMID: 39061402 PMCID: PMC11274414 DOI: 10.3390/brainsci14070661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 06/24/2024] [Accepted: 06/25/2024] [Indexed: 07/28/2024] Open
Abstract
Respiratory dysfunction is an important hallmark of amyotrophic lateral sclerosis (ALS). Elevation of creatine kinase (CK) has been reported in 23-75% of ALS patients, but the underlying mechanisms remain unknown. This work aims to enlighten the role of CK as a prognostic factor of respiratory dysfunction in ALS. A retrospective analysis of demographic and clinical variables, CK, functional decline per month (ΔFS), forced vital capacity (%FVC), and mean amplitude of the phrenic nerve compound motor action potential (pCMAP) in 319 ALS patients was conducted. These measurements were evaluated at study entry, and patients were followed from the moment of first observation until death or last follow-up visit. High CK values were defined as above the 90th percentile (CK ≥ P90) adjusted to sex. We analyzed survival and time to non-invasive ventilation (NIV) as proxies for respiratory impairment. Linear regression analysis revealed that high CK was associated with male sex (p < 0.001), spinal onset (p = 0.018), and FVC ≥ 80% (p = 0.038). CK was 23.4% higher in spinal-onset ALS patients (p < 0.001). High CK levels were not linked with an increased risk of death (p = 0.334) in Cox multivariate regression analysis. CK ≥ P90 (HR = 1.001, p = 0.038), shorter disease duration (HR = 0.937, p < 0.001), lower pCMAP (HR = 0.082, p < 0.001), and higher ΔFS (HR = 1.968, p < 0.001) were risk factors for respiratory failure. The association between high CK levels and poorer respiratory outcomes could derive from cellular metabolic stress or a specific phenotype associated with faster respiratory decline. Our study suggests that CK measurement at diagnosis should be more extensively investigated as a possible marker of poor respiratory outcome in future studies, including a larger population of patients.
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Affiliation(s)
- João Pedro Correia
- Faculdade de Medicina, Instituto de Medicina Molecular, Universidade de Lisboa, 1649-004 Lisboa, Portugal; (J.P.C.); (M.G.); (A.C.P.-L.); (M.O.S.)
| | - Marta Gromicho
- Faculdade de Medicina, Instituto de Medicina Molecular, Universidade de Lisboa, 1649-004 Lisboa, Portugal; (J.P.C.); (M.G.); (A.C.P.-L.); (M.O.S.)
| | - Ana Catarina Pronto-Laborinho
- Faculdade de Medicina, Instituto de Medicina Molecular, Universidade de Lisboa, 1649-004 Lisboa, Portugal; (J.P.C.); (M.G.); (A.C.P.-L.); (M.O.S.)
| | - Miguel Oliveira Santos
- Faculdade de Medicina, Instituto de Medicina Molecular, Universidade de Lisboa, 1649-004 Lisboa, Portugal; (J.P.C.); (M.G.); (A.C.P.-L.); (M.O.S.)
- Centro de Estudos Egas Moniz, Faculdade de Medicina, Universidade de Lisboa, 1649-004 Lisboa, Portugal
- Departamento de Neurociências e Saúde Mental, Hospital (ULS) de Santa Maria, 1649-028 Lisboa, Portugal
| | - Mamede de Carvalho
- Faculdade de Medicina, Instituto de Medicina Molecular, Universidade de Lisboa, 1649-004 Lisboa, Portugal; (J.P.C.); (M.G.); (A.C.P.-L.); (M.O.S.)
- Centro de Estudos Egas Moniz, Faculdade de Medicina, Universidade de Lisboa, 1649-004 Lisboa, Portugal
- Departamento de Neurociências e Saúde Mental, Hospital (ULS) de Santa Maria, 1649-028 Lisboa, Portugal
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11
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Nersesova L, Petrosyan M, Tsakanova G. Review of the evidence of radioprotective potential of creatine and arginine as dietary supplements. Int J Radiat Biol 2024; 100:849-864. [PMID: 38683545 DOI: 10.1080/09553002.2024.2345098] [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: 12/29/2022] [Accepted: 04/10/2024] [Indexed: 05/01/2024]
Abstract
PURPOSE Creatine (Cr) and l-arginine are naturally occurring guanidino compounds, commonly used as ergogenic dietary supplements. Creatine and l-arginine exhibit also a number of non-energy-related features, such as antioxidant, anti-apoptotic, and anti-inflammatory properties, which contribute to their protective action against oxidative stress (OS). In this regard, there are a number of studies emphasizing the protective effect of Cr against OS, which develops in the process of aging, increased physical loads as part of athletes' workouts, as well as a number of neurological diseases and toxic effects associated with xenobiotics and UV irradiation. Against this backdrop, and since ionizing radiation causes OS in cells, leading to radiotoxicity, there is an increasing interest to understand whether Cr has the full potential to serve as an effective radioprotective agent. The extensive literature search did not provide any data on this issue. In this narrative review, we have summarized some of our own experimental data published over the last years addressing the respective radioprotective effects of Cr. Next, we have additionally reviewed the existing data on the radiomodifying effects of l-arginine presented earlier by other research groups. CONCLUSIONS Creatine possesses significant radioprotective potential including: (1) radioprotective effect on the survival rate of rats subjected to acute whole-body X-ray irradiation in a LD70/30 dose of 6.5 Gy, (2) radioprotective effect on the population composition of peripheral blood cells, (3) radioprotective effect on the DNA damage of peripheral blood mononuclear cells, (4) radioprotective effect on the hepatocyte nucleus-nucleolar apparatus, and (5) radioprotective effect on the brain and liver Cr-Cr kinase systems of the respective animals. Taking into account these cytoprotective, gene-protective, hepatoprotective and energy-stimulating features of Cr, as well as its significant radioprotective effect on the survival rate of rats, it can be considered as a potentially promising radioprotector for further preclinical and clinical studies. The review of the currently available data on radiomodifying effects of l-arginine has indicated its significant potential as a radioprotector, radiomitigator, and radiosensitizer. However, to prove the effectiveness of arginine (Arg) as a radioprotective agent, it appears necessary to expand and deepen the relevant preclinical studies, and, most importantly, increase the number of proof-of-concept clinical trials, which are evidently lacking as of now.
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Affiliation(s)
| | | | - Gohar Tsakanova
- Institute of Molecular Biology NAS RA, Yerevan, Armenia
- CANDLE Synchrotron Research Institute, Yerevan, Armenia
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12
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Clemente-Suárez VJ, Redondo-Flórez L, Beltrán-Velasco AI, Ramos-Campo DJ, Belinchón-deMiguel P, Martinez-Guardado I, Dalamitros AA, Yáñez-Sepúlveda R, Martín-Rodríguez A, Tornero-Aguilera JF. Mitochondria and Brain Disease: A Comprehensive Review of Pathological Mechanisms and Therapeutic Opportunities. Biomedicines 2023; 11:2488. [PMID: 37760929 PMCID: PMC10526226 DOI: 10.3390/biomedicines11092488] [Citation(s) in RCA: 52] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/02/2023] [Accepted: 09/04/2023] [Indexed: 09/29/2023] Open
Abstract
Mitochondria play a vital role in maintaining cellular energy homeostasis, regulating apoptosis, and controlling redox signaling. Dysfunction of mitochondria has been implicated in the pathogenesis of various brain diseases, including neurodegenerative disorders, stroke, and psychiatric illnesses. This review paper provides a comprehensive overview of the intricate relationship between mitochondria and brain disease, focusing on the underlying pathological mechanisms and exploring potential therapeutic opportunities. The review covers key topics such as mitochondrial DNA mutations, impaired oxidative phosphorylation, mitochondrial dynamics, calcium dysregulation, and reactive oxygen species generation in the context of brain disease. Additionally, it discusses emerging strategies targeting mitochondrial dysfunction, including mitochondrial protective agents, metabolic modulators, and gene therapy approaches. By critically analysing the existing literature and recent advancements, this review aims to enhance our understanding of the multifaceted role of mitochondria in brain disease and shed light on novel therapeutic interventions.
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Affiliation(s)
- Vicente Javier Clemente-Suárez
- Faculty of Sports Sciences, Universidad Europea de Madrid, Tajo Street, s/n, 28670 Madrid, Spain; (V.J.C.-S.); (J.F.T.-A.)
- Group de Investigación en Cultura, Educación y Sociedad, Universidad de la Costa, Barranquilla 080002, Colombia
| | - Laura Redondo-Flórez
- Department of Health Sciences, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, C/Tajo s/n, Villaviciosa de Odón, 28670 Madrid, Spain
| | - Ana Isabel Beltrán-Velasco
- Psychology Department, Facultad de Ciencias de la Vida y la Naturaleza, Universidad Antonio de Nebrija, 28240 Madrid, Spain
| | - Domingo Jesús Ramos-Campo
- LFE Research Group, Department of Health and Human Performance, Faculty of Physical Activity and Sport Science-INEF, Universidad Politécnica de Madrid, 28040 Madrid, Spain
| | - Pedro Belinchón-deMiguel
- Department of Nursing and Nutrition, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, 28670 Villaviciosa de Odón, Spain;
| | | | - Athanasios A. Dalamitros
- Laboratory of Evaluation of Human Biological Performance, School of Physical Education and Sport Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Rodrigo Yáñez-Sepúlveda
- Faculty of Education and Social Sciences, Universidad Andres Bello, Viña del Mar 2520000, Chile;
| | - Alexandra Martín-Rodríguez
- Faculty of Sports Sciences, Universidad Europea de Madrid, Tajo Street, s/n, 28670 Madrid, Spain; (V.J.C.-S.); (J.F.T.-A.)
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13
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Alraddadi EA, Khojah AM, Alamri FF, Kecheck HK, Altaf WF, Khouqeer Y. Potential role of creatine as an anticonvulsant agent: evidence from preclinical studies. Front Neurosci 2023; 17:1201971. [PMID: 37456992 PMCID: PMC10339234 DOI: 10.3389/fnins.2023.1201971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 06/12/2023] [Indexed: 07/18/2023] Open
Abstract
Epilepsy is one of the most common neurological disorders affecting people of all ages representing a significant social and public health burden. Current therapeutic options for epilepsy are not effective in a significant proportion of patients suggesting a need for identifying novel targets for the development of more effective therapeutics. There is growing evidence from animal and human studies suggesting a role of impaired brain energy metabolism and mitochondrial dysfunction in the development of epilepsy. Candidate compounds with the potential to target brain energetics have promising future in the management of epilepsy and other related neurological disorders. Creatine is a naturally occurring organic compound that serves as an energy buffer and energy shuttle in tissues, such as brain and skeletal muscle, that exhibit dynamic energy requirements. In this review, applications of creatine supplements in neurological conditions in which mitochondrial dysfunction is a central component in its pathology will be discussed. Currently, limited evidence mainly from preclinical animal studies suggest anticonvulsant properties of creatine; however, the exact mechanism remain to be elucidated. Future work should involve larger clinical trials of creatine used as an add-on therapy, followed by large clinical trials of creatine as monotherapy.
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Affiliation(s)
- Eman A. Alraddadi
- Department of Basic Sciences, College of Science and Health Professions, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Abdulrahman M. Khojah
- Department of Basic Sciences, College of Science and Health Professions, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
| | - Faisal F. Alamri
- Department of Basic Sciences, College of Science and Health Professions, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Husun K. Kecheck
- Department of Basic Sciences, College of Science and Health Professions, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
| | - Wid F. Altaf
- Department of Basic Sciences, College of Science and Health Professions, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
| | - Yousef Khouqeer
- Department of Basic Sciences, College of Science and Health Professions, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
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14
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Heland S, Fields N, Ellery SJ, Fahey M, Palmer KR. The role of nutrients in human neurodevelopment and their potential to prevent neurodevelopmental adversity. Front Nutr 2022; 9:992120. [PMID: 36483929 PMCID: PMC9722743 DOI: 10.3389/fnut.2022.992120] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 11/02/2022] [Indexed: 06/21/2024] Open
Abstract
Nutritional deficits or excesses affect a huge proportion of pregnant women worldwide. Maternal nutrition has a significant influence on the fetal environment and can dramatically impact fetal brain development. This paper reviews current nutritional supplements that can be used to optimise fetal neurodevelopment and prevent neurodevelopmental morbidities, including folate, iodine, vitamin B12, iron, and vitamin D. Interestingly, while correcting nutritional deficits can prevent neurodevelopmental adversity, overcorrecting them can in some cases be detrimental, so care needs to be taken when recommending supplementation in pregnancy. The potential benefits of using nutrition to prevent neurodiversity is shown by promising nutraceuticals, sulforaphane and creatine, both currently under investigation. They have the potential to promote improved neurodevelopmental outcomes through mitigation of pathological processes, including hypoxia, inflammation, and oxidative stress. Neurodevelopment is a complex process and whilst the role of micronutrients and macronutrients on the developing fetal brain is not completely understood, this review highlights the key findings thus far.
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Affiliation(s)
- Sarah Heland
- Monash Women’s and Newborn, Monash Health, Clayton, VIC, Australia
| | - Neville Fields
- Monash Women’s and Newborn, Monash Health, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
| | - Stacey Joan Ellery
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
| | - Michael Fahey
- Paediatric Neurology Unit, Monash Children’s Hospital, Clayton, VIC, Australia
- Department of Paediatrics, Monash University, Clayton, VIC, Australia
| | - Kirsten Rebecca Palmer
- Monash Women’s and Newborn, Monash Health, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
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15
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Functional Nutrients to Ameliorate Neurogenic Muscle Atrophy. Metabolites 2022; 12:metabo12111149. [DOI: 10.3390/metabo12111149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 11/15/2022] [Accepted: 11/17/2022] [Indexed: 11/22/2022] Open
Abstract
Neurogenic muscle atrophy is a debilitating condition that occurs from nerve trauma in association with diseases or during aging, leading to reduced interaction between motoneurons and skeletal fibers. Current therapeutic approaches aiming at preserving muscle mass in a scenario of decreased nervous input include physical activity and employment of drugs that slow down the progression of the condition yet provide no concrete resolution. Nutritional support appears as a precious tool, adding to the success of personalized medicine, and could thus play a relevant part in mitigating neurogenic muscle atrophy. We herein summarize the molecular pathways triggered by denervation of the skeletal muscle that could be affected by functional nutrients. In this narrative review, we examine and discuss studies pertaining to the use of functional ingredients to counteract neurogenic muscle atrophy, focusing on their preventive or curative means of action within the skeletal muscle. We reviewed experimental models of denervation in rodents and in amyotrophic lateral sclerosis, as well as that caused by aging, considering the knowledge generated with use of animal experimental models and, also, from human studies.
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16
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Pancotti C, Birolo G, Rollo C, Sanavia T, Di Camillo B, Manera U, Chiò A, Fariselli P. Deep learning methods to predict amyotrophic lateral sclerosis disease progression. Sci Rep 2022; 12:13738. [PMID: 35962027 PMCID: PMC9374680 DOI: 10.1038/s41598-022-17805-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 08/01/2022] [Indexed: 11/10/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a highly complex and heterogeneous neurodegenerative disease that affects motor neurons. Since life expectancy is relatively low, it is essential to promptly understand the course of the disease to better target the patient's treatment. Predictive models for disease progression are thus of great interest. One of the most extensive and well-studied open-access data resources for ALS is the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) repository. In 2015, the DREAM-Phil Bowen ALS Prediction Prize4Life Challenge was held on PRO-ACT data, where competitors were asked to develop machine learning algorithms to predict disease progression measured through the slope of the ALSFRS score between 3 and 12 months. However, although it has already been successfully applied in several studies on ALS patients, to the best of our knowledge deep learning approaches still remain unexplored on the ALSFRS slope prediction in PRO-ACT cohort. Here, we investigate how deep learning models perform in predicting ALS progression using the PRO-ACT data. We developed three models based on different architectures that showed comparable or better performance with respect to the state-of-the-art models, thus representing a valid alternative to predict ALS disease progression.
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Affiliation(s)
- Corrado Pancotti
- Department of Medical Sciences, University of Turin, 10126, Turin, Italy
| | - Giovanni Birolo
- Department of Medical Sciences, University of Turin, 10126, Turin, Italy.
| | - Cesare Rollo
- Department of Medical Sciences, University of Turin, 10126, Turin, Italy
| | - Tiziana Sanavia
- Department of Medical Sciences, University of Turin, 10126, Turin, Italy
| | - Barbara Di Camillo
- Department of Information Engineering, University of Padua, 35131, Padua, Italy
| | - Umberto Manera
- ALS Center, "Rita Levi Montalcini" Department of Neuroscience, University of Turin, 10126, Turin, Italy
| | - Adriano Chiò
- ALS Center, "Rita Levi Montalcini" Department of Neuroscience, University of Turin, 10126, Turin, Italy
| | - Piero Fariselli
- Department of Medical Sciences, University of Turin, 10126, Turin, Italy
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17
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Zhang S, Zhao J, Quan Z, Li H, Qing H. Mitochondria and Other Organelles in Neural Development and Their Potential as Therapeutic Targets in Neurodegenerative Diseases. Front Neurosci 2022; 16:853911. [PMID: 35450015 PMCID: PMC9016280 DOI: 10.3389/fnins.2022.853911] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 03/07/2022] [Indexed: 12/19/2022] Open
Abstract
The contribution of organelles to neural development has received increasing attention. Studies have shown that organelles such as mitochondria, endoplasmic reticulum (ER), lysosomes, and endosomes play important roles in neurogenesis. Specifically, metabolic switching, reactive oxygen species production, mitochondrial dynamics, mitophagy, mitochondria-mediated apoptosis, and the interaction between mitochondria and the ER all have roles in neurogenesis. Lysosomes and endosomes can regulate neurite growth and extension. Moreover, metabolic reprogramming represents a novel strategy for generating functional neurons. Accordingly, the exploration and application of mechanisms underlying metabolic reprogramming will be beneficial for neural conversion and regenerative medicine. There is adequate evidence implicating the dysfunction of cellular organelles—especially mitochondria—in neurodegenerative disorders, and that improvement of mitochondrial function may reverse the progression of these diseases through the reinforcement of adult neurogenesis. Therefore, these organelles have potential as therapeutic targets for the treatment of neurodegenerative diseases. In this review, we discuss the function of these organelles, especially mitochondria, in neural development, focusing on their potential as therapeutic targets in neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis.
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Affiliation(s)
- Shuyuan Zhang
- Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Juan Zhao
- Aerospace Medical Center, Aerospace Center Hospital, Beijing, China
| | - Zhenzhen Quan
- Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Hui Li
- Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, China
- *Correspondence: Hui Li,
| | - Hong Qing
- Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, China
- Hong Qing,
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18
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Nersesova LS, Petrosyan MS, Arutjunyan AV. Neuroprotective Potential of Creatine. Hidden Resources of Its Therapeutic and Preventive Use. NEUROCHEM J+ 2022. [DOI: 10.1134/s1819712422010093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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19
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Guitart-Mampel M, Urquiza P, Carnevale Neto F, Anderson JR, Hambardikar V, Scoma ER, Merrihew GE, Wang L, MacCoss MJ, Raftery D, Peffers MJ, Solesio ME. Mitochondrial Inorganic Polyphosphate (polyP) Is a Potent Regulator of Mammalian Bioenergetics in SH-SY5Y Cells: A Proteomics and Metabolomics Study. Front Cell Dev Biol 2022; 10:833127. [PMID: 35252194 PMCID: PMC8892102 DOI: 10.3389/fcell.2022.833127] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 01/21/2022] [Indexed: 01/04/2023] Open
Abstract
Inorganic polyphosphate (polyP) is an ancient, ubiquitous, and well-conserved polymer which is present in all the studied organisms. It is formed by individual subunits of orthophosphate which are linked by structurally similar bonds and isoenergetic to those found in ATP. While the metabolism and the physiological roles of polyP have already been described in some organisms, including bacteria and yeast, the exact role of this polymer in mammalian physiology still remains poorly understood. In these organisms, polyP shows a co-localization with mitochondria, and its role as a key regulator of the stress responses, including the maintenance of appropriate bioenergetics, has already been demonstrated by our group and others. Here, using Wild-type (Wt) and MitoPPX (cells enzymatically depleted of mitochondrial polyP) SH-SY5Y cells, we have conducted a comprehensive study of the status of cellular physiology, using proteomics and metabolomics approaches. Our results suggest a clear dysregulation of mitochondrial physiology, especially of bioenergetics, in MitoPPX cells when compared with Wt cells. Moreover, the effects induced by the enzymatic depletion of polyP are similar to those present in the mitochondrial dysfunction that is observed in neurodegenerative disorders and in neuronal aging. Based on our findings, the metabolism of mitochondrial polyP could be a valid and innovative pharmacological target in these conditions.
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Affiliation(s)
| | - Pedro Urquiza
- Department of Biology, Rutgers University, Camden, NJ, United States
| | - Fausto Carnevale Neto
- Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, United States
| | - James R. Anderson
- Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Vedangi Hambardikar
- Center for Computational and Integrative Biology, Rutgers University, Camden, NJ, United States
| | - Ernest R. Scoma
- Center for Computational and Integrative Biology, Rutgers University, Camden, NJ, United States
| | - Gennifer E. Merrihew
- Department of Genome Sciences, University of Washington, Seattle, WA, United States
| | - Lu Wang
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, United States
| | - Michael J. MacCoss
- Department of Genome Sciences, University of Washington, Seattle, WA, United States
| | - Daniel Raftery
- Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, United States
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
| | - Mandy J. Peffers
- Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Maria E. Solesio
- Department of Biology, Rutgers University, Camden, NJ, United States
- Center for Computational and Integrative Biology, Rutgers University, Camden, NJ, United States
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20
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Role of Creatine Supplementation in Conditions Involving Mitochondrial Dysfunction: A Narrative Review. Nutrients 2022; 14:nu14030529. [PMID: 35276888 PMCID: PMC8838971 DOI: 10.3390/nu14030529] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/24/2022] [Accepted: 01/24/2022] [Indexed: 12/14/2022] Open
Abstract
Creatine monohydrate (CrM) is one of the most widely used nutritional supplements among active individuals and athletes to improve high-intensity exercise performance and training adaptations. However, research suggests that CrM supplementation may also serve as a therapeutic tool in the management of some chronic and traumatic diseases. Creatine supplementation has been reported to improve high-energy phosphate availability as well as have antioxidative, neuroprotective, anti-lactatic, and calcium-homoeostatic effects. These characteristics may have a direct impact on mitochondrion's survival and health particularly during stressful conditions such as ischemia and injury. This narrative review discusses current scientific evidence for use or supplemental CrM as a therapeutic agent during conditions associated with mitochondrial dysfunction. Based on this analysis, it appears that CrM supplementation may have a role in improving cellular bioenergetics in several mitochondrial dysfunction-related diseases, ischemic conditions, and injury pathology and thereby could provide therapeutic benefit in the management of these conditions. However, larger clinical trials are needed to explore these potential therapeutic applications before definitive conclusions can be drawn.
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21
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Effects of Delivering Guanidinoacetic Acid or Its Prodrug to the Neural Tissue: Possible Relevance for Creatine Transporter Deficiency. Brain Sci 2022; 12:brainsci12010085. [PMID: 35053827 PMCID: PMC8773658 DOI: 10.3390/brainsci12010085] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/30/2021] [Accepted: 01/06/2022] [Indexed: 12/03/2022] Open
Abstract
The creatine precursor guanidinoacetate (GAA) was used as a dietary supplement in humans with no adverse events. Nevertheless, it has been suggested that GAA is epileptogenic or toxic to the nervous system. However, increased GAA content in rodents affected by guanidinoacetate methyltransferase (GAMT) deficiency might be responsible for their spared muscle function. Given these conflicting data, and lacking experimental evidence, we investigated whether GAA affected synaptic transmission in brain hippocampal slices. Incubation with 11.5 μM GAA (the highest concentration in the cerebrospinal fluid of GAMT-deficient patients) did not change the postsynaptic compound action potential. Even 1 or 2 mM had no effect, while 4 mM caused a reversible decrease in the potential. Guanidinoacetate increased creatine and phosphocreatine, but not after blocking the creatine transporter (also used by GAA). In an attempt to allow the brain delivery of GAA when there was a creatine transporter deficiency, we synthesized diacetyl guanidinoacetic acid ethyl ester (diacetyl-GAAE), a lipophilic derivative. In brain slices, 0.1 mM did not cause electrophysiological changes and improved tissue viability after blockage of the creatine transporter. However, diacetyl-GAAE did not increase creatine nor phosphocreatine in brain slices after blockage of the creatine transporter. We conclude that: (1) upon acute administration, GAA is neither epileptogenic nor neurotoxic; (2) Diacetyl-GAAE improves tissue viability after blockage of the creatine transporter but not through an increase in creatine or phosphocreatine. Diacetyl-GAAE might give rise to a GAA–phosphoGAA system that vicariates the missing creatine–phosphocreatine system. Our in vitro data show that GAA supplementation may be safe in the short term, and that a lipophilic GAA prodrug may be useful in creatine transporter deficiency.
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22
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Song T, Song X, Zhu C, Patrick R, Skurla M, Santangelo I, Green M, Harper D, Ren B, Forester BP, Öngür D, Du F. Mitochondrial dysfunction, oxidative stress, neuroinflammation, and metabolic alterations in the progression of Alzheimer's disease: A meta-analysis of in vivo magnetic resonance spectroscopy studies. Ageing Res Rev 2021; 72:101503. [PMID: 34751136 PMCID: PMC8662951 DOI: 10.1016/j.arr.2021.101503] [Citation(s) in RCA: 168] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 10/19/2021] [Accepted: 10/25/2021] [Indexed: 12/13/2022]
Abstract
Accumulating evidence demonstrates that metabolic changes in the brain associated with neuroinflammation, oxidative stress, and mitochondrial dysfunction play an important role in the pathophysiology of mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, the neural signatures associated with these metabolic alterations and underlying molecular mechanisms are still elusive. Accordingly, we reviewed the literature on in vivo human brain 1H and 31P-MRS studies and use meta-analyses to identify patterns of brain metabolic alterations in MCI and AD. 40 and 39 studies on MCI and AD, respectively, were classified according to brain regions. Our results indicate decreased N-acetyl aspartate and creatine but increased myo-inositol levels in both MCI and AD, decreased glutathione level in MCI as well as disrupted energy metabolism in AD. In addition, the hippocampus shows the strongest alterations in most of these metabolites. This meta-analysis also illustrates progressive metabolite alterations from MCI to AD. Taken together, it suggests that 1) neuroinflammation and oxidative stress may occur in the early stages of AD, and likely precede neuron loss in its progression; 2) the hippocampus is a sensitive region of interest for early diagnosis and monitoring the response of interventions; 3) targeting bioenergetics associated with neuroinflammation/oxidative stress is a promising approach for treating AD.
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Affiliation(s)
- Tao Song
- Psychotic Disorders Division, McLean Hospital, 02478, USA; McLean Imaging Center, McLean Hospital, 02478, USA; Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Xiaopeng Song
- Psychotic Disorders Division, McLean Hospital, 02478, USA; McLean Imaging Center, McLean Hospital, 02478, USA; Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Chenyawen Zhu
- Psychotic Disorders Division, McLean Hospital, 02478, USA; McLean Imaging Center, McLean Hospital, 02478, USA
| | - Regan Patrick
- Division of Geriatric Psychiatry, McLean Hospital, 02478, USA; Department of Neuropsychology, McLean Hospital, 02478, USA; Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Miranda Skurla
- Division of Geriatric Psychiatry, McLean Hospital, 02478, USA
| | | | - Morgan Green
- Division of Geriatric Psychiatry, McLean Hospital, 02478, USA
| | - David Harper
- Division of Geriatric Psychiatry, McLean Hospital, 02478, USA; Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Boyu Ren
- Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Brent P Forester
- Division of Geriatric Psychiatry, McLean Hospital, 02478, USA; Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Dost Öngür
- Psychotic Disorders Division, McLean Hospital, 02478, USA; Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Fei Du
- Psychotic Disorders Division, McLean Hospital, 02478, USA; McLean Imaging Center, McLean Hospital, 02478, USA; Harvard Medical School, Boston, Massachusetts 02115, USA.
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Biomarkers Utility: At the Borderline between Cardiology and Neurology. J Cardiovasc Dev Dis 2021; 8:jcdd8110139. [PMID: 34821692 PMCID: PMC8621331 DOI: 10.3390/jcdd8110139] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 10/17/2021] [Accepted: 10/22/2021] [Indexed: 12/21/2022] Open
Abstract
Biomarkers are important diagnostic and prognostic tools as they provide results in a short time while still being an inexpensive, reproducible and accessible method. Their well-known benefits have placed them at the forefront of research in recent years, with new and innovative discoveries being implemented. Cardiovascular and neurological diseases often share common risk factors and pathological pathways which may play an important role in the use and interpretation of biomarkers' values. Among the biomarkers used extensively in clinical practice in cardiology, hs-TroponinT, CK-MB and NTproBNP have been shown to be strongly influenced by multiple neurological conditions. Newer ones such as galectin-3, lysophosphatidylcholine, copeptin, sST2, S100B, myeloperoxidase and GDF-15 have been extensively studied in recent years as alternatives with an increased sensitivity for cardiovascular diseases, but also with significant results in the field of neurology. Thus, given their low specificity, the values interpretation must be correlated with the clinical judgment and other available investigations.
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24
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Wang YY, Zhou N, Si YP, Bai ZY, Li M, Feng WS, Zheng XK. A UPLC-Q-TOF/MS-Based Metabolomics Study on the Effect of Corallodiscus flabellatus (Craib) B. L. Burtt Extract on Alzheimer's Disease. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2021; 2021:8868690. [PMID: 34135987 PMCID: PMC8177975 DOI: 10.1155/2021/8868690] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 05/16/2021] [Indexed: 11/24/2022]
Abstract
A UPLC-Q-TOF/MS-based metabolomics study was carried out to explore the intervening mechanism of Corallodiscus flabellatus (Craib) B. L. Burtt (CF) extract on Alzheimer's disease (AD). The AD model group consisted of senescence-accelerated mouse prone 8 (SAMP8) mice, and the control group consisted of senescence-accelerated mouse resistant 1 (SAMR1) mice. UPLC-Q-TOF/MS detection, multivariate statistical analysis, and pathway enrichment were jointly performed to research the change in metabolite profiling in the urine of AD mice. The result suggested that the metabolite profiling of SAMP8 mice significantly changed at the sixth month compared with SAMR1 mice of the same age, and the principal component analysis (PCA) score scatter plots of the CF group closely resembled those of the control and positive drug (huperzine A, HA) group. A total of 28 metabolites were considered potential biomarkers associated with the metabolism of beta-alanine, glycine, serine, threonine, cysteine, methionine, arginine, proline, and purines in AD mice. Furthermore, the CF group was clustered with the control and positive group and was clearly separated from the model group in the heat map. In conclusion, significant anti-AD effects were firstly observed in mice after treatment with the CF extract, and the urinary metabolomics approach assisted with dissecting the underlying mechanism.
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Affiliation(s)
- Yang-Yang Wang
- Henan University of Chinese Medicine, 156 Jinshui East Road, Zhengzhou 450046, China
- The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 156 Jinshui East Road, Zhengzhou 450046, China
- Key Laboratory of Chinese Materia Medica Ministry of Education, Heilongjiang University of Chinese Medicine, Harbin 150040, Heilongjiang, China
| | - Ning Zhou
- Henan University of Chinese Medicine, 156 Jinshui East Road, Zhengzhou 450046, China
- The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 156 Jinshui East Road, Zhengzhou 450046, China
| | - Yan-Po Si
- Henan University of Chinese Medicine, 156 Jinshui East Road, Zhengzhou 450046, China
- The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 156 Jinshui East Road, Zhengzhou 450046, China
| | - Zhi-Yao Bai
- Henan University of Chinese Medicine, 156 Jinshui East Road, Zhengzhou 450046, China
- The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 156 Jinshui East Road, Zhengzhou 450046, China
| | - Meng Li
- Henan University of Chinese Medicine, 156 Jinshui East Road, Zhengzhou 450046, China
- The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 156 Jinshui East Road, Zhengzhou 450046, China
| | - Wei-Sheng Feng
- Henan University of Chinese Medicine, 156 Jinshui East Road, Zhengzhou 450046, China
- The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 156 Jinshui East Road, Zhengzhou 450046, China
| | - Xiao-Ke Zheng
- Henan University of Chinese Medicine, 156 Jinshui East Road, Zhengzhou 450046, China
- The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 156 Jinshui East Road, Zhengzhou 450046, China
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25
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Ullah H, Di Minno A, Santarcangelo C, Khan H, Daglia M. Improvement of Oxidative Stress and Mitochondrial Dysfunction by β-Caryophyllene: A Focus on the Nervous System. Antioxidants (Basel) 2021; 10:546. [PMID: 33915950 PMCID: PMC8066981 DOI: 10.3390/antiox10040546] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 03/19/2021] [Accepted: 03/28/2021] [Indexed: 02/05/2023] Open
Abstract
Mitochondrial dysfunction results in a series of defective cellular events, including decreased adenosine triphosphate (ATP) production, enhanced reactive oxygen species (ROS) output, and altered proteastasis and cellular quality control. An enhanced output of ROS may damage mitochondrial components, such as mitochondrial DNA and elements of the electron transport chain, resulting in the loss of proper electrochemical gradient across the mitochondrial inner membrane and an ensuing shutdown of mitochondrial energy production. Neurons have an increased demand for ATP and oxygen, and thus are more prone to damage induced by mitochondrial dysfunction. Mitochondrial dysfunction, damaged electron transport chains, altered membrane permeability and Ca2+ homeostasis, and impaired mitochondrial defense systems induced by oxidative stress, are pathological changes involved in neurodegenerative disorders. A growing body of evidence suggests that the use of antioxidants could stabilize mitochondria and thus may be suitable for preventing neuronal loss. Numerous natural products exhibit the potential to counter oxidative stress and mitochondrial dysfunction; however, science is still looking for a breakthrough in the treatment of neurodegenerative disorders. β-caryophyllene is a bicyclic sesquiterpene, and an active principle of essential oils derived from a large number of spices and food plants. As a selective cannabinoid receptor 2 (CB2) agonist, several studies have reported it as possessing numerous pharmacological activities such as antibacterial (e.g., Helicobacter pylori), antioxidant, anti-inflammatory, analgesic (e.g., neuropathic pain), anti-neurodegenerative and anticancer properties. The present review mainly focuses on the potential of β-caryophyllene in reducing oxidative stress and mitochondrial dysfunction, and its possible links with neuroprotection.
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Affiliation(s)
- Hammad Ullah
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy; (H.U.); (A.D.M.); (C.S.)
| | - Alessandro Di Minno
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy; (H.U.); (A.D.M.); (C.S.)
- CEINGE-Biotecnologie Avanzate, 80131 Naples, Italy
| | - Cristina Santarcangelo
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy; (H.U.); (A.D.M.); (C.S.)
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan; or
| | - Maria Daglia
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy; (H.U.); (A.D.M.); (C.S.)
- International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang 212013, China
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26
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Ren X, Butterfield DA. Fidelity of the PINK1 knockout rat to oxidative stress and other characteristics of Parkinson disease. Free Radic Biol Med 2021; 163:88-101. [PMID: 33321180 DOI: 10.1016/j.freeradbiomed.2020.12.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 11/30/2020] [Accepted: 12/03/2020] [Indexed: 12/21/2022]
Abstract
Parkinson disease (PD) is the second most common age-related neurodegenerative disease in the world, and PD significantly impacts the quality of life, especially as in general people are living longer. Because of the numerous and complex features of sporadic PD that progressively develops, it is difficult to build an ideal animal model for PD research. Genetically modified PD rodent animal models are considered as a major tool with which to study the mechanisms and potential therapeutic targets for PD. Up to now, none of the rodent animal models displays all PD characteristics. The Michael J. Fox Foundation for Parkinson's Research (MJFF) funded SAGE Laboratories to generate a PTEN-induced putative kinase-1 (PINK1) knockout (KO) rat model for familial PD using zinc finger nuclease (ZFN) technology. In the current paper, we review all papers from PubMed that report studies with PINK1 KO rats, presenting the research results, and discussing the fidelity of this rat model to PD according to its phenotypes studied by several laboratories. This review will serve as a critical reference for future studies with this rodent model, providing a better understanding of PD etiology, pathology, and potential treatment strategies.
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Affiliation(s)
- Xiaojia Ren
- Department of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40506, USA
| | - D Allan Butterfield
- Department of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40506, USA.
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27
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Kreider RB, Stout JR. Creatine in Health and Disease. Nutrients 2021; 13:nu13020447. [PMID: 33572884 PMCID: PMC7910963 DOI: 10.3390/nu13020447] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/22/2021] [Accepted: 01/27/2021] [Indexed: 12/14/2022] Open
Abstract
Although creatine has been mostly studied as an ergogenic aid for exercise, training, and sport, several health and potential therapeutic benefits have been reported. This is because creatine plays a critical role in cellular metabolism, particularly during metabolically stressed states, and limitations in the ability to transport and/or store creatine can impair metabolism. Moreover, increasing availability of creatine in tissue may enhance cellular metabolism and thereby lessen the severity of injury and/or disease conditions, particularly when oxygen availability is compromised. This systematic review assesses the peer-reviewed scientific and medical evidence related to creatine's role in promoting general health as we age and how creatine supplementation has been used as a nutritional strategy to help individuals recover from injury and/or manage chronic disease. Additionally, it provides reasonable conclusions about the role of creatine on health and disease based on current scientific evidence. Based on this analysis, it can be concluded that creatine supplementation has several health and therapeutic benefits throughout the lifespan.
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Affiliation(s)
- Richard B. Kreider
- Human Clinical Research Facility, Exercise & Sport Nutrition Lab, Department of Health & Kinesiology, Texas A&M University, College Station, TX 77843, USA
- Correspondence:
| | - Jeffery R. Stout
- Physiology of Work and Exercise Response (POWER) Laboratory, Institute of Exercise Physiology and Rehabilitation Science, School of Kinesiology and Physical Therapy, University of Central Florida, 12494 University Blvd., Orlando, FL 32816, USA;
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28
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Forbes SC, Candow DG, Ferreira LHB, Souza-Junior TP. Effects of Creatine Supplementation on Properties of Muscle, Bone, and Brain Function in Older Adults: A Narrative Review. J Diet Suppl 2021; 19:318-335. [PMID: 33502271 DOI: 10.1080/19390211.2021.1877232] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Aging is associated with reductions in muscle and bone mass and brain function, which may be counteracted by several lifestyle factors, of which exercise appears to be most beneficial. However, less than 20% of older adults (> 55 years of age) adhere to performing the recommended amount of resistance training (≥ 2 days/week) and less than 12% regularly meet the aerobic exercise guidelines (≥ 150 min/week of moderate to vigorous intensity aerobic exercise) required to achieve significant health benefits. Therefore, from a healthy aging and clinical perspective, it is important to determine whether other lifestyle interventions (independent of exercise) can have beneficial effects on aging muscle quality and quantity, bone strength, and brain function. Creatine, a nitrogen containing organic compound found in all cells of the body, has the potential to have favorable effects on muscle, bone, and brain health (independent of exercise) in older adults. The purpose of this narrative review is to examine and summarize the small body of research investigating the effects of creatine supplementation alone on measures of muscle mass and performance, bone mineral and strength, and indices of brain health in older adults.
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Affiliation(s)
- Scott C Forbes
- Department of Physical Education, Faculty of Education, Brandon University, Brandon, MB, Canada
| | - Darren G Candow
- Faculty of Kinesiology and Health Studies, University of Regina, Regina, SK, Canada
| | - Luis H B Ferreira
- Research Group on Metabolism, Nutrition and Strength Training, Federal University of Paraná, Curitiba, PR, Brazil
| | - Tacito P Souza-Junior
- Research Group on Metabolism, Nutrition and Strength Training, Federal University of Paraná, Curitiba, PR, Brazil
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29
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Stares A, Bains M. The Additive Effects of Creatine Supplementation and Exercise Training in an Aging Population: A Systematic Review of Randomized Controlled Trials. J Geriatr Phys Ther 2021; 43:99-112. [PMID: 30762623 DOI: 10.1519/jpt.0000000000000222] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND AND PURPOSE The role of creatine supplementation in young athletes and bodybuilders is well established including ergogenic properties of muscular hypertrophy, strength, power, and endurance. Whether the benefits of creatine supplementation translate to an aging population with moderate training stimulus remains unclear especially in regard to gender, creatine dose, and duration. This systematic review assessed whether creatine supplementation combined with exercise results in additive improvements in indices of skeletal muscle, bone, and mental health over exercise alone in healthy older adults. METHODS PubMed, CINAHL, and Web of Science databases were utilized to identify randomized controlled trials of creatine supplementation combined with exercise in an aging population with additional predetermined inclusion and exclusion criteria. Two reviewers independently screened the titles and abstracts, reviewed full-text articles, and performed quality assessments using the Physiotherapy Evidence Database scale. RESULTS AND DISCUSSION Seventeen studies were comprehensively reviewed according to categories of strength, endurance, functional capacity, body composition, cognition, and safety. These studies suggest that any additive ergogenic creatine effects on upper and/or lower body strength, functional capacity, and lean mass in an older population would require a continuous and daily low-dose creatine supplementation combined with at least 12 weeks of resistance training. Potential creatine specific increases in regional bone mineral density of the femur are possible but may require at least 1 year of creatine supplementation combined with moderate resistance training, and additional long-term clinical trials are warranted. The limited data suggested no additive effects of creatine over exercise alone on indices of mental health. The beneficial effects of creatine supplementation are more consistent in older women than in men. CONCLUSIONS Creatine monohydrate is safe to use in older adults. While creatine in conjunction with moderate- to high-intensity exercise in an aging population may improve skeletal muscle health, additional studies are needed to determine the effective dosing and duration paradigm for potential combined creatine and exercise effects on bone and cognition in older adults.
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Affiliation(s)
- Aaron Stares
- School of Physical Therapy, University of the Incarnate Word, San Antonio, Texas
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30
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Bredahl EC, Najdawi W, Pass C, Siedlik J, Eckerson J, Drescher K. Use of Creatine and Creatinine to Minimize Doxorubicin-Induced Cytotoxicity in Cardiac and Skeletal Muscle Myoblasts. Nutr Cancer 2020; 73:2597-2604. [PMID: 33135456 DOI: 10.1080/01635581.2020.1842893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Doxorubicin (DOX), an effective anticancer agent, can damage cardiac and skeletal muscle tissue via excessive generation of reactive oxygen species (ROS). Supplemental creatine (Cr) has been shown to have a therapeutic role in disease states characterized by increased oxidative stress. To investigate the effects of Cr and creatinine (CrN) on DOX-induced cytotoxicity. Cultured L6 and H9C2 myoblasts were exposed to 25 μM DOX, 10 mM Cr, 10 mM CrN, 25 μM DOX + 10 mM Cr, 25 μM DOX + 10 mM CrN, or control media for 12 h. Viability was assessed using Confocal and Widefield imaging. Immunoblotting was used to determine protein expression. Viability was lowest in the DOX-treated group regardless of cell type; however, when DOX was combined with Cr or CrN, viability was improved. Levels of oxidative stress, as measured by 4-hydroxynonenal (4HNE), were significantly (p < 0.05) higher in the DOX treated cells vs. controls; however, Cr + DOX and CrN + DOX significantly lowered 4HNE levels compared to DOX-treated cells. Creatine kinase (CK), a key marker of cellular damage, was significantly higher in DOX-treated H9c2 cells vs. controls. However, Cr or CrN in combination with DOX, resulted in no significant differences in CK vs. controls. Supplementation with Cr or CrN may preserve cell viability during DOX treatment.
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Affiliation(s)
- Eric Christopher Bredahl
- Department of Exercise Science & Pre-Health Professions, Creighton University, Omaha, Nebraska, USA
| | - Wisam Najdawi
- Department of Exercise Science & Pre-Health Professions, Creighton University, Omaha, Nebraska, USA
| | - Caroline Pass
- Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, Nebraska, USA
| | - Jake Siedlik
- Department of Exercise Science & Pre-Health Professions, Creighton University, Omaha, Nebraska, USA
| | - Joan Eckerson
- Department of Exercise Science & Pre-Health Professions, Creighton University, Omaha, Nebraska, USA
| | - Kristen Drescher
- Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, Nebraska, USA
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Blasco H, Lanznaster D, Veyrat-Durebex C, Hergesheimer R, Vourch P, Maillot F, Andres CR, Pradat PF, Corcia P. Understanding and managing metabolic dysfunction in Amyotrophic Lateral Sclerosis. Expert Rev Neurother 2020; 20:907-919. [PMID: 32583696 DOI: 10.1080/14737175.2020.1788389] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Amyotrophic Lateral Sclerosis (ALS) is a fatal motor neuron disease that leads to death after a median survival of 36 months. The development of an effective treatment has proven to be extremely difficult due to the inadequate understanding of the pathogenesis of ALS. Energy metabolism is thoroughly involved in the disease based on the discoveries of hypermetabolism, lipid/glucose metabolism, the tricarboxylic acid (TCA) cycle, and mitochondrial impairment. AREA COVERED Many perturbed metabolites within these processes have been identified as promising therapeutic targets. However, the therapeutic strategies targeting these pathways have failed to produce clinically significant results. The authors present in this review the metabolic disturbances observed in ALS and the derived-therapeutics. EXPERT OPINION The authors suggest that this is due to the insufficient knowledge of the relationship between the metabolic targets and the type of ALS of the patient, depending on genetic and environmental factors. We must improve our understanding of the pathological mechanisms and pay attention to the subtle hidden effects of changing diet, for example, and to use this strategy in addition to other drugs or to use metabolism status to determine subgroups of patients.
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Affiliation(s)
- Helene Blasco
- Unité INSERM U1253, équipe, neurogénomique et physiopathologie neuronale, Université de Tours , Tours, France.,Laboratoire de Biochimie et Biologie Moléculaire, CHRU de Tours , Tours, France
| | - Debora Lanznaster
- Unité INSERM U1253, équipe, neurogénomique et physiopathologie neuronale, Université de Tours , Tours, France
| | - Charlotte Veyrat-Durebex
- Unité INSERM U1253, équipe, neurogénomique et physiopathologie neuronale, Université de Tours , Tours, France.,Laboratoire de Biochimie et Biologie Moléculaire, CHRU de Tours , Tours, France
| | - Rudolf Hergesheimer
- Unité INSERM U1253, équipe, neurogénomique et physiopathologie neuronale, Université de Tours , Tours, France
| | - Patrick Vourch
- Unité INSERM U1253, équipe, neurogénomique et physiopathologie neuronale, Université de Tours , Tours, France.,Laboratoire de Biochimie et Biologie Moléculaire, CHRU de Tours , Tours, France
| | - Francois Maillot
- Unité INSERM U1253, équipe, neurogénomique et physiopathologie neuronale, Université de Tours , Tours, France.,Service de Médecine Interne, CHRU de Tours , Tours, France
| | - Christian R Andres
- Unité INSERM U1253, équipe, neurogénomique et physiopathologie neuronale, Université de Tours , Tours, France.,Laboratoire de Biochimie et Biologie Moléculaire, CHRU de Tours , Tours, France
| | - Pierre-François Pradat
- Unité INSERM U1253, équipe, neurogénomique et physiopathologie neuronale, Université de Tours , Tours, France.,Biomedical Imaging Laboratory, CNRS, INSERM, Sorbonne University , Paris, France.,APHP, Department of Neurology, Paris ALS Center, Pitié Salpêtrière Hospital , Paris, France
| | - Phillipe Corcia
- Unité INSERM U1253, équipe, neurogénomique et physiopathologie neuronale, Université de Tours , Tours, France.,Service de Neurologie, CHRU de Tours , Tours, France
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Papukashvili D, Rcheulishvili N, Deng Y. Beneficial Impact of Semicarbazide-Sensitive Amine Oxidase Inhibition on the Potential Cytotoxicity of Creatine Supplementation in Type 2 Diabetes Mellitus. Molecules 2020; 25:molecules25092029. [PMID: 32349282 PMCID: PMC7248702 DOI: 10.3390/molecules25092029] [Citation(s) in RCA: 5] [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: 03/26/2020] [Revised: 04/16/2020] [Accepted: 04/24/2020] [Indexed: 02/06/2023] Open
Abstract
Creatine supplementation of the population with type 2 diabetes mellitus (T2DM) combined with an exercise program is known to be a possible therapy adjuvant with hypoglycemic effects. However, excessive administration of creatine leads to the production of methylamine which is deaminated by the enzyme semicarbazide-sensitive amine oxidase (SSAO) and as a result, cytotoxic compounds are produced. SSAO activity and reaction products are increased in the serum of T2DM patients. Creatine supplementation by diabetics will further augment the activity of SSAO. The current review aims to find a feasible way to ameliorate T2DM for patients who exercise and desire to consume creatine. Several natural agents present in food which are involved in the regulation of SSAO activity directly or indirectly are reviewed. Particularly, zinc-α2-glycoprotein (ZAG), zinc (Zn), copper (Cu), histamine/histidine, caffeine, iron (Fe), and vitamin D are discussed. Inhibiting SSAO activity by natural agents might reduce the potential adverse effects of creatine metabolism in population of T2DM.
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Affiliation(s)
- Dimitri Papukashvili
- School of Life Science, Beijing Institute of Technology, Beijing 100081, China; (D.P.); (N.R.)
| | - Nino Rcheulishvili
- School of Life Science, Beijing Institute of Technology, Beijing 100081, China; (D.P.); (N.R.)
| | - Yulin Deng
- School of Life Science, Beijing Institute of Technology, Beijing 100081, China; (D.P.); (N.R.)
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, Beijing 100081, China
- Correspondence: ; Tel./Fax: +86-10-68914907
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33
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Gkarane V, Ciulu M, Altmann B, Mörlein D. Effect of Alternative Protein Feeds on the Content of Selected Endogenous Bioactive and Flavour-Related Compounds in Chicken Breast Meat. Foods 2020; 9:E392. [PMID: 32231074 PMCID: PMC7231189 DOI: 10.3390/foods9040392] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 03/20/2020] [Accepted: 03/26/2020] [Indexed: 02/06/2023] Open
Abstract
Currently, soybean meal constitutes the main protein source for poultry production. However, the environmental and social issues related to soybean production are calling for more sustainable protein sources that can offset soybean requirements in animal production. Hermetia illucens larvae and the microalga spirulina (Arthrospira platensis) have proven to be effective alternatives to soybean meal for poultry production. In this study, the effect of 100% replacement of soy with partially defatted Hermetia illucens larvae and spirulina on the contents of selected endogenous bioactive (anserine, creatine and carnosine) and flavour-related (inosine and inosine-5´-monophosphate, IMP) compounds in chicken breast meat was evaluated. The results showed that the spirulina-based diet lowered the levels of anserine, carnosine and creatine compared to the control diet (3.3 vs. 4.1 mg/g, 0.15 vs. 0.72 mg/g and 1.49 vs. 2.49 mg/g, respectively) while IMP levels tended to be higher in spirulina-fed samples. Compared to the control group, Hermetia illucens-fed samples showed a lower content of bioactive peptides (anserine: 3.6 vs. 4.1 mg/g; carnosine: 0.39 vs. 0.72 mg/g; creatine: 2.03 vs. 2.49 mg/g), albeit to a lesser extent than the spirulina treatment group.
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Affiliation(s)
- Vasiliki Gkarane
- Department of Animal Sciences, University of Göttingen, 37075 Göttingen, Germany
| | - Marco Ciulu
- Department of Animal Sciences, University of Göttingen, 37075 Göttingen, Germany
| | - Brianne Altmann
- Department of Animal Sciences, University of Göttingen, 37075 Göttingen, Germany
| | - Daniel Mörlein
- Department of Animal Sciences, University of Göttingen, 37075 Göttingen, Germany
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34
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Wu G. Important roles of dietary taurine, creatine, carnosine, anserine and 4-hydroxyproline in human nutrition and health. Amino Acids 2020; 52:329-360. [PMID: 32072297 PMCID: PMC7088015 DOI: 10.1007/s00726-020-02823-6] [Citation(s) in RCA: 263] [Impact Index Per Article: 52.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Accepted: 01/29/2020] [Indexed: 12/24/2022]
Abstract
Taurine (a sulfur-containing β-amino acid), creatine (a metabolite of arginine, glycine and methionine), carnosine (a dipeptide; β-alanyl-L-histidine), and 4-hydroxyproline (an imino acid; also often referred to as an amino acid) were discovered in cattle, and the discovery of anserine (a methylated product of carnosine; β-alanyl-1-methyl-L-histidine) also originated with cattle. These five nutrients are highly abundant in beef, and have important physiological roles in anti-oxidative and anti-inflammatory reactions, as well as neurological, muscular, retinal, immunological and cardiovascular function. Of particular note, taurine, carnosine, anserine, and creatine are absent from plants, and hydroxyproline is negligible in many plant-source foods. Consumption of 30 g dry beef can fully meet daily physiological needs of the healthy 70-kg adult human for taurine and carnosine, and can also provide large amounts of creatine, anserine and 4-hydroxyproline to improve human nutrition and health, including metabolic, retinal, immunological, muscular, cartilage, neurological, and cardiovascular health. The present review provides the public with the much-needed knowledge of nutritionally and physiologically significant amino acids, dipeptides and creatine in animal-source foods (including beef). Dietary taurine, creatine, carnosine, anserine and 4-hydroxyproline are beneficial for preventing and treating obesity, cardiovascular dysfunction, and ageing-related disorders, as well as inhibiting tumorigenesis, improving skin and bone health, ameliorating neurological abnormalities, and promoting well being in infants, children and adults. Furthermore, these nutrients may promote the immunological defense of humans against infections by bacteria, fungi, parasites, and viruses (including coronavirus) through enhancing the metabolism and functions of monocytes, macrophages, and other cells of the immune system. Red meat (including beef) is a functional food for optimizing human growth, development and health.
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Affiliation(s)
- Guoyao Wu
- Department of Animal Science and Faculty of Nutrition, Texas A&M University, College Station, TX, 77843-2471, USA.
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Bax K, Isackson PJ, Moore M, Ambrus JL. Carnitine Palmitoyl Transferase Deficiency in a University Immunology Practice. Curr Rheumatol Rep 2020; 22:8. [PMID: 32067119 DOI: 10.1007/s11926-020-0879-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE This report describes the clinical manifestations of 35 patients sent to a University Immunology clinic with a diagnosis of fatigue and exercise intolerance who were identified to have low carnitine palmitoyl transferase activity on muscle biopsies. RECENT FINDINGS All of the patients presented with fatigue and exercise intolerance and many had been diagnosed with fibromyalgia. Their symptoms responded to treatment of the metabolic disease. Associated symptoms included bloating, diarrhea, constipation, gastrointestinal reflux symptoms, recurrent infections, arthritis, dyspnea, dry eye, visual loss, and hearing loss. Associated medical conditions included Hashimoto thyroiditis, Sjogren's syndrome, seronegative arthritis, food hypersensitivities, asthma, sleep apnea, and vasculitis. This study identifies clinical features that should alert physicians to the possibility of an underlying metabolic disease. Treatment of the metabolic disease leads to symptomatic improvement.
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Affiliation(s)
- Kiley Bax
- Department of Medicine, SUNY at Buffalo School of Medicine, Buffalo, NY, USA
| | - Paul J Isackson
- Department of Pediatrics, SUNY at Buffalo School of Medicine, Buffalo, NY, USA
| | - Molly Moore
- Department of Surgery, SUNY at Buffalo School of Medicine, Buffalo, NY, USA
| | - Julian L Ambrus
- Department of Medicine, SUNY at Buffalo School of Medicine, Buffalo, NY, USA.
- Division of Allergy, Immunology and Rheumatology SUNY at Buffalo School of Medicine, Room 8030C, Center for Translational Research, 875 Ellicott Street, Buffalo, NY, 14203, USA.
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Singh A, Debnath A, Cai K, Bagga P, Haris M, Hariharan H, Reddy R. Evaluating the feasibility of creatine-weighted CEST MRI in human brain at 7 T using a Z-spectral fitting approach. NMR IN BIOMEDICINE 2019; 32:e4176. [PMID: 31608510 PMCID: PMC11463199 DOI: 10.1002/nbm.4176] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 08/01/2019] [Accepted: 08/02/2019] [Indexed: 06/10/2023]
Abstract
The current study aims to evaluate the feasibility of creatine (Cr) chemical exchange saturation transfer (CEST)-weighted MRI at 7 T in the human brain by optimizing the saturation pulse parameters and computing contrast using a Z-spectral fitting approach. The Cr-weighted (Cr-w) CEST contrast was computed from phantoms data. Simulations were carried out to obtain the optimum saturation parameters for Cr-w CEST with lower contribution from other brain metabolites. CEST-w images were acquired from the brains of four human subjects at different saturation parameters. The Cr-w CEST contrast was computed using both asymmetry analysis and Z-spectra fitting approaches (models 1 and 2, respectively) based on Lorentzian functions. For broad magnetization transfer (MT) effect, Gaussian and Super-Lorentzian line shapes were also evaluated. In the phantom study, the Cr-w CEST contrast showed a linear dependence on concentration in physiological range and a nonlinear dependence on saturation parameters. The in vivo Cr-w CEST map generated using asymmetry analysis from the brain represents mixed contrast with contribution from other metabolites as well and relayed nuclear Overhauser effect (rNOE). Simulations provided an estimate for the optimum range of saturation parameters to be used for acquiring brain CEST data. The optimum saturation parameters for Cr-w CEST to be used for brain data were around B1rms = 1.45 μT and duration = 2 seconds. The Z-spectral fitting approach enabled computation of individual components. This also resulted in mitigating the contribution from MT and rNOE to Cr-w CEST contrast, which is a major source of underestimation in asymmetry analysis. The proposed modified z-spectra fitting approach (model 2) is more stable to noise compared with model 1. Cr-w CEST contrast obtained using fitting was 6.98 ± 0.31% in gray matter and 5.45 ± 0.16% in white matter. Optimal saturation parameters reduced the contribution from other CEST effects to Cr-w CEST contrast, and the proposed Z-spectral fitting approach enabled computation of individual components in Z-spectra of the brain. Therefore, it is feasible to compute Cr-w CEST contrast with a lower contribution from other CEST and rNOE.
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Affiliation(s)
- Anup Singh
- CBME, Indian Institute of Technology Delhi, New Delhi, India
- Department of Biomedical Engineering, AIIMS, Delhi, India
| | - Ayan Debnath
- CBME, Indian Institute of Technology Delhi, New Delhi, India
- CMROI, Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kejia Cai
- Radiology, University of Illinois at Chicago, Chicago, Illinois
| | - Puneet Bagga
- CMROI, Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Mohammad Haris
- CMROI, Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania
- Research Branch, Sidra Medical and Research Center, Doha, Qatar
| | - Hari Hariharan
- CMROI, Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ravinder Reddy
- CMROI, Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania
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Creatine nanoliposome reverts the HPA-induced damage in complex II–III activity of the rats’ cerebral cortex. Mol Biol Rep 2019; 46:5897-5908. [DOI: 10.1007/s11033-019-05023-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Accepted: 08/06/2019] [Indexed: 12/12/2022]
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Panchal K, Tiwari AK. Mitochondrial dynamics, a key executioner in neurodegenerative diseases. Mitochondrion 2019; 47:151-173. [PMID: 30408594 DOI: 10.1016/j.mito.2018.11.002] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 10/08/2018] [Accepted: 11/02/2018] [Indexed: 12/12/2022]
Abstract
Neurodegenerative diseases (NDs) are the group of disorder that includes brain, peripheral nerves, spinal cord and results in sensory and motor neuron dysfunction. Several studies have shown that mitochondrial dynamics and their axonal transport play a central role in most common NDs such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS) etc. In normal physiological condition, there is a balance between mitochondrial fission and fusion process while any alteration to these processes cause defect in ATP (Adenosine Triphosphate) biogenesis that lead to the onset of several NDs. Also, mitochondria mediated ROS may induce lipid and protein peroxidation, energy deficiency environment in the neurons and results in cell death and defective neurotransmission. Though, mitochondria is a well-studied cell organelle regulating the cellular energy demands but still, its detail role or association in NDs is under observation. In this review, we have summarized an updated mitochondria and their possible role in different NDs with the therapeutic strategy to improve the mitochondrial functions.
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Affiliation(s)
- Komal Panchal
- Genetics & Developmental Biology Laboratory, School of Biological Sciences & Biotechnology, Institute of Advanced Research (IAR), Koba, Institutional Area, Gandhinagar 382426, India
| | - Anand Krishna Tiwari
- Genetics & Developmental Biology Laboratory, School of Biological Sciences & Biotechnology, Institute of Advanced Research (IAR), Koba, Institutional Area, Gandhinagar 382426, India.
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UPLC-Q-TOF/MS-Based Plasma Metabolomics to Evaluate the Effects of Aspirin Eugenol Ester on Blood Stasis in Rats. Molecules 2019; 24:molecules24132380. [PMID: 31252591 PMCID: PMC6651160 DOI: 10.3390/molecules24132380] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Revised: 06/23/2019] [Accepted: 06/25/2019] [Indexed: 11/17/2022] Open
Abstract
Aspirin eugenol ester (AEE) is a novel compound that is formed from the esterification of aspirin (acetylsalicylic acid (ASA)) and eugenol. This study aimed to investigate the effects of AEE on blood stasis in rats and to characterize the underlying mechanisms using a plasma metabolomic study. The results indicate that AEE and ASA could modulate whole blood viscosity (WBV), plasma viscosity (PV), blood coagulation parameters, platelet count, platelet aggregation, lactate dehydrogenase (LDH), creatinine (CR) and the levels of thromboxane A2 (TXA2) and 6-keto prostaglandin F1α (6-keto-PGF1α). The metabolic profiles of the plasma samples from all groups were clearly separated in the score plots. Nineteen potential metabolites were selected and identified, and disordered levels of these metabolites could be regulated by AEE and ASA. Pathway analysis showed that the mechanism of action of AEE on blood stasis might be principally related to the metabolism of amino acid, fatty acid, energy and glycerophospholipid. The above results indicate that AEE protected the rats against blood stasis, and that this effect might have been caused by the anticoagulation activity of AEE and its abilities to maintain a balance between TXA2 and PGI2, reduce blood viscosity, inhibit platelet aggregation and normalize the plasma metabolic profile.
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Muddapu VR, Mandali A, Chakravarthy VS, Ramaswamy S. A Computational Model of Loss of Dopaminergic Cells in Parkinson's Disease Due to Glutamate-Induced Excitotoxicity. Front Neural Circuits 2019; 13:11. [PMID: 30858799 PMCID: PMC6397878 DOI: 10.3389/fncir.2019.00011] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Accepted: 02/05/2019] [Indexed: 01/04/2023] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disease associated with progressive and inexorable loss of dopaminergic cells in Substantia Nigra pars compacta (SNc). Although many mechanisms have been suggested, a decisive root cause of this cell loss is unknown. A couple of the proposed mechanisms, however, show potential for the development of a novel line of PD therapeutics. One of these mechanisms is the peculiar metabolic vulnerability of SNc cells compared to other dopaminergic clusters; the other is the SubThalamic Nucleus (STN)-induced excitotoxicity in SNc. To investigate the latter hypothesis computationally, we developed a spiking neuron network-model of SNc-STN-GPe system. In the model, prolonged stimulation of SNc cells by an overactive STN leads to an increase in ‘stress' variable; when the stress in a SNc neuron exceeds a stress threshold, the neuron dies. The model shows that the interaction between SNc and STN involves a positive-feedback due to which, an initial loss of SNc cells that crosses a threshold causes a runaway-effect, leading to an inexorable loss of SNc cells, strongly resembling the process of neurodegeneration. The model further suggests a link between the two aforementioned mechanisms of SNc cell loss. Our simulation results show that the excitotoxic cause of SNc cell loss might initiate by weak-excitotoxicity mediated by energy deficit, followed by strong-excitotoxicity, mediated by a disinhibited STN. A variety of conventional therapies were simulated to test their efficacy in slowing down SNc cell loss. Among them, glutamate inhibition, dopamine restoration, subthalamotomy and deep brain stimulation showed superior neuroprotective-effects in the proposed model.
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Affiliation(s)
| | - Alekhya Mandali
- Department of Psychiatry, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom
| | - V Srinivasa Chakravarthy
- Computational Neuroscience Lab, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, IIT-Madras, Chennai, India
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41
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Effects of whole linseed supplementation and treatment duration on fatty acid profile and endogenous bioactive compounds of beef muscle. Animal 2019; 13:444-452. [DOI: 10.1017/s1751731118001635] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
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Liu Y, Wei M, Yue K, Hu M, Li S, Men L, Pi Z, Liu Z, Liu Z. Study on Urine Metabolic Profile of Aβ25–35-Induced Alzheimer's Disease Using UHPLC-Q-TOF-MS. Neuroscience 2018; 394:30-43. [DOI: 10.1016/j.neuroscience.2018.10.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Revised: 08/28/2018] [Accepted: 10/01/2018] [Indexed: 12/22/2022]
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Jamalat Y, Gamallat Y, Jaceline Gislaine PS, Meyiah A, Shopit A, Li H, Ahmed B, Chu P, Wang H, Li X, Peng J, Ma X, Tang Z. Phosphocreatine attenuates endoplasmic reticulum stress-mediated hepatocellular apoptosis ameliorates insulin resistance in diabetes model. Biochem Biophys Res Commun 2018; 506:611-618. [PMID: 30366667 DOI: 10.1016/j.bbrc.2018.10.122] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Accepted: 10/19/2018] [Indexed: 12/12/2022]
Abstract
Diabetes mellitus (DM) associated liver damage is a major health burden. Hepatocellular-damage in DM characterized with elevated endoplasmic reticulum stress (ER) and may enhanced insulin-resistance. Phosphocreatine (PCr) a rapidly high-energy-reserve molecule of phosphates naturally occurs in liver, brain and skeletal muscle. This study aimed to investigate the protective effect of PCr on the liver-injury-associated with DM and to report the mechanism involved. Wistar rat's diabetes model was induced using streptozotocin (STZ), and the animals were treated with 20 mg/kg, or 50 mg/kg PCr injection. Blood glucose level, and body wt were recorded. Liver tissues homogenate were analyzed for liver damage markers alanine transaminase (ALT), aspartate transaminase (AST). Liver tissues proteins further evaluated for apoptosis, endoplasmic reticulum stress (ER), and insulin resistance biomarkers using western blotting. Our results revealed that PCr reduced blood glucose level, improved body wt, ameliorates liver function enzymes. Furthermore, PCr upregulates anti-apoptotic Bcl2 proteins expression, and down-regulates significantly pro-apoptotic casp3 and Bax proteins expression in vivo and invitro. Moreover, ER stress CHOP, GRP78 and ATF4 biomarkers level were significantly attenuated in PCr treated animals comparing to STZ diabetes associated liver-damage model with significant improving in insulin-resistance Akt and IRS-1. Our results revealed that treating with PCr in diabetes-associated liver injury models decreased blood glucose level and possess protective effect in-vitro and in-vivo, which could be suggested as potential therapeutic strategy for diabetes associated liver injury patients.
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Affiliation(s)
- Yazeed Jamalat
- Department of Pharmacology, Dalian Medical University, Dalian, Liaoning, 116044, China
| | - Yaser Gamallat
- Department of Biotechnology, Dalian Medical University, Dalian, Liaoning, 116044, China
| | | | - Abdo Meyiah
- Department of Biotechnology, Dalian Medical University, Dalian, Liaoning, 116044, China
| | - Abdullah Shopit
- Department of Pharmacology, Dalian Medical University, Dalian, Liaoning, 116044, China
| | - Hailong Li
- Department of Pharmacology, Dalian Medical University, Dalian, Liaoning, 116044, China
| | - Bashir Ahmed
- Department of Pathology and Forensic Medicine, Dalian Medical University, Dalian, Liaoning, 116044, China
| | - Peng Chu
- Department of Pharmacology, Dalian Medical University, Dalian, Liaoning, 116044, China
| | - Hongyang Wang
- Department of Pharmacology, Dalian Medical University, Dalian, Liaoning, 116044, China
| | - Xiaodong Li
- Department of Pharmacology, Dalian Medical University, Dalian, Liaoning, 116044, China
| | - Jinyong Peng
- Department of Pharmacology, Dalian Medical University, Dalian, Liaoning, 116044, China
| | - Xiaodong Ma
- Department of Pharmacology, Dalian Medical University, Dalian, Liaoning, 116044, China
| | - Zeyao Tang
- Department of Pharmacology, Dalian Medical University, Dalian, Liaoning, 116044, China.
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Abstract
The human brain weighs approximately 2% of the body; however, it consumes about 20% of a
person’s total energy intake. Cellular bioenergetics in the central nervous system
involves a delicate balance between biochemical processes engaged in energy conversion and
those responsible for respiration. Neurons have high energy demands, which rely on
metabolic coupling with glia, such as with oligodendrocytes and astrocytes. It has been
well established that astrocytes recycle and transport glutamine to neurons to make the
essential neurotransmitters, glutamate and GABA, as well as shuttle lactate to support
energy synthesis in neurons. However, the metabolic role of oligodendrocytes in the
central nervous system is less clear. In this review, we discuss the energetic demands of
oligodendrocytes in their survival and maturation, the impact of altered oligodendrocyte
energetics on disease pathology, and the role of energetic metabolites, taurine, creatine,
N-acetylaspartate, and biotin, in regulating oligodendrocyte
function.
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Affiliation(s)
- Lauren Rosko
- Department of Biology, Georgetown University, Washington, DC, USA.,Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC, USA
| | - Victoria N Smith
- Department of Biology, Georgetown University, Washington, DC, USA
| | - Reiji Yamazaki
- Department of Biology, Georgetown University, Washington, DC, USA
| | - Jeffrey K Huang
- Department of Biology, Georgetown University, Washington, DC, USA.,Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC, USA.,Center for Cell Reprogramming, Georgetown University, Washington, DC, USA
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Enciu AM, Codrici E, Mihai S, Manole E, Pop S, Codorean E, Niculite CM, Necula L, Tarcomnicu I, Gille E, Tanase CP. Role of Nutraceuticals in Modulation of Gut-Brain Axis in Elderly Persons. Gerontology 2018. [DOI: 10.5772/intechopen.73005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
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Terron A, Bal-Price A, Paini A, Monnet-Tschudi F, Bennekou SH, Leist M, Schildknecht S. An adverse outcome pathway for parkinsonian motor deficits associated with mitochondrial complex I inhibition. Arch Toxicol 2018; 92:41-82. [PMID: 29209747 PMCID: PMC5773657 DOI: 10.1007/s00204-017-2133-4] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 11/22/2017] [Indexed: 12/21/2022]
Abstract
Epidemiological studies have observed an association between pesticide exposure and the development of Parkinson's disease, but have not established causality. The concept of an adverse outcome pathway (AOP) has been developed as a framework for the organization of available information linking the modulation of a molecular target [molecular initiating event (MIE)], via a sequence of essential biological key events (KEs), with an adverse outcome (AO). Here, we present an AOP covering the toxicological pathways that link the binding of an inhibitor to mitochondrial complex I (i.e., the MIE) with the onset of parkinsonian motor deficits (i.e., the AO). This AOP was developed according to the Organisation for Economic Co-operation and Development guidelines and uploaded to the AOP database. The KEs linking complex I inhibition to parkinsonian motor deficits are mitochondrial dysfunction, impaired proteostasis, neuroinflammation, and the degeneration of dopaminergic neurons of the substantia nigra. These KEs, by convention, were linearly organized. However, there was also evidence of additional feed-forward connections and shortcuts between the KEs, possibly depending on the intensity of the insult and the model system applied. The present AOP demonstrates mechanistic plausibility for epidemiological observations on a relationship between pesticide exposure and an elevated risk for Parkinson's disease development.
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Affiliation(s)
| | | | - Alicia Paini
- European Commission Joint Research Centre, Ispra, Italy
| | | | | | - Marcel Leist
- In Vitro Toxicology and Biomedicine, Department of Biology, University of Konstanz, Universitätsstr. 10, PO Box M657, 78457, Konstanz, Germany
| | - Stefan Schildknecht
- In Vitro Toxicology and Biomedicine, Department of Biology, University of Konstanz, Universitätsstr. 10, PO Box M657, 78457, Konstanz, Germany.
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Skoczen A, Setkowicz Z, Janeczko K, Sandt C, Borondics F, Chwiej J. The influence of high fat diets with different ketogenic ratios on the hippocampal accumulation of creatine - FTIR microspectroscopy study. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2017; 184:13-22. [PMID: 28477512 DOI: 10.1016/j.saa.2017.04.085] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Revised: 04/12/2017] [Accepted: 04/30/2017] [Indexed: 06/07/2023]
Abstract
The main purpose of this study was the determination and comparison of anomalies in creatine (Cr) accumulation occurring within CA3 and DG areas of hippocampal formation as a result of two high-fat, carbohydrate-restricted ketogenic diets (KD) with different ketogenic ratio (KR). To reach this goal, Fourier transformed infrared microspectroscopy with synchrotron radiation source (SRFTIR microspectroscopy) was applied for chemical mapping of creatine absorption bands, occurring around 1304, 1398 and 2800 cm-1. The samples were taken from three groups of experimental animals: control group (N) fed with standard laboratory diet, KD1 and KD2 groups fed with high-fat diets with KR 5:1 and 9:1 respectively. Additionally, the possible influence on the phosphocreatine (PhCr, the high energetic form of creatine) content was evaluated by comparative analysis of chemical maps obtained for creatine and for compounds containing phosphate groups which manifest in the spectra at the wavenumbers of around 1240 and 1080 cm-1. Our results showed that KD2 strongly modifies the frequency of Cr inclusions in both analyzed hippocampal areas. Statistical analysis, performed with Mann-Whitney U test revealed increased accumulation of Cr within CA3 and DG areas of KD2 fed rats compared to both normal rats and KD1 experimental group. Moreover, KD2 diet may modify the frequency of PhCr deposits as well as the PhCr to Cr ratio.
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Affiliation(s)
- A Skoczen
- AGH University of Science and Technology, Faculty of Physics and Applied Computer Science, Krakow, Poland.
| | - Z Setkowicz
- Jagiellonian University, Institute of Zoology, Krakow, Poland
| | - K Janeczko
- Jagiellonian University, Institute of Zoology, Krakow, Poland
| | | | | | - J Chwiej
- AGH University of Science and Technology, Faculty of Physics and Applied Computer Science, Krakow, Poland
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Severe Hyperhomocysteinemia Decreases Creatine Kinase Activity and Causes Memory Impairment: Neuroprotective Role of Creatine. Neurotox Res 2017; 32:585-593. [DOI: 10.1007/s12640-017-9767-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 05/30/2017] [Accepted: 06/08/2017] [Indexed: 12/26/2022]
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Kreider RB, Kalman DS, Antonio J, Ziegenfuss TN, Wildman R, Collins R, Candow DG, Kleiner SM, Almada AL, Lopez HL. International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine. J Int Soc Sports Nutr 2017; 14:18. [PMID: 28615996 PMCID: PMC5469049 DOI: 10.1186/s12970-017-0173-z] [Citation(s) in RCA: 381] [Impact Index Per Article: 47.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 05/30/2017] [Indexed: 12/16/2022] Open
Abstract
Creatine is one of the most popular nutritional ergogenic aids for athletes. Studies have consistently shown that creatine supplementation increases intramuscular creatine concentrations which may help explain the observed improvements in high intensity exercise performance leading to greater training adaptations. In addition to athletic and exercise improvement, research has shown that creatine supplementation may enhance post-exercise recovery, injury prevention, thermoregulation, rehabilitation, and concussion and/or spinal cord neuroprotection. Additionally, a number of clinical applications of creatine supplementation have been studied involving neurodegenerative diseases (e.g., muscular dystrophy, Parkinson's, Huntington's disease), diabetes, osteoarthritis, fibromyalgia, aging, brain and heart ischemia, adolescent depression, and pregnancy. These studies provide a large body of evidence that creatine can not only improve exercise performance, but can play a role in preventing and/or reducing the severity of injury, enhancing rehabilitation from injuries, and helping athletes tolerate heavy training loads. Additionally, researchers have identified a number of potentially beneficial clinical uses of creatine supplementation. These studies show that short and long-term supplementation (up to 30 g/day for 5 years) is safe and well-tolerated in healthy individuals and in a number of patient populations ranging from infants to the elderly. Moreover, significant health benefits may be provided by ensuring habitual low dietary creatine ingestion (e.g., 3 g/day) throughout the lifespan. The purpose of this review is to provide an update to the current literature regarding the role and safety of creatine supplementation in exercise, sport, and medicine and to update the position stand of International Society of Sports Nutrition (ISSN).
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Affiliation(s)
- Richard B. Kreider
- Exercise & Sport Nutrition Lab, Human Clinical Research Facility, Department of Health & Kinesiology, Texas A&M University, College Station, TX 77843-4243 USA
| | - Douglas S. Kalman
- Nutrition Research Unit, QPS, 6141 Sunset Drive Suite 301, Miami, FL 33143 USA
| | - Jose Antonio
- Department of Health and Human Performance, Nova Southeastern University, Davie, FL 33328 USA
| | - Tim N. Ziegenfuss
- The Center for Applied Health Sciences, 4302 Allen Road, STE 120, Stow, OH 44224 USA
| | - Robert Wildman
- Post Active Nutrition, 111 Leslie St, Dallas, TX 75208 USA
| | - Rick Collins
- Collins Gann McCloskey & Barry, PLLC, 138 Mineola Blvd., Mineola, NY 11501 USA
| | - Darren G. Candow
- Faculty of Kinesiology and Health Studies, University of Regina, Regina, SK S4S 0A2 Canada
| | | | | | - Hector L. Lopez
- The Center for Applied Health Sciences, 4302 Allen Road, STE 120, Stow, OH 44224 USA
- Supplement Safety Solutions, LLC, Bedford, MA 01730 USA
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Drake DF, Hudak AM, Robbins W. Integrative Medicine in Traumatic Brain Injury. Phys Med Rehabil Clin N Am 2017; 28:363-378. [DOI: 10.1016/j.pmr.2016.12.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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