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Li Z, Wang X, Du H, Liu W, Zhang C, Talifu Z, Xu X, Pan Y, Zhang J, Ke H, Yang D, Gao F, Yu Y, Jing Y, Li J. Unraveling Spinal Cord Injury Nutrition: Effects of Diet on the Host and Microbiome. Adv Nutr 2025:100448. [PMID: 40383300 DOI: 10.1016/j.advnut.2025.100448] [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: 12/23/2024] [Revised: 03/25/2025] [Accepted: 05/12/2025] [Indexed: 05/20/2025] Open
Abstract
Spinal cord injury (SCI) leads to severe neurological dysfunction with significant nutritional alterations. These alterations are closely associated with gut dysbiosis and neurogenic gut dysfunction after SCI, creating complex interactions that further exacerbate metabolic disturbances and impede neurological recovery. In the context of SCI, diet not only fulfills basic nutritional needs but also serves as an important therapeutic tool to modulate these interactions. This review provides a broad overview of existing research findings, analyzes the impact of existing dietary interventions on SCI, and attempts to clarify the complex relationship between diet and host and gut microbiota. We hope to provide a clear direction for future research and a scientific basis for the development of personalized dietary interventions to improve the nutritional status of SCI patients, reduce the incidence of complications such as metabolic disorders, and promote the recovery of neurological function and overall quality of life of SCI patients. STATEMENT OF SIGNIFICANCE: This review evaluates the nutritional changes in patients with spinal cord injury, comprehensively elucidating the effects of dietary interventions on SCI patients from both the host and gut microbiota perspectives. By revealing the complex interactions among them, it lays the foundation for developing personalized nutritional intervention strategies to optimize recovery and improve long-term health outcomes in the future.
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Affiliation(s)
- ZeHui Li
- School of Rehabilitation, Capital Medical University, Beijing, 100069, P.R. China; Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, 100069, P.R. China
| | - XiaoXin Wang
- School of Rehabilitation, Capital Medical University, Beijing, 100069, P.R. China; Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, 100069, P.R. China
| | - HuaYong Du
- School of Rehabilitation, Capital Medical University, Beijing, 100069, P.R. China; Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, 100069, P.R. China
| | - WuBo Liu
- School of Rehabilitation, Capital Medical University, Beijing, 100069, P.R. China; Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, 100069, P.R. China; Department of Orthopaedics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Shandong, 250012, P.R. China
| | - ChunJia Zhang
- School of Rehabilitation, Capital Medical University, Beijing, 100069, P.R. China; Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, 100069, P.R. China; Department of Rehabilitation Medicine, Peking University Third Hospital, Beijing, 100096, P.R. China
| | - Zuliyaer Talifu
- School of Rehabilitation, Capital Medical University, Beijing, 100069, P.R. China; Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, 100069, P.R. China; School of Population Medicine and Public Health, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing, 100005, P.R. China; University of Health and Rehabilitation Sciences, Shandong, 266100, P.R. China
| | - Xin Xu
- School of Rehabilitation, Capital Medical University, Beijing, 100069, P.R. China; Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, 100069, P.R. China; Department of Orthopaedics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Shandong, 250012, P.R. China
| | - Yunzhu Pan
- School of Rehabilitation, Capital Medical University, Beijing, 100069, P.R. China; Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, 100069, P.R. China; University of Health and Rehabilitation Sciences, Shandong, 266100, P.R. China; Rehabilitation Department, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, 100005, P.R. China
| | - JinMing Zhang
- School of Rehabilitation, Capital Medical University, Beijing, 100069, P.R. China; Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, 100069, P.R. China
| | - Han Ke
- School of Rehabilitation, Capital Medical University, Beijing, 100069, P.R. China; Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, 100069, P.R. China; Department of Orthopaedics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Shandong, 250012, P.R. China; Department of Orthopedics, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100013, P.R. China
| | - DeGang Yang
- School of Rehabilitation, Capital Medical University, Beijing, 100069, P.R. China; Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, 100069, P.R. China
| | - Feng Gao
- School of Rehabilitation, Capital Medical University, Beijing, 100069, P.R. China; Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, 100069, P.R. China
| | - Yan Yu
- School of Rehabilitation, Capital Medical University, Beijing, 100069, P.R. China; Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, 100069, P.R. China; Institute of Rehabilitation medicine, China Rehabilitation Research Center, Beijing, 100069, P.R. China
| | - YingLi Jing
- School of Rehabilitation, Capital Medical University, Beijing, 100069, P.R. China; Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, 100069, P.R. China; Institute of Rehabilitation medicine, China Rehabilitation Research Center, Beijing, 100069, P.R. China.
| | - JianJun Li
- School of Rehabilitation, Capital Medical University, Beijing, 100069, P.R. China; Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, 100069, P.R. China; Department of Orthopaedics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Shandong, 250012, P.R. China; University of Health and Rehabilitation Sciences, Shandong, 266100, P.R. China.
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Nabakhteh S, Lotfi A, Afsartaha A, Khodadadi ES, Abdolghaderi S, Mohammadpour M, Shokri Y, Kiani P, Ehtiati S, Khakshournia S, Khatami SH. Nutritional Interventions in Amyotrophic Lateral Sclerosis: From Ketogenic Diet and Neuroprotective Nutrients to the Microbiota-Gut-Brain Axis Regulation. Mol Neurobiol 2025:10.1007/s12035-025-04830-8. [PMID: 40097762 DOI: 10.1007/s12035-025-04830-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 03/09/2025] [Indexed: 03/19/2025]
Abstract
Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease with significant challenges in diagnosis and treatment. Recent research has highlighted the complex nature of ALS, encompassing behavioral impairments in addition to its neurological manifestations. While several medications have been approved to slow disease progression, ongoing research is focused on identifying new therapeutic targets. The current review focuses on emerging therapeutic strategies and personalized approaches aimed at improving patient outcomes. Recent advancements highlight the importance of targeting additional pathways such as mitochondrial dysfunction and neuroinflammation to develop more effective treatments. Personalized medicine, including genetic testing and biomarkers, is proving valuable in stratifying patients and tailoring treatment options. Complementary therapies, such as nutritional interventions like the ketogenic diet and microbiome modulation, also show promise. This review emphasizes the need for a multidisciplinary approach that integrates early diagnosis, targeted treatments, and supportive care to address the multisystemic nature of ALS and improve the quality of life for patients.
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Affiliation(s)
- Samira Nabakhteh
- Department of Biochemistry, School of Basic Sciences, Tehran Medical Branch, Islamic Azad University, Tehran, Iran
| | - Anahita Lotfi
- Department of Food Sciences and Industry, School of Agricultural Sciences and Natural Resources, Islamic Azad University, Khorasgan Branch, Isfahan, Iran
| | - Arman Afsartaha
- Department of Nutrition, Faculty of Medical Sciences and Technologies, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Elaheh Sadat Khodadadi
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, 35122, Italy
| | - Siavash Abdolghaderi
- Department of Physical Medicine and Rehabilitation, Iran University of Medical Sciences, Tehran, Iran
| | - Mozhdeh Mohammadpour
- Department of Physical Medicine and Rehabilitation, Iran University of Medical Sciences, Tehran, Iran
| | - Yasaman Shokri
- Department of Clinical Biochemistry and Genetics, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Pouria Kiani
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sajad Ehtiati
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sara Khakshournia
- Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
- Autophagy Research Center, Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Seyyed Hossein Khatami
- Student Research Committee, Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Zhou C, Qu S. Application and Mechanism of Action of a Ketogenic Diet in Antiepileptic Therapy. ACS Chem Neurosci 2025; 16:284-291. [PMID: 39787038 DOI: 10.1021/acschemneuro.4c00695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2025] Open
Abstract
Epilepsy is a chronic neurological disorder caused by abnormal discharges of neurons in the brain, which seriously affects the quality of life of patients. Although there are various drug treatments available, many epilepsy patients still experience seizures with the effect of drugs and develop refractory epilepsy. The ketogenic diet can treat drug-refractory epilepsy by regulating the body's metabolism and can enhance the quality of life by improving their cognition, behavior, and sleep quality. However, there is no unified conclusion on the mechanism through which the ketogenic diet plays a therapeutic role in epilepsy. This article provides a review of the possible mechanisms of how the ketogenic diet exerts a protective effect on epilepsy.
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Affiliation(s)
- Chang Zhou
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
- Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
- Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, Guangdong 510515, P.R. China
| | - Shaogang Qu
- Department of Neurology, Ganzhou Hospital-Nanfang Hospital, Southern Medical University, Ganzhou, Jiangxi 341000, China
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
- Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
- Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, Guangdong 510515, P.R. China
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Wang J, Xie L, Jiang L. Potential inflammatory mechanisms of the ketogenic diet against febrile infection-related epilepsy syndrome. ACTA EPILEPTOLOGICA 2025; 7:3. [PMID: 40217546 PMCID: PMC11960355 DOI: 10.1186/s42494-024-00187-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 09/12/2024] [Indexed: 04/14/2025] Open
Abstract
Febrile infection-related epilepsy syndrome (FIRES) is a rare epilepsy syndrome with unclear pathogenesis, characterized by fever-induced, super-refractory status epilepticus and high mortality. Studies have shown that ketogenic diet (KD) is effective in controlling convulsions in FIRES, but its mechanisms are unclear. This paper intends to summarize the mechanisms by which KD may exert effects against FIRES. Clinical studies have shown that patients with FIRES have elevated levels of various inflammatory factors such as interleukin (IL)-6, IL-8, IL-10, and so on. KD may exert anti-FIRES effects through several potential inflammatory pathways, including nuclear factor -κB (NF-κB) and NLR family pyrin domain containing 3 (NLRP3). Furthermore, the Kyoto Encyclopedia of Genes and Genomes (KEGG) network suggested that KD may play an anti-inflammatory role through several pathways such as cellular senescence and neutrophil extracellular trap formation. These mechanisms need to be further investigated.
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Affiliation(s)
- Juan Wang
- Department of Neurology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, No. 136, Zhongshan 2nd Road, Yuzhong District, Chongqing, 400014, China
- Chongqing Key Laboratory of Neurodevelopment and Cognitive Disorders, Chongqing, 400014, China
| | - Lingling Xie
- Department of Neurology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, No. 136, Zhongshan 2nd Road, Yuzhong District, Chongqing, 400014, China
- Chongqing Key Laboratory of Neurodevelopment and Cognitive Disorders, Chongqing, 400014, China
| | - Li Jiang
- Department of Neurology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, No. 136, Zhongshan 2nd Road, Yuzhong District, Chongqing, 400014, China.
- Chongqing Key Laboratory of Neurodevelopment and Cognitive Disorders, Chongqing, 400014, China.
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Cigliano L, De Palma F, Petecca N, Fasciolo G, Panico G, Venditti P, Lombardi A, Spagnuolo MS. 1,3-butanediol administration as an alternative strategy to calorie restriction for neuroprotection - Insights into modulation of stress response in hippocampus of healthy rats. Biomed Pharmacother 2025; 182:117774. [PMID: 39693909 DOI: 10.1016/j.biopha.2024.117774] [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: 07/30/2024] [Revised: 11/24/2024] [Accepted: 12/15/2024] [Indexed: 12/20/2024] Open
Abstract
Ketogenic diet has a wide range of beneficial effects but presents practical limitations due to its low compliance, hence dietary supplements have been developed to induce ketosis without nutrient deprivation. The alcohol 1,3-butanediol (BD) is a promising molecule for its ability to induce ketosis, but its effects on brain have been investigated so far only in disease models, but never in physiological conditions. To support BD use to preserve brain health, the analysis of its activity is mandatory. Therefore, we investigated, in healthy rats, the effect of a fourteen-days BD-administration on the hippocampus, an area particularly vulnerable to oxidative and inflammatory damage. Since BD treatment has been reported to reduce energy intake, results were compared with those obtained from rats undergoing a restricted dietary regimen, isoenergetic with BD group (pair fed, PF). Reduced pro-inflammatory signaling pathways and glial activation were revealed in hippocampus of BD treated rats in comparison to control (C) and PF groups. ROS content and the extent of protein oxidative damage were lower in BD and PF groups than in C. Interestingly, higher amounts of nuclear factor erythroid 2-related factor 2 (Nrf2), decreased level of lipid hydroperoxides, lower susceptibility to oxidative insult, higher amounts of superoxide dismutase-2, glutathione reductase and glutathione peroxidase (GPx), and increased GPx activity were observed in BD animals. BD administration, but not dietary restriction, attenuated endoplasmic reticulum stress, reduced autophagic response activation, and was associated with an increase of both the neurotrophin BDNF and pre-synaptic proteins synaptophysin and synaptotagmin. Our results highlight that BD plays a neuroprotective role in healthy conditions, thus emerging as an effective strategy to support brain function without the need of implementing ketogenic nutritional interventions.
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Affiliation(s)
- Luisa Cigliano
- Department of Biology, University of Naples Federico II, Naples 80121, Italy.
| | - Francesca De Palma
- Department of Biology, University of Naples Federico II, Naples 80121, Italy.
| | - Natasha Petecca
- Department of Biology, University of Naples Federico II, Naples 80121, Italy.
| | - Gianluca Fasciolo
- Department of Biology, University of Naples Federico II, Naples 80121, Italy.
| | - Giuliana Panico
- Department of Biology, University of Naples Federico II, Naples 80121, Italy.
| | - Paola Venditti
- Department of Biology, University of Naples Federico II, Naples 80121, Italy.
| | - Assunta Lombardi
- Department of Biology, University of Naples Federico II, Naples 80121, Italy.
| | - Maria Stefania Spagnuolo
- Institute for the Animal Production System in the Mediterranean Environment, National Research Council, Portici, 80055, Italy.
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Yan H, Yin Y, Zhou Y, Li Z, Li Y, Ren L, Wen J, Wang W. Regulation of cardiovascular diseases by histone deacetylases and NADPH oxidases. Redox Biol 2024; 77:103379. [PMID: 39378612 PMCID: PMC11491726 DOI: 10.1016/j.redox.2024.103379] [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: 07/26/2024] [Revised: 09/14/2024] [Accepted: 09/30/2024] [Indexed: 10/10/2024] Open
Abstract
Histone deacetylases (HDACs) play critical roles in cardiovascular diseases (CVDs). In addition, reactive oxygen species (ROS) produced by NADPH oxidases (NOXs) exert damaging effects due to oxidative stress on heart and blood vessels. Although NOX-dependent ROS production is implicated in pathogenesis, the relationship between HDACs and NOXs in CVDs remains to be elucidated. Here, we present an overview of the regulatory effects and interconnected signaling pathways of HDACs and NOXs in CVDs. Improved insights into these relationships will facilitate the discovery of novel therapeutic agents that target HDACs, oxidase stress pathways, and the interactions between these systems which may be highly effective in the prevention and treatment of cardiovascular disorders.
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Affiliation(s)
- Hui Yan
- Institute of Cardiovascular Science, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China; Department of Medical Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
| | - Yidan Yin
- Institute of Cardiovascular Science, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China; Department of Medical Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
| | - Yichen Zhou
- Institute of Cardiovascular Science, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China; Department of Medical Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
| | - Zhanghang Li
- Institute of Cardiovascular Science, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China; Department of Medical Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
| | - Yuxing Li
- Institute of Cardiovascular Science, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China; Department of Medical Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
| | - Lingxuan Ren
- Institute of Cardiovascular Science, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China; Department of Medical Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
| | - Jiazheng Wen
- Institute of Cardiovascular Science, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China; Department of Medical Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
| | - Weirong Wang
- Institute of Cardiovascular Science, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China; Department of Medical Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.
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Feng G, Wu Z, Yang L, Wang K, Wang H. β-hydroxybutyrate and ischemic stroke: roles and mechanisms. Mol Brain 2024; 17:48. [PMID: 39075604 PMCID: PMC11287974 DOI: 10.1186/s13041-024-01119-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 07/14/2024] [Indexed: 07/31/2024] Open
Abstract
Stroke is a significant global burden, causing extensive morbidity and mortality. In metabolic states where glucose is limited, ketone bodies, predominantly β-hydroxybutyrate (BHB), act as alternative fuel sources. Elevated levels of BHB have been found in the ischemic hemispheres of animal models of stroke, supporting its role in the pathophysiology of cerebral ischemia. Clinically, higher serum and urinary BHB concentrations have been associated with adverse outcomes in ischemic stroke, highlighting its potential utility as a prognostic biomarker. In both animal and cellular models, exogenous BHB administration has exhibited neuroprotective effects, reduction of infarct size, and improvement of neurological outcomes. In this review, we focus on the role of BHB before and after ischemic stroke, with an emphasis on the therapeutic potential and mechanisms of ketone administration after ischemic stroke.
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Affiliation(s)
- Ge Feng
- Graduate School of Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Neurology, Hebei General Hospital, No. 348 21 Heping West Road, Shijiazhuang, 050051, Hebei, China
| | - Zongkai Wu
- Department of Neurology, Hebei General Hospital, No. 348 21 Heping West Road, Shijiazhuang, 050051, Hebei, China
| | - Leyi Yang
- Graduate School of Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Neurology, Hebei General Hospital, No. 348 21 Heping West Road, Shijiazhuang, 050051, Hebei, China
| | - Kaimeng Wang
- Graduate School of Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Neurology, Hebei General Hospital, No. 348 21 Heping West Road, Shijiazhuang, 050051, Hebei, China
| | - Hebo Wang
- Department of Neurology, Hebei General Hospital, No. 348 21 Heping West Road, Shijiazhuang, 050051, Hebei, China.
- Hebei Provincial Key Laboratory of Cerebral Networks and Cognitive Disorders, Shijiazhuang, Hebei, China.
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Xu L, An T, Jia B, Wu Q, Shen J, Jin J, Liu J, Li C. Histone deacetylase 3-specific inhibitor RGFP966 attenuates oxidative stress and inflammation after traumatic brain injury by activating the Nrf2 pathway. BURNS & TRAUMA 2024; 12:tkad062. [PMID: 38708192 PMCID: PMC11069425 DOI: 10.1093/burnst/tkad062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 12/08/2023] [Accepted: 12/12/2023] [Indexed: 05/07/2024]
Abstract
Background Oxidative stress (OS) and inflammatory reactions play pivotal roles in secondary brain injury after traumatic brain injury (TBI). Histone deacetylase 3 (HDAC3) controls the acetylation of histones and non-histones, which has a significant impact on the central nervous system's reaction to damage. This research determined the implications of RGFP966, a new and specific inhibitor of HDAC3, for the antioxidant (AO) systems mediated by nuclear factor erythroid2-related factor 2 (Nrf2) and the Nod-like receptor protein 3 (NLRP3) inflammasome in TBI. The study also studied the underlying mechanisms of RGFP966's actions. Our objective was to examine the impacts and underlying RGFP966 mechanisms in TBI. Methods In vitro, a rat cortical neuron OS model was induced by H2O2, followed by the addition of RGFP966 to the culture medium. Neurons were collected after 24 h for western blot (WB), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and 2'-7'-dichlorodihydrofluorescein diacetate staining. In vivo, RGFP966 (10 mg/kg) was administered post-TBI. Brain tissue water content and modified neurological severity scores were assessed 72 h post-injury. Cortical tissues surrounding the focal injury were subjected to western blot, TUNEL staining, Nissl staining and immunofluorescence/immunohistochemistry staining, and malondialdehyde level, hindered glutathione content and superoxide dismutase activity were measured. Serum was collected for the enzyme-linked immunosorbent assay. Nrf2-specific shRNA lentivirus was injected into the lateral ventricle of rats for 7 days, and cerebral cortex tissue was analyzed by WB and real-time polymerase chain reaction. Results During in vitro and in vivo experiments, RGFP966 suppressed HDAC3 expression, promoted Nrf2 nuclear translocation, activated downstream AO enzymes, mitigated excessive reactive oxygen species production and alleviated nerve cell apoptosis. RGFP966 effectively reduced brain edema and histological damage and enhanced neurological and cognitive function in rats with TBI. RGFP966 markedly inhibited NLRP3 inflammasome activation mediated by high-mobility group box 1 (HMGB1)/toll-like receptor 4 (TLR4). Nrf2 knockdown in TBI rats attenuated the AO and anti-inflammatory, neuroprotective impacts of RGFP966. Conclusions Overall, our findings demonstrate that RGFP966 can mitigate the first brain damage and neurological impairments in TBI. The underlying mechanism involves triggering the Nrf2-mediated AO system and negatively regulating the HMGB1/TLR4-mediated NLRP3 inflammasome pathway.
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Affiliation(s)
- Lanjuan Xu
- Department of Critical Care Medicine, Zhengzhou Central Hospital affiliated to Zhengzhou University, Zhengzhou, Henan Province 450001, China
| | - Tingting An
- Department of Critical Care Medicine, Zhengzhou Central Hospital affiliated to Zhengzhou University, Zhengzhou, Henan Province 450001, China
| | - Baohui Jia
- Department of Critical Care Medicine, Zhengzhou Central Hospital affiliated to Zhengzhou University, Zhengzhou, Henan Province 450001, China
| | - Qiong Wu
- Department of Critical Care Medicine, Zhengzhou Central Hospital affiliated to Zhengzhou University, Zhengzhou, Henan Province 450001, China
| | - Jinggui Shen
- Department of Critical Care Medicine, Zhengzhou Central Hospital affiliated to Zhengzhou University, Zhengzhou, Henan Province 450001, China
| | - Jie Jin
- Department of Critical Care Medicine, Zhengzhou Central Hospital affiliated to Zhengzhou University, Zhengzhou, Henan Province 450001, China
| | - Jing Liu
- Department of Critical Care Medicine, Zhengzhou Central Hospital affiliated to Zhengzhou University, Zhengzhou, Henan Province 450001, China
| | - Chengjian Li
- Department of Critical Care Medicine, Zhengzhou Central Hospital affiliated to Zhengzhou University, Zhengzhou, Henan Province 450001, China
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9
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Giuliani G, Longo VD. Ketone bodies in cell physiology and cancer. Am J Physiol Cell Physiol 2024; 326:C948-C963. [PMID: 38189128 DOI: 10.1152/ajpcell.00441.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 01/03/2024] [Accepted: 01/03/2024] [Indexed: 01/09/2024]
Abstract
Ketogenic diets (KDs), fasting, or prolonged physical activity elevate serum ketone bodies (KBs) levels, providing an alternative fuel source for the brain and other organs. However, KBs play pleiotropic roles that go beyond their role in energy production. KBs can act as signaling metabolites, influence gene expression, proteins' posttranslational modifications (PTMs), inflammation, and oxidative stress. Here, we explore the impact of KBs on mammalian cell physiology, including aging and tissue regeneration. We also concentrate on KBs and cancer, given the extensive evidence that dietary approaches inducing ketosis, including fasting-mimicking diets (FMDs) and KDs, can prevent cancer and affect tumor progression.
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Affiliation(s)
- Giacomo Giuliani
- Longevity Institute and Davis School of Gerontology, University of Southern California, Los Angeles, California, United States
| | - Valter D Longo
- Longevity Institute and Davis School of Gerontology, University of Southern California, Los Angeles, California, United States
- IFOM, FIRC Institute of Molecular Oncology, Milan, Italy
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Kawakatsu R, Tadagaki K, Yamasaki K, Yoshida T. Venetoclax efficacy on acute myeloid leukemia is enhanced by the combination with butyrate. Sci Rep 2024; 14:4975. [PMID: 38424468 PMCID: PMC10904797 DOI: 10.1038/s41598-024-55286-0] [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: 11/24/2023] [Accepted: 02/22/2024] [Indexed: 03/02/2024] Open
Abstract
Venetoclax has been approved recently for treatment of Acute myeloid leukemia (AML). Venetoclax is a BH3-mimetic and induces apoptosis via Bcl-2 inhibition. However, venetoclax's effect is still restrictive and a novel strategy is needed. In the present study, we demonstrate that sodium butyrate (NaB) facilitates the venetoclax's efficacy of cell death in AML cells. As a single agent, NaB or venetoclax exerted just a weak effect on cell death induction for AML cell line KG-1. The combination with NaB and venetoclax drastically induced cell death. NaB upregulated pro-apoptotic factors, Bax and Bak, indicating the synergistic effect by the collaboration with Bcl-2 inhibition by venetoclax. The combined treatment with NaB and venetoclax strongly cleaved a caspase substrate poly (ADP-ribose) polymerase (PARP) and a potent pan-caspase inhibitor Q-VD-OPh almost completely blocked the cell death induced by the combination, meaning that the combination mainly induced apoptosis. The combination with NaB and venetoclax also strongly induced cell death in another AML cell line SKNO-1 but did not affect chronic myeloid leukemia (CML) cell line K562, indicating that the effect was specific for AML cells. Our results provide a novel strategy to strengthen the effect of venetoclax for AML treatment.
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Affiliation(s)
- Renshi Kawakatsu
- Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Kenjiro Tadagaki
- Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Kenta Yamasaki
- Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Tatsushi Yoshida
- Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.
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11
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Soni S, Tabatabaei Dakhili SA, Ussher JR, Dyck JRB. The therapeutic potential of ketones in cardiometabolic disease: impact on heart and skeletal muscle. Am J Physiol Cell Physiol 2024; 326:C551-C566. [PMID: 38193855 PMCID: PMC11192481 DOI: 10.1152/ajpcell.00501.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 12/15/2023] [Accepted: 12/15/2023] [Indexed: 01/10/2024]
Abstract
β-Hydroxybutyrate (βOHB) is the major ketone in the body, and it is recognized as a metabolic energy source and an important signaling molecule. While ketone oxidation is essential in the brain during prolonged fasting/starvation, other organs such as skeletal muscle and the heart also use ketones as metabolic substrates. Additionally, βOHB-mediated molecular signaling events occur in heart and skeletal muscle cells, and via metabolism and/or signaling, ketones may contribute to optimal skeletal muscle health and cardiac function. Of importance, when the use of ketones for ATP production and/or as signaling molecules becomes disturbed in the presence of underlying obesity, type 2 diabetes, and/or cardiovascular diseases, these changes may contribute to cardiometabolic disease. As a result of these disturbances in cardiometabolic disease, multiple approaches have been used to elevate circulating ketones with the goal of optimizing either ketone metabolism or ketone-mediated signaling. These approaches have produced significant improvements in heart and skeletal muscle during cardiometabolic disease with a wide range of benefits that include improved metabolism, weight loss, better glycemic control, improved cardiac and vascular function, as well as reduced inflammation and oxidative stress. Herein, we present the evidence that indicates that ketone therapy could be used as an approach to help treat cardiometabolic diseases by targeting cardiac and skeletal muscles.
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Affiliation(s)
- Shubham Soni
- Cardiovascular Research Centre, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada
- Department of Pediatrics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Seyed Amirhossein Tabatabaei Dakhili
- Cardiovascular Research Centre, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - John R Ussher
- Cardiovascular Research Centre, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Jason R B Dyck
- Cardiovascular Research Centre, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada
- Department of Pediatrics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada
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12
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Jang J, Kim SR, Lee JE, Lee S, Son HJ, Choe W, Yoon KS, Kim SS, Yeo EJ, Kang I. Molecular Mechanisms of Neuroprotection by Ketone Bodies and Ketogenic Diet in Cerebral Ischemia and Neurodegenerative Diseases. Int J Mol Sci 2023; 25:124. [PMID: 38203294 PMCID: PMC10779133 DOI: 10.3390/ijms25010124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 12/18/2023] [Accepted: 12/18/2023] [Indexed: 01/12/2024] Open
Abstract
Ketone bodies (KBs), such as acetoacetate and β-hydroxybutyrate, serve as crucial alternative energy sources during glucose deficiency. KBs, generated through ketogenesis in the liver, are metabolized into acetyl-CoA in extrahepatic tissues, entering the tricarboxylic acid cycle and electron transport chain for ATP production. Reduced glucose metabolism and mitochondrial dysfunction correlate with increased neuronal death and brain damage during cerebral ischemia and neurodegeneration. Both KBs and the ketogenic diet (KD) demonstrate neuroprotective effects by orchestrating various cellular processes through metabolic and signaling functions. They enhance mitochondrial function, mitigate oxidative stress and apoptosis, and regulate epigenetic and post-translational modifications of histones and non-histone proteins. Additionally, KBs and KD contribute to reducing neuroinflammation and modulating autophagy, neurotransmission systems, and gut microbiome. This review aims to explore the current understanding of the molecular mechanisms underpinning the neuroprotective effects of KBs and KD against brain damage in cerebral ischemia and neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease.
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Affiliation(s)
- Jiwon Jang
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (J.J.); (S.R.K.); (J.E.L.); (S.L.); (H.J.S.); (W.C.); (K.-S.Y.); (S.S.K.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Su Rim Kim
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (J.J.); (S.R.K.); (J.E.L.); (S.L.); (H.J.S.); (W.C.); (K.-S.Y.); (S.S.K.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Jo Eun Lee
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (J.J.); (S.R.K.); (J.E.L.); (S.L.); (H.J.S.); (W.C.); (K.-S.Y.); (S.S.K.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Seoyeon Lee
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (J.J.); (S.R.K.); (J.E.L.); (S.L.); (H.J.S.); (W.C.); (K.-S.Y.); (S.S.K.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Hyeong Jig Son
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (J.J.); (S.R.K.); (J.E.L.); (S.L.); (H.J.S.); (W.C.); (K.-S.Y.); (S.S.K.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Wonchae Choe
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (J.J.); (S.R.K.); (J.E.L.); (S.L.); (H.J.S.); (W.C.); (K.-S.Y.); (S.S.K.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Kyung-Sik Yoon
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (J.J.); (S.R.K.); (J.E.L.); (S.L.); (H.J.S.); (W.C.); (K.-S.Y.); (S.S.K.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Sung Soo Kim
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (J.J.); (S.R.K.); (J.E.L.); (S.L.); (H.J.S.); (W.C.); (K.-S.Y.); (S.S.K.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Eui-Ju Yeo
- Department of Biochemistry, College of Medicine, Gachon University, Incheon 21999, Republic of Korea
| | - Insug Kang
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (J.J.); (S.R.K.); (J.E.L.); (S.L.); (H.J.S.); (W.C.); (K.-S.Y.); (S.S.K.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
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13
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He Y, Cheng X, Zhou T, Li D, Peng J, Xu Y, Huang W. β-Hydroxybutyrate as an epigenetic modifier: Underlying mechanisms and implications. Heliyon 2023; 9:e21098. [PMID: 37928021 PMCID: PMC10623287 DOI: 10.1016/j.heliyon.2023.e21098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 09/09/2023] [Accepted: 10/16/2023] [Indexed: 11/07/2023] Open
Abstract
Previous studies have found that β-Hydroxybutyrate (BHB), the main component of ketone bodies, is of physiological importance as a backup energy source during starvation or induces diabetic ketoacidosis when insulin deficiency occurs. Ketogenic diets (KD) have been used as metabolic therapy for over a hundred years, it is well known that ketone bodies and BHB not only serve as ancillary fuel substituting for glucose but also induce anti-oxidative, anti-inflammatory, and cardioprotective features via binding to several target proteins, including histone deacetylase (HDAC), or G protein-coupled receptors (GPCRs). Recent advances in epigenetics, especially novel histone post-translational modifications (HPTMs), have continuously updated our understanding of BHB, which also acts as a signal transduction molecule and modification substrate to regulate a series of epigenetic phenomena, such as histone acetylation, histone β-hydroxybutyrylation, histone methylation, DNA methylation, and microRNAs. These epigenetic events alter the activity of genes without changing the DNA structure and further participate in the pathogenesis of related diseases. This review focuses on the metabolic process of BHB and BHB-mediated epigenetics in cardiovascular diseases, diabetes and complications of diabetes, neuropsychiatric diseases, cancers, osteoporosis, liver and kidney injury, embryonic and fetal development, and intestinal homeostasis, and discusses potential molecular mechanisms, drug targets, and application prospects.
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Affiliation(s)
- Yanqiu He
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
- Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou, Sichuan, 646000, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, 646000, China
- Sichuan Clinical Research Center for Diabetes and Metabolic Diseases, Luzhou, Sichuan, 646000, China
| | - Xi Cheng
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
- Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou, Sichuan, 646000, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, 646000, China
- Sichuan Clinical Research Center for Diabetes and Metabolic Diseases, Luzhou, Sichuan, 646000, China
| | - Tingting Zhou
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
- Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou, Sichuan, 646000, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, 646000, China
- Sichuan Clinical Research Center for Diabetes and Metabolic Diseases, Luzhou, Sichuan, 646000, China
| | - Dongze Li
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
- Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou, Sichuan, 646000, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, 646000, China
- Sichuan Clinical Research Center for Diabetes and Metabolic Diseases, Luzhou, Sichuan, 646000, China
| | - Juan Peng
- Department of Rehabilitation, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Yong Xu
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
- Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou, Sichuan, 646000, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, 646000, China
- Sichuan Clinical Research Center for Diabetes and Metabolic Diseases, Luzhou, Sichuan, 646000, China
| | - Wei Huang
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
- Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou, Sichuan, 646000, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, 646000, China
- Sichuan Clinical Research Center for Diabetes and Metabolic Diseases, Luzhou, Sichuan, 646000, China
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14
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Duan H, Wang L, Huangfu M, Li H. The impact of microbiota-derived short-chain fatty acids on macrophage activities in disease: Mechanisms and therapeutic potentials. Biomed Pharmacother 2023; 165:115276. [PMID: 37542852 DOI: 10.1016/j.biopha.2023.115276] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 07/28/2023] [Accepted: 07/31/2023] [Indexed: 08/07/2023] Open
Abstract
Short-chain fatty acids (SCFAs) derived from the fermentation of carbohydrates by gut microbiota play a crucial role in regulating host physiology. Among them, acetate, propionate, and butyrate are key players in various biological processes. Recent research has revealed their significant functions in immune and inflammatory responses. For instance, butyrate reduces the development of interferon-gamma (IFN-γ) generating cells while promoting the development of regulatory T (Treg) cells. Propionate inhibits the initiation of a Th2 immune response by dendritic cells (DCs). Notably, SCFAs have an inhibitory impact on the polarization of M2 macrophages, emphasizing their immunomodulatory properties and potential for therapeutics. In animal models of asthma, both butyrate and propionate suppress the M2 polarization pathway, thus reducing allergic airway inflammation. Moreover, dysbiosis of gut microbiota leading to altered SCFA production has been implicated in prostate cancer progression. SCFAs trigger autophagy in cancer cells and promote M2 polarization in macrophages, accelerating tumor advancement. Manipulating microbiota- producing SCFAs holds promise for cancer treatment. Additionally, SCFAs enhance the expression of hypoxia-inducible factor 1 (HIF-1) by blocking histone deacetylase, resulting in increased production of antibacterial effectors and improved macrophage-mediated elimination of microorganisms. This highlights the antimicrobial potential of SCFAs and their role in host defense mechanisms. This comprehensive review provides an in-depth analysis of the latest research on the functional aspects and underlying mechanisms of SCFAs in relation to macrophage activities in a wide range of diseases, including infectious diseases and cancers. By elucidating the intricate interplay between SCFAs and macrophage functions, this review aims to contribute to the understanding of their therapeutic potential and pave the way for future interventions targeting SCFAs in disease management.
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Affiliation(s)
- Hongliang Duan
- Department of Thyroid Surgery, the Second Hospital of Jilin University, Changchun 130000, China
| | - LiJuan Wang
- Department of Endocrinology, the Second Hospital of Jilin University, Changchun 130000, China.
| | - Mingmei Huangfu
- Department of Thyroid Surgery, the Second Hospital of Jilin University, Changchun 130000, China
| | - Hanyang Li
- Department of Endocrinology, the Second Hospital of Jilin University, Changchun 130000, China
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15
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He R, Liu B, Geng B, Li N, Geng Q. The role of HDAC3 and its inhibitors in regulation of oxidative stress and chronic diseases. Cell Death Discov 2023; 9:131. [PMID: 37072432 PMCID: PMC10113195 DOI: 10.1038/s41420-023-01399-w] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 03/01/2023] [Accepted: 03/06/2023] [Indexed: 04/20/2023] Open
Abstract
HDAC3 is a specific and crucial member of the HDAC family. It is required for embryonic growth, development, and physiological function. The regulation of oxidative stress is an important factor in intracellular homeostasis and signal transduction. Currently, HDAC3 has been found to regulate several oxidative stress-related processes and molecules dependent on its deacetylase and non-enzymatic activities. In this review, we comprehensively summarize the knowledge of the relationship of HDAC3 with mitochondria function and metabolism, ROS-produced enzymes, antioxidant enzymes, and oxidative stress-associated transcription factors. We also discuss the role of HDAC3 and its inhibitors in some chronic cardiovascular, kidney, and neurodegenerative diseases. Due to the simultaneous existence of enzyme activity and non-enzyme activity, HDAC3 and the development of its selective inhibitors still need further exploration in the future.
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Affiliation(s)
- Ruyuan He
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Bohao Liu
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Boxin Geng
- School of Basic Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Ning Li
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
| | - Qing Geng
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
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16
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Rondanelli M, Patelli Z, Gasparri C, Mansueto F, Ferraris C, Nichetti M, Alalwan TA, Sajoux I, Maugeri R, Perna S. Very low calorie ketogenic diet and common rheumatic disorders: A case report. World J Clin Cases 2023; 11:1985-1991. [PMID: 36998951 PMCID: PMC10044955 DOI: 10.12998/wjcc.v11.i9.1985] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 11/10/2022] [Accepted: 01/09/2023] [Indexed: 03/16/2023] Open
Abstract
BACKGROUND The scientific literature provides evidence that nutritional ketosis can be an important support in the treatment of pathologies in which inflammation is present, as recent studies have shown that ketone bodies have anti-inflammatory activity in numerous diseases, including rheumatic diseases. We report the case of a 22-year-old woman with class I obesity and juvenile idiopathic arthritis who started treatment with a very low calorie ketogenic diet (VLCKD).
CASE SUMMARY The patient was a 22-year-old woman diagnosed with juvenile idiopathic arthritis at age 4 years and with a body mass index (BMI) of 30.8 kg/m2, waist circumference (WC) 80 cm, fat mass (FM) 28.1 kg, free FM 45.7 kg, and visceral adipose tissue (VAT) 3.5 kg, assessed on bioimpedance analysis. She was treated using a commercial VLCKD weight-loss program (PNK® method); this program provides high-biological-value protein preparations and natural foods. Each protein preparation contains 15 g protein, 4 g carbohydrate, 3 g fat, and 50 mg omega-3 docosahexaenoic acid, with an energy content of 90–120 kcal. After four months on the program, the BMI was 28.6 kg/m2, WC 73 cm, FM 23.2 kg, free FM 41.9 kg, and VAT 2.9 kg.
CONCLUSION VLCKD enabled the patient to reach her target weight and to reduce her joint pain and headaches. Laboratory inflammatory indices also normalized.
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Affiliation(s)
- Mariangela Rondanelli
- Department of Public Health, Experimental and Forensic Medicine, Unit of Human and Clinical Nutrition, IRCCS Mondino Foundation, Pavia 27100, Italy
| | - Zaira Patelli
- Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona ‘‘Istituto Santa Margherita’’, University of Pavia, Pavia 27100, Italy
| | - Clara Gasparri
- Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona ‘‘Istituto Santa Margherita’’, University of Pavia, Pavia 27100, Italy
| | - Francesca Mansueto
- Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona ‘‘Istituto Santa Margherita’’, University of Pavia, Pavia 27100, Italy
| | - Cinzia Ferraris
- Food Education and Sport Nutrition Laboratory, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia 27100, Italy
| | - Mara Nichetti
- Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona ‘‘Istituto Santa Margherita’’, University of Pavia, Pavia 27100, Italy
| | - Tariq A Alalwan
- Department of Biology, College of Science, University of Bahrain, Sakhir 32038, Bahrain
| | - Ignacio Sajoux
- Chief Scientific Office, Medical Department Pronokal Group, Barcelona 08001, Spain
| | | | - Simone Perna
- Department of Biology, College of Science, University of Bahrain, Sakhir 32038, Bahrain
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17
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Khayrullina G, Bermudez S, Hopkins D, Yauger Y, Byrnes KR. Differential effects of NOX2 and NOX4 inhibition after rodent spinal cord injury. PLoS One 2023; 18:e0281045. [PMID: 36897852 PMCID: PMC10004500 DOI: 10.1371/journal.pone.0281045] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 01/17/2023] [Indexed: 03/11/2023] Open
Abstract
Reactive oxygen species (ROS) are a contributing factor to impaired function and pathology after spinal cord injury (SCI). The NADPH oxidase (NOX) enzyme is a key source of ROS; there are several NOX family members, including NOX2 and NOX4, that may play a role in ROS production after SCI. Previously, we showed that a temporary inhibition of NOX2 by intrathecal administration of gp91ds-tat immediately after injury improved recovery in a mouse SCI model. However, chronic inflammation was not affected by this single acute treatment, and other NOX family members were not assessed. Therefore, we aimed to explore the effect of genetic knockout (KO) of NOX2 or acute inhibition of NOX4 with GKT137831. A moderate SCI contusion injury was performed in 3 month old NOX2 KO and wild-type (WT) mice, who received no treatment or GKT137831/vehicle 30 minutes post-injury. Motor function was assessed using the Basso Mouse Scale (BMS), followed by evaluation of inflammation and oxidative stress markers. NOX2 KO mice, but not GKT137831 treated mice, demonstrated significantly improved BMS scores at 7, 14, and 28 days post injury (DPI) in comparison to WT mice. However, both NOX2 KO and GKT137831 significantly reduced ROS production and oxidative stress markers. Furthermore, a shift in microglial activation toward a more neuroprotective, anti-inflammatory state was observed in KO mice at 7 DPI and a reduction of microglial markers at 28 days. While acute alterations in inflammation were noted with GKT137831 administration, this was not sustained through 28 days. In vitro analysis also showed that while GKT137831 reduced ROS production by microglia, it did not translate to changes in pro-inflammatory marker expression within these cells. These data demonstrate that NOX2 and NOX4 play a role in post-injury ROS, but a single dose of NOX4 inhibitor fails to enhance long-term recovery.
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Affiliation(s)
- Guzal Khayrullina
- Anatomy, Physiology and Genetics Department, Uniformed Services University, Bethesda, MD, United States of America
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, United States of America
| | - Sara Bermudez
- Anatomy, Physiology and Genetics Department, Uniformed Services University, Bethesda, MD, United States of America
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, United States of America
| | - Deanna Hopkins
- Anatomy, Physiology and Genetics Department, Uniformed Services University, Bethesda, MD, United States of America
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, United States of America
| | - Young Yauger
- Neuroscience Graduate Program, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America
| | - Kimberly R. Byrnes
- Anatomy, Physiology and Genetics Department, Uniformed Services University, Bethesda, MD, United States of America
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18
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Poorshiri B, Barzegar M, Afghan M, Shiva S, Shahabi P, Golchinfar Z, Yousefi Nodeh HR, Raeisi S. The effects of ketogenic diet on beta-hydroxybutyrate, arachidonic acid, and oxidative stress in pediatric epilepsy. Epilepsy Behav 2023; 140:109106. [PMID: 36745963 DOI: 10.1016/j.yebeh.2023.109106] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 01/02/2023] [Accepted: 01/19/2023] [Indexed: 02/06/2023]
Abstract
The exact mechanism of a ketogenic diet (KD) as a suitable alternative therapeutic approach for drug-resistant epilepsy (DRE) in alleviating seizures is not yet fully understood. The present study aimed to evaluate the role of the KD in reducing oxidative stress (OS) by increasing the ketone body beta-hydroxybutyrate (BHB) and Arachidonic acid (ARA), an essential polyunsaturated fatty acid, as a possible mechanism in relieving seizure attacks in children with DRE. Forty children with refractory epilepsy were included in the present study. The serum levels of BHB, ARA, and OS markers, malondialdehyde (MDA), and 8-hydroxyl-deoxyguanosine (8-OHdG), were evaluated in children with DRE and compared before and after the three months of KD therapy. Thirty-four of 40 included children could complete the three-month KD therapy. Twenty-one (61.76%) patients had more than a 50% reduction in seizure frequency after the KD (responders). The remaining 13 children were considered non-responders to the diet. The serum levels of ARA and BHB significantly (p < 0.05) increased after the KD therapy. The serum levels of OS parameters MDA and 8-OHdG before the diet therapy were significantly (p < 0.05) higher than those after the administration. The serum levels of BHB and MDA after the KD therapy in the responders were respectively higher and lower than those in the non-responders (p < 0.001). Ketogenic diet might reduce brain OS by increasing BHB and ARA. The role of BHB in diminishing OS and seizure might be more remarkable than ARA.
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Affiliation(s)
- Bita Poorshiri
- Pediatric Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Barzegar
- Pediatric Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammadreza Afghan
- Pediatric Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Siamak Shiva
- Pediatric Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parviz Shahabi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zahra Golchinfar
- Department of Food Science and Technology, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Sina Raeisi
- Pediatric Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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19
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Abstract
The prevalence of neonatal hypoxic-ischemic encephalopathy (HIE), a devastating neurological injury, is increasing; thus, effective treatments and preventions are urgently needed. The underlying pathology of HIE remains unclear; recent research has focused on elucidating key features of the disease. A variety of diseases can be alleviated by consuming a ketogenic diet (KD) despite differences in pathogenesis and features, given the common mechanisms of KD-induced effects. Dietary modification is the most translatable, cost-efficient, and safest approach to treat acute or chronic neurological disorders and reduces reliance on pharmaceutical treatments. Evidence suggests that the KD can exert beneficial effects in animal models and in humans with brain injuries. The efficacy of the KD in preventing neuronal damage, motor alterations, and cognitive decline varies. Moreover, the KD may provide an alternative source of energy, enhance mitochondrial function, and reduce the expression of inflammatory and apoptotic mediators. Thus, this diet has attracted interest as a potential therapy for HIE. This review examined the role of the KD in HIE treatment and described the mechanisms by which ketone bodies (KBs) exert effects under pathological conditions and protect against brain damage; the evidence supports the implementation of dietary interventions as a therapeutic strategy for HIE. Future research should aim to elucidate the underlying mechanisms of the KD in patients with HIE and determine whether the effect of the KD on clinical outcomes can be reproduced in humans.
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Affiliation(s)
- Yue Zhou
- Department of Pharmacy, Xindu District People's Hospital of Chengdu, 610500 Chengdu, China
| | - Luqiang Sun
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, 610075 Chengdu, China
| | - Haichuan Wang
- Department of Paediatrics, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, 610072 Chengdu, China
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20
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Field R, Field T, Pourkazemi F, Rooney K. Ketogenic diets and the nervous system: a scoping review of neurological outcomes from nutritional ketosis in animal studies. Nutr Res Rev 2022; 35:268-281. [PMID: 34180385 DOI: 10.1017/s0954422421000214] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVES Ketogenic diets have reported efficacy for neurological dysfunctions; however, there are limited published human clinical trials elucidating the mechanisms by which nutritional ketosis produces therapeutic effects. The purpose of this present study was to investigate animal models that report variations in nervous system function by changing from a standard animal diet to a ketogenic diet, synthesise these into broad themes, and compare these with mechanisms reported as targets in pain neuroscience to inform human chronic pain trials. METHODS An electronic search of seven databases was conducted in July 2020. Two independent reviewers screened studies for eligibility, and descriptive outcomes relating to nervous system function were extracted for a thematic analysis, then synthesised into broad themes. RESULTS In total, 170 studies from eighteen different disease models were identified and grouped into fourteen broad themes: alterations in cellular energetics and metabolism, biochemical, cortical excitability, epigenetic regulation, mitochondrial function, neuroinflammation, neuroplasticity, neuroprotection, neurotransmitter function, nociception, redox balance, signalling pathways, synaptic transmission and vascular supply. DISCUSSION The mechanisms presented centred around the reduction of inflammation and oxidative stress as well as a reduction in nervous system excitability. Given the multiple potential mechanisms presented, it is likely that many of these are involved synergistically and undergo adaptive processes within the human body, and controlled animal models that limit the investigation to a particular pathway in isolation may reach differing conclusions. Attention is required when translating this information to human chronic pain populations owing to the limitations outlined from the animal research.
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Affiliation(s)
- Rowena Field
- The University of Sydney, Faculty of Medicine and Health, Sydney, Australia
| | - Tara Field
- The New South Wales Ministry of Health (NSW Health), Sydney, Australia
| | | | - Kieron Rooney
- The University of Sydney, Faculty of Medicine and Health, Sydney, Australia
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21
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Hwang CY, Choe W, Yoon KS, Ha J, Kim SS, Yeo EJ, Kang I. Molecular Mechanisms for Ketone Body Metabolism, Signaling Functions, and Therapeutic Potential in Cancer. Nutrients 2022; 14:nu14224932. [PMID: 36432618 PMCID: PMC9694619 DOI: 10.3390/nu14224932] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 11/15/2022] [Accepted: 11/17/2022] [Indexed: 11/23/2022] Open
Abstract
The ketone bodies (KBs) β-hydroxybutyrate and acetoacetate are important alternative energy sources for glucose during nutrient deprivation. KBs synthesized by hepatic ketogenesis are catabolized to acetyl-CoA through ketolysis in extrahepatic tissues, followed by the tricarboxylic acid cycle and electron transport chain for ATP production. Ketogenesis and ketolysis are regulated by the key rate-limiting enzymes, 3-hydroxy-3-methylglutaryl-CoA synthase 2 and succinyl-CoA:3-oxoacid-CoA transferase, respectively. KBs participate in various cellular processes as signaling molecules. KBs bind to G protein-coupled receptors. The most abundant KB, β-hydroxybutyrate, regulates gene expression and other cellular functions by inducing post-translational modifications. KBs protect tissues by regulating inflammation and oxidative stress. Recently, interest in KBs has been increasing due to their potential for treatment of various diseases such as neurological and cardiovascular diseases and cancer. Cancer cells reprogram their metabolism to maintain rapid cell growth and proliferation. Dysregulation of KB metabolism also plays a role in tumorigenesis in various types of cancer. Targeting metabolic changes through dietary interventions, including fasting and ketogenic diets, has shown beneficial effects in cancer therapy. Here, we review current knowledge of the molecular mechanisms involved in the regulation of KB metabolism and cellular signaling functions, and the therapeutic potential of KBs and ketogenic diets in cancer.
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Affiliation(s)
- Chi Yeon Hwang
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Wonchae Choe
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Kyung-Sik Yoon
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Joohun Ha
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Sung Soo Kim
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Eui-Ju Yeo
- Department of Biochemistry, College of Medicine, Gachon University, Incheon 21999, Republic of Korea
- Correspondence: (E.-J.Y.); (I.K.); Tel.: +82-32-899-6050 (E.-J.Y.); +82-2-961-0922 (I.K.)
| | - Insug Kang
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
- Correspondence: (E.-J.Y.); (I.K.); Tel.: +82-32-899-6050 (E.-J.Y.); +82-2-961-0922 (I.K.)
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22
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Tao Y, Leng SX, Zhang H. Ketogenic Diet: An Effective Treatment Approach for Neurodegenerative Diseases. Curr Neuropharmacol 2022; 20:2303-2319. [PMID: 36043794 PMCID: PMC9890290 DOI: 10.2174/1570159x20666220830102628] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 06/13/2022] [Accepted: 07/03/2022] [Indexed: 12/29/2022] Open
Abstract
This review discusses the effects and mechanisms of a ketogenic diet on neurodegenerative diseases on the basis of available evidence. A ketogenic diet refers to a high-fat, mediumprotein, and low-carbohydrate diet that leads to a metabolic shift to ketosis. This review systematically summarizes the scientific literature supporting this effective treatment approach for neurodegenerative diseases, including effects on mitochondrial function, oxidative stress, neuronal apoptosis, neuroinflammation, and the microbiota-gut-brain axis. It also highlights the clinical evidence for the effects of the ketogenic diet in the treatment of Alzheimer's disease, Parkinson's disease, and motor neuron disease. Finally, it discusses the common adverse effects of ketogenic therapy. Although the complete mechanism of the ketogenic diet in the treatment of neurodegenerative diseases remains to be elucidated, its clinical efficacy has attracted many new followers. The ketogenic diet is a good candidate for adjuvant therapy, but its specific applicability depends on the type and the degree of the disease.
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Affiliation(s)
- Ye Tao
- Department of Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Sean X Leng
- Division of Geriatric Medicine and Gerontology, Department of Medicine, Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Circle - Room 1A.38A, Baltimore, MD, 21224, USA
| | - Haiyan Zhang
- Department of Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang 110001, China
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23
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Krakovski MA, Arora N, Jain S, Glover J, Dombrowski K, Hernandez B, Yadav H, Sarma AK. Diet-microbiome-gut-brain nexus in acute and chronic brain injury. Front Neurosci 2022; 16:1002266. [PMID: 36188471 PMCID: PMC9523267 DOI: 10.3389/fnins.2022.1002266] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 08/29/2022] [Indexed: 11/13/2022] Open
Abstract
In recent years, appreciation for the gut microbiome and its relationship to human health has emerged as a facilitator of maintaining healthy physiology and a contributor to numerous human diseases. The contribution of the microbiome in modulating the gut-brain axis has gained significant attention in recent years, extensively studied in chronic brain injuries such as Epilepsy and Alzheimer’s Disease. Furthermore, there is growing evidence that gut microbiome also contributes to acute brain injuries like stroke(s) and traumatic brain injury. Microbiome-gut-brain communications are bidirectional and involve metabolite production and modulation of immune and neuronal functions. The microbiome plays two distinct roles: it beneficially modulates immune system and neuronal functions; however, abnormalities in the host’s microbiome also exacerbates neuronal damage or delays the recovery from acute injuries. After brain injury, several inflammatory changes, such as the necrosis and apoptosis of neuronal tissue, propagates downward inflammatory signals to disrupt the microbiome homeostasis; however, microbiome dysbiosis impacts the upward signaling to the brain and interferes with recovery in neuronal functions and brain health. Diet is a superlative modulator of microbiome and is known to impact the gut-brain axis, including its influence on acute and neuronal injuries. In this review, we discussed the differential microbiome changes in both acute and chronic brain injuries, as well as the therapeutic importance of modulation by diets and probiotics. We emphasize the mechanistic studies based on animal models and their translational or clinical relationship by reviewing human studies.
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Affiliation(s)
| | - Niraj Arora
- Department of Neurology, University of Missouri, Columbia, MO, United States
| | - Shalini Jain
- Department of Neurosurgery and Brain Repair, University of South Florida, Tampa, FL, United States
| | - Jennifer Glover
- Department of Neurosurgery and Brain Repair, University of South Florida, Tampa, FL, United States
| | - Keith Dombrowski
- Department of Neurosurgery and Brain Repair, University of South Florida, Tampa, FL, United States
| | - Beverly Hernandez
- Clinical Nutrition Services, Tampa General Hospital, Tampa, FL, United States
| | - Hariom Yadav
- Department of Neurosurgery and Brain Repair, University of South Florida, Tampa, FL, United States
- USF Center for Microbiome Research, Microbiomes Institute, University of South Florida, Tampa, FL, United States
- *Correspondence: Hariom Yadav,
| | - Anand Karthik Sarma
- Wake Forest University School of Medicine, Winston-Salem, NC, United States
- Department of Neurology, Atrium Health Wake Forest Baptist, Winston-Salem, NC, United States
- Anand Karthik Sarma,
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24
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Zhou T, Cheng X, He Y, Xie Y, Xu F, Xu Y, Huang W. Function and mechanism of histone β-hydroxybutyrylation in health and disease. Front Immunol 2022; 13:981285. [PMID: 36172354 PMCID: PMC9511043 DOI: 10.3389/fimmu.2022.981285] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 08/22/2022] [Indexed: 11/24/2022] Open
Abstract
Histone post-translational modifications (HPTMs) are essential epigenetic mechanisms that affect chromatin-associated nuclear processes without altering the DNA sequence. With the application of mass spectrometry-based proteomics, novel histone lysine acylation, such as propionylation, butyrylation, crotonylation, malonylation, succinylation, glutarylation, and lactoylation have been successively discovered. The emerging diversity of the lysine acylation landscape prompted us to investigate the function and mechanism of these novel HPTMs in health and disease. Recently, it has been reported that β-hydroxybutyrate (BHB), the main component of the ketone body, has various protective roles beyond alternative fuel provision during starvation. Histone lysine β-hydroxybutyrylation (Kbhb) is a novel HPTMs identified by mass spectrometry, which regulates gene transcription in response to carbohydrate restriction or elevated BHB levels in vivo and vitro. Recent studies have shown that histone Kbhb is strongly associated with the pathogenesis of metabolic cardiovascular diseases, kidney diseases, tumors, neuropsychiatric disorders, and metabolic diseases suggesting it has different functions from histone acetylation and methylation. This review focuses on the writers, erasers, sites, and underlying functions of histone Kbhb, providing a glimpse into their complex regulation mechanism.
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Affiliation(s)
- Tingting Zhou
- Department of Endocrinology, Affiliated Hospital of Southwest Medical University, Luzhou, China
- Metabolism, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, China
- Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China
| | - Xi Cheng
- Department of Endocrinology, Affiliated Hospital of Southwest Medical University, Luzhou, China
- Metabolism, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, China
- Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China
| | - Yanqiu He
- Department of Endocrinology, Affiliated Hospital of Southwest Medical University, Luzhou, China
- Metabolism, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, China
- Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China
| | - Yumei Xie
- Department of Endocrinology, Affiliated Hospital of Southwest Medical University, Luzhou, China
- Metabolism, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, China
- Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China
| | - Fangyuan Xu
- Department of Rehabilitation, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yong Xu
- Department of Endocrinology, Affiliated Hospital of Southwest Medical University, Luzhou, China
- Metabolism, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, China
- Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China
- *Correspondence: Wei Huang, ; Yong Xu,
| | - Wei Huang
- Department of Endocrinology, Affiliated Hospital of Southwest Medical University, Luzhou, China
- Metabolism, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, China
- Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China
- *Correspondence: Wei Huang, ; Yong Xu,
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25
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Ketogenic diet attenuates post-cardiac arrest brain injury by upregulation of pentose phosphate pathway-mediated antioxidant defense in a mouse model of cardiac arrest. Nutrition 2022; 103-104:111814. [DOI: 10.1016/j.nut.2022.111814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 06/24/2022] [Accepted: 08/05/2022] [Indexed: 11/19/2022]
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Ketone Body Improves Neurological Outcomes after Cardiac Arrest by Inhibiting Mitochondrial Fission in Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7736416. [PMID: 35847595 PMCID: PMC9283010 DOI: 10.1155/2022/7736416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 06/17/2022] [Indexed: 11/17/2022]
Abstract
Ketone bodies including β-hydroxybutyrate (β-HB) have been proved the therapeutic potential in diverse neurological disorders. However, the role of β-HB in the regulation of neurological injury after cardiac arrest (CA) remains unclear. We investigated the effect of β-HB on brain mitochondrial dysfunction and neurological function after CA. A rat model of CA was established by asphyxia. The rats were randomly divided into three groups: sham group, control group, and β-HB group. Animals received 200 mg/kg β-HB or same volume vehicle at 10 minutes after return of spontaneous circulation by intraperitoneal injection. Neurological function was evaluated by neurologic deficit score and Y-maze. Neuronal cell loss and apoptosis were detected through hematoxylin-eosin staining, Nissl staining, and TdT-mediated dUTP nick-end labeling assay. Oxidative stress levels were determined by immunohistochemical staining of 4-hydoxynonenal and 8-hydroxy-2′-deoxyguanosine. Furthermore, mitochondrial ultrastructure of brain cells was observed by transmission electron microscopy. In addition, the protein expression levels of Bak, caspase 3, gasdermin D, caspase 1, brain-derived neurotrophic factor, dynamin-related protein 1 (Drp1), and phospho-Drp1 (ser616) were measured. We found that neurological function and survival rate were significantly higher in the β-HB group compared with the control group. β-HB also reduced neurons death and neurological oxidative stress after CA. Moreover, β-HB reduced neurological injury from apoptosis and pyroptosis after CA. In addition, β-HB maintained the structural integrity of brain mitochondria, prevented mitochondrial fission, and increased brain energy metabolism after CA. In conclusion, β-HB beneficially affected the neurological function of rats after global cerebral ischemia, associated with decreased mitochondrial fission, and improved mitochondrial function. Our results suggest that β-HB might benefit patients suffering from neurological dysfunction after CA.
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27
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Mooli RGR, Ramakrishnan SK. Emerging Role of Hepatic Ketogenesis in Fatty Liver Disease. Front Physiol 2022; 13:946474. [PMID: 35860662 PMCID: PMC9289363 DOI: 10.3389/fphys.2022.946474] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 06/08/2022] [Indexed: 11/18/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver diseases, arise from non-alcoholic fatty liver (NAFL) characterized by excessive fat accumulation as triglycerides. Although NAFL is benign, it could progress to non-alcoholic steatohepatitis (NASH) manifested with inflammation, hepatocyte damage and fibrosis. A subset of NASH patients develops end-stage liver diseases such as cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is highly complex and strongly associated with perturbations in lipid and glucose metabolism. Lipid disposal pathways, in particular, impairment in condensation of acetyl-CoA derived from β-oxidation into ketogenic pathway strongly influence the hepatic lipid loads and glucose metabolism. Current evidence suggests that ketogenesis dispose up to two-thirds of the lipids entering the liver, and its dysregulation significantly contribute to the NAFLD pathogenesis. Moreover, ketone body administration in mice and humans shows a significant improvement in NAFLD. This review focuses on hepatic ketogenesis and its role in NAFLD pathogenesis. We review the possible mechanisms through which impaired hepatic ketogenesis may promote NAFLD progression. Finally, the review sheds light on the therapeutic implications of a ketogenic diet in NAFLD.
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28
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Kong G, Wang J, Li R, Huang Z, Wang L. Ketogenic diet ameliorates inflammation by inhibiting the NLRP3 inflammasome in osteoarthritis. Arthritis Res Ther 2022; 24:113. [PMID: 35585627 PMCID: PMC9116003 DOI: 10.1186/s13075-022-02802-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 05/10/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome has been reported to be involved in the pathological process of osteoarthritis (OA) inflammation. Here, we investigated the ketogenic diet (KD), which has been previously demonstrated to inhibit NLRP3 inflammasome activation, to elucidate its protective mechanism against OA in rats. METHODS Anterior cruciate ligament transaction (ACLT) together with partial medial meniscectomy was used to create a rat knee joint OA model. After treatment with KD or standard diet (SD) for 8 weeks, the knee specimens were obtained for testing. RESULTS The KD significantly increased the content of β-hydroxybutyrate (βOHB) in rats. Compared to the SD group, the KD significantly reduced the damage caused by OA in the articular cartilage and subchondral bone. The NLRP3 inflammasome and inflammatory cytokines interleukin-1 β (IL-1β) and IL-18 were significantly increased in the SD group compared with the sham group, while their expression was significantly decreased in rats treated with the KD. In addition, MMP13 was significantly decreased in the KD group compared to that in the SD group, while COL2 was significantly increased. CONCLUSIONS KD can protect the articular cartilage and subchondral bone in a rat OA model by inhibiting NLRP3 inflammasome activation and reducing the OA inflammatory response.
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Affiliation(s)
- Ganggang Kong
- Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Department of Spinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, No.58, Zhong Shan Er Lu, Guangzhou, 510080, China.
- Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Jinyang Wang
- Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Rong Li
- Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhiping Huang
- Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Le Wang
- Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Department of Spinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, No.58, Zhong Shan Er Lu, Guangzhou, 510080, China.
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29
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Ketone Body β-Hydroxybutyrate Prevents Myocardial Oxidative Stress in Septic Cardiomyopathy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:2513837. [PMID: 35340211 PMCID: PMC8956399 DOI: 10.1155/2022/2513837] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 01/27/2022] [Accepted: 02/15/2022] [Indexed: 02/05/2023]
Abstract
Septic cardiomyopathy is a life-threatening complication of severe sepsis and septic shock. Oxidative stress and mitochondrial dysfunction have been identified as significant abnormalities in septic cardiomyopathy. However, specific treatments are rare. This study aims to investigate the impact of β-hydroxybutyrate (β-OHB) on septic cardiomyopathy and explore the underlying mechanism(s). We found that pretreatment of D-β-hydroxybutyrate-(R)-1,3 butanediol monoester (ketone ester, 3 mg/g body weight, once daily) by gavage for three days elevated the levels of ketone bodies, especially that of β-hydroxybutyrate (β-OHB) in the circulation and mouse hearts, which exerted a protective effect against lipopolysaccharide (LPS, 20 mg/kg)-induced septic cardiomyopathy in mice. In addition, an LPS-stimulated macrophage-conditioned medium (MCM) was used to mimic the pathological process of septic cardiomyopathy. Mechanistically, β-OHB alleviated myocardial oxidative stress and improved mitochondrial respiratory function through the antioxidant FoxO3a/MT2 pathway activated via histone deacetylase (HDAC) inhibition, which ultimately enhanced heart performance in septic cardiomyopathy. Our results, therefore, suggested an unappreciated critical role of β-OHB in septic heart protection as well as highlighted the potential of β-OHB as a simple remedy for the septic cardiomyopathy population.
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30
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Zhu H, Bi D, Zhang Y, Kong C, Du J, Wu X, Wei Q, Qin H. Ketogenic diet for human diseases: the underlying mechanisms and potential for clinical implementations. Signal Transduct Target Ther 2022; 7:11. [PMID: 35034957 PMCID: PMC8761750 DOI: 10.1038/s41392-021-00831-w] [Citation(s) in RCA: 133] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 10/21/2021] [Accepted: 11/09/2021] [Indexed: 02/06/2023] Open
Abstract
The ketogenic diet (KD) is a high-fat, adequate-protein, and very-low-carbohydrate diet regimen that mimics the metabolism of the fasting state to induce the production of ketone bodies. The KD has long been established as a remarkably successful dietary approach for the treatment of intractable epilepsy and has increasingly garnered research attention rapidly in the past decade, subject to emerging evidence of the promising therapeutic potential of the KD for various diseases, besides epilepsy, from obesity to malignancies. In this review, we summarize the experimental and/or clinical evidence of the efficacy and safety of the KD in different diseases, and discuss the possible mechanisms of action based on recent advances in understanding the influence of the KD at the cellular and molecular levels. We emphasize that the KD may function through multiple mechanisms, which remain to be further elucidated. The challenges and future directions for the clinical implementation of the KD in the treatment of a spectrum of diseases have been discussed. We suggest that, with encouraging evidence of therapeutic effects and increasing insights into the mechanisms of action, randomized controlled trials should be conducted to elucidate a foundation for the clinical use of the KD.
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Affiliation(s)
- Huiyuan Zhu
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Dexi Bi
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Youhua Zhang
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Cheng Kong
- Research Institute of Intestinal Diseases, Tongji University School of Medicine, Shanghai, China
- Department of Gastrointestinal Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jiahao Du
- Research Institute of Intestinal Diseases, Tongji University School of Medicine, Shanghai, China
| | - Xiawei Wu
- Research Institute of Intestinal Diseases, Tongji University School of Medicine, Shanghai, China
- Shanghai Clinical College, Anhui Medical University, Hefei, China
| | - Qing Wei
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
| | - Huanlong Qin
- Research Institute of Intestinal Diseases, Tongji University School of Medicine, Shanghai, China.
- Department of Gastrointestinal Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
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31
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Poff AM, Moss S, Soliven M, D'Agostino DP. Ketone Supplementation: Meeting the Needs of the Brain in an Energy Crisis. Front Nutr 2022; 8:783659. [PMID: 35004814 PMCID: PMC8734638 DOI: 10.3389/fnut.2021.783659] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 12/03/2021] [Indexed: 12/11/2022] Open
Abstract
Diverse neurological disorders are associated with a deficit in brain energy metabolism, often characterized by acute or chronic glucose hypometabolism. Ketones serve as the brain's only significant alternative fuel and can even become the primary fuel in conditions of limited glucose availability. Thus, dietary supplementation with exogenous ketones represents a promising novel therapeutic strategy to help meet the energetic needs of the brain in an energy crisis. Preliminary evidence suggests ketosis induced by exogenous ketones may attenuate damage or improve cognitive and motor performance in neurological conditions such as seizure disorders, mild cognitive impairment, Alzheimer's disease, and neurotrauma.
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Affiliation(s)
- Angela M Poff
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - Sara Moss
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - Maricel Soliven
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - Dominic P D'Agostino
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
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Liu Y, Liu Q, Yang Z, Li R, Huang Z, Huang Z, Liu J, Wu X, Lin J, Wu X, Zhu Q. Trihydroxyethyl Rutin Provides Neuroprotection in Rats With Cervical Spinal Cord Hemi-Contusion. Front Neurosci 2021; 15:759325. [PMID: 34867167 PMCID: PMC8637531 DOI: 10.3389/fnins.2021.759325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 10/18/2021] [Indexed: 12/03/2022] Open
Abstract
Objective: To investigate the neuroprotective effects of trihydroxyethyl rutin in rats with cervical spinal cord hemi-contusion. Methods: Adult male Sprague–Dawley rats were subjected to hemi-contusion at a stroke depth of 1.2 mm, and then intraperitoneally injected with 50 or 100 mg/kg trihydroxyethyl rutin per day for 12 weeks (T50 and T100 groups, respectively). Changes in somatosensory evoked potentials (SEPs), motor evoked potentials (MEPs), and behavior were continuously monitored. At 12 weeks post-injury, immunohistochemical staining was performed to assess changes in cervical spinal cord microvascular morphology. Magnetic resonance imaging (MRI) scans were performed to examine end-stage injury in the cervical spinal cord, and Eriochrome cyanine-stained slices of spinal cord tissue were evaluated for injury. Results: There were no significant differences in biomechanical parameters among the spinal cord injury, T50 and T100 rat groups. At 3 days-post-injury, there was a significant decrease in grip strength. At 12 weeks post-injury, grip strength recovery was significantly better in the T50 and T100 groups than in the injury group. Compared with the injury group, the total limb placement frequency was significantly higher in the T50 group at 2, 4, 6, 10, and 12 weeks post-injury and in the T100 group at 2, 6, 8, and 10 weeks post-injury. Ipsilateral SEPs and MEPs were dynamic, increasing in latency and decreasing in amplitude in the injury compared with sham group. MRI scanning demonstrated that the coronal, sagittal, and transversal lesion areas were smaller in the T50 and T100 groups than in the injury group. Microvascular density showed a greater reduction in the injury group compared with the T50 and T100 groups. Eriochrome cyanine staining showed that the ipsilateral side, residual parenchyma, and gray matter areas were larger in the T50 and T100 groups than in the injury group. Conclusion: Trihydroxyethyl rutin exhibits robust neuroprotective effects, improving limb motor function and nerve electrophysiological parameters after spinal cord injury, maintaining microvascular density, and reducing the area of injury and degree of demyelination.
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Affiliation(s)
- Yapu Liu
- Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Spinal Surgery, Second Affiliated Hospital of Luohe Medical College, Luohe, China
| | - Qi Liu
- Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhou Yang
- Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Rong Li
- Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhiping Huang
- Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zucheng Huang
- Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Junhao Liu
- Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiuhua Wu
- Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Junyu Lin
- Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoliang Wu
- Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qingan Zhu
- Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Sridharan B, Lee MJ. Ketogenic diet: A promising neuroprotective composition for managing Alzheimer's diseases and its pathological mechanisms. Curr Mol Med 2021; 22:640-656. [PMID: 34607541 DOI: 10.2174/1566524021666211004104703] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 08/03/2021] [Accepted: 08/05/2021] [Indexed: 11/22/2022]
Abstract
Ketogenic diet and ketone bodies gained significant attention in recent years due to their ability to influence the specific energy metabolism and restoration of mitochondrial homeostasis that can help in hindering the progression of many metabolic diseases including diabetes and neurodegenerative diseases. Ketogenic diet consists of high fat and low carbohydrate contents which makes the body glucose deprived and rely on alternative sources (ketone bodies) for energy. It has been initially designed and supplemented for the treatment of epilepsy and later its influence on many energy-deriving biochemical pathways made it a highly sorted food supplement for many metabolic diseases and even by healthy individuals for body building and calorie restriction. Among the reported therapeutic action over a range of diseases, neurodegenerative disorders especially Alzheimer's disease gained the attention of many researchers and clinicians because of its potency and its easier supplementation as a food additive. Complex pathology and multiple influencing factors of Alzheimer's disease make exploration of its therapeutic strategies a demanding task. It was a common phenomenon that energy deprivation in neurological disorders including Alzheimer's disease, to progress rapidly. The ability of ketone bodies to stabilize the mitochondrial energy metabolism makes it a suitable intervening agent. In this review, we will discuss various research progress made with regards to ketone bodies/ketogenic diet for management of Alzheimer's disease and elaborate in detail about the mechanisms that are influenced during their therapeutic action.
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Affiliation(s)
- Badrinathan Sridharan
- Department of Applied Chemistry, Chaoyang University of Technology, 168 Jifeng East Road, Taichung. Taiwan
| | - Meng-Jen Lee
- Department of Applied Chemistry, Chaoyang University of Technology, 168 Jifeng East Road, Taichung. Taiwan
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Bal E, Hanalioğlu Ş, Apaydın AS, Bal C, Şenat A, Öcal BG, Bahadır B, Türkoğlu ÖF. Anti-inflammatory and antioxidative effects of genistein in a model of spinal cord injury in rats. ASIAN BIOMED 2021; 15:233-243. [PMID: 37551326 PMCID: PMC10388775 DOI: 10.2478/abm-2021-0029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Background Neurological damage from spinal cord injury (SCI) is a result of primary mechanical injury and secondary damage from oxidative stress and neuroinflammation. Although genistein has been shown to have potent antioxidant and anti-inflammatory effects in studies of brain injury, its effect on secondary damage in SCI has remained unknown. Objective To determine effects of genistein in a model of SCI in rats. Methods We divided 21 rats evenly into 3 groups, a control group, in which only a laminectomy was performed; a trauma group in which SCI was induced; and a genistein group in which genistein was administered subcutaneously after SCI. The rats were assessed using a Basso-Beattie and Bresnahan functional score at the 12th hour and on the 1st, 3rd, 5th, and 7th days. Biochemical analyses were conducted at the same time points to determine the serum levels of catalase, ischemia-modified albumin (IMA), disulfide (SS), total thiol (TT), native thiol (NT), disulfide/total thiol (SS/TT), and native thiol/total thiol (NT/TT). Total oxidant and antioxidant capacity, and oxidative stress index were determined in spinal cord tissue obtained on the 7th day together with immunohistochemistry for cyclooxygenase-2 levels. Result Catalase activity on the 7th day was significantly (P = 0.001) higher in the genistein-treated rats than in other groups, and IMA levels became stable earlier (3rd day) in the genistein group. SS values were significantly (P = 0.004) lower in the genistein group. NT/TT ratio were significantly (P = 0.049) higher in the genistein-treated rats on the 7th day. Conclusion Genistein has antioxidant, anti-inflammatory, and protective effects in a model of SCI in rats and warrants further study.
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Affiliation(s)
- Ercan Bal
- Department of Neurosurgery, Ankara Yıldırım Beyazıt University, School of Medicine, Ankara06760, Turkey
- Department of Neurosurgery, Ankara City Hospital, Ankara06800, Turkey
| | - Şahin Hanalioğlu
- Department of Neurosurgery, Ankara Hacettepei, University, School of Medicine, Ankara06230, Turkey
| | | | - Ceylan Bal
- Department of Neurosurgery, Ankara Yıldırım Beyazıt University, School of Medicine, Ankara06760, Turkey
| | - Almila Şenat
- Department of Neurosurgery, Ankara Yıldırım Beyazıt University, School of Medicine, Ankara06760, Turkey
| | - Berrak Gümüşkaya Öcal
- Department of Pathology, Ankara Yıldırım Beyazıt University, School of Medicine, Ankara06760, Turkey
| | - Burak Bahadır
- Department of Neurosurgery, Ankara City Hospital, Ankara06800, Turkey
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Ketogenesis controls mitochondrial gene expression and rescues mitochondrial bioenergetics after cervical spinal cord injury in rats. Sci Rep 2021; 11:16359. [PMID: 34381166 PMCID: PMC8357839 DOI: 10.1038/s41598-021-96003-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 07/29/2021] [Indexed: 11/08/2022] Open
Abstract
A better understanding of the secondary injury mechanisms that occur after traumatic spinal cord injury (SCI) is essential for the development of novel neuroprotective strategies linked to the restoration of metabolic deficits. We and others have shown that Ketogenic diet (KD), a high fat, moderate in proteins and low in carbohydrates is neuroprotective and improves behavioural outcomes in rats with acute SCI. Ketones are alternative fuels for mitochondrial ATP generation, and can modulate signaling pathways via targeting specific receptors. Here, we demonstrate that ad libitum administration of KD for 7 days after SCI rescued mitochondrial respiratory capacity, increased parameters of mitochondrial biogenesis, affected the regulation of mitochondrial-related genes, and activated the NRF2-dependent antioxidant pathway. This study demonstrates that KD improves post-SCI metabolism by rescuing mitochondrial function and supports the potential of KD for treatment of acute SCI in humans.
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Zeng H, Lu Y, Huang MJ, Yang YY, Xing HY, Liu XX, Zhou MW. Ketogenic diet-mediated steroid metabolism reprogramming improves the immune microenvironment and myelin growth in spinal cord injury rats according to gene and co-expression network analyses. Aging (Albany NY) 2021; 13:12973-12995. [PMID: 33962394 PMCID: PMC8148504 DOI: 10.18632/aging.202969] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 03/27/2021] [Indexed: 01/08/2023]
Abstract
The ketogenic diet has been widely used in the treatment of various nervous system and metabolic-related diseases. Our previous research found that a ketogenic diet exerts a protective effect and promotes functional recovery after spinal cord injury. However, the mechanism of action is still unclear. In this study, different dietary feeding methods were used, and myelin expression and gene level changes were detected among different groups. We established 15 RNA-seq cDNA libraries from among 4 different groups. First, KEGG pathway enrichment of upregulated differentially expressed genes and gene set enrichment analysis of the ketogenic diet and normal diet groups indicated that a ketogenic diet significantly improved the steroid anabolic pathway in rats with spinal cord injury. Through cluster analysis, protein-protein interaction analysis and visualization of iPath metabolic pathways, it was determined that Sqle, Sc5d, Cyp51, Dhcr24, Msmo1, Hsd17b7, and Fdft1 expression changed significantly. Second, through weighted gene co-expression network analysis showed that rats fed a ketogenic diet showed a significant reduction in the expression of genes involved in immune-related pathways, including those associated with immunity and infectious diseases. A ketogenic diet may improve the immune microenvironment and myelin growth in rats with spinal cord injury through reprogramming of steroid metabolism.
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Affiliation(s)
- Hong Zeng
- Department of Rehabilitation Medicine, Peking University Third Hospital, Beijing 100191, China.,Department of Rehabilitation Medicine, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Huangpu 200011, China
| | - Yao Lu
- Department of Rehabilitation Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Meng-Jie Huang
- Department of Rehabilitation Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Yan-Yan Yang
- Department of Rehabilitation Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Hua-Yi Xing
- Department of Rehabilitation Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Xiao-Xie Liu
- Department of Rehabilitation Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Mou-Wang Zhou
- Department of Rehabilitation Medicine, Peking University Third Hospital, Beijing 100191, China
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Zhou J, Liu Q, Yang Z, Xie C, Ling L, Hu H, Cao Y, Huang Y, Hua Y. Rutin maintains redox balance to relieve oxidative stress induced by TBHP in nucleus pulposus cells. In Vitro Cell Dev Biol Anim 2021; 57:448-456. [PMID: 33909255 DOI: 10.1007/s11626-021-00581-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Accepted: 04/06/2021] [Indexed: 10/21/2022]
Abstract
Rutin is well known for its anti-inflammatory and antioxidant properties against oxidative stress. However, its protective function in nucleus pulposus cells (NPCs) remains unclear. This study was aimed to explore the effects of rutin on oxidative stress in NPCs. Primary NPCs were obtained from 1-mo-old SD rats. The NPCs were treated with tert-butyl hydrogen peroxide (TBHP) to obtain the oxidative stress, and different concentrations of rutin were used to observe its influence on the oxidative stress in NPCs. Fluorescent probe DCFH-DA was used to detect reactive oxide species (ROS). The antioxidant proteins and genes of heat shock protein 70 (HSP70), manganese superoxide dismutase (Mn-SOD), catalase, aggrecan and collagen II in NPCs were measured by western blot and real-time PCR. With the stimulation of TBHP, the content of ROS in NPCs increased significantly and showed solubility correlation. Rutin effectively reduced the accumulation of ROS in a dose-dependent manner. The antioxidant proteins of HSP70, Mn-SOD, and catalase and the matrix proteins of aggrecan and collagen II decreased remarkably with the stimulation of TBHP, while the matrix metalloproteinase-13 (MMP-13) significantly increased after TBHP intervention. Rutin boosted the expressions of the HSP70, Mn-SOD, and catalase, elevated the contents of aggrecan and collagen II, and inhibited the expression of MMP-13 in NPCs. The findings of this study suggested that rutin is able to reverse oxidative stress and maintain cellular function of NPCs, and it was indicated that rutin could be a possible therapeutic option for intervertebral disc degeneration.
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Affiliation(s)
- Jian Zhou
- Department of Spine and Joint Surgery, Nanchang Hongdu Hospital of TCM, Nanchang, Jiangxi, China
| | - Qi Liu
- Department of Orthopaedic Surgery, The Second Affiliated Hospital of Guangzhou Medical University, 250 Chang-gang-dong Road, Guangzhou, 510260, Guangdong, China.
| | - Zhou Yang
- Department of Orthopaedic Surgery, Southern University of Science and Technology Hospital, Shenzhen, China
| | - Chuhai Xie
- Department of Orthopaedic Surgery, The Second Affiliated Hospital of Guangzhou Medical University, 250 Chang-gang-dong Road, Guangzhou, 510260, Guangdong, China
| | - Long Ling
- Department of Orthopaedic Surgery, The Second Affiliated Hospital of Guangzhou Medical University, 250 Chang-gang-dong Road, Guangzhou, 510260, Guangdong, China
| | - Hailan Hu
- Department of Orthopaedic Surgery, The Second Affiliated Hospital of Guangzhou Medical University, 250 Chang-gang-dong Road, Guangzhou, 510260, Guangdong, China
| | - Yanming Cao
- Department of Orthopaedic Surgery, The Second Affiliated Hospital of Guangzhou Medical University, 250 Chang-gang-dong Road, Guangzhou, 510260, Guangdong, China
| | - Yan Huang
- Department of Orthopaedic Surgery, The Second Affiliated Hospital of Guangzhou Medical University, 250 Chang-gang-dong Road, Guangzhou, 510260, Guangdong, China
| | - Yue Hua
- School of Traditional Chinese Medicine, Southern Medical University, 1063 Shatai Road, Guangzhou, 510515, Guangdong, China.
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Zhang N, Liu C, Zhang R, Jin L, Yin X, Zheng X, Siebert HC, Li Y, Wang Z, Loers G, Petridis AK. Amelioration of clinical course and demyelination in the cuprizone mouse model in relation to ketogenic diet. Food Funct 2021; 11:5647-5663. [PMID: 32539054 DOI: 10.1039/c9fo02944c] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Ketogenic diet (KD) is defined as a high-fat, low-carbohydrate diet with appropriate amounts of protein, which has broad neuroprotective effects. However, the mechanisms of ameliorating the demyelination and of the neuroprotective effects of KD have not yet been completely elucidated. Therefore, the present study investigated the protection mechanism of KD treatment in the cuprizone (bis-cyclohexanone oxalydihydrazone, CPZ)-induced demyelination mice model, with special emphasis on neuroinflammation. After the KD treatment, an increased ketone body level in the blood of mice was detected, and a significant increase in the distance traveled within the central area was observed in the open field test, which reflected the increased exploration and decreased anxiety of mice that received CPZ. The results of Luxol fast blue and myelin basic protein (MBP) immunohistochemistry staining for the evaluation of the myelin content within the corpus callosum revealed a noticeable increase in the number of myelinated fibers and myelin score after KD administration in these animals. Concomitant, the protein expressions of glial fibrillary acidic protein (GFAP, an astrocyte marker), ionized calcium-binding adaptor molecule 1 (Iba-1, a microglial marker), CD68 (an activated microglia marker) and CD16/32 (a M1 microglial marker) were down-regulated, while the expression of oligodendrocyte lineage transcription factor 2 (OLIG2, an oligodendrocyte precursor cells marker) was up-regulated by the KD treatment. In addition, the KD treatment not only reduced the level of the C-X-C motif chemokine 10 (CXCL10), which is correlated to the recruitment of activated microglia, but also inhibited the production of proinflammatory cytokines, including interleukin 1β (IL-1β) and tumor necrosis factor-α (TNF-α), which are closely correlated to the M1 phenotype microglia. It is noteworthy, that the expression levels of histone deacetylase 3 (HADC3) and nod-like receptor pyrin domain containing 3 (NLRP3) significantly decreased after KD administration. In conclusion, these data demonstrate that KD decreased the reactive astrocytes and activated the microglia in the corpus callosum, and that KD inhibited the HADC3 and NLRP3 inflammasome signaling pathway in CPZ-treated mice. This suggests that the inhibition of the HADC3 and NLRP3 signaling pathway may be a novel mechanism by which KD exerts its protective actions for the treatment of demyelinating diseases.
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Affiliation(s)
- Ning Zhang
- Institute of Biopharmaceutical Research, Liaocheng University, Liaocheng, Shandong 252000, China.
| | - Chunhong Liu
- Institute of Biopharmaceutical Research, Liaocheng University, Liaocheng, Shandong 252000, China.
| | - Ruiyan Zhang
- Institute of Biopharmaceutical Research, Liaocheng University, Liaocheng, Shandong 252000, China.
| | - Li Jin
- Institute of Biopharmaceutical Research, Liaocheng University, Liaocheng, Shandong 252000, China.
| | - Xiaohan Yin
- Institute of Biopharmaceutical Research, Liaocheng University, Liaocheng, Shandong 252000, China.
| | - Xuexing Zheng
- Department of Virology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
| | - Hans-Christian Siebert
- RI-B-NT - Research Institute of Bioinformatics and Nanotechnology, Schauenburgerstr. 116, 24118 Kiel, Germany
| | - Yubao Li
- College of agriculture, Liaocheng University, Liaocheng, Shandong 252000, China
| | - Zhengping Wang
- Institute of Biopharmaceutical Research, Liaocheng University, Liaocheng, Shandong 252000, China.
| | - Gabriele Loers
- Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, University of Hamburg, Falkenried 94, 20251 Hamburg, Germany
| | - Athanasios K Petridis
- Neurosurgical Department, Heinrich Heine University of Düsseldorf, Moorenstraße 5, 40255 Düsseldorf, Germany
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Liu Y, Wei X, Wu M, Xu J, Xu B, Kang L. Cardioprotective Roles of β-Hydroxybutyrate Against Doxorubicin Induced Cardiotoxicity. Front Pharmacol 2021; 11:603596. [PMID: 33935690 PMCID: PMC8082360 DOI: 10.3389/fphar.2020.603596] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 11/30/2020] [Indexed: 12/21/2022] Open
Abstract
Background: β-Hydroxybutyrate (BHB) is produced by fatty acid oxidation in the liver under the fasting state and confirmed to play a cardioprotective role in ischemia and hypertensive settings. Doxorubicin (DOX) is an effective chemotherapeutic drug, but limited by serious irreversible cardiotoxicity. However, whether BHB can protect from DOX-induced cardiotoxicity remains unknown. Methods and Results: C57BL/6 mice were intraperitoneally injected with DOX to induce cardiac toxicity and intragastrically administered into BHB for treatment. They were randomly divided into three groups, namely a sham group (Sham), a doxorubicin group (DOX), and a doxorubicin+β-Hydroxybutyrate group (DOX + BHB). Echocardiography and pathological staining were performed to evaluate cardiac function and fibrosis. H9c2 cardiomyocyte was treated with DOX or BHB for in vitro experiments. Cell apoptosis and ROS were determined by flow cytometry. BHB significantly restored DOX-induced cardiac function decline and partially prevented cardiac reverse remodeling, characterized by increased cell size and decreased fibrosis. In vitro, BHB treatment decreased cellular injury and apoptosis. Also, BHB alleviated oxidative stress level and increased mitochondrial membrane potential. Conclusion: Our results suggested that BHB could protected from DOX-induced cardiotoxicity by inhibiting cell apoptosis and oxidative stress and maintaining mitochondrial membrane integrity.
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Affiliation(s)
- Yihai Liu
- Department of Cardiology, Nanjing Drum Tower Hospital as Affiliated Drum Tower Hospital, Nanjing, China
| | - Xuan Wei
- Department of Cardiology, Nanjing Drum Tower Hospital as Affiliated Drum Tower Hospital, Nanjing, China
| | - Mingyue Wu
- Department of Cardiology, Nanjing Drum Tower Hospital as Affiliated Drum Tower Hospital, Nanjing, China
| | - Jiamin Xu
- Department of Cardiology, Nanjing Drum Tower Hospital as Affiliated Drum Tower Hospital, Nanjing, China
| | - Biao Xu
- Department of Cardiology, Nanjing Drum Tower Hospital as Affiliated Drum Tower Hospital, Nanjing, China
| | - Lina Kang
- Department of Cardiology, Nanjing Drum Tower Hospital as Affiliated Drum Tower Hospital, Nanjing, China
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NLRP3 as a sensor of metabolism gone awry. Curr Opin Biotechnol 2021; 68:300-309. [PMID: 33862489 DOI: 10.1016/j.copbio.2021.03.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 03/25/2021] [Accepted: 03/29/2021] [Indexed: 12/28/2022]
Abstract
The NLRP3 inflammasome is an important player in innate immunity and pathogenic inflammation. Numerous studies have implicated it in sensing endogenous danger signals, yet the precise mechanisms remain unknown. Here, we review the current knowledge on the organismal and cellular metabolic triggers engaging NLRP3, and the mechanisms involved in integrating the diverse signals.
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Kwak SE, Bae JH, Lee JH, Shin HE, Zhang D, Cho SC, Song W. Effects of exercise-induced beta-hydroxybutyrate on muscle function and cognitive function. Physiol Rep 2021; 9:e14497. [PMID: 33547753 PMCID: PMC7865404 DOI: 10.14814/phy2.14497] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 05/31/2020] [Accepted: 06/01/2020] [Indexed: 12/14/2022] Open
Abstract
Recent studies have shown that exercise improves skeletal muscle and cognitive function by stimulating the secretion of numerous molecules. In particular, previous studies have suggested that exercise-induced beta-hydroxybutyrate (BHB) release might improve skeletal muscle and cognitive function, but to date these studies have been limited to cell and animal models. Therefore, we aimed to determine how an exercise-induced increase in BHB affects skeletal muscle and cognitive function at a cellular level, in an animal model, and in humans. The effects of BHB on skeletal muscle and cognitive function were determined by treating C2C12 and C6 cell lines with BHB, and by measuring the skeletal muscle and serum BHB concentrations in aged mice after endurance or resistance exercise. In addition, serum BHB concentration was measured before and after high-speed band exercise in elderly people, and its relationships with muscle and cognitive function were analyzed. We found that BHB increased cell viability and brain-derived neurotrophic factor expression level in C6 cells, and endurance exercise, but not resistance exercise, increased the muscle BHB concentration in aged mice. Furthermore, the BHB concentration was positively related to skeletal muscle and cognitive function. Exercise did not increase the serum BHB concentration in the elderly people and BHB did not correlate with cognitive function, but after excluding the five people with the highest preexisting serum concentrations of BHB, the BHB concentrations of the remaining participants were increased by exercise, and the concentration showed a tendency toward a positive correlation with cognitive function. Thus, the BHB released by skeletal muscle following endurance exercise may improve muscle and cognitive function in animals and humans.
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Affiliation(s)
- Seong Eun Kwak
- Institute of Sport ScienceSeoul National UniversitySeoulKorea
| | - Jun Hyun Bae
- Institute of Sport ScienceSeoul National UniversitySeoulKorea
| | - Ji Heun Lee
- Institute of Sport ScienceSeoul National UniversitySeoulKorea
| | - Hyung Eun Shin
- Institute of Sport ScienceSeoul National UniversitySeoulKorea
| | - DiDi Zhang
- Institute of Sport ScienceSeoul National UniversitySeoulKorea
| | | | - Wook Song
- Institute of Sport ScienceSeoul National UniversitySeoulKorea
- Institue on AgingSeoul National UniversitySeoulKorea
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Kong G, Liu J, Li R, Lin J, Huang Z, Yang Z, Wu X, Huang Z, Zhu Q, Wu X. Ketone Metabolite β-Hydroxybutyrate Ameliorates Inflammation After Spinal Cord Injury by Inhibiting the NLRP3 Inflammasome. Neurochem Res 2021; 46:213-229. [PMID: 33108630 DOI: 10.1007/s11064-020-03156-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 09/18/2020] [Accepted: 10/21/2020] [Indexed: 12/18/2022]
Abstract
Ketogenic diet (KD) has been shown to be beneficial in a range of neurological disorders, with ketone metabolite β-hydroxybutyrate (βOHB) reported to block the nucleotide oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in bone marrow-derived macrophages. In this study, we show that pretreatment with KD or in situ βOHB suppressed macrophages/microglia activation and the overproduction of inflammatory cytokines, while KD downregulated the expression of NLRP3 inflammasome. Moreover, KD promoted macrophages/microglia transformation from the M1 phenotype to the M2a phenotype following spinal cord injury (SCI) in the in vivo study. Rats in the KD group demonstrated improved behavioral and electrophysiological recovery after SCI when compared to those rats in the standard diet group. The in vitro study performed on BV2 cells indicated that βOHB inhibited an LPS+ATP-induced inflammatory response and decreased NLRP3 protein levels. Our data demonstrated that pretreatment with KD attenuated neuroinflammation following SCI, probably by inhibiting NLRP3 inflammasome and shifting the activation state of macrophages/microglia from the M1 to the M2a phenotype. Therefore, the ketone metabolite βOHB might provide a potential future therapeutic strategy for SCI.
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Affiliation(s)
- Ganggang Kong
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, China
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Junhao Liu
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, China
| | - Rong Li
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, China
| | - Junyu Lin
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, China
| | - Zucheng Huang
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, China
| | - Zhou Yang
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, China
| | - Xiuhua Wu
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, China
| | - Zhiping Huang
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, China
| | - Qingan Zhu
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, China.
| | - Xiaoliang Wu
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, China.
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Ruskin DN, Sturdevant IC, Wyss LS, Masino SA. Ketogenic diet effects on inflammatory allodynia and ongoing pain in rodents. Sci Rep 2021; 11:725. [PMID: 33436956 PMCID: PMC7804255 DOI: 10.1038/s41598-020-80727-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Accepted: 12/22/2020] [Indexed: 12/31/2022] Open
Abstract
Ketogenic diets are very low carbohydrate, high fat, moderate protein diets used to treat medication-resistant epilepsy. Growing evidence suggests that one of the ketogenic diet’s main mechanisms of action is reducing inflammation. Here, we examined the diet’s effects on experimental inflammatory pain in rodent models. Young adult rats and mice were placed on the ketogenic diet or maintained on control diet. After 3–4 weeks on their respective diets, complete Freund’s adjuvant (CFA) was injected in one hindpaw to induce inflammation; the contralateral paw was used as the control. Tactile sensitivity (von Frey) and indicators of spontaneous pain were quantified before and after CFA injection. Ketogenic diet treatment significantly reduced tactile allodynia in both rats and mice, though with a species-specific time course. There was a strong trend to reduced spontaneous pain in rats but not mice. These data suggest that ketogenic diets or other ketogenic treatments might be useful treatments for conditions involving inflammatory pain.
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Affiliation(s)
- David N Ruskin
- Neuroscience Program and Department of Psychology, Trinity College, 300 Summit St., Hartford, CT, 06106, USA.
| | - Isabella C Sturdevant
- Neuroscience Program and Department of Psychology, Trinity College, 300 Summit St., Hartford, CT, 06106, USA
| | - Livia S Wyss
- Neuroscience Program and Department of Psychology, Trinity College, 300 Summit St., Hartford, CT, 06106, USA
| | - Susan A Masino
- Neuroscience Program and Department of Psychology, Trinity College, 300 Summit St., Hartford, CT, 06106, USA
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Yarar-Fisher C, Li J, Womack ED, Alharbi A, Seira O, Kolehmainen KL, Plunet WT, Alaeiilkhchi N, Tetzlaff W. Ketogenic regimens for acute neurotraumatic events. Curr Opin Biotechnol 2021; 70:68-74. [PMID: 33445134 DOI: 10.1016/j.copbio.2020.12.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 11/14/2020] [Accepted: 12/07/2020] [Indexed: 12/20/2022]
Abstract
Dietary modification would be the most translatable, cost-efficient, and, likely, the safest approach available that can reduce the reliance on pharmaceutical treatments for treating acute or chronic neurological disorders. A wide variety of evidence suggests that the ketogenic diet (KD) could have beneficial effects in acute traumatic events, such as spinal cord injury and traumatic brain injury. Review of existing human and animal studies revealed that KD can improve motor neuro-recovery, gray matter sparing, pain thresholds, and neuroinflammation and decrease depression. Although the exact mechanism by which the KD provides neuroprotection is not fully understood, its effects on cellular energetics, mitochondria function and inflammation are likely to have a role.
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Affiliation(s)
- Ceren Yarar-Fisher
- Department of Physical Medicine and Rehabilitation, School of Medicine, The University of Alabama at Birmingham, USA.
| | - Jia Li
- Department of Physical Medicine and Rehabilitation, School of Medicine, The University of Alabama at Birmingham, USA
| | - Erika D Womack
- Department of Physical Medicine and Rehabilitation, School of Medicine, The University of Alabama at Birmingham, USA
| | - Amal Alharbi
- Department of Physical Medicine and Rehabilitation, School of Medicine, The University of Alabama at Birmingham, USA; Graduate Program in School of Health Professions, The University of Alabama at Birmingham, 1716 9th Avenue South Birmingham, AL 35294, USA
| | - Oscar Seira
- International Collaboration on Repair Discoveries, University of British Columbia, Blusson Spinal Cord Centre, 818 West 10th Avenue, Vancouver, BC, V5Z 1M9, Canada; Department of Zoology, University of British Columbia, 4200 - 6270 University Blvd, Vancouver, BC V6T 1Z4, Canada
| | - Kathleen L Kolehmainen
- International Collaboration on Repair Discoveries, University of British Columbia, Blusson Spinal Cord Centre, 818 West 10th Avenue, Vancouver, BC, V5Z 1M9, Canada; Graduate Program in Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada
| | - Ward T Plunet
- International Collaboration on Repair Discoveries, University of British Columbia, Blusson Spinal Cord Centre, 818 West 10th Avenue, Vancouver, BC, V5Z 1M9, Canada
| | - Nima Alaeiilkhchi
- International Collaboration on Repair Discoveries, University of British Columbia, Blusson Spinal Cord Centre, 818 West 10th Avenue, Vancouver, BC, V5Z 1M9, Canada; Graduate Program in Neuroscience, University of British Columbia, Canada
| | - Wolfram Tetzlaff
- International Collaboration on Repair Discoveries, University of British Columbia, Blusson Spinal Cord Centre, 818 West 10th Avenue, Vancouver, BC, V5Z 1M9, Canada
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45
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Sayadi JJ, Sayadi L, Satteson E, Chopan M. Nerve injury and repair in a ketogenic milieu: A systematic review of traumatic injuries to the spinal cord and peripheral nervous tissue. PLoS One 2021; 16:e0244244. [PMID: 33395427 PMCID: PMC7781473 DOI: 10.1371/journal.pone.0244244] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 12/04/2020] [Indexed: 12/26/2022] Open
Abstract
Dietary interventions such as intermittent fasting and the ketogenic diet have demonstrated neuroprotective effects in various models of neurological insult. However, there has been a lack of evaluation of these interventions from a surgical perspective despite their potential to augment reparative processes that occur following nerve injury. Thus, we sought to analyze the effects of these dietary regimens on nerve regeneration and repair by critical appraisal of the literature. Following PRISMA guidelines, a systematic review was performed to identify studies published between 1950 and 2020 that examined the impact of either the ketogenic diet or intermittent fasting on traumatic injuries to the spinal cord or peripheral nerves. Study characteristics and outcomes were analyzed for each included article. A total of 1,890 articles were reviewed, of which 11 studies met inclusion criteria. Each of these articles was then assessed based on a variety of qualitative parameters, including type of injury, diet composition, timing, duration, and outcome. In total, seven articles examined the ketogenic diet, while four examined intermittent fasting. Only three studies examined peripheral nerves. Neuroprotective effects manifested as either improved histological or functional benefits in most of the included studies. Overall, we conclude that intermittent fasting and the ketogenic diet may promote neuroprotection and facilitate the regeneration and repair of nerve fibers following injury; however, lack of consistency between the studies in terms of animal models, diet compositions, and timing of dietary interventions preclude synthesis of their outcomes as a whole.
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Affiliation(s)
- Jamasb Joshua Sayadi
- Stanford University School of Medicine, Stanford, California, United States of America
| | - Lohrasb Sayadi
- Department of Plastic Surgery, University of California, Irvine, California, United States of America
| | - Ellen Satteson
- Division of Plastic and Reconstructive Surgery, Department of Surgery, University of Florida Health, Gainesville, Florida, United States of America
| | - Mustafa Chopan
- Division of Plastic and Reconstructive Surgery, Department of Surgery, University of Florida Health, Gainesville, Florida, United States of America
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Wang J, Chen Y, Chen L, Duan Y, Kuang X, Peng Z, Li C, Li Y, Xiao Y, Jin H, Tan Q, Zhang S, Zhu B, Tang Y. EGCG modulates PKD1 and ferroptosis to promote recovery in ST rats. Transl Neurosci 2020; 11:173-181. [PMID: 33335755 PMCID: PMC7712186 DOI: 10.1515/tnsci-2020-0119] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 04/25/2020] [Accepted: 04/28/2020] [Indexed: 12/18/2022] Open
Abstract
Background Spinal cord injury (SCI) causes devastating loss of function and neuronal death without effective treatment. (−)-Epigallocatechin-3-gallate (EGCG) has antioxidant properties and plays an essential role in the nervous system. However, the underlying mechanism by which EGCG promotes neuronal survival and functional recovery in complete spinal cord transection (ST) remains unclear. Methods In the present study, we established primary cerebellar granule neurons (CGNs) and a T10 ST rat model to investigate the antioxidant effects of EGCG via its modulation of protein kinase D1 (PKD1) phosphorylation and inhibition of ferroptosis. Results We revealed that EGCG significantly increased the cell survival rate of CGNs and PKD1 phosphorylation levels in comparison to the vehicle control, with a maximal effect observed at 50 µM. EGCG upregulated PKD1 phosphorylation levels and inhibited ferroptosis to reduce the cell death of CGNs under oxidative stress and to promote functional recovery and ERK phosphorylation in rats following complete ST. Conclusion Together, these results lay the foundation for EGCG as a novel strategy for the treatment of SCI related to PKD1 phosphorylation and ferroptosis.
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Affiliation(s)
- Jianjun Wang
- Affiliated Hospital, Xiangnan University, Chenzhou 423000, Hunan Province, China.,Department of Clinical, Xiangnan University, Chenzhou 423000, Hunan Province, China
| | - Ying Chen
- Jilong Union School of Hengnan County, Hengyang 421000, Hunan Province, China
| | - Long Chen
- Department of Clinical, Xiangnan University, Chenzhou 423000, Hunan Province, China
| | - Yanzhi Duan
- Department of Clinical, Xiangnan University, Chenzhou 423000, Hunan Province, China
| | - Xuejun Kuang
- Affiliated Hospital, Xiangnan University, Chenzhou 423000, Hunan Province, China
| | - Zhao Peng
- Affiliated Hospital, Xiangnan University, Chenzhou 423000, Hunan Province, China
| | - Conghui Li
- Affiliated Hospital, Xiangnan University, Chenzhou 423000, Hunan Province, China
| | - Yuanhao Li
- Department of Clinical, Xiangnan University, Chenzhou 423000, Hunan Province, China
| | - Yang Xiao
- Department of Clinical, Xiangnan University, Chenzhou 423000, Hunan Province, China
| | - Hao Jin
- Department of Clinical, Xiangnan University, Chenzhou 423000, Hunan Province, China
| | - Quandan Tan
- Department of Clinical, Xiangnan University, Chenzhou 423000, Hunan Province, China
| | - Shaofeng Zhang
- Department of Clinical, Xiangnan University, Chenzhou 423000, Hunan Province, China
| | - Bopei Zhu
- Department of Clinical, Xiangnan University, Chenzhou 423000, Hunan Province, China
| | - Yinjuan Tang
- Department of Basic Medical Sciences, Xiangnan University, Chenzhou 423000, Hunan Province, China
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Stubbs BJ, Koutnik AP, Goldberg EL, Upadhyay V, Turnbaugh PJ, Verdin E, Newman JC. Investigating Ketone Bodies as Immunometabolic Countermeasures against Respiratory Viral Infections. MED 2020; 1:43-65. [PMID: 32838361 PMCID: PMC7362813 DOI: 10.1016/j.medj.2020.06.008] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Respiratory viral infections remain a scourge, with seasonal influenza infecting millions and killing many thousands annually and viral pandemics, such as COVID-19, recurring every decade. Age, cardiovascular disease, and diabetes mellitus are risk factors for severe disease and death from viral infection. Immunometabolic therapies for these populations hold promise to reduce the risks of death and disability. Such interventions have pleiotropic effects that might not only target the virus itself but also enhance supportive care to reduce cardiopulmonary complications, improve cognitive resilience, and facilitate functional recovery. Ketone bodies are endogenous metabolites that maintain cellular energy but also feature drug-like signaling activities that affect immune activity, metabolism, and epigenetics. Here, we provide an overview of ketone body biology relevant to respiratory viral infection, focusing on influenza A and severe acute respiratory syndrome (SARS)-CoV-2, and discuss the opportunities, risks, and research gaps in the study of exogenous ketone bodies as novel immunometabolic interventions in these diseases.
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Affiliation(s)
| | - Andrew P Koutnik
- Institute for Human and Machine Cognition, Pensacola, FL, USA
- Department of Molecular Pharmacology and Physiology, USF, Tampa, FL, USA
| | | | - Vaibhav Upadhyay
- Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, UCSF, San Francisco, CA, USA
- Department of Microbiology and Immunology, UCSF, San Francisco, CA, USA
| | - Peter J Turnbaugh
- Department of Microbiology and Immunology, UCSF, San Francisco, CA, USA
| | - Eric Verdin
- Buck Institute for Research on Aging, Novato, CA, USA
| | - John C Newman
- Buck Institute for Research on Aging, Novato, CA, USA
- Division of Geriatrics, UCSF, San Francisco, CA, USA
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48
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Lin J, Huang Z, Liu J, Huang Z, Liu Y, Liu Q, Yang Z, Li R, Wu X, Shi Z, Zhu Q, Wu X. Neuroprotective Effect of Ketone Metabolism on Inhibiting Inflammatory Response by Regulating Macrophage Polarization After Acute Cervical Spinal Cord Injury in Rats. Front Neurosci 2020; 14:583611. [PMID: 33192269 PMCID: PMC7645058 DOI: 10.3389/fnins.2020.583611] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 09/29/2020] [Indexed: 11/13/2022] Open
Abstract
Objective To investigate the effects of ketogenic metabolism on macrophage polarization, inflammation inhibition, and function recovery after acute spinal cord injury (SCI) in rats. Methods Sixty-four adult male Sprague-Dawley rats were randomly and equally divided into sham, standard diet (SD), ketone diet (KD), and 1, 3-butanediol (BD) groups. All animals underwent C5 unilateral laminectomy, whereas the SD, KD, and BD groups underwent C5 spinal cord hemi-contusion. The impact rod with a diameter of 1.5 mm was aligned 22.5° to the left and 1.4 mm to the midline, and then triggered to deliver a set displacement of 1.5 mm at a speed of 100 mm/s. The gene expression of inflammatory factors as well as the protein expression of inducible nitric oxide synthase, arginase-1, and inflammatory factors were measured at 1 week post-injury. Serum ketone and behavior were evaluated every second week for 12 weeks. Then, histological analyses of the gray and white matter at the epicenter were conducted at 12 weeks post-injury. Results The serum ketone levels of the KD and BD groups were significantly increased when compared with the SD group. The gene and protein expression of TNF-α and IL-1β tended to increase after the SCI, but were inhibited in the KD and BD groups. The protein expression of inducible nitric oxide synthase, marker of M1 macrophage, was inhibited in the KD and BD groups; on the other hand, the expression of arginase-1, marker of M2 macrophage, was boosted in the KD and BD groups. The usage of the ipsilateral forelimb was higher in the KD group than in the SD group. The hemi-contusive injury resulted in an obvious ipsilateral lesion area at the epicenter, and there was no significant difference between groups regarding the lesion size. However, the spared gray matter area was significantly greater in the KD group than in the SD and BD groups. Conclusion The present study suggests that ketogenic metabolism promotes macrophage polarization to M2, inhibits an inflammatory response, and alleviates the loss of gray matter after SCI. A higher ketone level, such as that induced by the ketogenic diet, seems to benefit function recovery after SCI.
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Affiliation(s)
- Junyu Lin
- Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zucheng Huang
- Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Junhao Liu
- Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhiping Huang
- Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yapu Liu
- Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qi Liu
- Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhou Yang
- Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ruoyao Li
- Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiuhua Wu
- Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhe Shi
- Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qingan Zhu
- Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoliang Wu
- Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Stubbs BJ, Koutnik AP, Volek JS, Newman JC. From bedside to battlefield: intersection of ketone body mechanisms in geroscience with military resilience. GeroScience 2020; 43:1071-1081. [PMID: 33006708 PMCID: PMC8190215 DOI: 10.1007/s11357-020-00277-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 09/22/2020] [Indexed: 12/15/2022] Open
Abstract
Ketone bodies are endogenous metabolites that are linked to multiple mechanisms of aging and resilience. They are produced by the body when glucose availability is low, including during fasting and dietary carbohydrate restriction, but also can be consumed as exogenous ketone compounds. Along with supplying energy to peripheral tissues such as brain, heart, and skeletal muscle, they increasingly are understood to have drug-like protein binding activities that regulate inflammation, epigenetics, and other cellular processes. While these energy and signaling mechanisms of ketone bodies are currently being studied in a variety of aging-related diseases such as Alzheimer’s disease and type 2 diabetes mellitus, they may also be relevant to military service members undergoing stressors that mimic or accelerate aging pathways, particularly traumatic brain injury and muscle rehabilitation and recovery. Here we summarize the biology of ketone bodies relevant to resilience and rehabilitation, strategies for translational use of ketone bodies, and current clinical investigations in this area.
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Affiliation(s)
| | - Andrew P Koutnik
- Institute for Human and Machine Cognition, Pensacola, FL, USA.,Department of Molecular Pharmacology and Physiology, USF, Tampa, FL, USA
| | - Jeff S Volek
- Department of Human Sciences, Ohio State University, Columbus, OH, USA
| | - John C Newman
- Buck Institute for Research on Aging, Novato, CA, USA. .,Division of Geriatrics, UCSF, San Francisco, CA, USA.
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50
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Mitochondria focused neurotherapeutics for spinal cord injury. Exp Neurol 2020; 330:113332. [DOI: 10.1016/j.expneurol.2020.113332] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 04/21/2020] [Accepted: 04/26/2020] [Indexed: 02/06/2023]
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