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Zheng Q, Wang D, Lin R, Xu W. Pyroptosis, ferroptosis, and autophagy in spinal cord injury: regulatory mechanisms and therapeutic targets. Neural Regen Res 2025; 20:2787-2806. [PMID: 39101602 PMCID: PMC11826477 DOI: 10.4103/nrr.nrr-d-24-00112] [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: 01/28/2024] [Revised: 04/24/2024] [Accepted: 06/07/2024] [Indexed: 08/06/2024] Open
Abstract
Regulated cell death is a form of cell death that is actively controlled by biomolecules. Several studies have shown that regulated cell death plays a key role after spinal cord injury. Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords. Autophagy, a complex form of cell death that is interconnected with various regulated cell death mechanisms, has garnered significant attention in the study of spinal cord injury. This injury triggers not only cell death but also cellular survival responses. Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis, ferroptosis, and autophagy. Therefore, this review aims to comprehensively examine the mechanisms underlying regulated cell deaths, the signaling pathways that modulate these mechanisms, and the potential therapeutic targets for spinal cord injury. Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury. Moreover, a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury.
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Affiliation(s)
- Qingcong Zheng
- Department of Spinal Surgery, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Du Wang
- Arthritis Clinical and Research Center, Peking University People’s Hospital, Beijing, China
| | - Rongjie Lin
- Department of Orthopedic Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Weihong Xu
- Department of Spinal Surgery, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
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Paik S, Kim JK, Shin HJ, Park EJ, Kim IS, Jo EK. Updated insights into the molecular networks for NLRP3 inflammasome activation. Cell Mol Immunol 2025; 22:563-596. [PMID: 40307577 DOI: 10.1038/s41423-025-01284-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Accepted: 03/17/2025] [Indexed: 05/02/2025] Open
Abstract
Over the past decade, significant advances have been made in our understanding of how NACHT-, leucine-rich-repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasomes are activated. These findings provide detailed insights into the transcriptional and posttranslational regulatory processes, the structural-functional relationship of the activation processes, and the spatiotemporal dynamics of NLRP3 activation. Notably, the multifaceted mechanisms underlying the licensing of NLRP3 inflammasome activation constitute a focal point of intense research. Extensive research has revealed the interactions of NLRP3 and its inflammasome components with partner molecules in terms of positive and negative regulation. In this Review, we provide the current understanding of the complex molecular networks that play pivotal roles in regulating NLRP3 inflammasome priming, licensing and assembly. In addition, we highlight the intricate and interconnected mechanisms involved in the activation of the NLRP3 inflammasome and the associated regulatory pathways. Furthermore, we discuss recent advances in the development of therapeutic strategies targeting the NLRP3 inflammasome to identify potential therapeutics for NLRP3-associated inflammatory diseases. As research continues to uncover the intricacies of the molecular networks governing NLRP3 activation, novel approaches for therapeutic interventions against NLRP3-related pathologies are emerging.
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Affiliation(s)
- Seungwha Paik
- Department of Microbiology, Chungnam National University College of Medicine, Daejeon, Republic of Korea
- Department of Medical Science, Chungnam National University College of Medicine, Daejeon, Republic of Korea
- System Network Inflammation Control Research Center, Chungnam National University College of Medicine, Daejeon, Republic of Korea
- Biomedical Research Institute, Chungnam National University Hospital, Daejeon, Republic of Korea
| | - Jin Kyung Kim
- Department of Microbiology, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Hyo Jung Shin
- Department of Medical Science, Chungnam National University College of Medicine, Daejeon, Republic of Korea
- Department of Biochemistry and Cell Biology, Eulji University School of Medicine, Daejeon, Republic of Korea
- Brain Research Institute, Chungnam National University College of Medicine, Daejeon, Republic of Korea
| | - Eun-Jin Park
- Department of Microbiology, Chungnam National University College of Medicine, Daejeon, Republic of Korea
- Department of Medical Science, Chungnam National University College of Medicine, Daejeon, Republic of Korea
| | - In Soo Kim
- Department of Medical Science, Chungnam National University College of Medicine, Daejeon, Republic of Korea
- Biomedical Research Institute, Chungnam National University Hospital, Daejeon, Republic of Korea
- Department of Pharmacology, Chungnam National University College of Medicine, Daejeon, Republic of Korea
| | - Eun-Kyeong Jo
- Department of Microbiology, Chungnam National University College of Medicine, Daejeon, Republic of Korea.
- Department of Medical Science, Chungnam National University College of Medicine, Daejeon, Republic of Korea.
- Biomedical Research Institute, Chungnam National University Hospital, Daejeon, Republic of Korea.
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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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Chen J, Chen J, Yu C, Xia K, Yang B, Wang R, Li Y, Shi K, Zhang Y, Xu H, Zhang X, Wang J, Chen Q, Liang C. Metabolic reprogramming: a new option for the treatment of spinal cord injury. Neural Regen Res 2025; 20:1042-1057. [PMID: 38989936 PMCID: PMC11438339 DOI: 10.4103/nrr.nrr-d-23-01604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Accepted: 02/27/2024] [Indexed: 07/12/2024] Open
Abstract
Spinal cord injuries impose a notably economic burden on society, mainly because of the severe after-effects they cause. Despite the ongoing development of various therapies for spinal cord injuries, their effectiveness remains unsatisfactory. However, a deeper understanding of metabolism has opened up a new therapeutic opportunity in the form of metabolic reprogramming. In this review, we explore the metabolic changes that occur during spinal cord injuries, their consequences, and the therapeutic tools available for metabolic reprogramming. Normal spinal cord metabolism is characterized by independent cellular metabolism and intercellular metabolic coupling. However, spinal cord injury results in metabolic disorders that include disturbances in glucose metabolism, lipid metabolism, and mitochondrial dysfunction. These metabolic disturbances lead to corresponding pathological changes, including the failure of axonal regeneration, the accumulation of scarring, and the activation of microglia. To rescue spinal cord injury at the metabolic level, potential metabolic reprogramming approaches have emerged, including replenishing metabolic substrates, reconstituting metabolic couplings, and targeting mitochondrial therapies to alter cell fate. The available evidence suggests that metabolic reprogramming holds great promise as a next-generation approach for the treatment of spinal cord injury. To further advance the metabolic treatment of the spinal cord injury, future efforts should focus on a deeper understanding of neurometabolism, the development of more advanced metabolomics technologies, and the design of highly effective metabolic interventions.
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Affiliation(s)
- Jiangjie Chen
- Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Orthopedics Research Institute of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang Province, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang Province, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang Province, China
| | - Jinyang Chen
- Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Orthopedics Research Institute of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang Province, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang Province, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang Province, China
| | - Chao Yu
- Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Orthopedics Research Institute of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang Province, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang Province, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang Province, China
| | - Kaishun Xia
- Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Orthopedics Research Institute of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang Province, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang Province, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang Province, China
| | - Biao Yang
- Qiandongnan Prefecture People's Hospital, Kaili, Guizhou Province, China
| | - Ronghao Wang
- Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Orthopedics Research Institute of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang Province, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang Province, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang Province, China
| | - Yi Li
- Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Orthopedics Research Institute of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang Province, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang Province, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang Province, China
| | - Kesi Shi
- Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Orthopedics Research Institute of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang Province, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang Province, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang Province, China
| | - Yuang Zhang
- Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Orthopedics Research Institute of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang Province, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang Province, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang Province, China
| | - Haibin Xu
- Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Orthopedics Research Institute of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang Province, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang Province, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang Province, China
| | - Xuesong Zhang
- Department of Orthopedics, Fourth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Jingkai Wang
- Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Orthopedics Research Institute of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang Province, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang Province, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang Province, China
| | - Qixin Chen
- Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Orthopedics Research Institute of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang Province, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang Province, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang Province, China
| | - Chengzhen Liang
- Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Orthopedics Research Institute of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang Province, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang Province, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang Province, China
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Flower L, Vozza EG, Bryant CE, Summers C. Role of inflammasomes in acute respiratory distress syndrome. Thorax 2025; 80:255-263. [PMID: 39884849 PMCID: PMC12015084 DOI: 10.1136/thorax-2024-222596] [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: 10/16/2024] [Accepted: 01/10/2025] [Indexed: 02/01/2025]
Abstract
Acute respiratory distress syndrome (ARDS) is present in >10% of all people admitted to critical care and is associated with severe morbidity and mortality. Despite more than half a century since its first description, no efficacious pharmacological therapies have been developed, and little progress has been made in improving clinical outcomes. Neutrophils are the principal drivers of ARDS, with their priming and subsequent aberrant downstream functions, including interleukin (IL) 1β and IL-18 secretion, central to the disease pathogenesis. The dominant pathways through which IL-1β and IL-18 are believed to be elaborated are multimeric protein structures called inflammasomes that consist of sensor proteins, adaptor proteins and an effector enzyme. The inflammasome's initial activation depends on one of a variety of damage-associated (DAMP) or pathogen-associated (PAMP) molecular patterns. However, once activated, a common downstream inflammatory pathway is initiated regardless of the specific DAMP or PAMP involved. Several inflammasomes exist in humans. The nucleotide-binding domain leucine-rich repeat (NLR) family, pyrin domain-containing 3 (NLRP3), inflammasome is the best described in the context of ARDS and is known to be activated in both infective and sterile cases. The NLR family, caspase activation and recruitment domain-containing 4 (NLRC4) and absent in melanoma 2 (AIM2) inflammasomes have also been implicated in various ARDS settings, as have inflammasome-independent pathways. Further work is required to understand human biology as much of our knowledge is extrapolated from rodent experimental models. Experimental lung injury models have demonstrated beneficial responses to inflammasome, IL-1β and IL-18 blockade. However, findings have yet to be successfully translated into humans with ARDS, likely due to an underappreciation of the central role of the neutrophil inflammasome. A thorough understanding of inflammasome pathways is vital for critical care clinicians and researchers and for the development of beneficial therapies. In this review, we describe the central role of the inflammasome in the development of ARDS and its potential for immunomodulation, highlighting key areas for future research.
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Affiliation(s)
- Luke Flower
- Victor Phillip Dahdaleh Heart & Lung Research Institute, University of Cambridge, Cambridge, UK
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Emilio G Vozza
- Victor Phillip Dahdaleh Heart & Lung Research Institute, University of Cambridge, Cambridge, UK
| | - Clare E Bryant
- Victor Phillip Dahdaleh Heart & Lung Research Institute, University of Cambridge, Cambridge, UK
| | - Charlotte Summers
- Victor Phillip Dahdaleh Heart & Lung Research Institute, University of Cambridge, Cambridge, UK
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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Gu HY, Liu N. Mechanism of effect and therapeutic potential of NLRP3 inflammasome in spinal cord injury. Exp Neurol 2025; 384:115059. [PMID: 39571746 DOI: 10.1016/j.expneurol.2024.115059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 11/10/2024] [Accepted: 11/12/2024] [Indexed: 11/25/2024]
Abstract
Spinal cord injury (SCI) is a serious and disabling central nervous system injury that can trigger various neuropathological conditions, resulting in neuronal damage and release of various pro-inflammatory mediators, leading to neurological dysfunction. Currently, surgical decompression, drugs and rehabilitation are primarily used to relieve symptoms and improve endogenous repair mechanisms; however, they cannot directly promote nerve regeneration and functional recovery. SCI can be divided into primary and secondary injuries. Secondary injury is key to determining the severity of injury, whereas inflammation and cell death are important pathological mechanisms in the process of secondary SCI. The activation of the inflammasome complex is thought to be a necessary step in neuro-inflammation and a key trigger for neuronal death. The NLRP3 inflammasome is a cytoplasmic multiprotein complex that is considered an important factor in the development of SCI. Once the NLRP3 inflammasome is activated after SCI, NLRP3 nucleates the assembly of an inflammasome, leading to caspase 1-mediated proteolytic activation of the interleukin-1β (IL-1β) family of cytokines, and induces an inflammatory, pyroptotic cell death. Inhibition of inflammasomes can effectively inhibit inflammation and cell death in the body and promote the recovery of nerve function after SCI. Therefore, inhibition of NLRP3 inflammasome activation may be a promising approach for the treatment of SCI. In this review, we describe the current understanding of NLRP3 inflammasome activation in SCI pathogenesis and its subsequent impact on SCI and summarize drugs and other potential inhibitors based on NLRP3 inflammasome regulation. The objective of this study was to emphasize the role of the NLRP3 inflammasome in SCI, and provide a new therapeutic strategy and theoretical basis for targeting the NLRP3 inflammasome as a therapy for SCI.
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Affiliation(s)
- Hou-Yun Gu
- Department of Spine Surgery, Ganzhou People's Hospital, 16 Meiguan Avenue, Ganzhou, Jiangxi Province 341000, PR China; Department of Spine Surgery, The Affiliated Ganzhou Hospital of Nanchang University (Ganzhou Hospital-Nanfang Hospital), Southern Medical University, 16 Meiguan Avenue, Ganzhou, Jiangxi Province 341000, PR China.
| | - Ning Liu
- Department of Spine Surgery, Ganzhou People's Hospital, 16 Meiguan Avenue, Ganzhou, Jiangxi Province 341000, PR China; Department of Spine Surgery, The Affiliated Ganzhou Hospital of Nanchang University (Ganzhou Hospital-Nanfang Hospital), Southern Medical University, 16 Meiguan Avenue, Ganzhou, Jiangxi Province 341000, PR China.
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Li D, Dai Y, Li Z, Bi H, Li H, Wang Y, Liu Y, Tian X, Chen L. Resveratrol Upregulates miR-124-3p Expression to Target DAPK1, Regulating the NLRP3/Caspase-1/GSDMD Pathway to Inhibit Pyroptosis and Alleviate Spinal Cord Injury. J Cell Mol Med 2025; 29:e70338. [PMID: 39833100 PMCID: PMC11745821 DOI: 10.1111/jcmm.70338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 11/29/2024] [Accepted: 12/23/2024] [Indexed: 01/30/2025] Open
Abstract
Currently, an effective treatment for spinal cord injury (SCI) is not available. Due to the irreversible primary injury associated with SCI, the prevention and treatment of secondary injury are very important. In the secondary injury stage, pyroptosis exacerbates the deterioration of the spinal cord injury, and inhibiting pyroptosis is beneficial for recovery from SCI. The aim of this study was to clarify the role of resveratrol (RES) and the antipyroptotic mechanisms of RES and miR-124-3p in SCI to lay a theoretical foundation for the clinical treatment of SCI and provide new therapeutic approaches. Using cell staining and related molecular protein detection techniques to assess DAPK1, the effects of miR-124-3p and RES on pyroptosis were investigated, and the effects of RES on injured spinal cord repair in rats were evaluated using tissue staining and related functional recovery experiments. In vitro, DAPK1 interacts with NLRP3, exerting a pyroptotic effect through the NLRP3/Caspase-1/GSDMD pathway and DAPK1 knockdown inhibits pyroptosis. miR-124-3P negatively regulates the level of DAPK1 and reduced cell pyroptosis. RES increased miR-124-3p expression and reduces DAPK1 expression, affecting the NLRP3/Caspase-1/GSDMD pathway and inhibiting pyroptosis. In vivo, RES reduces GSDMD-N levels in rats with SCI, promotes functional recovery, and thus promotes recovery from SCI. Therefore, we concluded that RES increases the level of miR-124-3p, which targets DAPK1, regulates the NLRP3/Caspase-1/GSDMD pathway, inhibits pyroptosis and alleviates SCI.
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Affiliation(s)
- Daohui Li
- Department of OrthopedicsThe First Affiliated Hospital of Kunming Medical UniversityYunnanChina
| | - Yongwen Dai
- Department of OrthopedicsThe First Affiliated Hospital of Kunming Medical UniversityYunnanChina
| | - Zhengtao Li
- Department of OrthopedicsThe First Affiliated Hospital of Kunming Medical UniversityYunnanChina
| | - Hangchuan Bi
- Department of OrthopedicsThe First Affiliated Hospital of Kunming Medical UniversityYunnanChina
| | - Haotian Li
- Department of OrthopedicsThe First Affiliated Hospital of Kunming Medical UniversityYunnanChina
| | - Yongquan Wang
- Department of OrthopedicsThe First Affiliated Hospital of Kunming Medical UniversityYunnanChina
| | - Yuan Liu
- Department of OrthopedicsThe First Affiliated Hospital of Kunming Medical UniversityYunnanChina
| | - Xinpeng Tian
- Department of Critical Care MedicineXi Chang People's HospitalSichuanChina
| | - Lingqiang Chen
- Department of OrthopedicsThe First Affiliated Hospital of Kunming Medical UniversityYunnanChina
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8
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Kolpek DJ, Kim J, Mohammed H, Gensel JC, Park J. Physicochemical Property Effects on Immune Modulating Polymeric Nanoparticles: Potential Applications in Spinal Cord Injury. Int J Nanomedicine 2024; 19:13357-13374. [PMID: 39691455 PMCID: PMC11649979 DOI: 10.2147/ijn.s497859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 11/26/2024] [Indexed: 12/19/2024] Open
Abstract
Nanoparticles (NPs) offer promising potential as therapeutic agents for inflammation-related diseases, owing to their capabilities in drug delivery and immune modulation. In preclinical studies focusing on spinal cord injury (SCI), polymeric NPs have demonstrated the ability to reprogram innate immune cells. This reprogramming results in redirecting immune cells away from the injury site, downregulating pro-inflammatory signaling, and promoting a regenerative environment post-injury. However, to fully understand the mechanisms driving these effects and maximize therapeutic efficacy, it is crucial to assess NP interactions with innate immune cells. This review examines how the physicochemical properties of polymeric NPs influence their modulation of the immune system. To achieve this, the review delves into the roles played by innate immune cells in SCI and investigates how various NP properties influence cellular interactions and subsequent immune modulation. Key NP properties such as size, surface charge, molecular weight, shape/morphology, surface functionalization, and polymer composition are thoroughly examined. Furthermore, the review establishes connections between these properties and their effects on the immunomodulatory functions of NPs. Ultimately, this review suggests that leveraging NPs and their physicochemical properties could serve as a promising therapeutic strategy for treating SCI and potentially other inflammatory diseases.
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Affiliation(s)
- Daniel J Kolpek
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA
| | - Jaechang Kim
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA
| | - Hisham Mohammed
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA
| | - John C Gensel
- Spinal Cord and Brain Injury Research Center, Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA
| | - Jonghyuck Park
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA
- Spinal Cord and Brain Injury Research Center, Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA
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9
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González Ibáñez F, VanderZwaag J, Deslauriers J, Tremblay MÈ. Ultrastructural features of psychological stress resilience in the brain: a microglial perspective. Open Biol 2024; 14:240079. [PMID: 39561812 PMCID: PMC11576122 DOI: 10.1098/rsob.240079] [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: 03/28/2024] [Revised: 07/25/2024] [Accepted: 10/15/2024] [Indexed: 11/21/2024] Open
Abstract
Psychological stress is the major risk factor for major depressive disorder. Sustained stress causes changes in behaviour, brain connectivity and in its cells and organelles. Resilience to stress is understood as the ability to recover from stress in a positive way or the resistance to the negative effects of psychological stress. Microglia, the resident immune cells of the brain, are known players of stress susceptibility, but less is known about their role in stress resilience and the cellular changes involved. Ultrastructural analysis has been a useful tool in the study of microglia and their function across contexts of health and disease. Despite increased access to electron microscopy, the interpretation of electron micrographs remains much less accessible. In this review, we will first present microglia and the concepts of psychological stress susceptibility and resilience. Afterwards, we will describe ultrastructural analysis, notably of microglia, as a readout to study the mechanisms underlying psychological stress resilience. Lastly, we will cover nutritional ketosis as a therapeutic intervention that was shown to be effective in promoting psychological stress resilience as well as modifying microglial function and ultrastructure.
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Affiliation(s)
- Fernando González Ibáñez
- Axe Neurosciences, Centre de recherche du CHU de Québec-Université Laval, Québec, Québec, Canada
- Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada
| | - Jared VanderZwaag
- Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada
- Neuroscience Graduate Program, University of Victoria, Victoria, British Columbia, Canada
| | | | - Marie-Ève Tremblay
- Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada
- Department of Molecular Medicine, Université Laval, Québec, Québec, Canada
- Neurology and Neurosurgery Department, McGill University, Montréal, Québec, Canada
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada
- Centre for Advanced Materials and Related Technology, University of Victoria, Victoria, British Columbia, Canada
- Institute on Aging and Lifelong Health, University of Victoria, Victoria, British Columbia, Canada
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10
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Zhang A, Wang J, Zhao Y, He Y, Sun N. Intermittent fasting, fatty acid metabolism reprogramming, and neuroimmuno microenvironment: mechanisms and application prospects. Front Nutr 2024; 11:1485632. [PMID: 39512520 PMCID: PMC11541237 DOI: 10.3389/fnut.2024.1485632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Accepted: 10/15/2024] [Indexed: 11/15/2024] Open
Abstract
Intermittent fasting (IF) has demonstrated extensive health benefits through the regulation of fatty acid metabolism and modulation of the neuroimmune microenvironment, primarily via the activation of key signaling pathways such as AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1). IF not only facilitates fatty acid oxidation and improves metabolic health, but also enhances mitochondrial function, mitigates oxidative stress, promotes autophagy, and inhibits apoptosis and ferroptosis. These mechanisms contribute to its substantial preventive and therapeutic potential in various conditions, including neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, autoimmune diseases, and neurotraumatic conditions. While supportive evidence has been obtained from animal models and preliminary clinical studies, further large-scale, long-term randomized controlled trials are imperative to establish its safety and evaluate its clinical efficacy comprehensively.
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Affiliation(s)
- Anren Zhang
- Department of Rehabilitation, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Junyu Wang
- Department of Rehabilitation, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yinuo Zhao
- Department of Rehabilitation, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yu He
- Department of Rehabilitation, Shengjing Hospital of China Medical University, Shenyang, China
| | - Nianyi Sun
- Department of Rehabilitation, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
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11
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Seira O, Park H(D, Liu J, Poovathukaran M, Clarke K, Boushel R, Tetzlaff W. Ketone Esters Partially and Selectively Rescue Mitochondrial Bioenergetics After Acute Cervical Spinal Cord Injury in Rats: A Time-Course. Cells 2024; 13:1746. [PMID: 39513853 PMCID: PMC11545339 DOI: 10.3390/cells13211746] [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: 06/07/2024] [Revised: 10/11/2024] [Accepted: 10/15/2024] [Indexed: 11/16/2024] Open
Abstract
Spinal cord injury (SCI) pathology and pathophysiology can be attributed to both primary physical injury and secondary injury cascades. Secondary injury cascades involve dysregulated metabolism and energetic deficits directly linked to compromised mitochondrial bioenergetics. Rescuing mitochondrial function and reducing oxidative stress are associated with neuroprotection. In this regard, ketosis after traumatic brain injury (TBI), or after SCI, improves secondary neuropathology by decreasing oxidative stress, increasing antioxidants, reducing inflammation, and improving mitochondrial bioenergetics. Here, we follow up on our previous study and have used an exogenous ketone monoester, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KE), as an alternative to a ketogenic diet, focusing on mitochondrial function between 1 and 14 days after injury. Starting 3 h following a cervical level 5 (C5) hemi-contusion injury, animals were fed either a standard control diet (SD) or a ketone ester diet (KED) combined with KE administered orally (OKE). We found that mitochondrial function was reduced after SCI at all times post-SCI, accompanied by reduced expression of most of the components of the electron transport chain (ETC). The KE rescued some of the bioenergetic parameters 1 day after SCI when D-β-Hydroxybutyrate (BHB) concentrations were ~2 mM. Still, most of the beneficial effects were observed 14 days after injury, with BHB concentrations reaching values of 4-6 mM. To our knowledge, this is the first report to show the beneficial effects of KE in rescuing mitochondrial function after SCI and demonstrates the suitability of KE in ameliorating the metabolic dysregulation that occurs after traumatic SCI without requiring a restrictive dietary regime.
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Affiliation(s)
- Oscar Seira
- International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, BC V5Z 1M9, Canada; (J.L.)
| | - HyoJoon (David) Park
- Department of Zoology, University of British Columbia, Vancouver, BC V6T 1Z1, Canada;
| | - Jie Liu
- International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, BC V5Z 1M9, Canada; (J.L.)
| | - Michelle Poovathukaran
- International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, BC V5Z 1M9, Canada; (J.L.)
| | - Kieran Clarke
- Department of Physiology, University of Oxford, Oxford OX1 2JD, UK;
| | - Robert Boushel
- School of Kinesiology, University of British Columbia, Vancouver, BC V6T 1Z1, Canada;
| | - Wolfram Tetzlaff
- International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, BC V5Z 1M9, Canada; (J.L.)
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12
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Shahpasand S, Khatami SH, Ehtiati S, Alehossein P, Salmani F, Toutounchi AH, Zarei T, Shahmohammadi MR, Khodarahmi R, Aghamollaii V, Tafakhori A, Karima S. Therapeutic potential of the ketogenic diet: A metabolic switch with implications for neurological disorders, the gut-brain axis, and cardiovascular diseases. J Nutr Biochem 2024; 132:109693. [PMID: 38880191 DOI: 10.1016/j.jnutbio.2024.109693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 06/11/2024] [Accepted: 06/11/2024] [Indexed: 06/18/2024]
Abstract
The Ketogenic Diet (KD) is a dietary regimen that is low in carbohydrates, high in fats, and contains adequate protein. It is designed to mimic the metabolic state of fasting. This diet triggers the production of ketone bodies through a process known as ketosis. The primary objective of KD is to induce and sustain ketosis, which has been associated with numerous health benefits. Recent research has uncovered promising therapeutic potential for KD in the treatment of various diseases. This includes evidence of its effectiveness as a dietary strategy for managing intractable epilepsy, a form of epilepsy that is resistant to medication. We are currently assessing the efficacy and safety of KD through laboratory and clinical studies. This review focuses on the anti-inflammatory properties of the KD and its potential benefits for neurological disorders and the gut-brain axis. We also explore the existing literature on the potential effects of KD on cardiac health. Our aim is to provide a comprehensive overview of the current knowledge in these areas. Given the encouraging preliminary evidence of its therapeutic effects and the growing understanding of its mechanisms of action, randomized controlled trials are warranted to further explore the rationale behind the clinical use of KD. These trials will ultimately enhance our understanding of how KD functions and its potential benefits for various health conditions. We hope that our research will contribute to the body of knowledge in this field and provide valuable insights for future studies.
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Affiliation(s)
- Sheyda Shahpasand
- Department of Biology, Faculty of Basic Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Seyyed Hossein Khatami
- Student Research Committee, Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sajad Ehtiati
- Student Research Committee, Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parsa Alehossein
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Farzaneh Salmani
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences (SBMU), Tehran, Iran
| | - Alireza Haghbin Toutounchi
- Department of general surgery,Imam Hosein medical and educational center, Shahid Beheshti University of medical sciences, Tehran, Iran
| | - Tayebe Zarei
- Clinical Trial Department, Behbalin Co., Ltd., Tehran, Iran
| | - Mohammad Reza Shahmohammadi
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reza Khodarahmi
- Medical Biology Research Center, Research Institute for Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Vajiheh Aghamollaii
- Neurology Department, Roozbeh Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Tafakhori
- Department of Neurology, School of Medicine, Iranian Center of Neurological Research, Neuroscience Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeed Karima
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences (SBMU), Tehran, Iran.
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Torres JA, Holznecht N, Asplund DA, Kroes BC, Amarlkhagva T, Haeffner MM, Sharpe EH, Koestner S, Strubl S, Schimmel MF, Kruger S, Agrawal S, Aceves BA, Thangaraju M, Weimbs T. β-hydroxybutyrate recapitulates the beneficial effects of ketogenic metabolic therapy in polycystic kidney disease. iScience 2024; 27:110773. [PMID: 39314240 PMCID: PMC11418134 DOI: 10.1016/j.isci.2024.110773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 05/30/2024] [Accepted: 08/15/2024] [Indexed: 09/25/2024] Open
Abstract
Autosomal-dominant polycystic kidney disease (ADPKD) is a common monogenic disease characterized by the formation of fluid-filled renal cysts, loss of mitochondrial function, decreased fatty acid oxidation, increased glycolysis, and likely renal failure. We previously demonstrated that inducing a state of ketosis ameliorates or reverses PKD progression in multiple animal models. In this study, we compare time-restricted feeding and 48-h periodic fasting regimens in both juvenile and adult Cy/+ rats. Both fasting regimens potently prevent juvenile disease progression and partially reverse PKD in adults. To explore the mechanism of fasting, we administered β-hydroxybutyrate (BHB) to Cy/+ rats and orthologous mouse models of PKD (Pkd1 RC/RC , Pkd1-Ksp:Cre). BHB recapitulated the effects of fasting in these models independent of stereoisomer, suggesting the effects of BHB are largely due to its signaling functions. These findings implicate the use of ketogenic metabolic therapy and BHB supplementation as potential disease modifiers of PKD and point toward underlying mechanisms.
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Affiliation(s)
- Jacob A. Torres
- Department of Molecular, Cellular, Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, USA
| | - Nickolas Holznecht
- Department of Molecular, Cellular, Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, USA
| | - David A. Asplund
- Department of Molecular, Cellular, Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, USA
| | - Bradley C. Kroes
- Department of Molecular, Cellular, Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, USA
| | - Tselmeg Amarlkhagva
- Department of Molecular, Cellular, Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, USA
| | - Matthias M. Haeffner
- Department of Molecular, Cellular, Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, USA
| | - Elizabeth H. Sharpe
- Department of Molecular, Cellular, Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, USA
| | - Stella Koestner
- Department of Molecular, Cellular, Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, USA
| | - Sebastian Strubl
- Department of Molecular, Cellular, Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, USA
| | - Margaret F. Schimmel
- Department of Molecular, Cellular, Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, USA
| | - Samantha Kruger
- Department of Molecular, Cellular, Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, USA
| | - Shagun Agrawal
- Department of Molecular, Cellular, Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, USA
| | - Brina A. Aceves
- Department of Molecular, Cellular, Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, USA
| | - Muthusamy Thangaraju
- Department of Biochemistry and Molecular Biology, University of Augusta, Augusta, GA, USA
| | - Thomas Weimbs
- Department of Molecular, Cellular, Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, USA
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14
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Horiuchi T, Furukawa K, Kikusato M. Suppressive Effects of β-Hydroxybutyrate Administration on Lipopolysaccharide-Induced Inflammation in Broiler Chickens. Vet Sci 2024; 11:405. [PMID: 39330784 PMCID: PMC11436216 DOI: 10.3390/vetsci11090405] [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: 07/21/2024] [Revised: 08/19/2024] [Accepted: 08/29/2024] [Indexed: 09/28/2024] Open
Abstract
BACKGROUND This study aimed to evaluate the suppressive effects of β-hydroxybutyrate (BHB) administration on lipopolysaccharide (LPS)-induced inflammation in broiler chickens. METHODS Twenty-day-old male broiler chickens were randomly allocated to three groups, each of which was treated with saline (control), intraperitoneal administration of LPS [1.5 mg/kg body weight (BW), Escherichia coli O127:B8], or LPS plus BHB (3 mmol/kg BW). RESULTS Plasma albumin and total protein concentration were significantly reduced by LPS administration, while BHB co-treatment partially attenuated the effects. The LPS treatment significantly induced plasma aspartate and alanine aminotransferase activities, and interleukin (IL)-6 concentration, with the increases suppressed by BHB co-treatment (p < 0.05). The LPS treatment significantly increased the gene expression levels of IL-1β, IL-6, and IL-18 in the spleen and peripheral blood monocytes (PBMC), while the increases were partially attenuated by BHB in the spleen. Relatively higher levels of BHB dehydrogenase 1 and succinyl-CoA:3-ketoacid CoA transferase were observed in the spleen and skeletal muscle, while these gene levels were lower in PBMC and the liver. CONCLUSIONS The present results suggest that BHB can suppress LPS-induced inflammation, in which ketolytic enzyme expression levels may be involved in broiler chickens.
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Affiliation(s)
- Tae Horiuchi
- Laboratory of Animal Nutrition, Graduate School of Agricultural Science, Tohoku University, Aramaki Aza-Aoba, Sendai 980-8572, Japan
| | - Kyohei Furukawa
- Laboratory of Animal Nutrition, Graduate School of Agricultural Science, Tohoku University, Aramaki Aza-Aoba, Sendai 980-8572, Japan
- Laboratory of Animal Nutrition, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
| | - Motoi Kikusato
- Laboratory of Animal Nutrition, Graduate School of Agricultural Science, Tohoku University, Aramaki Aza-Aoba, Sendai 980-8572, Japan
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15
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Lun H, Li P, Li J, Liu F. The effect of intestinal flora metabolites on macrophage polarization. Heliyon 2024; 10:e35755. [PMID: 39170251 PMCID: PMC11337042 DOI: 10.1016/j.heliyon.2024.e35755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 07/28/2024] [Accepted: 08/02/2024] [Indexed: 08/23/2024] Open
Abstract
Intestinal flora metabolites played a crucial role in immunomodulation by influencing host immune responses through various pathways. Macrophages, as a type of innate immune cell, were essential in chemotaxis, phagocytosis, inflammatory responses, and microbial elimination. Different macrophage phenotypes had distinct biological functions, regulated by diverse factors and mechanisms. Advances in intestinal flora sequencing and metabolomics have enhanced understanding of how intestinal flora metabolites affect macrophage phenotypes and functions. These metabolites had varying effects on macrophage polarization and different mechanisms of influence. This study summarized the impact of gut microbiota metabolites on macrophage phenotype and function, along with the underlying mechanisms associated with different metabolites produced by intestinal flora.
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Affiliation(s)
- Hengzhong Lun
- Department of Clinical Laboratory, The Affiliated Taian City Central Hospital of Qingdao University, Taian, Shandong, China
| | - Peilong Li
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Juan Li
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Fenfen Liu
- Department of Nephrology, The Affiliated Taian City Central Hospital of Qingdao University, Taian, Shandong, China
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16
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Yamagishi H, Kirai N, Morita A, Kashihara T, Nakahara T. Role of monocarboxylate transporters in AMPK-mediated protection against excitotoxic injury in the rat retina. Eur J Pharmacol 2024; 970:176510. [PMID: 38493917 DOI: 10.1016/j.ejphar.2024.176510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 03/04/2024] [Accepted: 03/14/2024] [Indexed: 03/19/2024]
Abstract
Activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway protects against N-methyl-D-aspartic acid (NMDA)-induced excitotoxic retinal injury. AMPK activation enhances fatty acid metabolism and ketone body synthesis. Ketone bodies are transported into neurons by monocarboxylate transporters (MCTs) and exert neuroprotective effects. In this study, we examined the distribution and expression levels of MCT1 and MCT2 in the retina and analyzed the effects of pharmacological inhibition of MCTs on the protective effects of metformin and 5-aminoimidazole-4-carboxamide (AICAR), activators of AMPK, against NMDA-induced retinal injury in rats. MCT1 was expressed in the blood vessels, processes of astrocytes and Müller cells, and inner segments of photoreceptors in the rat retina, whereas MCT2 was expressed in neuronal cells in the ganglion cell layer (GCL) and in astrocyte processes. The expression levels of MCT2, but not MCT1, decreased one day after intravitreal injection of NMDA (200 nmol). Intravitreal injection of NMDA decreased the number of cells in the GCL compared to the vehicle seven days after injection. Simultaneous injection of metformin (20 nmol) or AICAR (50 nmol) with NMDA attenuated NMDA-induced cell loss in the GCL, and these protective effects were attenuated by AR-C155858 (1 pmol), an inhibitor of MCTs. AR-C155858 alone had no significant effect on the retinal structure. These results suggest that AMPK-activating compounds protect against NMDA-induced excitotoxic retinal injury via mechanisms involving MCTs in rats. NMDA-induced neurotoxicity may be associated with retinal neurodegenerative changes in glaucoma and diabetic retinopathy. Therefore, AMPK-activating compounds may be effective in managing these retinal diseases.
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Affiliation(s)
- Honoka Yamagishi
- Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan
| | - Nozomu Kirai
- Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan
| | - Akane Morita
- Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan
| | - Toshihide Kashihara
- Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan
| | - Tsutomu Nakahara
- Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
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17
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Ding P, Song Y, Yang Y, Zeng C. NLRP3 inflammasome and pyroptosis in cardiovascular diseases and exercise intervention. Front Pharmacol 2024; 15:1368835. [PMID: 38681198 PMCID: PMC11045953 DOI: 10.3389/fphar.2024.1368835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 04/02/2024] [Indexed: 05/01/2024] Open
Abstract
NOD-like receptor protein 3 (NLRP3) inflammasome is an intracellular sensing protein complex that possesses NACHT, leucine-rich repeat, and pyrin domain, playing a crucial role in innate immunity. Activation of the NLRP3 inflammasome leads to the production of pro-inflammatory cellular contents, such as interleukin (IL)-1β and IL-18, and induction of inflammatory cell death known as pyroptosis, thereby amplifying or sustaining inflammation. While a balanced inflammatory response is beneficial for resolving damage and promoting tissue healing, excessive activation of the NLRP3 inflammasome and pyroptosis can have harmful effects. The involvement of the NLRP3 inflammasome has been observed in various cardiovascular diseases (CVD). Indeed, the NLRP3 inflammasome and its associated pyroptosis are closely linked to key cardiovascular risk factors including hyperlipidemia, diabetes, hypertension, obesity, and hyperhomocysteinemia. Exercise compared with medicine is a highly effective measure for both preventing and treating CVD. Interestingly, emerging evidence suggests that exercise improves CVD and inhibits the activity of NLRP3 inflammasome and pyroptosis. In this review, the activation mechanisms of the NLRP3 inflammasome and its pathogenic role in CVD are critically discussed. Importantly, the purpose is to emphasize the crucial role of exercise in managing CVD by suppressing NLRP3 inflammasome activity and proposes it as the foundation for developing novel treatment strategies.
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Affiliation(s)
- Ping Ding
- Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yuanming Song
- Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yang Yang
- Zhuhai People’s Hospital, Zhuhai Clinical Medical College of Jinan University, Zhuhai, China
| | - Cheng Zeng
- Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, China
- Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou, China
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18
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Sun X, Zhang B, Sun K, Li F, Hu D, Chen J, Kong F, Xie Y. Liver-Derived Ketogenesis via Overexpressing HMGCS2 Promotes the Recovery of Spinal Cord Injury. Adv Biol (Weinh) 2024; 8:e2300481. [PMID: 37990936 DOI: 10.1002/adbi.202300481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 11/01/2023] [Indexed: 11/23/2023]
Abstract
The liver is the major ketogenic organ of the body, and ketones are reported to possess favorable neuroprotective effects. This study aims to elucidate whether ketone bodies generated from the liver play a critical role in bridging the liver and spinal cord. Mice model with a contusive spinal cord injury (SCI) surgery is established, and SCI induces significant histological changes in mice liver. mRNA-seq of liver tissue shows the temporal changes of ketone bodies-related genes, β-hydroxybutyrate dehydrogenase (BDH1) and solute carrier family 16 (monocarboxylic acid transporters), member 6 (SLC16A6). Then, an activated ketogenesis model is created with adult C57BL/6 mice receiving the tail intravenous injection of GPAAV8-TBG-Mouse-Hmgcs2-CMV- mCherry -WPRE (HMGCS2liver ) and mice receiving equal AAV8-Null being the control group (Vectorliver ). Then, the mice undergo either a contusive SCI or sham surgery. The results show that overexpression of HMG-CoA synthase (Hmgcs2) in mice liver dramatically alleviates SCI-mediated pathological changes and promotes ketogenesis in the liver. Amazingly, liver-derived ketogenesis evidently alleviates neuron apoptosis and inflammatory microglia activation and improves the recovery of motor function of SCI mice. In conclusion, a liver-spinal cord axis can be bridged via ketone bodies, and enhancing the production of the ketone body within the liver has neuroprotective effects on traumatic SCI.
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Affiliation(s)
- Xiaofei Sun
- Department of spine surgery, Changzheng Hospital, Naval Medical University, No.415 Fengyang Road, Shanghai, 200003, China
| | - Bin Zhang
- Department of spine surgery, Changzheng Hospital, Naval Medical University, No.415 Fengyang Road, Shanghai, 200003, China
| | - Kaiqiang Sun
- Department of spine surgery, Changzheng Hospital, Naval Medical University, No.415 Fengyang Road, Shanghai, 200003, China
| | - Fudong Li
- Department of spine surgery, Changzheng Hospital, Naval Medical University, No.415 Fengyang Road, Shanghai, 200003, China
| | - Dongping Hu
- Shanghai Zechong Biotechnology Co., Ltd., Shanghai, China
| | - Juxiang Chen
- Department of Surgery, Changhai Hospital, Naval Medical University, No. 168 Changhai Road, Shanghai, 200433, China
| | - Fanqi Kong
- Department of spine surgery, Changzheng Hospital, Naval Medical University, No.415 Fengyang Road, Shanghai, 200003, China
| | - Yang Xie
- Department of Surgery, Changhai Hospital, Naval Medical University, No. 168 Changhai Road, Shanghai, 200433, China
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19
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Neudorf H, Little JP. Impact of fasting & ketogenic interventions on the NLRP3 inflammasome: A narrative review. Biomed J 2024; 47:100677. [PMID: 37940045 PMCID: PMC10821592 DOI: 10.1016/j.bj.2023.100677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 10/27/2023] [Accepted: 10/30/2023] [Indexed: 11/10/2023] Open
Abstract
Overactivation of the NLRP3 inflammasome is implicated in chronic low-grade inflammation associated with various disease states, including obesity, type 2 diabetes, atherosclerosis, Alzheimer's disease, and Parkinson's disease. Emerging evidence, mostly from cell and animal models of disease, supports a role for ketosis in general, and the main circulating ketone body beta-hydroxybutyrate (BHB) in particular, in reducing NLRP3 inflammasome activation to improve chronic inflammation. As a result, interventions that can induce ketosis (e.g., fasting, intermittent fasting, time-restricted feeding/eating, very low-carbohydrate high-fat ketogenic diets) and/or increase circulating BHB (e.g., exogenous ketone supplementation) have garnered increasing interest for their therapeutic potential. The purpose of the present review is to summarize our current understanding of the literature on how ketogenic interventions impact the NLRP3 inflammasome across human, rodent and cell models. Overall, there is convincing evidence that ketogenic interventions, likely acting through multiple interacting mechanisms in a cell-, disease- and context-specific manner, can reduce NLRP3 inflammasome activation. The evidence supports a direct effect of BHB, although it is important to consider the myriad of other metabolic responses to fasting or ketogenic diet interventions (e.g., elevated lipolysis, low insulin, stable glucose, negative energy balance) that may also impact innate immune responses. Future research is needed to translate promising findings from discovery science to clinical application.
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Affiliation(s)
- Helena Neudorf
- University of British Columbia, Okanagan Campus, Kelowna, BC, Canada
| | - Jonathan P Little
- University of British Columbia, Okanagan Campus, Kelowna, BC, Canada.
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Strogulski NR, Portela LV, Polster BM, Loane DJ. Fundamental Neurochemistry Review: Microglial immunometabolism in traumatic brain injury. J Neurochem 2023; 167:129-153. [PMID: 37759406 PMCID: PMC10655864 DOI: 10.1111/jnc.15959] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/28/2023] [Accepted: 08/29/2023] [Indexed: 09/29/2023]
Abstract
Traumatic brain injury (TBI) is a devastating neurological disorder caused by a physical impact to the brain that promotes diffuse damage and chronic neurodegeneration. Key mechanisms believed to support secondary brain injury include mitochondrial dysfunction and chronic neuroinflammation. Microglia and brain-infiltrating macrophages are responsible for neuroinflammatory cytokine and reactive oxygen species (ROS) production after TBI. Their production is associated with loss of homeostatic microglial functions such as immunosurveillance, phagocytosis, and immune resolution. Beyond providing energy support, mitochondrial metabolic pathways reprogram the pro- and anti-inflammatory machinery in immune cells, providing a critical immunometabolic axis capable of regulating immunologic response to noxious stimuli. In the brain, the capacity to adapt to different environmental stimuli derives, in part, from microglia's ability to recognize and respond to changes in extracellular and intracellular metabolite levels. This capacity is met by an equally plastic metabolism, capable of altering immune function. Microglial pro-inflammatory activation is associated with decreased mitochondrial respiration, whereas anti-inflammatory microglial polarization is supported by increased oxidative metabolism. These metabolic adaptations contribute to neuroimmune responses, placing mitochondria as a central regulator of post-traumatic neuroinflammation. Although it is established that profound neurometabolic changes occur following TBI, key questions related to metabolic shifts in microglia remain unresolved. These include (a) the nature of microglial mitochondrial dysfunction after TBI, (b) the hierarchical positions of different metabolic pathways such as glycolysis, pentose phosphate pathway, glutaminolysis, and lipid oxidation during secondary injury and recovery, and (c) how immunometabolism alters microglial phenotypes, culminating in chronic non-resolving neuroinflammation. In this basic neurochemistry review article, we describe the contributions of immunometabolism to TBI, detail primary evidence of mitochondrial dysfunction and metabolic impairments in microglia and macrophages, discuss how major metabolic pathways contribute to post-traumatic neuroinflammation, and set out future directions toward advancing immunometabolic phenotyping in TBI.
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Affiliation(s)
- Nathan R. Strogulski
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Luis V. Portela
- Neurotrauma and Biomarkers Laboratory, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Brian M. Polster
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research Center, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - David J. Loane
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research Center, University of Maryland School of Medicine, Baltimore, Maryland, USA
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Kong D, Sun JX, Yang JQ, Li YS, Bi K, Zhang ZY, Wang KH, Luo HY, Zhu M, Xu Y. Ketogenic diet: a potential adjunctive treatment for substance use disorders. Front Nutr 2023; 10:1191903. [PMID: 37575322 PMCID: PMC10414993 DOI: 10.3389/fnut.2023.1191903] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 07/13/2023] [Indexed: 08/15/2023] Open
Abstract
Substance use disorders (SUD) can lead to serious health problems, and there is a great interest in developing new treatment methods to alleviate the impact of substance abuse. In recent years, the ketogenic diet (KD) has shown therapeutic benefits as a dietary therapy in a variety of neurological disorders. Recent studies suggest that KD can compensate for the glucose metabolism disorders caused by alcohol use disorder by increasing ketone metabolism, thereby reducing withdrawal symptoms and indicating the therapeutic potential of KD in SUD. Additionally, SUD often accompanies increased sugar intake, involving neural circuits and altered neuroplasticity similar to substance addiction, which may induce cross-sensitization and increased use of other abused substances. Reducing carbohydrate intake through KD may have a positive effect on this. Finally, SUD is often associated with mitochondrial damage, oxidative stress, inflammation, glia dysfunction, and gut microbial disorders, while KD may potentially reverse these abnormalities and serve a therapeutic role. Although there is much indirect evidence that KD has a positive effect on SUD, the small number of relevant studies and the fact that KD leads to side effects such as metabolic abnormalities, increased risk of malnutrition and gastrointestinal symptoms have led to the limitation of KD in the treatment of SUD. Here, we described the organismal disorders caused by SUD and the possible positive effects of KD, aiming to provide potential therapeutic directions for SUD.
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Affiliation(s)
- Deshenyue Kong
- General Hospital of Eastern Theater Command, Nanjing, China
- Yunnan Technological Innovation Centre of Drug Addiction Medicine, Yunnan University, Kunming, China
- First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jia-xue Sun
- Yunnan Technological Innovation Centre of Drug Addiction Medicine, Yunnan University, Kunming, China
- First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Ji-qun Yang
- Third People’s Hospital of Kunming City/Drug Rehabilitation Hospital of Kunming City, Kunming, China
| | - Yuan-sen Li
- Yunnan Technological Innovation Centre of Drug Addiction Medicine, Yunnan University, Kunming, China
- First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Ke Bi
- Yunnan Technological Innovation Centre of Drug Addiction Medicine, Yunnan University, Kunming, China
- First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Zun-yue Zhang
- Yunnan Technological Innovation Centre of Drug Addiction Medicine, Yunnan University, Kunming, China
| | - Kun-hua Wang
- Yunnan Technological Innovation Centre of Drug Addiction Medicine, Yunnan University, Kunming, China
| | - Hua-you Luo
- First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Mei Zhu
- First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yu Xu
- General Hospital of Eastern Theater Command, Nanjing, China
- Yunnan Technological Innovation Centre of Drug Addiction Medicine, Yunnan University, Kunming, China
- First Affiliated Hospital of Kunming Medical University, Kunming, China
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Altınöz S, Micili SC, Soy S, Engür D, Baysal B, Kumral A. Impact of Maternal Ketogenic Diet on NLRP3 Inflammasome Response in the Offspring Brain. Nutrients 2023; 15:nu15081994. [PMID: 37111213 PMCID: PMC10144516 DOI: 10.3390/nu15081994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 03/23/2023] [Accepted: 03/31/2023] [Indexed: 04/29/2023] Open
Abstract
The effects of maternal diet on the neuroimmune responses of the offspring remain to be elucidated. We investigated the impact of maternal ketogenic diet (KD) on the NLRP3 inflammasome response in the offspring's brain. C57BL/6 female mice were randomly allocated into standard diet (SD) and ketogenic diet (KD) groups for 30 days. After mating, the presence of sperm in the vaginal smear was considered day 0 of pregnancy, and female mice continued their respective diets during pregnancy and the lactation period. Following birth, pups were further allocated into two groups and given either LPS or intraperitoneal saline on postnatal (PN) days 4, 5 and 6; they were sacrificed on PN11 or PN21. Neuronal densities were significantly lower globally in the KD group when compared to the SD group at PN11. Neuronal density in the prefrontal cortex (PFC) and dentate gyrus (DG) regions were also significantly lower in the KD group when compared to the SD group at PN21. Following administration of LPS, the decrease in the neuronal count was more prominent in the SD group when compared to the KD group in the PFC and DG regions at PN11 and PN21. NLRP3 and IL-1β were higher in the KD group than in the SD group at PN21 in the PFC, CA1 and DG regions, and were significantly lower in the DG region of the KD group especially when compared to the SD group following LPS. Results of our study reveal that maternal KD negatively affects the offspring's brain in the mouse model. The effects of KD exhibited regional variations. On the other hand, in the presence of KD exposure, NLRP3 expression after LPS injection was lower in the DG and CA1 areas but not in the PFC when compared to SD group. Further experimental and clinical studies are warranted to elucidate the molecular mechanisms underlying the impact of antenatal KD exposure and regional discrepancies on the developing brain.
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Affiliation(s)
- Sevsen Altınöz
- Department of Pediatrics, Faculty of Medicine, Dokuz Eylul University, Izmir 35330, Turkey
| | - Serap Cilaker Micili
- Department of Histology and Embryology, Faculty of Medicine, Dokuz Eylul University, Izmir 35330, Turkey
| | - Sıla Soy
- Department of Histology and Embryology, Faculty of Medicine, Dokuz Eylul University, Izmir 35330, Turkey
| | - Defne Engür
- İzmir International Biomedicine and Genome Center, Dokuz Eylul University, Izmir 35330, Turkey
- Division of Neonatology, Department of Pediatrics, Izmir Faculty of Medicine, University of Health Sciences, Izmir 35330, Turkey
| | - Bora Baysal
- Division of Neonatology, Department of Pediatrics, Faculty of Medicine, Istinye University, Istanbul 34517, Turkey
| | - Abdullah Kumral
- İzmir International Biomedicine and Genome Center, Dokuz Eylul University, Izmir 35330, Turkey
- Division of Neonatology, Department of Pediatrics, Faculty of Medicine, Dokuz Eylul University, Izmir 35330, Turkey
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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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Falkenhain K, Islam H, Little JP. Exogenous ketone supplementation: an emerging tool for physiologists with potential as a metabolic therapy. Exp Physiol 2023; 108:177-187. [PMID: 36533967 PMCID: PMC10103874 DOI: 10.1113/ep090430] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 11/28/2022] [Indexed: 12/23/2022]
Abstract
NEW FINDINGS What is the topic of this review? The integrative physiological response to exogenous ketone supplementation. What advances does it highlight? The physiological effects and therapeutic potential of exogenous ketones on metabolic health, cardiovascular function, cognitive processing, and modulation of inflammatory pathways and immune function. Also highlighted are current challenges and future directions of the field. ABSTRACT Exogenous oral ketone supplements, primarily in form of ketone salts or esters, have emerged as a useful research tool for manipulating metabolism with potential therapeutic application targeting various aspects of several common chronic diseases. Recent literature has investigated the effects of exogenously induced ketosis on metabolic health, cardiovascular function, cognitive processing, and modulation of inflammatory pathways and immune function. This narrative review provides an overview of the integrative physiological effects of exogenous ketone supplementation and highlights current challenges and future research directions. Much of the existing research on therapeutic applications - particularly mechanistic studies - has involved pre-clinical rodent and/or cellular models, requiring further validation in human clinical studies. Existing human studies report that exogenous ketones can lower blood glucose and improve some aspects of cognitive function, highlighting the potential therapeutic application of exogenous ketones for type 2 diabetes and neurological diseases. There is also support for the ability of exogenous ketosis to improve cardiac metabolism in rodent models of heart failure with supporting human studies emerging; long-terms effects of exogenous ketone supplementation on the human cardiovascular system and lipid profiles are needed. An important avenue for future work is provided by research accelerating technologies that enable continuous ketone monitoring and/or the development of more palatable ketone mixtures that optimize plasma ketone kinetics to enable sustained ketosis. Lastly, research exploring the physiological interactions between exogenous ketones and varying metabolic states (e.g., exercise, fasting, metabolic disease) should yield important insights that can be used to maximize the health benefits of exogenous ketosis.
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Affiliation(s)
- Kaja Falkenhain
- School of Health and Exercise SciencesUniversity of British Columbia OkanaganKelownaBritish ColumbiaCanada
| | - Hashim Islam
- School of Health and Exercise SciencesUniversity of British Columbia OkanaganKelownaBritish ColumbiaCanada
| | - Jonathan P. Little
- School of Health and Exercise SciencesUniversity of British Columbia OkanaganKelownaBritish ColumbiaCanada
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Jayashankar SS, Arifin KT, Nasaruddin ML. β-Hydroxybutyrate Regulates Activated Microglia to Alleviate Neurodegenerative Processes in Neurological Diseases: A Scoping Review. Nutrients 2023; 15:524. [PMID: 36771231 PMCID: PMC9921456 DOI: 10.3390/nu15030524] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 01/05/2023] [Accepted: 01/11/2023] [Indexed: 01/20/2023] Open
Abstract
This scoping review aimed to summarise the effects of the ketone body β-hydroxybutyrate. The review details the revealed pathways and functional properties following its intervention in the context of neurodegenerative diseases. In this study, 5 research publications that met the inclusion and exclusion criteria were shortlisted. Following the intervention, we discovered a tendency of reduced inflammatory status in microglia, as evidenced by lower levels of pro-inflammatory mediators produced, reduced microgliosis in afflicted tissues, and enhanced cognitive functions in neurodegenerative models. We found that there is a significant overlap in the mechanism of action of β-hydroxybutyrate (BHB) via activation of the G-protein-Coupled Receptor 109A (GPR109a) receptor and deactivation of the inflammasome complex. Furthermore, although comparing outcomes can be challenging due to the heterogeneity in the study model, the results we have assembled here were consistent, giving us confidence in the intervention's efficacy. We also discussed new studies where BHB is involved in various roles in regulating inflammation in microglia, allowing for fresh therapeutic targets against neurodegeneration. This brief review provides evidence to support the huge potential of BHB in the treatment of neurodegenerative illnesses.
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Affiliation(s)
| | | | - Muhammad Luqman Nasaruddin
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre (UKM-MC), Kuala Lumpur 56000, Malaysia
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Feng C, Deng L, Yong YY, Wu JM, Qin DL, Yu L, Zhou XG, Wu AG. The Application of Biomaterials in Spinal Cord Injury. Int J Mol Sci 2023; 24:816. [PMID: 36614259 PMCID: PMC9821025 DOI: 10.3390/ijms24010816] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/19/2022] [Accepted: 12/30/2022] [Indexed: 01/05/2023] Open
Abstract
The spinal cord and the brain form the central nervous system (CNS), which is the most important part of the body. However, spinal cord injury (SCI) caused by external forces is one of the most difficult types of neurological injury to treat, resulting in reduced or even absent motor, sensory and autonomic functions. It leads to the reduction or even disappearance of motor, sensory and self-organizing nerve functions. Currently, its incidence is increasing each year worldwide. Therefore, the development of treatments for SCI is urgently needed in the clinic. To date, surgery, drug therapy, stem cell transplantation, regenerative medicine, and rehabilitation therapy have been developed for the treatment of SCI. Among them, regenerative biomaterials that use tissue engineering and bioscaffolds to transport cells or drugs to the injured site are considered the most promising option. In this review, we briefly introduce SCI and its molecular mechanism and summarize the application of biomaterials in the repair and regeneration of tissue in various models of SCI. However, there is still limited evidence about the treatment of SCI with biomaterials in the clinic. Finally, this review will provide inspiration and direction for the future study and application of biomaterials in the treatment of SCI.
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Affiliation(s)
| | | | | | | | | | | | - Xiao-Gang Zhou
- Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Key Laboratory of Medical Electrophysiology of Ministry of Education, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
| | - An-Guo Wu
- Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Key Laboratory of Medical Electrophysiology of Ministry of Education, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
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Zhang Y, Liu K, Li Y, Ma Y, Wang Y, Fan Z, Li Y, Qi J. D-beta-hydroxybutyrate protects against microglial activation in lipopolysaccharide-treated mice and BV-2 cells. Metab Brain Dis 2022; 38:1115-1126. [PMID: 36543978 DOI: 10.1007/s11011-022-01146-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022]
Abstract
Microglial activation is a key event in neuroinflammation, which, in turn, is a central process in neurological disorders. In this study, we investigated the protective effects of D-beta-hydroxybutyrate (BHB) against microglial activation in lipopolysaccharide (LPS)-treated mice and BV-2 cells. The effects of BHB in mice were assessed using behavioral testing, morphological analysis and immunofluorescence labeling for the microglial marker ionizing calcium-binding adaptor molecule 1 (IBA-1) and the inflammatory cytokine interleukin-6 (IL-6) in the hippocampus. Moreover, we examined the levels of the inflammatory IL-6 and tumor necrosis factor-α (TNF-α), as well as those of the neuroprotective brain-derived neurotrophic factor (BDNF) and transforming growth factor-β (TGF-β) in the brain. In addition, we examined the effects of BHB on IL-6, TNF-α, BDNF, TGF-β, reactive oxygen species (ROS) level and cell viability in LPS-stimulated BV-2 cells. BHB treatments attenuated behavioral abnormalities, reduced the number of IBA-1-positive cells and the intensity of IL-6 fluorescence in the hippocampus, with amelioration of microglia morphological changes in the LPS-treated mice. Furthermore, BHB inhibited IL-6 and TNF-α generation, but promoted BDNF and TGF-β production in the brain of LPS-treated mice. In vitro, BHB inhibited IL-6 and TNF-α generation, increased BDNF and TGF-β production, reduced ROS level, ameliorated morphological changes and elevated cell viability of LPS-stimulated BV-2 cells. Together, our findings suggest that BHB exerts protective effects against microglial activation in vitro and in vivo, thereby reducing neuroinflammation.
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Affiliation(s)
- Yuping Zhang
- Department of Molecular Biology, Hebei Key Lab of Laboratory Animal Science, Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, People's Republic of China
| | - Kun Liu
- Department of Biochemistry, College of Integrated Chinese and Western Medicine, Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, People's Republic of China
| | - Yunpeng Li
- Department of Molecular Biology, Hebei Key Lab of Laboratory Animal Science, Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, People's Republic of China
| | - Yujie Ma
- Department of Molecular Biology, Hebei Key Lab of Laboratory Animal Science, Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, People's Republic of China
| | - Yu Wang
- Department of Molecular Biology, Hebei Key Lab of Laboratory Animal Science, Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, People's Republic of China
| | - Zihan Fan
- Department of Biochemistry, College of Integrated Chinese and Western Medicine, Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, People's Republic of China
| | - Yanning Li
- Department of Molecular Biology, Hebei Key Lab of Laboratory Animal Science, Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, People's Republic of China.
| | - Jinsheng Qi
- Department of Biochemistry, College of Integrated Chinese and Western Medicine, Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, People's Republic of China.
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The Anti-Inflammatory Effect of Preventive Intervention with Ketogenic Diet Mediated by the Histone Acetylation of mGluR5 Promotor Region in Rat Parkinson’s Disease Model: A Dual-Tracer PET Study. PARKINSON'S DISEASE 2022; 2022:3506213. [PMID: 36105302 PMCID: PMC9467749 DOI: 10.1155/2022/3506213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 08/05/2022] [Indexed: 11/24/2022]
Abstract
Materials and Methods The neuroprotective effect of ketosis state prior to the onset of PD (preventive KD, KDp) was compared with that receiving KD after the onset (therapeutic KD, KDt) in the lipopolysaccharide- (LPS-) induced rat PD model. A total of 100 rats were randomly assigned to the following 4 groups: sham, LPS, LPS + KDp, and LPS + KDt groups. Results Significant dopamine deficient behaviors (rotational behavior and contralateral forelimb akinesia), upregulation of proinflammatory mediators (TNF-α, IL-1β, and IL-6), loss of dopaminergic neurons, reduction of mGluR5+ microglia cells, increase of TSPO+ microglia cells, reduction of H3K9 acetylation in the mGluR5 promoter region and mGluR5 mRNA expression, and decline in the phosphorylation levels of Akt/GSK-3β/CREB pathway were observed after the intervention of LPS (P < 0.01). TSPO and DAT PET imaging revealed the increased uptake of 18F-DPA-714 in substantia nigra and decreased uptake of 18F-FP-CIT in substantia nigra and striatum in LPS-treated rats (P < 0.001). These impairments were alleviated by the dietary intervention of KD, especially with the strategy of KDp (P < 0.05). Conclusions The anti-inflammatory effect of KD on PD was supposed to be related to the modulation of Akt/GSK-3β/CREB signaling pathway mediated by the histone acetylation of mGluR5 promotor region. The KD intervention should be initiated prior to the PD onset in high-risk population to achieve a more favorable outcome.
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Eller OC, Willits AB, Young EE, Baumbauer KM. Pharmacological and non-pharmacological therapeutic interventions for the treatment of spinal cord injury-induced pain. FRONTIERS IN PAIN RESEARCH 2022; 3:991736. [PMID: 36093389 PMCID: PMC9448954 DOI: 10.3389/fpain.2022.991736] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 08/05/2022] [Indexed: 11/29/2022] Open
Abstract
Spinal cord injury (SCI) is a complex neurophysiological disorder, which can result in many long-term complications including changes in mobility, bowel and bladder function, cardiovascular function, and metabolism. In addition, most individuals with SCI experience some form of chronic pain, with one-third of these individuals rating their pain as severe and unrelenting. SCI-induced chronic pain is considered to be "high impact" and broadly affects a number of outcome measures, including daily activity, physical and cognitive function, mood, sleep, and overall quality of life. The majority of SCI pain patients suffer from pain that emanates from regions located below the level of injury. This pain is often rated as the most severe and the underlying mechanisms involve injury-induced plasticity along the entire neuraxis and within the peripheral nervous system. Unfortunately, current therapies for SCI-induced chronic pain lack universal efficacy. Pharmacological treatments, such as opioids, anticonvulsants, and antidepressants, have been shown to have limited success in promoting pain relief. In addition, these treatments are accompanied by many adverse events and safety issues that compound existing functional deficits in the spinally injured, such as gastrointestinal motility and respiration. Non-pharmacological treatments are safer alternatives that can be specifically tailored to the individual and used in tandem with pharmacological therapies if needed. This review describes existing non-pharmacological therapies that have been used to treat SCI-induced pain in both preclinical models and clinical populations. These include physical (i.e., exercise, acupuncture, and hyper- or hypothermia treatments), psychological (i.e., meditation and cognitive behavioral therapy), and dietary interventions (i.e., ketogenic and anti-inflammatory diet). Findings on the effectiveness of these interventions in reducing SCI-induced pain and improving quality of life are discussed. Overall, although studies suggest non-pharmacological treatments could be beneficial in reducing SCI-induced chronic pain, further research is needed. Additionally, because chronic pain, including SCI pain, is complex and has both emotional and physiological components, treatment should be multidisciplinary in nature and ideally tailored specifically to the patient.
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Affiliation(s)
- Olivia C. Eller
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Adam B. Willits
- Department of Anesthesiology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Erin E. Young
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, United States
- Department of Anesthesiology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Kyle M. Baumbauer
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, United States
- Department of Anesthesiology, University of Kansas Medical Center, Kansas City, KS, United States
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Luo S, Yang M, Han Y, Zhao H, Jiang N, Li L, Chen W, Li C, Yang J, Liu Y, Liu C, Zhao C, Sun L. β-Hydroxybutyrate against Cisplatin-Induced acute kidney injury via inhibiting NLRP3 inflammasome and oxidative stress. Int Immunopharmacol 2022; 111:109101. [PMID: 35940076 DOI: 10.1016/j.intimp.2022.109101] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 07/18/2022] [Accepted: 07/25/2022] [Indexed: 02/07/2023]
Abstract
Cisplatin, as a commonly used anticancer drug, can easily lead to acute kidney injury (AKI), and has received more and more attention in clinical practice. β-hydroxybutyric acid (BHB) is a metabolite in the body and acts as an inhibitor of oxidative stress and NLRP3 inflammasome, reducing inflammatory responses and apoptosis. However, the role of BHB in cisplatin-induced AKI is currently not fully elucidated. In this study, C57BL/6 male mice were randomly divided into normal control group, cisplatin-induced AKI group and AKI with BHB treatment group. Compared to the control, cisplatin-treated mice exhibited high level of serum creatinine, blood urea nitrogen and severe tubular injury, which accompanied with significantly increased expression level of NLRP3, IL-1β, IL-18, BAX, cleaved-caspase 3, as well as aggravated oxidative stress and renal tubular cell apoptosis. However, these changes were significantly improved in that of BHB treatment. In vitro, our study showed that the expression of cleaved-caspase3, IL-1β and IL-18 were significantly increased in human proximal tubular epithelial cell line (HK-2) treated with cisplatin compared with the control group, while decreased in cells treated with BHB. Furthermore, a significantly increased expression of cGAS and STING in HK-2 cells treated with cisplatin were found, whereas notably decreased in cells treated with BHB. This data indicates that BHB protects against cisplatin-induced AKI and renal tubular damage mediated by NLRP3 inflammasome and cGAS-STING pathway.
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Affiliation(s)
- Shilu Luo
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Ming Yang
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Yachun Han
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Hao Zhao
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Na Jiang
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Li Li
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Wei Chen
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Chenrui Li
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Jinfei Yang
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Yan Liu
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Chongbin Liu
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Chanyue Zhao
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Lin Sun
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China.
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31
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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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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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Dai C, Liu B, Peng B, Qu B, Lin J, Peng B, Li DM. Entinostat Improves Motor Function and Neuronal Damage Via Downregulating NLRP3 Inflammasome Activation After Spinal Cord Injury. Front Pharmacol 2021; 12:774539. [PMID: 34899337 PMCID: PMC8664236 DOI: 10.3389/fphar.2021.774539] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Accepted: 10/25/2021] [Indexed: 01/11/2023] Open
Abstract
Background: Spinal cord injury (SCI), a major public health problem, has no effective treatment. A large number of studies have confirmed that histone deacetylases (HDACs) are involved in the physiologic processes that occur following SCI. We tried to uncover the potential neuroprotective role of entinostat (a class I HDAC inhibitor) in SCI. Methods: We conducted a study on a preclinical mouse model of SCI and OGD-induced neuronal damage to present the role of entinostat by the analysis of motor function, histopathologic damage, local NLRP3 inflammasome activation, and neuronal damage. Results: The results showed that entinostat suppressed HDAC activation (including HDAC1 and HDAC3 expression), improved the grip strength and BMS score, spinal edema, cell death, and local NLRP3 inflammasome activation in the spinal cord following SCI. Furthermore, entinostat significantly increased OGD-inhibited neuronal activity and decreased PI-positive cells, HDAC activation, caspase-1 activation, IL-1β and IL-18 levels, and NLRP3 expression. Conclusion: In summary, we first documented that entinostat improved the motor function, histopathologic damage, and local inflammatory response and NLRP3 inflammasome activation in the spinal cord following SCI and also presented the neuroprotective role of OGD-induced neuronal damage via the NLRP3 inflammasome. Thus, our study has the potential to reveal the interaction between the HDAC and NLRP3 inflammasome in the pathologic process as well as SCI and further promote the clinical indications of HDACi entinostat and clinical treatment for the inflammatory response after SCI.
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Affiliation(s)
- Chen Dai
- Orthopedics and Trauma Department, The 963rd (224th) Hospital of People’s Liberation Army, 963rd Hospital of Joint Logistics Support Force of PLA, Jiamusi, China
- Department of Orthopedics, The Third Medical Center, General Hospital of the Chinese People’s Liberation Army, Beijing, China
| | - Bin Liu
- Department of Orthopaedics, General Hospital of Northern Theater Command, Shenyang, China
| | - Bibo Peng
- Outpatient Department, The Third Medical Center of Chinese People’s Liberation Army General Hospital, Beijing, China
| | - Bo Qu
- Tianjin University, Tianjin Key Laboratory for Disaster and Emergency Medicine Technology, Tianjin, China
| | - Jiezhi Lin
- Military Burn Center, The 963rd (224th) Hospital of People’s Liberation Army, 963rd Hospital of Joint Logistics Support Force of PLA, Jiamusi, China
| | - Baogan Peng
- Department of Orthopedics, The Third Medical Center, General Hospital of the Chinese People’s Liberation Army, Beijing, China
| | - Duan-Ming Li
- Department of Orthopedics, The Third Medical Center, General Hospital of the Chinese People’s Liberation Army, Beijing, China
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Intrathecal implantation surgical considerations in rodents; a review. J Neurosci Methods 2021; 363:109327. [PMID: 34418443 DOI: 10.1016/j.jneumeth.2021.109327] [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: 01/20/2021] [Revised: 07/16/2021] [Accepted: 08/16/2021] [Indexed: 11/20/2022]
Abstract
Intrathecal access in humans is a routine clinical intervention. However, intrathecal access is limited to drug delivery purposes in rodents, and intrathecal implantation is not a common surgical practice. Preclinically, we have successfully adopted different intrathecal implantation surgical methods for different implant materials in rodents. However, employing the appropriate intrathecal implantation method is a challenging process for surgeons, which includes several steps such as preoperative evaluations and postoperative care. The aim of this review is to define and compare the major documented surgical approaches applicable for intrathecal implantation in rodents along with the associated side effects, as well as highlighting the critical preoperative and postoperative considerations. Overall, this review will provide surgeons with the principles of intrathecal implantation approaches applicable for different implant materials.
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Daines SA. The Therapeutic Potential and Limitations of Ketones in Traumatic Brain Injury. Front Neurol 2021; 12:723148. [PMID: 34777197 PMCID: PMC8579274 DOI: 10.3389/fneur.2021.723148] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 09/13/2021] [Indexed: 12/21/2022] Open
Abstract
Traumatic brain injury (TBI) represents a significant health crisis. To date, no FDA approved pharmacotherapies are available to prevent the neurological deficits caused by TBI. As an alternative to pharmacotherapy treatment of TBI, ketones could be used as a metabolically based therapeutic strategy. Ketones can help combat post-traumatic cerebral energy deficits while also reducing inflammation, oxidative stress, and neurodegeneration. Experimental models of TBI suggest that administering ketones to TBI patients may provide significant benefits to improve recovery. However, studies evaluating the effectiveness of ketones in human TBI are limited. Unanswered questions remain about age- and sex-dependent factors, the optimal timing and duration of ketone supplementation, and the optimal levels of circulating and cerebral ketones. Further research and improvements in metabolic monitoring technology are also needed to determine if ketone supplementation can improve TBI recovery outcomes in humans.
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Affiliation(s)
- Savannah Anne Daines
- Department of Biology, Utah State University, Logan, UT, United States
- Department of Kinesiology and Health Science, Utah State University, Logan, UT, United States
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Yang YR, Kwon KS. Potential Roles of Exercise-Induced Plasma Metabolites Linking Exercise to Health Benefits. Front Physiol 2020; 11:602748. [PMID: 33343398 PMCID: PMC7744613 DOI: 10.3389/fphys.2020.602748] [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: 09/04/2020] [Accepted: 11/19/2020] [Indexed: 12/30/2022] Open
Abstract
Regular exercise has a myriad of health benefits. An increase in circulating exercise factors following exercise is a critical physiological response. Numerous studies have shown that exercise factors released from tissues during physical activity may contribute to health benefits via autocrine, paracrine, and endocrine mechanisms. Myokines, classified as proteins secreted from skeletal muscle, are representative exercise factors. The roles of myokines have been demonstrated in a variety of exercise-related functions linked to health benefits. In addition to myokines, metabolites are also exercise factors. Exercise changes the levels of various metabolites via metabolic reactions. Several studies have identified exercise-induced metabolites that positively influence organ functions. Here, we provide an overview of selected metabolites secreted into the circulation upon exercise.
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Affiliation(s)
- Yong Ryoul Yang
- Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea
| | - Ki-Sun Kwon
- Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.,Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, South Korea
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