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Moldovan A, Wagner F, Schumacher F, Wigger D, Kessie DK, Rühling M, Stelzner K, Tschertok R, Kersting L, Fink J, Seibel J, Kleuser B, Rudel T. Chlamydia trachomatis exploits sphingolipid metabolic pathways during infection of phagocytes. mBio 2025; 16:e0398124. [PMID: 40249190 PMCID: PMC12077188 DOI: 10.1128/mbio.03981-24] [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: 01/13/2025] [Accepted: 02/19/2025] [Indexed: 04/19/2025] Open
Abstract
Chlamydiae are obligate intracellular pathogens that utilize host cell metabolites for catabolic and anabolic processes. The bacteria replicate in epithelial cells from which they take up sphingolipids (SL) and incorporate them into the chlamydial membrane and the vacuole (termed inclusion). SL uptake is essential for Chlamydia trachomatis (Ctr) in epithelial cells; however, they can also infect phagocytes, but the consequences for the SL metabolism have not yet been investigated in these cells. We performed a quantitative sphingolipidome analysis of infected primary neutrophils, macrophages, and immortalized fallopian tube epithelial cells. Sphingosine (Sph) levels are elevated in primary M2-like macrophages and human neutrophils infected with C. trachomatis. Human neutrophils respond to the pathogen by markedly upregulating sphingosine kinase 1 (SPHK1). We show in M2-like macrophages, by RNAseq, that two counteracting pathways involving upregulation of SPHK1, but also sphingosine-1-phosphate phosphatases 1 and 2 (SGPP1 and SGPP2) and sphingosine-1-phosphate lyase (SGPL1), maintain a steady pool of S1P. Using click chemistry, we show that exogenously added sphingomyelin (SM) and ceramide (Cer) are efficiently taken up into the chlamydial inclusion and are integrated into bacterial membranes in infected M2-like macrophages. Exogenous Sph reduces chlamydial infectivity, is transported into the inclusion lumen, and integrates into chlamydial membranes, suggesting that this particular SL species could represent a host defense mechanism. Taken together, our data indicate an important role for Sph/Sph kinase vs S1P/S1P phosphatase balance in infected phagocytes and a previously unrecognized role for sphingosine in the immune defense against chlamydial infection.IMPORTANCEChlamydia trachomatis (Ctr) is the leading cause of sexually transmitted diseases worldwide. Left untreated, it can cause severe complications such as blindness, pelvic inflammatory disease, or infertility. To date, no vaccines are available, and antibiotic treatment represents the only therapeutic approach to cure the infection. Limited access to antibiotics and displaced antibiotic intake increase the risk of developing recurring infections. Immune cells which fail to clear the infection and serve as a niche for chlamydial survival and replication, favor this outcome. Our research aims to elucidate the influence of sphingolipids (SL) during chlamydial infection, especially of phagocytic cells. Identifying relevant targets offers new strategies to develop alternative treatment methods.
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Affiliation(s)
- Adriana Moldovan
- Department of Microbiology, University of Würzburg, Würzburg, Bavaria, Germany
| | - Fabienne Wagner
- Department of Microbiology, University of Würzburg, Würzburg, Bavaria, Germany
| | - Fabian Schumacher
- Institute of Pharmacy, Freie Universität Berlin, Berlin, Berlin, Germany
| | - Dominik Wigger
- Institute of Pharmacy, Freie Universität Berlin, Berlin, Berlin, Germany
| | - David Komla Kessie
- Department of Microbiology, University of Würzburg, Würzburg, Bavaria, Germany
| | - Marcel Rühling
- Department of Microbiology, University of Würzburg, Würzburg, Bavaria, Germany
| | - Kathrin Stelzner
- Department of Microbiology, University of Würzburg, Würzburg, Bavaria, Germany
| | - Regina Tschertok
- Department of Microbiology, University of Würzburg, Würzburg, Bavaria, Germany
| | - Louise Kersting
- Institute of Organic Chemistry, University of Würzburg, Würzburg, Bavaria, Germany
| | - Julian Fink
- Institute of Organic Chemistry, University of Würzburg, Würzburg, Bavaria, Germany
| | - Jürgen Seibel
- Institute of Organic Chemistry, University of Würzburg, Würzburg, Bavaria, Germany
| | - Burkhard Kleuser
- Institute of Pharmacy, Freie Universität Berlin, Berlin, Berlin, Germany
| | - Thomas Rudel
- Department of Microbiology, University of Würzburg, Würzburg, Bavaria, Germany
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Bie X, Zhang M, Wang Q, Wang Y. An unraveled mystery: What's the role of brain sphingolipids in neurodegenerative and psychiatric disorders. Neurobiol Dis 2025; 207:106852. [PMID: 39986545 DOI: 10.1016/j.nbd.2025.106852] [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: 10/29/2024] [Revised: 02/18/2025] [Accepted: 02/19/2025] [Indexed: 02/24/2025] Open
Abstract
Sphingolipids are a class of lipids highly expressed in brain, especially in the myelin sheath of white matter. In recent years, with the development of lipidomics, the role of brain sphingolipids in neurological disorders have raised lots of interests due to their function in neuronal signal transduction and survival. Although not thoroughly investigated, some previous studies have indicated that sphingolipids homeostasis are closely linked to the etiology and development of some neurological disorders. For example, disrupted sphingolipids level have been found in clinic patients with neurological disorders, such as neurodegeneration and psychiatric disorders. Conversely, intervention of sphingolipids metabolism by modulating activity of related enzymes also could result in pathological deficits identified in neurological disorders. Moreover, the alteration of sphingolipids catabolic pathway in the brain could be partly represented in cerebrospinal fluid and blood tissues, which show diagnostic potential for neurological disorders. Therefore, our review aims to summarize and discuss the known contents of bioactive sphingolipid metabolism with their related studies in neurodegenerative and psychiatric disorders, to help understand the potential mechanism underlying sphingolipid regulation of neural function and provide possible directions for further study. The new perspectives in this promising field will open up new therapeutic options for neurological disorders.
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Affiliation(s)
- Xintian Bie
- Basic School of Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 260071, China
| | - Maoxing Zhang
- Basic School of Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 260071, China
| | - Qingyu Wang
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Ying Wang
- Basic School of Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 260071, China.
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Liu X, Liu X, Liu Y, Long A, Liu W, Sun S, Lu S, Wu X, Jia X, Jose PA, Wei Q, Jiang X, Zhang H, Yang Z. Intestinal Gastrin/CCKBR Axis Protects against Type 2 Diabetes by Reducing Intestinal Glucose Absorption through the PI3K/Akt/eIF4B Signaling Pathway. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2410032. [PMID: 39950948 PMCID: PMC11967862 DOI: 10.1002/advs.202410032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 12/31/2024] [Indexed: 04/05/2025]
Abstract
The Gastrin/CCKBR axis is essential for inhibiting intestinal sodium absorption, but its effects on intestinal glucose metabolism remain elusive. This study aims to determine the role of intestinal Gastrin/CCKBR on glucose absorption in the development of type 2 diabetes (T2D). Intestinal epithelial cell-specific Cckbr knockout mice and control wild-type mice are fed normal diet (ND, 10% fat) or high fat diet (HFD, 60% fat) to study the effect of intestinal Gastrin/CCKBR on blood glucose levels. Gastrin-SiO2 microspheres (20 mg kg-1 d-1) are designed so that gastrin specifically stimulates intestinal CCKBR, without its absorption into the circulation. Mice with silenced intestinal Cckbr has pre-diabetes mellitus (Pre-DM) that rapidly progressed into T2D when fed HFD. Moreover, Gastrin-SiO2 microspheres markedly reduce glucose absorption in duodenum obtained from patients with T2D. In mice with HFD-induced T2D, Gastrin-SiO2 microspheres reduce intestinal glucose absorption by down-regulating intestinal SGLT1 and GLUT2 expressions and stimulating incretin secretion. This study shows the important role of intestinal Gastrin/CCKBR in intestinal glucose absorption. Gastrin-SiO2 microspheres may be a promising strategy for the treatment of patients with T2D.
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Affiliation(s)
- Xue Liu
- Institute of Laboratory Animal Sciences (CAMS & PUMC)National Center of Technology Innovation for Animal ModelNational Human Diseases Animal Model Resource CenterNHC Key Laboratory of Human Disease Comparative MedicineBeijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases100021BeijingChina
- Department of Cardiologythe Second Affiliated HospitalSchool of MedicineZhejiang UniversityState Key Laboratory of Transvascular Implantation DevicesHeart Regeneration and Repair Key Laboratory Zhejiang Province310009HangzhouChina
| | - Xing Liu
- Institute of Laboratory Animal Sciences (CAMS & PUMC)National Center of Technology Innovation for Animal ModelNational Human Diseases Animal Model Resource CenterNHC Key Laboratory of Human Disease Comparative MedicineBeijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases100021BeijingChina
| | - Yunpeng Liu
- Institute of Laboratory Animal Sciences (CAMS & PUMC)National Center of Technology Innovation for Animal ModelNational Human Diseases Animal Model Resource CenterNHC Key Laboratory of Human Disease Comparative MedicineBeijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases100021BeijingChina
| | - Anxiong Long
- Institute of Laboratory Animal Sciences (CAMS & PUMC)National Center of Technology Innovation for Animal ModelNational Human Diseases Animal Model Resource CenterNHC Key Laboratory of Human Disease Comparative MedicineBeijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases100021BeijingChina
| | - Wei Liu
- Graduate School of Hebei North UniversityZhangjiakouHebei075031China
| | - Shiyun Sun
- Institute of Laboratory Animal Sciences (CAMS & PUMC)National Center of Technology Innovation for Animal ModelNational Human Diseases Animal Model Resource CenterNHC Key Laboratory of Human Disease Comparative MedicineBeijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases100021BeijingChina
| | - Shuaibing Lu
- Department of Colorectal SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical College100021BeijingChina
- State Key Laboratory of Molecular OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100021China
| | - Xianxian Wu
- Institute of Laboratory Animal Sciences (CAMS & PUMC)National Center of Technology Innovation for Animal ModelNational Human Diseases Animal Model Resource CenterNHC Key Laboratory of Human Disease Comparative MedicineBeijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases100021BeijingChina
| | - Xiaodi Jia
- Taihe County People's HospitalThe Taihe Hospital of Wannan Medical College21 Jiankang RoadTaihe CountyAnhui Province236600China
| | - Pedro A Jose
- Department of Pharmacology and PhysiologyThe George Washington University School of Medicine & Health SciencesWashingtonDC20052USA
- Department of MedicineDivision of Kidney Diseases & HypertensionThe George Washington University School of Medicine & Health SciencesWashingtonDC20052USA
| | - Qiang Wei
- Institute of Laboratory Animal Sciences (CAMS & PUMC)National Center of Technology Innovation for Animal ModelNational Human Diseases Animal Model Resource CenterNHC Key Laboratory of Human Disease Comparative MedicineBeijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases100021BeijingChina
| | - Xiaoliang Jiang
- Institute of Laboratory Animal Sciences (CAMS & PUMC)National Center of Technology Innovation for Animal ModelNational Human Diseases Animal Model Resource CenterNHC Key Laboratory of Human Disease Comparative MedicineBeijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases100021BeijingChina
| | - Haizeng Zhang
- Department of Colorectal SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical College100021BeijingChina
- State Key Laboratory of Molecular OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100021China
| | - Zhiwei Yang
- Institute of Laboratory Animal Sciences (CAMS & PUMC)National Center of Technology Innovation for Animal ModelNational Human Diseases Animal Model Resource CenterNHC Key Laboratory of Human Disease Comparative MedicineBeijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases100021BeijingChina
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Kalecký K, Buitrago L, Alarcon JM, Singh A, Bottiglieri T, Kaddurah-Daouk R, Hernández AI. Rescue of hippocampal synaptic plasticity and memory performance by Fingolimod (FTY720) in APP/PS1 model of Alzheimer's disease is accompanied by correction in metabolism of sphingolipids, polyamines, and phospholipid saturation composition. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.17.633452. [PMID: 39868189 PMCID: PMC11761635 DOI: 10.1101/2025.01.17.633452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
Previously, our metabolomic, transcriptomic, and genomic studies characterized the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimer's disease, and we demonstrated that FTY720, a sphingosine-1-phospahate receptor modulator approved for treatment of multiple sclerosis, recovers synaptic plasticity and memory in APP/PS1 mice. To further investigate how FTY720 rescues the pathology, we performed metabolomic analysis in brain, plasma, and liver of trained APP/PS1 and wild-type mice. APP/PS1 mice showed area-specific brain disturbances in polyamines, phospholipids, and sphingolipids. Most changes were completely or partially normalized in FTY720-treated subjects, indicating rebalancing the "sphingolipid rheostat", reactivating phosphatidylethanolamine synthesis via mitochondrial phosphatidylserine decarboxylase pathway, and normalizing polyamine levels that support mitochondrial activity. Synaptic plasticity and memory were rescued, with spermidine synthesis in temporal cortex best corresponding to hippocampal CA3-CA1 plasticity normalization. FTY720 effects, also reflected in other pathways, are consistent with promotion of mitochondrial function, synaptic plasticity, and anti-inflammatory environment, while reducing pro-apoptotic and pro-inflammatory signals.
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Affiliation(s)
- Karel Kalecký
- Center of Metabolomics, Institute of Metabolic Disease, Baylor Scott & White Research Institute, Dallas, TX, USA
| | - Luna Buitrago
- Neural and Behavioral Sciences Program, School of Graduate Studies, Department of Neurology/Pharmacology, SUNY Downstate Health Sciences University, Brooklyn, NY, USA
| | - Juan Marcos Alarcon
- Neural and Behavioral Sciences Program, School of Graduate Studies, The Robert F. Furchgott Center for Neural and Behavioral Science, Department of Pathology, SUNY Downstate Health Sciences University, Brooklyn, NY, USA
| | - Abanish Singh
- Department of Psychiatry and Behavioral Sciences; and Department of Medicine, Duke University School of Medicine, Durham, Durham, NC, USA
| | - Teodoro Bottiglieri
- Center of Metabolomics, Institute of Metabolic Disease, Baylor Scott & White Research Institute, Dallas, TX, USA
| | - Rima Kaddurah-Daouk
- Department of Psychiatry and Behavioural Sciences, Duke University, Durham, NC, USA
- Duke Institute of Brain Sciences, Duke University, Durham, NC, USA
- Department of Medicine, Duke University, Durham, NC, USA
| | - Alejandro Iván Hernández
- Neural and Behavioral Sciences Program, School of Graduate Studies, The Robert F. Furchgott Center for Neural and Behavioral Science, Department of Pathology, SUNY Downstate Health Sciences University, Brooklyn, NY, USA
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Gong J, Duan X, Xiang B, Qin L, Hu J. Transcriptomic changes in the hypothalamus of mice with chronic migraine: Activation of pathways associated with neuropathic inflammation and central sensitization. Mol Cell Neurosci 2024; 131:103968. [PMID: 39251101 DOI: 10.1016/j.mcn.2024.103968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 08/29/2024] [Accepted: 09/02/2024] [Indexed: 09/11/2024] Open
Abstract
Chronic migraine is a common central nervous system disorder characterized by recurrent, pulsating headaches. However, the extent and mechanisms of hypothalamic involvement in disease progression have not been thoroughly investigated. Herein, we created a chronic migraine mouse model using repeated intraperitoneal injections of nitroglycerin. We performed transcriptomic sequencing on the hypothalamus of mice with chronic migraine and control mice under normal physiological conditions, followed by differential gene set enrichment and functional analysis of the data. Additionally, we examined the intrinsic connection between chronic migraine and sleep disorders using transcriptomic sequencing data from sleep-deprived mice available in public databases. We identified 39 differentially expressed genes (DEGs) in the hypothalamus of a mouse model of chronic migraine. Functional analysis of DEGs revealed enrichment primarily in signaling transduction, immune-inflammatory responses, and the cellular microenvironment. A comparison of the transcriptomic data of sleep-deprived mice revealed two commonly expressed DEGs. Our findings indicate that the hypothalamic DEGs are primarily enriched in the PI3K/AKT/mTOR pathway and associated with the NF-κB/NLRP3/IL-1 β pathway activation to maintain the central sensitization of the chronic migraine. Chronic migraine-induced gene expression changes in the hypothalamus may help better understand the underlying mechanisms and identify therapeutic targets.
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Affiliation(s)
- Junyou Gong
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
| | - Xianghan Duan
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Biyu Xiang
- Department of Blood Transfusion, the First Hospital of Nanchang City, Nanchang, China
| | - Lijun Qin
- Department of Cardiology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
| | - Jiejie Hu
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China.
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Yu Z, Luo F. The Role of Reactive Oxygen Species in Alzheimer's Disease: From Mechanism to Biomaterials Therapy. Adv Healthc Mater 2024; 13:e2304373. [PMID: 38508583 DOI: 10.1002/adhm.202304373] [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: 12/09/2023] [Revised: 03/13/2024] [Indexed: 03/22/2024]
Abstract
Alzheimer's disease (AD) is a chronic, insidious, and progressive neurodegenerative disease that remains a clinical challenge for society. The fully approved drug lecanemab exhibits the prospect of therapy against the pathological processes, while debatable adverse events conflict with the drug concentration required for the anticipated therapeutic effects. Reactive oxygen species (ROS) are involved in the pathological progression of AD, as has been demonstrated in much research regarding oxidative stress (OS). The contradiction between anticipated dosage and adverse event may be resolved through targeted transport by biomaterials and get therapeutic effects through pathological progression via regulation of ROS. Besides, biomaterials fix delivery issues by promoting the penetration of drugs across the blood-brain barrier (BBB), protecting the drug from peripheral degradation, and elevating bioavailability. The goal is to comprehensively understand the mechanisms of ROS in the progression of AD disease and the potential of ROS-related biomaterials in the treatment of AD. This review focuses on OS and its connection with AD and novel biomaterials in recent years against AD via OS to inspire novel biomaterial development. Revisiting these biomaterials and mechanisms associated with OS in AD via thorough investigations presents a considerable potential and bright future for improving effective interventions for AD.
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Affiliation(s)
- Zhuohang Yu
- State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Feng Luo
- State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
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Fredman G, Serhan CN. Specialized pro-resolving mediators in vascular inflammation and atherosclerotic cardiovascular disease. Nat Rev Cardiol 2024; 21:808-823. [PMID: 38216693 DOI: 10.1038/s41569-023-00984-x] [Citation(s) in RCA: 38] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/07/2023] [Indexed: 01/14/2024]
Abstract
Timely resolution of the acute inflammatory response (or inflammation resolution) is an active, highly coordinated process that is essential to optimal health. Inflammation resolution is regulated by specific endogenous signalling molecules that function as 'stop signals' to terminate the inflammatory response when it is no longer needed; to actively promote healing, regeneration and tissue repair; and to limit pain. Specialized pro-resolving mediators are a superfamily of signalling molecules that initiate anti-inflammatory and pro-resolving actions. Without an effective and timely resolution response, inflammation can become chronic, a pathological state that is associated with many widely occurring human diseases, including atherosclerotic cardiovascular disease. Uncovering the mechanisms of inflammation resolution failure in cardiovascular diseases and identifying useful biomarkers for non-resolving inflammation are unmet needs. In this Review, we discuss the accumulating evidence that supports the role of non-resolving inflammation in atherosclerosis and the use of specialized pro-resolving mediators as therapeutic tools for the treatment of atherosclerotic cardiovascular disease. We highlight open questions about therapeutic strategies and mechanisms of disease to provide a framework for future studies on the prevention and treatment of atherosclerosis.
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Affiliation(s)
- Gabrielle Fredman
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA.
| | - Charles N Serhan
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anaesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
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Chen C, Shu Y, Yan C, Li H, Huang Z, Shen S, Liu C, Jiang Y, Huang S, Wang Z, Mei F, Qin F, Liu X, Qiu W. Astrocyte-derived clusterin disrupts glial physiology to obstruct remyelination in mouse models of demyelinating diseases. Nat Commun 2024; 15:7791. [PMID: 39242637 PMCID: PMC11379856 DOI: 10.1038/s41467-024-52142-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 08/26/2024] [Indexed: 09/09/2024] Open
Abstract
Multiple sclerosis (MS) is a debilitating demyelinating disease characterized by remyelination failure attributed to inadequate oligodendrocyte precursor cells (OPCs) differentiation and aberrant astrogliosis. A comprehensive cell atlas reanalysis of clinical specimens brings to light heightened clusterin (CLU) expression in a specific astrocyte subtype links to active lesions in MS patients. Our investigation reveals elevated astrocytic CLU levels in both active lesions of patient tissues and female murine MS models. CLU administration stimulates primary astrocyte proliferation while concurrently impeding astrocyte-mediated clearance of myelin debris. Intriguingly, CLU overload directly impedes OPC differentiation and induces OPCs and OLs apoptosis. Mechanistically, CLU suppresses PI3K-AKT signaling in primary OPCs via very low-density lipoprotein receptor. Pharmacological activation of AKT rescues the damage inflicted by excess CLU on OPCs and ameliorates demyelination in the corpus callosum. Furthermore, conditional knockout of CLU emerges as a promising intervention, showcasing improved remyelination processes and reduced severity in murine MS models.
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Affiliation(s)
- Chen Chen
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Department of Neurosurgery, Lingnan Hospital, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yaqing Shu
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Chengkai Yan
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Huilu Li
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zhenchao Huang
- Department of Neurosurgery, Lingnan Hospital, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - ShiShi Shen
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Chunxin Liu
- Department of Emergency, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yanjun Jiang
- Department of Anaesthesia and Intensive Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China
- Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Shixiong Huang
- Department of Neurology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, Hainan, China
| | - Zhanhang Wang
- Department of Neurology, 999 Brain Hospital, Guangzhou, China
| | - Feng Mei
- Department of Histology and Embryology, Third Military Medical University (Army Medical University), Chongqing, China
| | - Feng Qin
- Department of Neurosurgery, Lingnan Hospital, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
| | - Xiaodong Liu
- Department of Anaesthesia and Intensive Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
- Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China.
- Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Wei Qiu
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
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Iezhitsa I, Agarwal R, Agarwal P. Unveiling enigmatic essence of Sphingolipids: A promising avenue for glaucoma treatment. Vision Res 2024; 221:108434. [PMID: 38805893 DOI: 10.1016/j.visres.2024.108434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 05/05/2024] [Accepted: 05/06/2024] [Indexed: 05/30/2024]
Abstract
Treatment of glaucoma, the leading cause of irreversible blindness, remains challenging. The apoptotic loss of retinal ganglion cells (RGCs) in glaucoma is the pathological hallmark. Current treatments often remain suboptimal as they aim to halt RGC loss secondary to reduction of intraocular pressure. The pathophysiological targets for exploring direct neuroprotective approaches, therefore are highly relevant. Sphingolipids have emerged as significant target molecules as they are not only the structural components of various cell constituents, but they also serve as signaling molecules that regulate molecular pathways involved in cell survival and death. Investigations have shown that a critical balance among various sphingolipid species, particularly the ceramide and sphingosine-1-phosphate play a role in deciding the fate of the cell. In this review we briefly discuss the metabolic interconversion of sphingolipid species to get an insight into "sphingolipid rheostat", the dynamic balance among metabolites. Further we highlight the role of sphingolipids in the key pathophysiological mechanisms that lead to glaucomatous loss of RGCs. Lastly, we summarize the potential drug candidates that have been investigated for their neuroprotective effects in glaucoma via their effects on sphingolipid axis.
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Minamihata T, Takano-Kawabe K, Moriyama M. Inhibition of Sphingosine Kinase 1 Reduces Sphingosine-1-Phosphate and Exacerbates Amyloid-Beta-Induced Neuronal Cell Death in Mixed-Glial-Cell Culture. Neurol Int 2024; 16:709-730. [PMID: 39051215 PMCID: PMC11270188 DOI: 10.3390/neurolint16040054] [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: 04/30/2024] [Revised: 06/24/2024] [Accepted: 07/02/2024] [Indexed: 07/27/2024] Open
Abstract
In Alzheimer's disease (AD) pathology, the accumulation of amyloid-beta (Aβ), a main component of senile plaques, activates glial cells and causes neuroinflammation. Excessive neuroinflammation results in neuronal dropouts and finally produces the symptoms of AD. Recent studies suggest that disorder in sphingosine-1-phosphate (S1P) metabolism, especially the decreased expression of sphingosine kinase (SK)1, followed by the reduction in the amount of S1P, can be a promotive factor in AD onset. Thus, we explored the possibility that dysregulated S1P metabolism affects AD through the altered function in glial cells. We evaluated the effect of PF-543, a pharmacological inhibitor of SK1, on the inflammatory responses by lipopolysaccharide (LPS)-activated glial cells, microglia, and astrocytes. The treatment with PF-543 decreased the intracellular S1P content in glial cells. The PF-543 treatment enhanced the nitric oxide (NO) production in the LPS-treated neuron/glia mixed culture. Furthermore, we found that the augmented production of NO and reactive oxygen species (ROS) in the PF-543-treated astrocytes affected the microglial inflammatory responses through humoral factors in the experiment using an astrocyte-conditioned medium. The PF-543 treatment also decreased the microglial Aβ uptake and increased the number of injured neurons in the Aβ-treated neuron/glia mixed culture. These results suggest that a decrease in the glial S1P content can exacerbate neuroinflammation and neurodegeneration through altered glial cell functions.
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Affiliation(s)
| | | | - Mitsuaki Moriyama
- Laboratory of Integrative Physiology in Veterinary Sciences, Osaka Metropolitan University, Izumisano 598-8531, Osaka, Japan; (T.M.); (K.T.-K.)
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Santiago-Balmaseda A, Aguirre-Orozco A, Valenzuela-Arzeta IE, Villegas-Rojas MM, Pérez-Segura I, Jiménez-Barrios N, Hurtado-Robles E, Rodríguez-Hernández LD, Rivera-German ER, Guerra-Crespo M, Martinez-Fong D, Ledesma-Alonso C, Diaz-Cintra S, Soto-Rojas LO. Neurodegenerative Diseases: Unraveling the Heterogeneity of Astrocytes. Cells 2024; 13:921. [PMID: 38891053 PMCID: PMC11172252 DOI: 10.3390/cells13110921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Accepted: 05/22/2024] [Indexed: 06/20/2024] Open
Abstract
The astrocyte population, around 50% of human brain cells, plays a crucial role in maintaining the overall health and functionality of the central nervous system (CNS). Astrocytes are vital in orchestrating neuronal development by releasing synaptogenic molecules and eliminating excessive synapses. They also modulate neuronal excitability and contribute to CNS homeostasis, promoting neuronal survival by clearance of neurotransmitters, transporting metabolites, and secreting trophic factors. Astrocytes are highly heterogeneous and respond to CNS injuries and diseases through a process known as reactive astrogliosis, which can contribute to both inflammation and its resolution. Recent evidence has revealed remarkable alterations in astrocyte transcriptomes in response to several diseases, identifying at least two distinct phenotypes called A1 or neurotoxic and A2 or neuroprotective astrocytes. However, due to the vast heterogeneity of these cells, it is limited to classify them into only two phenotypes. This review explores the various physiological and pathophysiological roles, potential markers, and pathways that might be activated in different astrocytic phenotypes. Furthermore, we discuss the astrocyte heterogeneity in the main neurodegenerative diseases and identify potential therapeutic strategies. Understanding the underlying mechanisms in the differentiation and imbalance of the astrocytic population will allow the identification of specific biomarkers and timely therapeutic approaches in various neurodegenerative diseases.
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Affiliation(s)
- Alberto Santiago-Balmaseda
- Laboratorio de Patogénesis Molecular, Laboratorio 4 Edificio A4, Carrera Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Mexico City 54090, Mexico; (A.S.-B.); (A.A.-O.); (M.M.V.-R.); (I.P.-S.); (E.H.-R.); (L.D.R.-H.); (E.R.R.-G.)
| | - Annai Aguirre-Orozco
- Laboratorio de Patogénesis Molecular, Laboratorio 4 Edificio A4, Carrera Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Mexico City 54090, Mexico; (A.S.-B.); (A.A.-O.); (M.M.V.-R.); (I.P.-S.); (E.H.-R.); (L.D.R.-H.); (E.R.R.-G.)
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City 07360, Mexico; (I.E.V.-A.); (N.J.-B.); (D.M.-F.)
| | - Irais E. Valenzuela-Arzeta
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City 07360, Mexico; (I.E.V.-A.); (N.J.-B.); (D.M.-F.)
| | - Marcos M. Villegas-Rojas
- Laboratorio de Patogénesis Molecular, Laboratorio 4 Edificio A4, Carrera Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Mexico City 54090, Mexico; (A.S.-B.); (A.A.-O.); (M.M.V.-R.); (I.P.-S.); (E.H.-R.); (L.D.R.-H.); (E.R.R.-G.)
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de Mexico 11340, Mexico
| | - Isaac Pérez-Segura
- Laboratorio de Patogénesis Molecular, Laboratorio 4 Edificio A4, Carrera Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Mexico City 54090, Mexico; (A.S.-B.); (A.A.-O.); (M.M.V.-R.); (I.P.-S.); (E.H.-R.); (L.D.R.-H.); (E.R.R.-G.)
| | - Natalie Jiménez-Barrios
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City 07360, Mexico; (I.E.V.-A.); (N.J.-B.); (D.M.-F.)
| | - Ernesto Hurtado-Robles
- Laboratorio de Patogénesis Molecular, Laboratorio 4 Edificio A4, Carrera Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Mexico City 54090, Mexico; (A.S.-B.); (A.A.-O.); (M.M.V.-R.); (I.P.-S.); (E.H.-R.); (L.D.R.-H.); (E.R.R.-G.)
| | - Luis Daniel Rodríguez-Hernández
- Laboratorio de Patogénesis Molecular, Laboratorio 4 Edificio A4, Carrera Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Mexico City 54090, Mexico; (A.S.-B.); (A.A.-O.); (M.M.V.-R.); (I.P.-S.); (E.H.-R.); (L.D.R.-H.); (E.R.R.-G.)
| | - Erick R. Rivera-German
- Laboratorio de Patogénesis Molecular, Laboratorio 4 Edificio A4, Carrera Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Mexico City 54090, Mexico; (A.S.-B.); (A.A.-O.); (M.M.V.-R.); (I.P.-S.); (E.H.-R.); (L.D.R.-H.); (E.R.R.-G.)
| | - Magdalena Guerra-Crespo
- Laboratorio de Medicina Regenerativa, Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de Mexico, Mexico City 04510, Mexico;
| | - Daniel Martinez-Fong
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City 07360, Mexico; (I.E.V.-A.); (N.J.-B.); (D.M.-F.)
| | - Carlos Ledesma-Alonso
- Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de Mexico, Querétaro 76230, Mexico;
| | - Sofía Diaz-Cintra
- Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de Mexico, Querétaro 76230, Mexico;
| | - Luis O. Soto-Rojas
- Laboratorio de Patogénesis Molecular, Laboratorio 4 Edificio A4, Carrera Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Mexico City 54090, Mexico; (A.S.-B.); (A.A.-O.); (M.M.V.-R.); (I.P.-S.); (E.H.-R.); (L.D.R.-H.); (E.R.R.-G.)
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12
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Sukocheva OA, Neganova ME, Aleksandrova Y, Burcher JT, Chugunova E, Fan R, Tse E, Sethi G, Bishayee A, Liu J. Signaling controversy and future therapeutical perspectives of targeting sphingolipid network in cancer immune editing and resistance to tumor necrosis factor-α immunotherapy. Cell Commun Signal 2024; 22:251. [PMID: 38698424 PMCID: PMC11064425 DOI: 10.1186/s12964-024-01626-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 04/21/2024] [Indexed: 05/05/2024] Open
Abstract
Anticancer immune surveillance and immunotherapies trigger activation of cytotoxic cytokine signaling, including tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) pathways. The pro-inflammatory cytokine TNF-α may be secreted by stromal cells, tumor-associated macrophages, and by cancer cells, indicating a prominent role in the tumor microenvironment (TME). However, tumors manage to adapt, escape immune surveillance, and ultimately develop resistance to the cytotoxic effects of TNF-α. The mechanisms by which cancer cells evade host immunity is a central topic of current cancer research. Resistance to TNF-α is mediated by diverse molecular mechanisms, such as mutation or downregulation of TNF/TRAIL receptors, as well as activation of anti-apoptotic enzymes and transcription factors. TNF-α signaling is also mediated by sphingosine kinases (SphK1 and SphK2), which are responsible for synthesis of the growth-stimulating phospholipid, sphingosine-1-phosphate (S1P). Multiple studies have demonstrated the crucial role of S1P and its transmembrane receptors (S1PR) in both the regulation of inflammatory responses and progression of cancer. Considering that the SphK/S1P/S1PR axis mediates cancer resistance, this sphingolipid signaling pathway is of mechanistic significance when considering immunotherapy-resistant malignancies. However, the exact mechanism by which sphingolipids contribute to the evasion of immune surveillance and abrogation of TNF-α-induced apoptosis remains largely unclear. This study reviews mechanisms of TNF-α-resistance in cancer cells, with emphasis on the pro-survival and immunomodulatory effects of sphingolipids. Inhibition of SphK/S1P-linked pro-survival branch may facilitate reactivation of the pro-apoptotic TNF superfamily effects, although the role of SphK/S1P inhibitors in the regulation of the TME and lymphocyte trafficking should be thoroughly assessed in future studies.
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Affiliation(s)
- Olga A Sukocheva
- Department of Hepatology, Royal Adelaide Hospital, Adelaide, SA, 5000, Australia.
| | - Margarita E Neganova
- Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka, 142432, Russian Federation
- Arbuzov Institute of Organic and Physical Chemistry, Federal Research Center, Kazan Scientific Center, Russian Academy of Sciences, Kazan, 420088, Russian Federation
| | - Yulia Aleksandrova
- Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka, 142432, Russian Federation
- Arbuzov Institute of Organic and Physical Chemistry, Federal Research Center, Kazan Scientific Center, Russian Academy of Sciences, Kazan, 420088, Russian Federation
| | - Jack T Burcher
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, 34211, USA
| | - Elena Chugunova
- Arbuzov Institute of Organic and Physical Chemistry, Federal Research Center, Kazan Scientific Center, Russian Academy of Sciences, Kazan, 420088, Russian Federation
| | - Ruitai Fan
- Department of Radiation Oncology, Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Edmund Tse
- Department of Hepatology, Royal Adelaide Hospital, Adelaide, SA, 5000, Australia
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, 34211, USA.
| | - Junqi Liu
- Department of Radiation Oncology, Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
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13
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Liu J, Tan J, Tang B, Guo J. Unveiling the role of iPLA 2β in neurodegeneration: From molecular mechanisms to advanced therapies. Pharmacol Res 2024; 202:107114. [PMID: 38395207 DOI: 10.1016/j.phrs.2024.107114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 02/08/2024] [Accepted: 02/20/2024] [Indexed: 02/25/2024]
Abstract
Calcium-independent phospholipase A2β (iPLA2β), a member of the phospholipase A2 (PLA2s) superfamily, is encoded by the PLA2G6 gene. Mutations in the PLA2G6 gene have been identified as the primary cause of infantile neuroaxonal dystrophy (INAD) and, less commonly, as a contributor to Parkinson's disease (PD). Recent studies have revealed that iPLA2β deficiency leads to neuroinflammation, iron accumulation, mitochondrial dysfunction, lipid dysregulation, and other pathological changes, forming a complex pathogenic network. These discoveries shed light on potential mechanisms underlying PLA2G6-associated neurodegeneration (PLAN) and offer valuable insights for therapeutic development. This review provides a comprehensive analysis of the fundamental characteristics of iPLA2β, its association with neurodegeneration, the pathogenic mechanisms involved in PLAN, and potential targets for therapeutic intervention. It offers an overview of the latest advancements in this field, aiming to contribute to ongoing research endeavors and facilitate the development of effective therapies for PLAN.
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Affiliation(s)
- Jiabin Liu
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jieqiong Tan
- Centre for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410008, China
| | - Beisha Tang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jifeng Guo
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Centre for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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14
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Zhang Y, Pei Y, Sun Y, Yang X, Liang J, Yin Z, Liu QS, Zhou Q, Jiang G. AhR Agonistic Components in Urban Particulate Matter Regulate Astrocytic Activation and Function. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2024; 58:4571-4580. [PMID: 38430186 DOI: 10.1021/acs.est.4c00237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/03/2024]
Abstract
Exposure to atmospheric particulate matter (PM) has been found to accelerate the onset of neurological disorders via the induction of detrimental neuroinflammatory responses. To reveal how astrocytes respond to urban atmospheric PM stimulation, a commercially available standard reference material (SRM1648a) was tested in this study on the activation of rat cortical astrocytes. The results showed that SRM1648a stimulation induced both A1 and A2 phenotypes in astrocytes, as characterized by the exposure concentration-dependent increases in Fkbp5, Sphk1, S100a10, and Il6 mRNA levels. Studying the functional alterations of astrocytes indicated that the neurotrophic factors of Gdnf and Ngf were transcriptionally upregulated due to astrocytic A2-type activation. SRM1648a also promoted autonomous motility of astrocytes and elevated the expressions of chemokines. The aryl hydrocarbon receptor (AhR) agonistic components, such as polycyclic aromatic hydrocarbons (PAHs), were recognized to greatly contribute to SRM1648a-induced effects on astrocytes, which was confirmed by the attenuation of PM-disturbed astrocytic effects via AhR blockage. This study, for the first time, uncovered the direct regulation of urban atmospheric PM on astrocytic activation and function and traced the containing bioactive components (e.g., PAHs) with AhR agonistic activity. The findings provided new knowledge on understanding the ambiguous neurological disturbance from ambient fine PM pollution.
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Affiliation(s)
- Yuzhu Zhang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yao Pei
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yumiao Sun
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Xiaoxi Yang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Jiefeng Liang
- Shandong Key Laboratory of Environmental Processes and Health, School of Environmental Science and Engineering, Shandong University, Qingdao 266237, China
| | - Zhipeng Yin
- Shandong Key Laboratory of Environmental Processes and Health, School of Environmental Science and Engineering, Shandong University, Qingdao 266237, China
| | - Qian S Liu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Qunfang Zhou
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
- School of Environment, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
| | - Guibin Jiang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
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15
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Bai H, Zeng HM, Zhang QF, Hu YZ, Deng FF. Correlative factors of poor prognosis and abnormal cellular immune function in patients with Alzheimer's disease. World J Clin Cases 2024; 12:1063-1075. [PMID: 38464932 PMCID: PMC10921302 DOI: 10.12998/wjcc.v12.i6.1063] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 12/21/2023] [Accepted: 01/29/2024] [Indexed: 02/20/2024] Open
Abstract
BACKGROUND Alzheimer's disease (AD) is a serious disease causing human dementia and social problems. The quality of life and prognosis of AD patients have attracted much attention. The role of chronic immune inflammation in the pathogenesis of AD is becoming more and more important. AIM To study the relationship among cognitive dysfunction, abnormal cellular immune function, neuroimaging results and poor prognostic factors in patients. METHODS A retrospective analysis of 62 hospitalized patients clinical diagnosed with AD who were admitted to our hospital from November 2015 to November 2020. Collect cognitive dysfunction performance characteristics, laboratory test data and neuroimaging data from medical records within 24 h of admission, including Mini Mental State Examination Scale score, drawing clock test, blood T lymphocyte subsets, and neutrophils and lymphocyte ratio (NLR), disturbance of consciousness, extrapyramidal symptoms, electroencephalogram (EEG) and head nucleus magnetic spectroscopy (MRS) and other data. Multivariate logistic regression analysis was used to determine independent prognostic factors. the modified Rankin scale (mRS) was used to determine whether the prognosis was good. The correlation between drug treatment and prognostic mRS score was tested by the rank sum test. RESULTS Univariate analysis showed that abnormal cellular immune function, extrapyramidal symptoms, obvious disturbance of consciousness, abnormal EEG, increased NLR, abnormal MRS, and complicated pneumonia were related to the poor prognosis of AD patients. Multivariate logistic regression analysis showed that the decrease in the proportion of T lymphocytes in the blood after abnormal cellular immune function (odd ratio: 2.078, 95% confidence interval: 1.156-3.986, P < 0.05) was an independent risk factor for predicting the poor prognosis of AD. The number of days of donepezil treatment to improve cognitive function was negatively correlated with mRS score (r = 0.578, P < 0.05). CONCLUSION The decrease in the proportion of T lymphocytes may have predictive value for the poor prognosis of AD. It is recommended that the proportion of T lymphocytes < 55% is used as the cut-off threshold for predicting the poor prognosis of AD. The early and continuous drug treatment is associated with a good prognosis.
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Affiliation(s)
- Hua Bai
- Department of Neurology, The Third Affiliated Hospital of Guizhou Medical University in China, Duyun 558099, Guizhou Province, China
| | - Hong-Mei Zeng
- Department of Neurology, Guizhou Medical University, Duyun 558099, Guizhou Province, China
| | - Qi-Fang Zhang
- Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Yue-Zhi Hu
- Department of Neurology, Guizhou Medical University, Duyun 558099, Guizhou Province, China
| | - Fei-Fei Deng
- Department of Neurology, Guizhou Medical University, Duyun 558099, Guizhou Province, China
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Zhu L, Deng F, Bai D, Hou J, Jia Q, Zhang C, Ou K, Li S, Li XJ, Yin P. Loss of TDP-43 mediates severe neurotoxicity by suppressing PJA1 gene transcription in the monkey brain. Cell Mol Life Sci 2024; 81:16. [PMID: 38194085 PMCID: PMC11072099 DOI: 10.1007/s00018-023-05066-2] [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: 09/12/2023] [Revised: 11/19/2023] [Accepted: 11/27/2023] [Indexed: 01/10/2024]
Abstract
The nuclear loss and cytoplasmic accumulation of TDP-43 (TAR DNA/RNA binding protein 43) are pathological hallmarks of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Previously, we reported that the primate-specific cleavage of TDP-43 accounts for its cytoplasmic mislocalization in patients' brains. This prompted us to investigate further whether and how the loss of nuclear TDP-43 mediates neuropathology in primate brain. In this study, we report that TDP-43 knockdown at the similar effectiveness, induces more damage to neuronal cells in the monkey brain than rodent mouse. Importantly, the loss of TDP-43 suppresses the E3 ubiquitin ligase PJA1 expression in the monkey brain at transcriptional level, but yields an opposite upregulation of PJA1 in the mouse brain. This distinct effect is due to the species-dependent binding of nuclear TDP-43 to the unique promoter sequences of the PJA1 genes. Further analyses reveal that the reduction of PJA1 accelerates neurotoxicity, whereas overexpressing PJA1 diminishes neuronal cell death by the TDP-43 knockdown in vivo. Our findings not only uncover a novel primate-specific neurotoxic contribution to the loss of function theory of TDP-43 proteinopathy, but also underscore a potential therapeutic approach of PJA1 to the loss of nuclear TDP-43.
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Affiliation(s)
- Longhong Zhu
- Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, 510632, China
| | - Fuyu Deng
- Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, 510632, China
| | - Dazhang Bai
- Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, 510632, China
- Department of Neurology, Affiliated Hospital of North Sichuan Medical College, North Sichuan Medical College, Nanchong, 637000, China
- Institute of Neurological Diseases, North Sichuan Medical College, Nanchong, 637000, China
| | - Junqi Hou
- Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, 510632, China
| | - Qingqing Jia
- Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, 510632, China
| | - Chen Zhang
- Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, 510632, China
| | - Kaili Ou
- Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, 510632, China
| | - Shihua Li
- Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, 510632, China
- Ministry of Education Key Laboratory of CNS Regeneration, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, 510632, China
| | - Xiao-Jiang Li
- Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, 510632, China.
- Ministry of Education Key Laboratory of CNS Regeneration, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, 510632, China.
| | - Peng Yin
- Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, 510632, China.
- Ministry of Education Key Laboratory of CNS Regeneration, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, 510632, China.
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17
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Wang X, Li B, Yu X, Zhou Y, Wang K, Gao Y. Notoginsenoside R1 ameliorates the inflammation induced by amyloid‑β by suppressing SphK1‑mediated NF‑κB activation in PC12 cells. Mol Med Rep 2024; 29:16. [PMID: 38063180 PMCID: PMC10716814 DOI: 10.3892/mmr.2023.13139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 10/25/2023] [Indexed: 12/18/2023] Open
Abstract
Alzheimer's disease (AD) is the most common type of age‑related dementia, and causes progressive memory degradation, neuronal loss and brain atrophy. The pathological hallmarks of AD consist of amyloid‑β (Aβ) plaque accumulation and abnormal neurofibrillary tangles. Amyloid fibrils are constructed from Aβ peptides, which are recognized to assemble into toxic oligomers and exert cytotoxicity. The fibrillar Aβ‑protein fragment 25‑35 (Aβ25‑35) induces local inflammation, thereby exacerbating neuronal apoptosis. Notoginsenoside R1 (NGR1), one of the primary bioactive ingredients isolated from Panax notoginseng, exhibits effective anti‑inflammatory and anti‑oxidative activities. However, NGR1 pharmacotherapies targeting Aβ‑induced inflammation and cell injury cascade remain to be elucidated. The present study investigated the effect and mechanism of NGR1 in Aβ25‑35‑treated PC12 cells. NGR1 doses between 250 and 1,000 µg/ml significantly increased cell viability suppressed by 20 µM Aβ25‑35 peptide treatment. Notably, the present study demonstrated that Aβ25‑35 peptide‑induced sphingosine kinase 1 (SphK1) signaling activation was reduced after NGR1 treatment, further inhibiting the downstream NF‑κB inflammatory signaling pathway. In addition, administration of SphK1 inhibitor II (SKI‑II), a SphK1 inhibitor, also significantly reduced Aβ25‑35 peptide‑induced apoptosis and the ratio of NF‑κB p‑p65/p65. Furthermore, SphK1 knockdown in PC12 cells using small interfering RNA alleviated Aβ‑induced cell apoptosis and inflammation, suggesting a pivotal role of SphK1 signaling in the anti‑inflammatory effect of NGR1. In summary, NGR1 alleviated inflammation and apoptosis stimulated by Aβ25‑35 by inhibiting the SphK1/NF‑κB signaling pathway and may be a promising agent for future AD treatment.
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Affiliation(s)
- Xiaonan Wang
- Department of Geriatric Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Bei Li
- Department of Geriatric Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Xiaohong Yu
- Department of Geriatric Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Ye Zhou
- Department of Geriatric Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Kaile Wang
- Department of Geriatric Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Yue Gao
- Department of Geriatric Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
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Irún P, Carrera-Lasfuentes P, Sánchez-Luengo M, Belio Ú, Domper-Arnal MJ, Higuera GA, Hawkins M, de la Rosa X, Lanas A. Pharmacokinetics and Changes in Lipid Mediator Profiling after Consumption of Specialized Pro-Resolving Lipid-Mediator-Enriched Marine Oil in Healthy Subjects. Int J Mol Sci 2023; 24:16143. [PMID: 38003333 PMCID: PMC10671020 DOI: 10.3390/ijms242216143] [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: 10/14/2023] [Revised: 11/04/2023] [Accepted: 11/06/2023] [Indexed: 11/26/2023] Open
Abstract
Omega-3 polyunsaturated fatty acids (PUFAs) play a vital role in human health, well-being, and the management of inflammatory diseases. Insufficient intake of omega-3 is linked to disease development. Specialized pro-resolving mediators (SPMs) are derived from omega-3 PUFAs and expedite the resolution of inflammation. They fall into categories known as resolvins, maresins, protectins, and lipoxins. The actions of SPMs in the resolution of inflammation involve restricting neutrophil infiltration, facilitating the removal of apoptotic cells and cellular debris, promoting efferocytosis and phagocytosis, counteracting the production of pro-inflammatory molecules like chemokines and cytokines, and encouraging a pro-resolving macrophage phenotype. This is an experimental pilot study in which ten healthy subjects were enrolled and received a single dose of 6 g of an oral SPM-enriched marine oil emulsion. Peripheral blood was collected at baseline, 3, 6, 9, 12, and 24 h post-administration. Temporal increases in plasma and serum SPM levels were found by using LC-MS/MS lipid profiling. Additionally, we characterized the temporal increases in omega-3 levels and established fundamental pharmacokinetics in both aforementioned matrices. These findings provide substantial evidence of the time-dependent elevation of SPMs, reinforcing the notion that oral supplementation with SPM-enriched products represents a valuable source of essential bioactive SPMs.
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Affiliation(s)
- Pilar Irún
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), 50009 Zaragoza, Spain; (P.C.-L.); (M.J.D.-A.); (A.L.)
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), 50009 Zaragoza, Spain;
- Centro Mixto de Investigación con Empresas (CEMINEM), Campus Rio Ebro, Universidad de Zaragoza, 50018 Zaragoza, Spain; (Ú.B.); (G.A.H.); (M.H.)
| | - Patricia Carrera-Lasfuentes
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), 50009 Zaragoza, Spain; (P.C.-L.); (M.J.D.-A.); (A.L.)
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), 50009 Zaragoza, Spain;
- Faculty of Health Sciences, Campus Universitario Villanueva de Gállego, Universidad San Jorge, Villanueva de Gállego, 50830 Zaragoza, Spain
| | - Marta Sánchez-Luengo
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), 50009 Zaragoza, Spain;
- Service of Digestive Diseases, Hospital Clínico Universitario Lozano Blesa, 50009 Zaragoza, Spain
| | - Úrsula Belio
- Centro Mixto de Investigación con Empresas (CEMINEM), Campus Rio Ebro, Universidad de Zaragoza, 50018 Zaragoza, Spain; (Ú.B.); (G.A.H.); (M.H.)
- SOLUTEX GC, SL., 50180 Zaragoza, Spain
| | - María José Domper-Arnal
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), 50009 Zaragoza, Spain; (P.C.-L.); (M.J.D.-A.); (A.L.)
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), 50009 Zaragoza, Spain;
- Service of Digestive Diseases, Hospital Clínico Universitario Lozano Blesa, 50009 Zaragoza, Spain
| | - Gustavo A. Higuera
- Centro Mixto de Investigación con Empresas (CEMINEM), Campus Rio Ebro, Universidad de Zaragoza, 50018 Zaragoza, Spain; (Ú.B.); (G.A.H.); (M.H.)
- SOLUTEX GC, SL., 50180 Zaragoza, Spain
| | - Malena Hawkins
- Centro Mixto de Investigación con Empresas (CEMINEM), Campus Rio Ebro, Universidad de Zaragoza, 50018 Zaragoza, Spain; (Ú.B.); (G.A.H.); (M.H.)
- SOLUTEX GC, SL., 50180 Zaragoza, Spain
| | - Xavier de la Rosa
- Centro Mixto de Investigación con Empresas (CEMINEM), Campus Rio Ebro, Universidad de Zaragoza, 50018 Zaragoza, Spain; (Ú.B.); (G.A.H.); (M.H.)
- SOLUTEX GC, SL., 50180 Zaragoza, Spain
| | - Angel Lanas
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), 50009 Zaragoza, Spain; (P.C.-L.); (M.J.D.-A.); (A.L.)
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), 50009 Zaragoza, Spain;
- Centro Mixto de Investigación con Empresas (CEMINEM), Campus Rio Ebro, Universidad de Zaragoza, 50018 Zaragoza, Spain; (Ú.B.); (G.A.H.); (M.H.)
- Service of Digestive Diseases, Hospital Clínico Universitario Lozano Blesa, 50009 Zaragoza, Spain
- Departamento de Medicina, Psiquiatría y Dermatología, Facultad de Medicina, Campus Plaza San Francisco, Universidad de Zaragoza, 50009 Zaragoza, Spain
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Spanos F, Deleidi M. Glycolipids in Parkinson's disease: beyond neuronal function. FEBS Open Bio 2023; 13:1558-1579. [PMID: 37219461 PMCID: PMC10476577 DOI: 10.1002/2211-5463.13651] [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: 03/13/2023] [Revised: 05/10/2023] [Accepted: 05/22/2023] [Indexed: 05/24/2023] Open
Abstract
Glycolipid balance is key to normal body function, and its alteration can lead to a variety of diseases involving multiple organs and tissues. Glycolipid disturbances are also involved in Parkinson's disease (PD) pathogenesis and aging. Increasing evidence suggests that glycolipids affect cellular functions beyond the brain, including the peripheral immune system, intestinal barrier, and immunity. Hence, the interplay between aging, genetic predisposition, and environmental exposures could initiate systemic and local glycolipid changes that lead to inflammatory reactions and neuronal dysfunction. In this review, we discuss recent advances in the link between glycolipid metabolism and immune function and how these metabolic changes can exacerbate immunological contributions to neurodegenerative diseases, with a focus on PD. Further understanding of the cellular and molecular mechanisms that control glycolipid pathways and their impact on both peripheral tissues and the brain will help unravel how glycolipids shape immune and nervous system communication and the development of novel drugs to prevent PD and promote healthy aging.
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Affiliation(s)
- Fokion Spanos
- Institut Imagine, INSERM UMR1163Paris Cité UniversityFrance
- Aligning Science Across Parkinson's (ASAP) Collaborative Research NetworkChevy ChaseMDUSA
| | - Michela Deleidi
- Institut Imagine, INSERM UMR1163Paris Cité UniversityFrance
- Aligning Science Across Parkinson's (ASAP) Collaborative Research NetworkChevy ChaseMDUSA
- Department of Neurodegenerative Diseases, Center of Neurology, Hertie Institute for Clinical Brain ResearchUniversity of TübingenGermany
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Lee M, Lee SY, Bae YS. Functional roles of sphingolipids in immunity and their implication in disease. Exp Mol Med 2023; 55:1110-1130. [PMID: 37258585 PMCID: PMC10318102 DOI: 10.1038/s12276-023-01018-9] [Citation(s) in RCA: 48] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/14/2023] [Accepted: 03/16/2023] [Indexed: 06/02/2023] Open
Abstract
Sphingolipids, which are components of cellular membranes and organ tissues, can be synthesized or degraded to modulate cellular responses according to environmental cues, and the balance among the different sphingolipids is important for directing immune responses, regardless of whether they originate, as intra- or extracellular immune events. Recent progress in multiomics-based analyses and methodological approaches has revealed that human health and diseases are closely related to the homeostasis of sphingolipid metabolism, and disease-specific alterations in sphingolipids and related enzymes can be prognostic markers of human disease progression. Accumulating human clinical data from genome-wide association studies and preclinical data from disease models provide support for the notion that sphingolipids are the missing pieces that supplement our understanding of immune responses and diseases in which the functions of the involved proteins and nucleotides have been established. In this review, we analyze sphingolipid-related enzymes and reported human diseases to understand the important roles of sphingolipid metabolism. We discuss the defects and alterations in sphingolipid metabolism in human disease, along with functional roles in immune cells. We also introduce several methodological approaches and provide summaries of research on sphingolipid modulators in this review that should be helpful in studying the roles of sphingolipids in preclinical studies for the investigation of experimental and molecular medicines.
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Affiliation(s)
- Mingyu Lee
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06355, Republic of Korea
| | - Suh Yeon Lee
- Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Yoe-Sik Bae
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06355, Republic of Korea.
- Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
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Jiang ZJ, Gong LW. The SphK1/S1P Axis Regulates Synaptic Vesicle Endocytosis via TRPC5 Channels. J Neurosci 2023; 43:3807-3824. [PMID: 37185099 PMCID: PMC10217994 DOI: 10.1523/jneurosci.1494-22.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 04/13/2023] [Accepted: 04/17/2023] [Indexed: 05/17/2023] Open
Abstract
Sphingosine-1-phosphate (S1P), a bioactive sphingolipid concentrated in the brain, is essential for normal brain functions, such as learning and memory and feeding behaviors. Sphingosine kinase 1 (SphK1), the primary kinase responsible for S1P production in the brain, is abundant within presynaptic terminals, indicating a potential role of the SphK1/S1P axis in presynaptic physiology. Altered S1P levels have been highlighted in many neurologic diseases with endocytic malfunctions. However, it remains unknown whether the SphK1/S1P axis may regulate synaptic vesicle endocytosis in neurons. The present study evaluates potential functions of the SphK1/S1P axis in synaptic vesicle endocytosis by determining effects of a dominant negative catalytically inactive SphK1. Our data for the first time identify a critical role of the SphK1/S1P axis in endocytosis in both neuroendocrine chromaffin cells and neurons from mice of both sexes. Furthermore, our Ca2+ imaging data indicate that the SphK1/S1P axis may be important for presynaptic Ca2+ increases during prolonged stimulations by regulating the Ca2+ permeable TRPC5 channels, which per se regulate synaptic vesicle endocytosis. Collectively, our data point out a critical role of the regulation of TRPC5 by the SphK1/S1P axis in synaptic vesicle endocytosis.SIGNIFICANCE STATEMENT Sphingosine kinase 1 (SphK1), the primary kinase responsible for brain sphingosine-1-phosphate (S1P) production, is abundant within presynaptic terminals. Altered SphK1/S1P metabolisms has been highlighted in many neurologic disorders with defective synaptic vesicle endocytosis. However, whether the SphK1/S1P axis may regulate synaptic vesicle endocytosis is unknown. Here, we identify that the SphK1/S1P axis regulates the kinetics of synaptic vesicle endocytosis in neurons, in addition to controlling fission-pore duration during single vesicle endocytosis in neuroendocrine chromaffin cells. The regulation of the SphK1/S1P axis in synaptic vesicle endocytosis is specific since it has a distinguished signaling pathway, which involves regulation of Ca2+ influx via TRPC5 channels. This discovery may provide novel mechanistic implications for the SphK1/S1P axis in brain functions under physiological and pathologic conditions.
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Affiliation(s)
- Zhong-Jiao Jiang
- Department of Biological Sciences, University of Illinois Chicago, Chicago, Illinois 60607
| | - Liang-Wei Gong
- Department of Biological Sciences, University of Illinois Chicago, Chicago, Illinois 60607
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Rastegar-Moghaddam SH, Ebrahimzadeh-Bideskan A, Shahba S, Malvandi AM, Mohammadipour A. Roles of the miR-155 in Neuroinflammation and Neurological Disorders: A Potent Biological and Therapeutic Target. Cell Mol Neurobiol 2023; 43:455-467. [PMID: 35107690 PMCID: PMC11415209 DOI: 10.1007/s10571-022-01200-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 01/23/2022] [Indexed: 12/19/2022]
Abstract
Neuroinflammation plays a crucial role in the development and progression of neurological disorders. MicroRNA-155 (miR-155), a miR is known to play in inflammatory responses, is associated with susceptibility to inflammatory neurological disorders and neurodegeneration, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis as well as epilepsy, stroke, and brain malignancies. MiR-155 damages the central nervous system (CNS) by enhancing the expression of pro-inflammatory cytokines, like IL-1β, IL-6, TNF-α, and IRF3. It also disturbs the blood-brain barrier by decreasing junctional complex molecules such as claudin-1, annexin-2, syntenin-1, and dedicator of cytokinesis 1 (DOCK-1), a hallmark of many neurological disorders. This review discusses the molecular pathways which involve miR-155 as a critical component in the progression of neurological disorders, representing miR-155 as a viable therapeutic target.
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Affiliation(s)
- Seyed Hamidreza Rastegar-Moghaddam
- Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, PO Box 91779-48564, Mashhad, Iran
- Applied Biomedical Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Ebrahimzadeh-Bideskan
- Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, PO Box 91779-48564, Mashhad, Iran
- Applied Biomedical Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sara Shahba
- Medical Biotechnology Research Center, School of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Amir Mohammad Malvandi
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Via Riccardo Galeazzi, 4, 20161, Milan, Italy.
| | - Abbas Mohammadipour
- Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, PO Box 91779-48564, Mashhad, Iran.
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Ding N, Meng Y, Liu L, Ma S, Chen Y. Sphingosine Kinase-1 (SPHK1) promotes inflammation in infantile pneumonia by regulating NLRP3 inflammasome and SIRT1 expression. Histol Histopathol 2022; 37:1227-1240. [PMID: 35796424 DOI: 10.14670/hh-18-491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Infantile pneumonia is an acute inflammatory disorder of the lung caused by mycoplasma pneumonia. SPHK1 (sphingosine kinase-1) signaling pathway is involved in the process of inflammatory diseases. However, whether SphK1 regulates inflammatory responses in infantile pneumonia remains unclear. In this study, we investigated the role of SPHK1 in infantile pneumonia and its underlying mechanisms. METHODS Serum samples of 12 patients with infantile pneumonia and healthy controls were obtained from Hunan Children's Hospital. To induce pneumonia, mice were administrated with LPS (lipopolysaccharide) into the lung. RAW264.7 cells were used as an in vitro macrophage model stimulated with LPS or PBS for 4 h. RESULTS SPHK1 mRNA level and protein level in the LPS-treated mice and patients with infantile pneumonia were significantly increased. SPHK1 promoted inflammation and lung injury in mice with infantile pneumonia. The knockdown of SPHK1 expression inhibited inflammation and restrained lung injury in mice with infantile pneumonia. SPHK1 overexpression also exacerbated inflammation in RAW264.7 cells stimulated by LPS, and SPHK1 silencing reduced inflammatory responses. We further showed that SPHK1 induced NLRP3 (NLR Family Pyrin Domain Containing 3) activity by inhibiting SIRT1 expression. CONCLUSION Our study demonstrated that SPHK1 promotes inflammation of infantile pneumonia by modulating NLRP3 inflammasome via the regulation of SIRT1 expression and mitochondrial permeability transition.
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Affiliation(s)
- Niu Ding
- Department of Respiratory Medicine, Hunan Children's Hospital, Changsha, Hunan Province, PR China
| | - Yanni Meng
- Department of Respiratory Medicine, Hunan Children's Hospital, Changsha, Hunan Province, PR China
| | - Lianhong Liu
- Department of Respiratory Medicine, Hunan Children's Hospital, Changsha, Hunan Province, PR China
| | - Song Ma
- College of Clinical Medicine, Hunan University of Traditional Chinese Medicine, Changsha, Hunan Province, PR China
| | - Yanping Chen
- Department of Respiratory Medicine, Hunan Children's Hospital, Changsha, Hunan Province, PR China.
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24
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Metabolic and Cellular Compartments of Acetyl-CoA in the Healthy and Diseased Brain. Int J Mol Sci 2022; 23:ijms231710073. [PMID: 36077475 PMCID: PMC9456256 DOI: 10.3390/ijms231710073] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 08/29/2022] [Accepted: 08/31/2022] [Indexed: 11/25/2022] Open
Abstract
The human brain is characterised by the most diverse morphological, metabolic and functional structure among all body tissues. This is due to the existence of diverse neurons secreting various neurotransmitters and mutually modulating their own activity through thousands of pre- and postsynaptic interconnections in each neuron. Astroglial, microglial and oligodendroglial cells and neurons reciprocally regulate the metabolism of key energy substrates, thereby exerting several neuroprotective, neurotoxic and regulatory effects on neuronal viability and neurotransmitter functions. Maintenance of the pool of mitochondrial acetyl-CoA derived from glycolytic glucose metabolism is a key factor for neuronal survival. Thus, acetyl-CoA is regarded as a direct energy precursor through the TCA cycle and respiratory chain, thereby affecting brain cell viability. It is also used for hundreds of acetylation reactions, including N-acetyl aspartate synthesis in neuronal mitochondria, acetylcholine synthesis in cholinergic neurons, as well as divergent acetylations of several proteins, peptides, histones and low-molecular-weight species in all cellular compartments. Therefore, acetyl-CoA should be considered as the central point of metabolism maintaining equilibrium between anabolic and catabolic pathways in the brain. This review presents data supporting this thesis.
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Hamidzadeh K, Westcott J, Wourms N, Shay AE, Panigrahy A, Martin MJ, Nshimiyimana R, Serhan CN. A newly synthesized 17-epi-NeuroProtectin D1/17-epi-Protectin D1: Authentication and functional regulation of Inflammation-Resolution. Biochem Pharmacol 2022; 203:115181. [PMID: 35850309 PMCID: PMC9398963 DOI: 10.1016/j.bcp.2022.115181] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 07/12/2022] [Accepted: 07/13/2022] [Indexed: 12/15/2022]
Abstract
The production of specialized pro-resolving mediators (SPMs) during the resolution phase in the inflammatory milieu is key to orchestrating the resolution of the acute inflammatory response. 17-epi-neuroprotectin D1/17-epi-protectin D1 (17-epi-NPD1/17-epi-PD1: 10R,17R-dihydroxy-4Z,7Z,11E,13E,15Z,19Z-docosahexaenoic acid) is an SPM of the protectin family, biosynthesized from docosahexaenoic acid (DHA), that exhibits both potent anti-inflammatory and neuroprotective functions. Here, we carried out a new commercial-scale synthesis of 17-epi-NPD1/17-epi-PD1 that enabled the authentication and confirmation of its potent bioactions in vivo and determination of its ability to activate human leukocyte phagocytosis. We provide evidence that this new synthetic 17-epi-NPD1/17-epi-PD1 statistically significantly increases human macrophage uptake of E. coli in vitro and confirm that it limits neutrophilic infiltration in vivo in a murine model of peritonitis. The physical properties of the new synthetic 17-epi-NPD1/17-epi-PD1, namely its ultra-violet absorbance, chromatography, and tandem mass spectrometry fragmentation pattern, matched those of the originally synthesized 17-epi-NPD1/17-epi-PD1. In addition, we verified the structure and complete stereochemical assignment of this new synthetic 17-epi-NPD1/17-epi-PD1 using nuclear magnetic resonance (NMR) spectroscopy. Together, these results authenticate this 17-epi-NPD1/17-epi-PD1 for its structure and potent pro-resolving functions.
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Affiliation(s)
- Kajal Hamidzadeh
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | | | | | - Ashley E Shay
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Anand Panigrahy
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | | | - Robert Nshimiyimana
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Charles N Serhan
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
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Huo C, Chen MH, Hour TC, Huang LC, Fong YO, Kuo YY, Yang YH, Chuu CP. Application of Micro-Western Array for Identifying Different Serum Protein Expression Profile among Healthy Control, Alzheimer’s Disease Patients and Patients’ Adult Children. Brain Sci 2022; 12:brainsci12091134. [PMID: 36138870 PMCID: PMC9496696 DOI: 10.3390/brainsci12091134] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 08/17/2022] [Accepted: 08/23/2022] [Indexed: 12/03/2022] Open
Abstract
(1) Background: Alzheimer’s disease (AD) is the most common form of dementia. Increased levels of inflammatory proteins have been observed in brain and plasma samples of AD patients; however, it is not clear if other serum proteins correlate to the development or disease progression of AD. (2) Methods: Micro-Western Array (MWA) is a high-throughput antibody-based proteomics system which allows detection of the expression levels of 24–96 different proteins within 6–30 samples simultaneously. We applied MWA to explore potential serum protein biomarkers correlated to the development and progression of AD by examining the difference in serum protein profile of 31 healthy control (HC), 30 patients with AD and 30 patients’ adult children (ACS). (3) Results: Compared to HC, AD and ACS express similar pattern of serum proteins, including higher protein levels of ABCA1, ABCG1, SREBP1 and LXRβ but lower protein levels of ApoD, ApoE, ApoH, c_Myc, COX2 and Hippo-YAP signaling proteins. AD patients had higher serum levels of ABCG1, ApoD, ApoH, COX2, LXRα and YAP, but lower levels of ABCA1, ApoE, c_Myc, LATS1, MST1, MST2, Nanog, NFκB_p50, PPARγ and SREBP2, as compared to ACS. Pearson’s correlation analysis revealed that the protein expression level of ApoE, c_Myc, LATS1, MST2, NFκB p50, PPARγ and SREBP1 was negatively correlated to age, while that of ApoE, c_Myc, LATS1, MST1, MST2, Nanog, NFκB p50 and PPARγ was positively correlated to age. (4) Conclusions: We identified a group of serum proteins which may correlate to disease progression of AD and can be potential diagnostic serum protein biomarkers.
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Affiliation(s)
- Chieh Huo
- Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 35053, Taiwan
| | - Ming-Hui Chen
- Neuroscience Research Center, Kaohsiung Medical University, Kaohsiung City 80708, Taiwan
| | - Tzyh-Chyuan Hour
- Neuroscience Research Center, Kaohsiung Medical University, Kaohsiung City 80708, Taiwan
- Department of Biochemistry, School of Medicine, Kaohsiung Medical University, Kaohsiung City 80708, Taiwan
| | - Ling-Chun Huang
- Department of Biochemistry, School of Medicine, Kaohsiung Medical University, Kaohsiung City 80708, Taiwan
- Department of Neurology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung City 80145, Taiwan
- Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung City 80756, Taiwan
| | - Yi-On Fong
- Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung City 80756, Taiwan
| | - Ying-Yu Kuo
- Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 35053, Taiwan
| | - Yuan-Han Yang
- Neuroscience Research Center, Kaohsiung Medical University, Kaohsiung City 80708, Taiwan
- Department of Neurology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung City 80145, Taiwan
- Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung City 80756, Taiwan
- School of Post-Baccalaureate Medicine, Kaohsiung Medical University, Kaohsiung City 80708, Taiwan
- Correspondence: (Y.-H.Y.); (C.-P.C.); Tel.: +886-7-3162-158 (Y.-H.Y.); +886-37-206-166 (ext. 37300) (C.-P.C.)
| | - Chih-Pin Chuu
- Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 35053, Taiwan
- Department of Life Sciences, National Central University, Taoyuan City 32031, Taiwan
- PhD Program for Aging, Graduate Institute of Basic Medical Science, China Medical University, Taichung City 40402, Taiwan
- Biotechnology Center, National Chung Hsing University, Taichung City 40227, Taiwan
- Correspondence: (Y.-H.Y.); (C.-P.C.); Tel.: +886-7-3162-158 (Y.-H.Y.); +886-37-206-166 (ext. 37300) (C.-P.C.)
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Abstract
OBJECTIVE This review aims to summarize the capability of lipoxin in regulating oxidative stress. BACKGROUND Oxidative stress is defined as an imbalance between the production of free radicals and the antioxidant system, and it is associated with the existence of a large number of oxidation products, such as reactive oxygen species (ROS) and reaction nitrogen species (RNS), causing damage to human tissues through immunoinflammatory responses. Therefore, reducing oxidative stress is vital to alleviate pathological damage. Lipoxin, an acronym for lipoxygenase interaction product, is a bioactive autacoid metabolite of arachidonic acid made by various cell types. Previous studies have shown that lipoxin is associated with a variety of biological functions, including anti-inflammatory, regulating immune responses, promoting the repair of damaged cells, etc. The deficiency of lipoxin is a critical pathological mechanism in different diseases. Moreover, the ability of lipoxin to attenuate oxidative stress is noteworthy, thereby protecting the human body from diverse diseases. METHODS We searched papers from PubMed database using search terms, such as lipoxin, lipoxin A4, oxidative stress, and other relevant terms. RESULTS A total of 103 articles published over the past 20 years were identified for inclusion. We summarized the capability of lipoxin in regulating oxidative stress and mechanism. CONCLUSION Lipoxin is provided with a protective role in attenuating oxidative stress.
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Lipidomics of Bioactive Lipids in Alzheimer's and Parkinson's Diseases: Where Are We? Int J Mol Sci 2022; 23:ijms23116235. [PMID: 35682914 PMCID: PMC9181703 DOI: 10.3390/ijms23116235] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 05/27/2022] [Accepted: 05/30/2022] [Indexed: 12/16/2022] Open
Abstract
Lipids are not only constituents of cellular membranes, but they are also key signaling mediators, thus acting as “bioactive lipids”. Among the prominent roles exerted by bioactive lipids are immune regulation, inflammation, and maintenance of homeostasis. Accumulated evidence indicates the existence of a bidirectional relationship between the immune and nervous systems, and lipids can interact particularly with the aggregation and propagation of many pathogenic proteins that are well-renowned hallmarks of several neurodegenerative disorders, including Alzheimer’s (AD) and Parkinson’s (PD) diseases. In this review, we summarize the current knowledge about the presence and quantification of the main classes of endogenous bioactive lipids, namely glycerophospholipids/sphingolipids, classical eicosanoids, pro-resolving lipid mediators, and endocannabinoids, in AD and PD patients, as well as their most-used animal models, by means of lipidomic analyses, advocating for these lipid mediators as powerful biomarkers of pathology, diagnosis, and progression, as well as predictors of response or activity to different current therapies for these neurodegenerative diseases.
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Yu CP, Pan YL, Wang XL, Xin R, Li HQ, Lei YT, Zhao FF, Zhang D, Zhou XR, Ma WW, Wang SY, Wu YH. Stimulating the expression of sphingosine kinase 1 (SphK1) is beneficial to reduce acrylamide-induced nerve cell damage. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 237:113511. [PMID: 35489137 DOI: 10.1016/j.ecoenv.2022.113511] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 02/03/2022] [Accepted: 04/08/2022] [Indexed: 06/14/2023]
Abstract
Sphingosine kinase 1 (SphK1) is an important signaling molecule for cell proliferation and survival. However, the role of SphK1 in acrylamide (ACR)-induced nerve injury remains unclear. The purpose of this study was to investigate the role and potential mechanism of SphK1 in ACR-induced nerve injury. Liquid chromatography triple quadrupole tandem mass spectrometry (LC-MS/MS) and reverse transcription-quantitative PCR (RT-qPCR) were used to detect sphingosine 1-phosphate (S1P) content in serum and SphK1 content in whole blood from an occupational work group exposed to ACR compared to a non-exposed group. For in vitro experiments, SphK1 in human SH-SY5Y neuroblastoma cells was activated using SphK1-specific activator phorbol 12-myristate 13-acetate (PMA). Our research also utilized cell viability assays, flow cytometry, western blots, RT-qPCR and related protein detection to assess activity of the mitogen activated protein kinase (MAPK) signaling pathway. The results of the population study showed that the contents of SphK1 and S1P in the ACR-exposed occupational contact group were lower than in the non-exposed group. The results of in vitro experiments showed that expression of SphK1 decreased with the increase in ACR concentration. Activating SphK1 improved the survival rate of SH-SY5Y cells and decreased the apoptosis rate. Activating SphK1 in SH-SY5Y cells also regulated MAPK signaling, including enhancing the phosphorylation of extracellular signal-regulated protein kinases (ERK) and inhibiting the phosphorylation of c-Jun N-terminal kinase (JNK) and p38. These results suggest that activating SphK1 can protect against nerve cell damage caused by ACR.
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Affiliation(s)
- Cui-Ping Yu
- Department of Occupational Health, Public Health College, Harbin Medical University, Harbin, PR China
| | - Yu-Lin Pan
- Department of Occupational Health, Public Health College, Harbin Medical University, Harbin, PR China
| | - Xiao-Li Wang
- Department of Occupational Health, Public Health College, Harbin Medical University, Harbin, PR China
| | - Rui Xin
- Department of Occupational Health, Public Health College, Harbin Medical University, Harbin, PR China
| | - Hong-Qiu Li
- Department of Occupational Health, Public Health College, Harbin Medical University, Harbin, PR China
| | - Ya-Ting Lei
- Department of Occupational Health, Public Health College, Harbin Medical University, Harbin, PR China
| | - Fang-Fang Zhao
- Department of Occupational Health, Public Health College, Harbin Medical University, Harbin, PR China
| | - Dan Zhang
- Department of Occupational Health, Public Health College, Harbin Medical University, Harbin, PR China
| | - Xiao-Rong Zhou
- Department of Occupational Health, Public Health College, Harbin Medical University, Harbin, PR China
| | - Wei-Wei Ma
- Harbin Railway Center for Disease Control and Prevention, Harbin, PR China
| | - Sheng-Yuan Wang
- Department of Occupational Health, Public Health College, Harbin Medical University, Harbin, PR China.
| | - Yong-Hui Wu
- Department of Occupational Health, Public Health College, Harbin Medical University, Harbin, PR China.
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Francesca P, Mauro P, Clerbaux LA, Leoni G, Ponti J, Bogni A, Brogna C, Cristoni S, Sanges R, Mendoza-de Gyves E, Fabbri M, Querci M, Soares H, Munoz Pineiro A, Whelan M, Van de Eede G. Effects of spike protein and toxin-like peptides found in COVID-19 patients on human 3D neuronal/glial model undergoing differentiation: possible implications for SARS-CoV-2 impact on brain development. Reprod Toxicol 2022; 111:34-48. [PMID: 35525527 PMCID: PMC9068247 DOI: 10.1016/j.reprotox.2022.04.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 03/28/2022] [Accepted: 04/30/2022] [Indexed: 12/13/2022]
Abstract
The possible neurodevelopmental consequences of SARS-CoV-2 infection are presently unknown. In utero exposure to SARS-CoV-2 has been hypothesized to affect the developing brain, possibly disrupting neurodevelopment of children. Spike protein interactors, such as ACE2, have been found expressed in the fetal brain, and could play a role in potential SARS-CoV-2 fetal brain pathogenesis. Apart from the possible direct involvement of SARS-CoV-2 or its specific viral components in the occurrence of neurological and neurodevelopmental manifestations, we recently reported the presence of toxin-like peptides in plasma, urine and fecal samples specifically from COVID-19 patients. In this study, we investigated the possible neurotoxic effects elicited upon 72-hour exposure to human relevant levels of recombinant spike protein, toxin-like peptides found in COVID-19 patients, as well as a combination of both in 3D human iPSC-derived neural stem cells differentiated for either 2 weeks (short-term) or 8 weeks (long-term, 2 weeks in suspension + 6 weeks on MEA) towards neurons/glia. Whole transcriptome and qPCR analysis revealed that spike protein and toxin-like peptides at non-cytotoxic concentrations differentially perturb the expression of SPHK1, ELN, GASK1B, HEY1, UTS2, ACE2 and some neuronal-, glia- and NSC-related genes critical during brain development. Additionally, exposure to spike protein caused a decrease of spontaneous electrical activity after two days in long-term differentiated cultures. The perturbations of these neurodevelopmental endpoints are discussed in the context of recent knowledge about the key events described in Adverse Outcome Pathways relevant to COVID-19, gathered in the context of the CIAO project (https://www.ciao-covid.net/).
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Affiliation(s)
| | - Petrillo Mauro
- Seidor Italy srl. Past affiliation (until 15/06/2021) European Commission, Joint Research Centre (JRC), Ispra, Italy
| | | | - Gabriele Leoni
- European Commission, Joint Research Centre (JRC), Ispra, Italy; International School for Advanced Studies (SISSA), Trieste, Italy
| | - Jessica Ponti
- European Commission, Joint Research Centre (JRC), Ispra, Italy
| | - Alessia Bogni
- European Commission, Joint Research Centre (JRC), Ispra, Italy
| | | | | | - Remo Sanges
- International School for Advanced Studies (SISSA), Trieste, Italy
| | | | - Marco Fabbri
- European Commission, Joint Research Centre (JRC), Ispra, Italy
| | | | - Helena Soares
- Human Immunobiology and Pathogenesis Group, CEDOC, NOVA Medical School
- Faculdade de Ciências Médicas, NOVA University of Lisbon, Lisbon, Portugal
| | | | - Maurice Whelan
- European Commission, Joint Research Centre (JRC), Ispra, Italy
| | - Guy Van de Eede
- European Commission, Joint Research Centre (JRC), Geel, Belgium
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31
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Zhang J, Li Z, Fan M, Jin W. Lipoxins in the Nervous System: Brighter Prospects for Neuroprotection. Front Pharmacol 2022; 13:781889. [PMID: 35153778 PMCID: PMC8826722 DOI: 10.3389/fphar.2022.781889] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 01/07/2022] [Indexed: 12/28/2022] Open
Abstract
Lipoxins (LXs) are generated from arachidonic acid and are involved in the resolution of inflammation and confer protection in a variety of pathological processes. In the nervous system, LXs exert an array of protective effects against neurological diseases, including ischemic or hemorrhagic stroke, neonatal hypoxia-ischemia encephalopathy, brain and spinal cord injury, Alzheimer's disease, multiple sclerosis, and neuropathic pain. Lipoxin administration is a potential therapeutic strategy in neurological diseases due to its notable efficiency and unique superiority regarding safety. Here, we provide an overview of LXs in terms of their synthesis, signaling pathways and neuroprotective evidence. Overall, we believe that, along with advances in lipoxin-related drug design, LXs will bring brighter prospects for neuroprotection.
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Affiliation(s)
- Jiayu Zhang
- Graduate School of Hebei Medical University, Shijiazhuang, China.,Department of Neurology, Hebei General Hospital, Shijiazhuang, China
| | - Zhe Li
- Department of Neurology, Hebei General Hospital, Shijiazhuang, China
| | - Mingyue Fan
- Department of Neurology, Hebei General Hospital, Shijiazhuang, China
| | - Wei Jin
- Department of Neurology, Hebei General Hospital, Shijiazhuang, China
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32
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Ayub M, Jin HK, Bae JS. Sphingosine kinase-dependent regulation of pro-resolving lipid mediators in Alzheimer's disease. Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867:159126. [DOI: 10.1016/j.bbalip.2022.159126] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 02/03/2022] [Indexed: 12/14/2022]
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Discovery of a dual-action small molecule that improves neuropathological features of Alzheimer's disease mice. Proc Natl Acad Sci U S A 2022; 119:2115082119. [PMID: 35027452 PMCID: PMC8784098 DOI: 10.1073/pnas.2115082119] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/15/2021] [Indexed: 12/28/2022] Open
Abstract
Since Alzheimer’s disease (AD) is a multifaceted neurodegenerative disease, multitargeted therapeutic approaches are likely required for effective AD treatment. The importance of acid sphingomyelinase (ASM) activation in the various neuropathological features of AD is well-known. Therefore, in this study, we focused on identifying an efficient, direct inhibitor of ASM activity. We found that KARI 201 was a highly selective ASM activity inhibitor without any off-target effects. Through RNA-sequencing analysis in brains of AD mice, we also unexpectedly uncovered the role of KARI 201 as a ghrelin receptor agonist. This dual role of KARI 201 in neurons led to improvement of Aβ accumulation, neuroinflammation, synapse loss, hippocampal neurogenesis, and memory dysfunction in AD mice. Alzheimer’s disease (AD) is characterized by complex, multifactorial neuropathology, suggesting that small molecules targeting multiple neuropathological factors are likely required to successfully impact clinical progression. Acid sphingomyelinase (ASM) activation has been recognized as an important contributor to these neuropathological features in AD, leading to the concept of using ASM inhibitors for the treatment of this disorder. Here we report the identification of KARI 201, a direct ASM inhibitor evaluated for AD treatment. KARI 201 exhibits highly selective inhibition effects on ASM, with excellent pharmacokinetic properties, especially with regard to brain distribution. Unexpectedly, we found another role of KARI 201 as a ghrelin receptor agonist, which also has therapeutic potential for AD treatment. This dual role of KARI 201 in neurons efficiently rescued neuropathological features in AD mice, including amyloid beta deposition, autophagy dysfunction, neuroinflammation, synaptic loss, and decreased hippocampal neurogenesis and synaptic plasticity, leading to an improvement in memory function. Our data highlight the possibility of potential clinical application of KARI 201 as an innovative and multifaceted drug for AD treatment.
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Paasila PJ, Aramideh JA, Sutherland GT, Graeber MB. Synapses, Microglia, and Lipids in Alzheimer's Disease. Front Neurosci 2022; 15:778822. [PMID: 35095394 PMCID: PMC8789683 DOI: 10.3389/fnins.2021.778822] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 12/06/2021] [Indexed: 12/17/2022] Open
Abstract
Alzheimer's disease (AD) is characterised by synaptic dysfunction accompanied by the microscopically visible accumulation of pathological protein deposits and cellular dystrophy involving both neurons and glia. Late-stage AD shows pronounced loss of synapses and neurons across several differentially affected brain regions. Recent studies of advanced AD using post-mortem brain samples have demonstrated the direct involvement of microglia in synaptic changes. Variants of the Apolipoprotein E and Triggering Receptors Expressed on Myeloid Cells gene represent important determinants of microglial activity but also of lipid metabolism in cells of the central nervous system. Here we review evidence that may help to explain how abnormal lipid metabolism, microglial activation, and synaptic pathophysiology are inter-related in AD.
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Affiliation(s)
- Patrick J. Paasila
- Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
- School of Medicine, Western Sydney University, Campbelltown, NSW, Australia
| | - Jason A. Aramideh
- Brain and Mind Centre, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
| | - Greg T. Sutherland
- Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
| | - Manuel B. Graeber
- Brain and Mind Centre, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
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35
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Bu Y, Wu H, Deng R, Wang Y. Therapeutic Potential of SphK1 Inhibitors Based on Abnormal Expression of SphK1 in Inflammatory Immune Related-Diseases. Front Pharmacol 2021; 12:733387. [PMID: 34737701 PMCID: PMC8560647 DOI: 10.3389/fphar.2021.733387] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 10/04/2021] [Indexed: 01/12/2023] Open
Abstract
Sphingosine kinase 1(SphK1) a key enzyme that catalyzes the conversion of sphingosine (Sph) to sphingosine 1-phosphate (S1P), so as to maintain the dynamic balance of sphingolipid-rheostat in cells and participate in cell growth and death, proliferation and migration, vasoconstriction and remodeling, inflammation and metabolism. The normal expression of SphK1 maintains the balance of physiological and pathological states, which is reflected in the regulation of inflammatory factor secretion, immune response in traditional immune cells and non-traditional immune cells, and complex signal transduction. However, abnormal SphK1 expression and activity are found in various inflammatory and immune related-diseases, such as hypertension, atherosclerosis, Alzheimer’s disease, inflammatory bowel disease and rheumatoid arthritis. In view of the therapeutic potential of regulating SphK1 and its signal, the current research is aimed at SphK1 inhibitors, such as SphK1 selective inhibitors and dual SphK1/2 inhibitor, and other compounds with inhibitory potency. This review explores the regulatory role of over-expressed SphK1 in inflammatory and immune related-diseases, and investigate the latest progress of SphK1 inhibitors and the improvement of disease or pathological state.
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Affiliation(s)
- Yanhong Bu
- Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei, China.,College of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.,Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, China.,Anhui Province Key Laboratory of Research and Development of Chinese Medicine, Hefei, China
| | - Hong Wu
- Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei, China.,College of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.,Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, China.,Anhui Province Key Laboratory of Research and Development of Chinese Medicine, Hefei, China
| | - Ran Deng
- Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei, China.,College of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.,Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, China.,Anhui Province Key Laboratory of Research and Development of Chinese Medicine, Hefei, China
| | - Yan Wang
- Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei, China.,College of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.,Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, China.,Anhui Province Key Laboratory of Research and Development of Chinese Medicine, Hefei, China
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36
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Chen K, Jiang X, Wu M, Cao X, Bao W, Zhu LQ. Ferroptosis, a Potential Therapeutic Target in Alzheimer's Disease. Front Cell Dev Biol 2021; 9:704298. [PMID: 34422824 PMCID: PMC8374166 DOI: 10.3389/fcell.2021.704298] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Accepted: 07/09/2021] [Indexed: 12/11/2022] Open
Abstract
Cell death is a common phenomenon in the progression of Alzheimer’s disease (AD). However, the mechanism of triggering the death of neuronal cells remains unclear. Ferroptosis is an iron-dependent lipid peroxidation-driven cell death and emerging evidences have demonstrated the involvement of ferroptosis in the pathological process of AD. Moreover, several hallmarks of AD pathogenesis were consistent with the characteristics of ferroptosis, such as excess iron accumulation, elevated lipid peroxides, and reactive oxygen species (ROS), reduced glutathione (GSH), and glutathione peroxidase 4 (GPX4) levels. Besides, some ferroptosis inhibitors can relieve AD-related pathological symptoms in AD mice and exhibit potential clinical benefits in AD patients. Therefore, ferroptosis is gradually being considered as a distinct cell death mechanism in the pathogenesis of AD. However, direct evidence is still lacking. In this review, we summarize the features of ferroptosis in AD, its underlying mechanisms in AD pathology, and review the application of ferroptosis inhibitors in both AD clinical trials and mice/cell models, to provide valuable information for future treatment and prevention of this devastating disease.
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Affiliation(s)
- Kai Chen
- Key Lab of Neurological Disorder of Education Ministry, Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Neurosurgery, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaobing Jiang
- Department of Neurosurgery, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Moxin Wu
- Department of Jiujiang Clinical Research Center for Precision Medicine, Affiliated Hospital of Jiujiang University, Jiujiang, China
| | - Xianming Cao
- Department of Jiujiang Clinical Research Center for Precision Medicine, Affiliated Hospital of Jiujiang University, Jiujiang, China
| | - Wendai Bao
- Key Lab of Neurological Disorder of Education Ministry, Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, China
| | - Ling-Qiang Zhu
- Key Lab of Neurological Disorder of Education Ministry, Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Li W, Wang S, Zhang H, Li B, Xu L, Li Y, Kong C, Jiao H, Wang Y, Pang Y, Qin W, Jia L, Jia J. Honokiol Restores Microglial Phagocytosis by Reversing Metabolic Reprogramming. J Alzheimers Dis 2021; 82:1475-1485. [PMID: 34151796 DOI: 10.3233/jad-210177] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Dysfunction of microglia has been increasingly recognized as a causative factor in Alzheimer's disease (AD); thus, developing medicines capable of restoring microglial functions is critically important and constitutes a promising therapeutic strategy. Honokiol is a natural neuroprotective compound extracted from Magnolia officinalis, which may play roles in AD therapy. OBJECTIVE This study aimed to evaluate the role and the underlying mechanisms of honokiol in microglial phagocytosis. METHODS MTT and flow cytometry were used to assess the cell viability and apoptosis, respectively. Phagocytic capacity, mitochondrial reactive oxygen species production, and membrane potential were evaluated using fluorescence microscopy. Seahorse XF24 extracellular flux analyzer was for cell glycolysis and oxidative phosphorylation detection. Mass spectrometry was applied for metabolites measurement. Quantitative real-time polymerase chain reaction and western blotting were performed to detect the mRNA and protein level of PPARγ and PGC1α, respectively. RESULTS Honokiol alleviated Aβ42-induced BV2 neurotoxicity. Honokiol promoted phagocytic efficiency of BV2 cells through reversing a metabolic switch from oxidative phosphorylation to anaerobic glycolysis and enhancing ATP production. Meanwhile, honokiol reduced mitochondrial reactive oxygen species production and elevated mitochondrial membrane potential. Moreover, honokiol increased the expression of PPARγ and PGC1α, which might play positive roles in energy metabolism and microglial phagocytosis. CONCLUSION In this study, honokiol was identified as an effect natural product capable of enhancing mitochondrial function thus promoting microglial phagocytic function.
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Affiliation(s)
- Wenwen Li
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing, China
| | - Shiyuan Wang
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing, China
| | - Heng Zhang
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing, China
| | - Bingqiu Li
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing, China
| | - Lingzhi Xu
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing, China
| | - Yan Li
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing, China
| | - Chaojun Kong
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing, China
| | - Haishan Jiao
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing, China
| | - Yan Wang
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing, China
| | - Yana Pang
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing, China
| | - Wei Qin
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing, China
| | - Longfei Jia
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing, China
| | - Jianping Jia
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing, China.,Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, China.,Clinical Center for Neurodegenerative Disease and Memory Impairment, Capital Medical University, Beijing, China.,Center of Alzheimer's Disease, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China
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Novelty of Sphingolipids in the Central Nervous System Physiology and Disease: Focusing on the Sphingolipid Hypothesis of Neuroinflammation and Neurodegeneration. Int J Mol Sci 2021; 22:ijms22147353. [PMID: 34298977 PMCID: PMC8303517 DOI: 10.3390/ijms22147353] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 07/05/2021] [Accepted: 07/06/2021] [Indexed: 12/30/2022] Open
Abstract
For decades, lipids were confined to the field of structural biology and energetics as they were considered only structural constituents of cellular membranes and efficient sources of energy production. However, with advances in our understanding in lipidomics and improvements in the technological approaches, astounding discoveries have been made in exploring the role of lipids as signaling molecules, termed bioactive lipids. Among these bioactive lipids, sphingolipids have emerged as distinctive mediators of various cellular processes, ranging from cell growth and proliferation to cellular apoptosis, executing immune responses to regulating inflammation. Recent studies have made it clear that sphingolipids, their metabolic intermediates (ceramide, sphingosine-1-phosphate, and N-acetyl sphingosine), and enzyme systems (cyclooxygenases, sphingosine kinases, and sphingomyelinase) harbor diverse yet interconnected signaling pathways in the central nervous system (CNS), orchestrate CNS physiological processes, and participate in a plethora of neuroinflammatory and neurodegenerative disorders. Considering the unequivocal importance of sphingolipids in CNS, we review the recent discoveries detailing the major enzymes involved in sphingolipid metabolism (particularly sphingosine kinase 1), novel metabolic intermediates (N-acetyl sphingosine), and their complex interactions in CNS physiology, disruption of their functionality in neurodegenerative disorders, and therapeutic strategies targeting sphingolipids for improved drug approaches.
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Li H, Hung A, Li M, Lu L, Yang AWH. Phytochemistry, pharmacodynamics, and pharmacokinetics of a classic Chinese herbal formula Danggui Beimu Kushen Wan: A review. Phytother Res 2021; 35:3673-3689. [PMID: 33751724 DOI: 10.1002/ptr.7063] [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: 11/08/2020] [Revised: 01/29/2021] [Accepted: 02/22/2021] [Indexed: 11/06/2022]
Abstract
Danggui Beimu Kushen Wan (DBKW) is a classic herbal formula for difficult urination and has been widely used for urinary-related disorders and cancers in current clinical practice. This study aimed to comprehensively review the phytochemistry, pharmacodynamics, and pharmacokinetics of DBKW in experimental studies. We searched 21 databases to identify experimental studies of DBKW. We also searched 11 databases to identify and summarize compounds from DBKW's ingredients. A total of 423 studies of DBKW were identified and 15 studies were included. For Angelicae Sinensis Radix (ASR) and Sophorae Flavescentis Radix (SFR), 2,425 and 2,843 studies were identified, and 42 and 33 studies were included, respectively. Eight compounds were found in the whole formula, 408 compounds from ASR, and 277 compounds from SFR. DBKW may have anticancer effects (inhibiting the growth of tumors, regulating cell proliferation, inducing tumor cell apoptosis, suppressing invasion and metastasis of cancer, enhancing the therapeutic effects of chemotherapy, and relieving toxicity of chemotherapy) and have benefits on chronic prostatitis (reducing inflammation, inhibiting oxidation, regulating sex hormone, and stimulating immune system). The pharmacokinetics of the seven primary compounds from DBKW were also summarized. DBKW contains multiple compounds that may act on more than one pathway of the conditions simultaneously.
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Affiliation(s)
- Hong Li
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Andrew Hung
- School of Science, RMIT University, Melbourne, Victoria, Australia
| | - Mingdi Li
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Leyao Lu
- School of Life Sciences, Guangzhou University, Guangzhou, China
| | - Angela Wei Hong Yang
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
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40
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Li H, Hung A, Yang AWH. Herb-target virtual screening and network pharmacology for prediction of molecular mechanism of Danggui Beimu Kushen Wan for prostate cancer. Sci Rep 2021; 11:6656. [PMID: 33758314 PMCID: PMC7988104 DOI: 10.1038/s41598-021-86141-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 02/24/2021] [Indexed: 12/24/2022] Open
Abstract
Prostate cancer (PCa) is a cancer that occurs in the prostate with high morbidity and mortality. Danggui Beimu Kushen Wan (DBKW) is a classic formula for patients with difficult urination including PCa. This study aimed to investigate the molecular mechanisms of DBKW for PCa. We obtained DBKW compounds from our previous reviews. We identified potential targets for PCa from literature search, currently approved drugs and Open Targets database and filtered them by protein-protein interaction network analysis. We selected 26 targets to predict three cancer-related pathways. A total of 621 compounds were screened via molecular docking using PyRx and AutoDock Vina against 21 targets for PCa, producing 13041 docking results. The binding patterns and positions showed that a relatively small number of tight-binding compounds from DBKW were predicted to interact strongly and selectively with three targets. The top five high-binding-affinity compounds were selected to generate a network, indicating that compounds from all three herbs had high binding affinity against the 21 targets and may have potential biological activities with the targets. DBKW contains multi-targeting agents that could act on more than one pathway of PCa simultaneously. Further studies could focus on validating the computational results via experimental studies.
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Affiliation(s)
- Hong Li
- Discipline of Chinese Medicine, School of Health and Biomedical Sciences, RMIT University, PO Box 71, Bundoora, VIC, 3083, Australia
| | - Andrew Hung
- School of Science, RMIT University, Melbourne, VIC, 3000, Australia
| | - Angela Wei Hong Yang
- Discipline of Chinese Medicine, School of Health and Biomedical Sciences, RMIT University, PO Box 71, Bundoora, VIC, 3083, Australia.
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41
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Wang C, Xu T, Lachance BB, Zhong X, Shen G, Xu T, Tang C, Jia X. Critical roles of sphingosine kinase 1 in the regulation of neuroinflammation and neuronal injury after spinal cord injury. J Neuroinflammation 2021; 18:50. [PMID: 33602274 PMCID: PMC7893778 DOI: 10.1186/s12974-021-02092-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 01/19/2021] [Indexed: 01/06/2023] Open
Abstract
Background The pathological process of traumatic spinal cord injury (SCI) involves excessive activation of microglia leading to the overproduction of proinflammatory cytokines and causing neuronal injury. Sphingosine kinase 1 (Sphk1), a key enzyme responsible for phosphorylating sphingosine into sphingosine-1-phosphate (S1P), plays an important role in mediating inflammation, cell proliferation, survival, and immunity. Methods We aim to investigate the mechanism and pathway of the Sphk1-mediated neuroinflammatory response in a rodent model of SCI. Sixty Sprague-Dawley rats were randomly assigned to sham surgery, SCI, or PF543 (a specific Sphk1 inhibitor) groups. Functional outcomes included blinded hindlimb locomotor rating and inclined plane test. Results We discovered that Sphk1 is upregulated in injured spinal cord tissue of rats after SCI and is associated with production of S1P and subsequent NF-κB p65 activation. PF543 attenuated p65 activation, reduced inflammatory response, and relieved neuronal damage, leading to improved functional recovery. Western blot analysis confirmed that expression of S1P receptor 3 (S1PR3) and phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) are activated in microglia of SCI rats and mitigated by PF543. In vitro, we demonstrated that Bay11-7085 suppressed NF-κB p65 and inhibited amplification of the inflammation cascade by S1P, reducing the release of proinflammatory TNF-α. We further confirmed that phosphorylation of p38 MAPK and activation of NF-κB p65 is inhibited by PF543 and CAY10444. p38 MAPK phosphorylation and NF-κB p65 activation were enhanced by exogenous S1P and inhibited by the specific inhibitor SB204580, ultimately indicating that the S1P/S1PR3/p38 MAPK pathway contributes to the NF-κB p65 inflammatory response. Conclusion Our results demonstrate a critical role of Sphk1 in the post-traumatic SCI inflammatory cascade and present the Sphk1/S1P/S1PR3 axis as a potential target for therapeutic intervention to control neuroinflammation, relieve neuronal damage, and improve functional outcomes in SCI.
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Affiliation(s)
- Chenjian Wang
- Department of Orthopaedics, The Third Affiliated Hospital of Wenzhou Medical University, Rui'an People's Hospital, Wenzhou, 325200, Zhejiang, China
| | - Tianzhen Xu
- Department of Orthopaedics, Zhu'ji People's Hospital, Shaoxing, 311800, Zhejiang, China
| | - Brittany Bolduc Lachance
- Program in Trauma, Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Xiqiang Zhong
- Department of Orthopaedics, The Third Affiliated Hospital of Wenzhou Medical University, Rui'an People's Hospital, Wenzhou, 325200, Zhejiang, China
| | - Guangjie Shen
- Department of Orthopaedics, The Third Affiliated Hospital of Wenzhou Medical University, Rui'an People's Hospital, Wenzhou, 325200, Zhejiang, China
| | - Tao Xu
- Department of Orthopaedics, The Third Affiliated Hospital of Wenzhou Medical University, Rui'an People's Hospital, Wenzhou, 325200, Zhejiang, China
| | - Chengxuan Tang
- Department of Orthopaedics, The Third Affiliated Hospital of Wenzhou Medical University, Rui'an People's Hospital, Wenzhou, 325200, Zhejiang, China.
| | - Xiaofeng Jia
- Department of Neurosurgery, University of Maryland School of Medicine, 10 South Pine Street, MSTF Building 823, Baltimore, MD, 21201, USA. .,Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. .,Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. .,Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. .,Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
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Giovagnoni C, Ali M, Eijssen LMT, Maes R, Choe K, Mulder M, Kleinjans J, Del Sol A, Glaab E, Mastroeni D, Delvaux E, Coleman P, Losen M, Pishva E, Martinez-Martinez P, van den Hove DLA. Altered sphingolipid function in Alzheimer's disease; a gene regulatory network approach. Neurobiol Aging 2021; 102:178-187. [PMID: 33773368 DOI: 10.1016/j.neurobiolaging.2021.02.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 11/04/2020] [Accepted: 02/02/2021] [Indexed: 10/22/2022]
Abstract
Sphingolipids (SLs) are bioactive lipids involved in various important physiological functions. The SL pathway has been shown to be affected in several brain-related disorders, including Alzheimer's disease (AD). Recent evidence suggests that epigenetic dysregulation plays an important role in the pathogenesis of AD as well. Here, we use an integrative approach to better understand the relationship between epigenetic and transcriptomic processes in regulating SL function in the middle temporal gyrus of AD patients. Transcriptomic analysis of 252 SL-related genes, selected based on GO term annotations, from 46 AD patients and 32 healthy age-matched controls, revealed 103 differentially expressed SL-related genes in AD patients. Additionally, methylomic analysis of the same subjects revealed parallel hydroxymethylation changes in PTGIS, GBA, and ITGB2 in AD. Subsequent gene regulatory network-based analysis identified 3 candidate genes, that is, SELPLG, SPHK1 and CAV1 whose alteration holds the potential to revert the gene expression program from a diseased towards a healthy state. Together, this epigenomic and transcriptomic approach highlights the importance of SL-related genes in AD, and may provide novel biomarkers and therapeutic alternatives to traditionally investigated biological pathways in AD.
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Affiliation(s)
- Caterina Giovagnoni
- School for Mental Health and Neuroscience (MHeNs), Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands.
| | - Muhammad Ali
- School for Mental Health and Neuroscience (MHeNs), Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands; Computational Biology Group, Luxembourg Centre for System Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg; Biomedical Data Science Group, Luxembourg Centre for System Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg
| | - Lars M T Eijssen
- School for Mental Health and Neuroscience (MHeNs), Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands; Department of Bioinformatics - BiGCaT, NUTRIM, Maastricht University, Maastricht, the Netherlands
| | - Richard Maes
- School for Mental Health and Neuroscience (MHeNs), Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands; Department of Bioinformatics - BiGCaT, NUTRIM, Maastricht University, Maastricht, the Netherlands
| | - Kyonghwan Choe
- School for Mental Health and Neuroscience (MHeNs), Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands
| | - Monique Mulder
- Department of Internal Medicine, Division of Pharmacology, Vascular and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Jos Kleinjans
- Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
| | - Antonio Del Sol
- Computational Biology Group, Luxembourg Centre for System Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain; CIC bioGUNE, Bizkaia Technology Park, Derio, Spain
| | - Enrico Glaab
- Biomedical Data Science Group, Luxembourg Centre for System Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg
| | - Diego Mastroeni
- Biodesign Institute, Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, USA
| | - Elaine Delvaux
- Biodesign Institute, Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, USA
| | - Paul Coleman
- Biodesign Institute, Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, USA
| | - Mario Losen
- School for Mental Health and Neuroscience (MHeNs), Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands
| | - Ehsan Pishva
- School for Mental Health and Neuroscience (MHeNs), Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands; University of Exeter Medical School, University of Exeter, Exeter, UK
| | - Pilar Martinez-Martinez
- School for Mental Health and Neuroscience (MHeNs), Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands
| | - Daniel L A van den Hove
- School for Mental Health and Neuroscience (MHeNs), Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands; Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany
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43
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de Wit NM, Mol K, Rodríguez-Lorenzo S, de Vries HE, Kooij G. The Role of Sphingolipids and Specialized Pro-Resolving Mediators in Alzheimer's Disease. Front Immunol 2021; 11:620348. [PMID: 33633739 PMCID: PMC7902029 DOI: 10.3389/fimmu.2020.620348] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 12/14/2020] [Indexed: 12/14/2022] Open
Abstract
Alzheimer’s disease (AD) is the leading cause of dementia worldwide giving rise to devastating forms of cognitive decline, which impacts patients’ lives and that of their proxies. Pathologically, AD is characterized by extracellular amyloid deposition, neurofibrillary tangles and chronic neuroinflammation. To date, there is no cure that prevents progression of AD. In this review, we elaborate on how bioactive lipids, including sphingolipids (SL) and specialized pro-resolving lipid mediators (SPM), affect ongoing neuroinflammatory processes during AD and how we may exploit them for the development of new biomarker panels and/or therapies. In particular, we here describe how SPM and SL metabolism, ranging from ω-3/6 polyunsaturated fatty acids and their metabolites to ceramides and sphingosine-1-phosphate, initiates pro- and anti-inflammatory signaling cascades in the central nervous system (CNS) and what changes occur therein during AD pathology. Finally, we discuss novel therapeutic approaches to resolve chronic neuroinflammation in AD by modulating the SPM and SL pathways.
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Affiliation(s)
- Nienke M de Wit
- Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Kevin Mol
- Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Sabela Rodríguez-Lorenzo
- Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Helga E de Vries
- Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Gijs Kooij
- Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
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Sun W, Liu C, Wang Y, Zhou X, Sui W, Zhang Y, Zhang Q, Han J, Li X, Han F. Rhodiola crenulata protects against Alzheimer's disease in rats: A brain lipidomics study by Fourier-transform ion cyclotron resonance mass spectrometry coupled with high-performance reversed-phase liquid chromatography and hydrophilic interaction liquid chromatography. RAPID COMMUNICATIONS IN MASS SPECTROMETRY : RCM 2021; 35:e8969. [PMID: 33047398 DOI: 10.1002/rcm.8969] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 09/28/2020] [Accepted: 10/04/2020] [Indexed: 06/11/2023]
Abstract
RATIONALE Alzheimer's disease (AD) is a chronic, severe, progressive neurodegenerative disorder associated with cognitive and memory impairment that ultimately causes death. Most approved drugs can only alleviate some of the symptoms of AD, but no interventions have been found that reverse the underlying disease mechanisms. Rhodiola crenulata extract (RCE) has been reported to alleviate AD symptoms in rats. However, its underlying mechanism of action is still unclear. METHODS A brain lipidomics study was conducted to investigate the protective effects of RCE against AD in rats to identify potential biomarkers of AD using Fourier-transform ion cyclotron resonance mass spectrometry (FT-ICR MS) coupled with high-performance reversed-phase liquid chromatography (RPLC) and hydrophilic interaction liquid chromatography (HILIC). Differences in lipid metabolism profiles were evaluated using multivariate statistical analysis. Finally, the possible mechanism of action of RCE on AD was investigated by analysing metabolic pathways. RESULTS The RPLCHILIC/FT-ICR MS results showed 20 lipid components with significant differences between the control and model groups. After administration of RCE, the levels of 10 lipids in AD rats tended to shift toward reference levels. The pathway analysis revealed that the protective effect of RCE against AD might be related to regulation of glycerophospholipid metabolism. CONCLUSIONS This study provides a novel perspective on the potential intervention mechanism of RCE in the treatment of AD.
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Affiliation(s)
- Wei Sun
- Department of Biomedical Engineering School of Medical Devices, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Chun Liu
- Hainan Institute for Drug Control, Haikou, 570311, China
| | - Yanan Wang
- School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China
| | - Xing Zhou
- Hainan Institute of Materia Medica, Haikou, 570311, China
| | - Wenwen Sui
- Shenyang Harmony Health Medical Laboratory, 15 Buildings, 19 Wenhui Street, JinPenglong Hightech Industry Park, Shenyang, 110016, China
| | - Yu Zhang
- School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China
| | - Qingyu Zhang
- School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China
| | - Jing Han
- School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China
| | - Xintong Li
- School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China
| | - Fei Han
- School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China
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Wang X, Miao Z, Xu X, Schultzberg M, Zhao Y. Reduced Levels of Plasma Lipoxin A4 Are Associated with Post-Stroke Cognitive Impairment. J Alzheimers Dis 2020; 79:607-613. [PMID: 33337374 DOI: 10.3233/jad-201050] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Specialized pro-resolving mediators (SPMs) are bioactive lipids derived from n-3 and n-6 polyunsaturated fatty acids. SPMs promote resolution of inflammation and are reduced in Alzheimer's disease. It is unknown whether SPMs are associated with post-stroke cognitive impairment (PSCI). OBJECTIVE In the present report, we aimed to study the levels of SPMs in PSCI patients in the acute phase of ischemic stroke. METHODS Levels of SPMs in the plasma from 36 patients with PSCI and 33 patients with post-stroke non-cognitive impairment (PSNCI) were measured by enzyme immunoassay. RESULTS We found that levels of the SPM lipoxin A4 (LXA4) were significantly reduced in PSCI patients compared with PSNCI patients. Interestingly, the LXA4 levels were positively correlated with Mini-Mental State Examination scores, but not with the National Institutes of Health Stroke Scale scores. Such alteration and correlation were not found in any of the other SPMs analyzed, i.e., including resolvin D1, resolvin D2, and maresin 1. CONCLUSION We conclude that the plasma levels of LXA4 were reduced in PSCI patents in the acute phase of ischemic stroke and were correlated to cognitive function.
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Affiliation(s)
- Xiuzhe Wang
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Zhijuan Miao
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Xiaofeng Xu
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Marianne Schultzberg
- Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
| | - Yuwu Zhao
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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46
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Xue G, Chen JP, Li Y, Zhang ZQ, Zhu JL, Dong W. MicroRNA-6862 inhibition elevates sphingosine kinase 1 and protects neuronal cells from MPP +-induced apoptosis. Aging (Albany NY) 2020; 13:1369-1382. [PMID: 33414358 PMCID: PMC7834988 DOI: 10.18632/aging.202335] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 10/22/2020] [Indexed: 02/07/2023]
Abstract
MPP+ (1-methyl-4-phenylpyridinium)-induced dopaminergic neuronal cell apoptosis is associated with sphingosine kinase 1 (SphK1) inhibition. We here tested the potential effect of microRNA-6862 (miR-6862), a novel SphK1-targeting miRNA, on MPP+-induced cytotoxicity in neuronal cells. MiR-6862 locates in the cytoplasm of SH-SY5Y neuronal cells. It directly binds to SphK1 mRNA. In SH-SY5Y cells and HCN-2 cells, ectopic overexpression of miR-6862 decreased SphK13'-untranslated region luciferase reporter activity and downregulated its expression. miR-6862 inhibition exerted opposite activity and elevated SphK1 expression. In neuronal cells, MPP+-induced cell death was significantly inhibited through miR-6862 inhibition. Conversely, ectopic overexpression of miR-6862 or CRISPR/Cas9-induced SphK1 knockout augmented MPP+-induced apoptosis in the neuronal cells. Importantly, antagomiR-6862 failed to inhibit MPP+-induced apoptosis in SphK1-knockout SH-SY5Y cells. These results suggest that inhibition of miR-6862 induces SphK1 elevation and protects neuronal cells from MPP+-induced cell death.
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Affiliation(s)
- Gang Xue
- Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Department of Neurology, Fengcheng Hospital of Fengxian Distric, Shanghai, China
| | - Ju-ping Chen
- Department of Neurology, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu, China
| | - Ya Li
- The Central Laboratory, North District, Suzhou Municipal Hospital Affiliated to Nanjing Medical University, Suzhou, China
| | - Zhi-qing Zhang
- Institute of Neuroscience, Soochow University, Suzhou, China
| | - Jian-liang Zhu
- Department of Emergency and Intensive Care Unit, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Wanli Dong
- Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, China
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Velazquez FN, Hernandez-Corbacho M, Trayssac M, Stith JL, Bonica J, Jean B, Pulkoski-Gross MJ, Carroll BL, Salama MF, Hannun YA, Snider AJ. Bioactive sphingolipids: Advancements and contributions from the laboratory of Dr. Lina M. Obeid. Cell Signal 2020; 79:109875. [PMID: 33290840 PMCID: PMC8244749 DOI: 10.1016/j.cellsig.2020.109875] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 12/01/2020] [Accepted: 12/02/2020] [Indexed: 02/06/2023]
Abstract
Sphingolipids and their synthetic enzymes have emerged as critical mediators in numerous diseases including inflammation, aging, and cancer. One enzyme in particular, sphingosine kinase (SK) and its product sphingosine-1-phosphate (S1P), has been extensively implicated in these processes. SK catalyzes the phosphorylation of sphingosine to S1P and exists as two isoforms, SK1 and SK2. In this review, we will discuss the contributions from the laboratory of Dr. Lina M. Obeid that have defined the roles for several bioactive sphingolipids in signaling and disease with an emphasis on her work defining SK1 in cellular fates and pathobiologies including proliferation, senescence, apoptosis, and inflammation.
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Affiliation(s)
- Fabiola N Velazquez
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Maria Hernandez-Corbacho
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Magali Trayssac
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Jeffrey L Stith
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Joseph Bonica
- Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11790, USA
| | - Bernandie Jean
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Michael J Pulkoski-Gross
- Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11790, USA
| | - Brittany L Carroll
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11790, USA
| | - Mohamed F Salama
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA; Department of Biochemistry, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Yusuf A Hannun
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Ashley J Snider
- Department of Nutritional Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson, AZ 85721, USA.
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Kim M, Park MH, Nam G, Lee M, Kang J, Song IS, Choi MK, Jin HK, Bae JS, Lim MH. A Glycosylated Prodrug to Attenuate Neuroinflammation and Improve Cognitive Deficits in Alzheimer's Disease Transgenic Mice. Mol Pharm 2020; 18:101-112. [PMID: 33241681 DOI: 10.1021/acs.molpharmaceut.0c00677] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
We report a prodrug, Glu-DAPPD, to overcome the shortcomings of an anti-neuroinflammatory molecule, N,N'-diacetyl-p-phenylenediamine (DAPPD), in biological applicability for potential therapeutic applications. We suspect that Glu-DAPPD can release DAPPD through endogenous enzymatic bioconversion. Consequently, Glu-DAPPD exhibits in vivo efficacies in alleviating neuroinflammation, reducing amyloid-β aggregate accumulation, and improving cognitive function in Alzheimer's disease transgenic mice. Our studies demonstrate that the prodrug approach is suitable and effective toward developing drug candidates against neurodegeneration.
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Affiliation(s)
- Mingeun Kim
- Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - Min Hee Park
- KNU Alzheimer's disease Research Institute, Kyungpook National University, Daegu 41566, Republic of Korea.,Department of Physiology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea.,Department of Biomedical Science, BK21 Plus Kyungpook National University Biomedical Convergence Program, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Geewoo Nam
- Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - Misun Lee
- Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea
| | - Juhye Kang
- Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.,Technical Support Center, Office of Research Affairs, Pohang University of Science and Technology, Pohang 37673, Republic of Korea
| | - Im-Sook Song
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Min-Koo Choi
- College of Pharmacy, Dankook University, Cheon-an 31116, Republic of Korea
| | - Hee Kyung Jin
- KNU Alzheimer's disease Research Institute, Kyungpook National University, Daegu 41566, Republic of Korea.,Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Jae-Sung Bae
- KNU Alzheimer's disease Research Institute, Kyungpook National University, Daegu 41566, Republic of Korea.,Department of Physiology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea.,Department of Biomedical Science, BK21 Plus Kyungpook National University Biomedical Convergence Program, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Mi Hee Lim
- Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
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49
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A New Therapeutic Strategy Targeting Protein Deacetylation for Spinal Cord Injury. Neuroscience 2020; 451:197-206. [PMID: 33039524 DOI: 10.1016/j.neuroscience.2020.09.060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 09/27/2020] [Accepted: 09/29/2020] [Indexed: 02/06/2023]
Abstract
Lysine acetylation is a post-translational modification that regulates a diversity of biological processes. However, its implication in spinal cord injury (SCI) remains unclear. Here we investigated the acetylation events in injured spinal cords on a proteomic scale for the first time. Additionally, whether promoting acetylation could mitigate SCI was evaluated. A total of 268 differentially acetylated peptides were identified. Among them, 2 peptides were up-acetylated and 141 peptides were down-acetylated in the injured spinal cord tissues (Fold change >2 and P < 0.05). There were also 116 unique acetylated peptides in the sham group and 9 unique acetylated peptides in the SCI group. Functional enrichment analysis revealed that differently acetylated proteins were involved in multiple cellular processes and metabolic processes. Kyoto Encyclopaedia of Genes and Genomes analysis showed that several pathways, including cGMP-PKG signaling pathway and hypoxia-inducible factor-1 (HIF-1) signaling pathway, were predominantly presented. Moreover, promoting acetylation using glycerol triacetate (GTA) showed a therapeutic effect on SCI, with improved Basso-Beattie-Bresnahan scores and histologic morphology, and decreased neuronal apoptosis and inflammation. In conclusion, our data indicated that protein deacetylation might play crucial roles in the development of secondary injury of SCI, and promoting acetylation by GTA effectively mitigated SCI. Our data not only enhance our understanding on acetylproteome dataset in the spinal cord tissues, but also provide novel insights for the treatment of SCI.
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Wang X, Yang Y, Cai WQ, Lu Y. The Relationship of Sphingosine Kinase 1 With Pyroptosis Provides a New Strategy for Tumor Therapy. Front Immunol 2020; 11:574990. [PMID: 33123153 PMCID: PMC7566665 DOI: 10.3389/fimmu.2020.574990] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 08/17/2020] [Indexed: 12/15/2022] Open
Abstract
Sphingosine kinase 1 (SPHK1) is a crucial molecule that catalyzes sphingosine to synthesize sphingosine-1-phosphate (S1P), facilitating cell survival signaling. Pyroptosis is a perplexing inflammatory mode of cell death primarily triggered by caspase-1, evoked by the NLRP3 inflammasome. Sphingosine is identified as a danger-associated molecular pattern (DAMP), which activates the NLRP3 inflammasome assembly and induces the pyroptosis. It has been demonstrated that macrophages play a pro-tumorigenic role and are closely associated with tumor progression. Attenuation of SPHK1 activity contributes significantly to macrophage pyroptosis and tumor inhibition. Calcium and integrin-binding protein 1 (CIB1) plays an important role in the translocation of SPHK1 from the cytoplasm to the plasma membrane, whereas CIB2 blocks the subcellular trafficking of SPHK1. Therefore, knockout of CIB1 or over-expression of CIB2 will result in sphingosine accumulation and contribute significantly to cancer treatment by several approaches. First, it directly provokes cancer cell apoptosis or triggers robust anti-tumor immunity by pyroptosis-induced inflammation. Second, it could restrain SPHK1 translocation from the cytoplasm to the plasma membrane and further pyroptosis, which not only drive M2 macrophages death but also facilitate tumor microenvironment inflammation as well as the further release of sphingosine from damaged macrophages. The perspective might provide novel insight into the association between SPHK1 and pyroptosis and suggest the potential target for cancer therapy.
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Affiliation(s)
- Xianwang Wang
- Department of Biochemistry and Molecular Biology, Health Science Center, Yangtze University, Jingzhou, China
| | - Yue Yang
- Department of Biochemistry and Molecular Biology, Health Science Center, Yangtze University, Jingzhou, China
| | - Wen-Qi Cai
- Department of Biochemistry and Molecular Biology, Health Science Center, Yangtze University, Jingzhou, China
| | - Yingying Lu
- The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
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