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Li F, Liu S, Han Z, Li Y, Chen H, Shi Q, Tan J, He X, Liu X, Zhao H, Wang F. The effects of caffeine and adenosine on the microbiome and lipidome of the scalp. Int J Cosmet Sci 2025. [PMID: 40395216 DOI: 10.1111/ics.13072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 04/15/2025] [Accepted: 04/15/2025] [Indexed: 05/22/2025]
Abstract
Hair loss is a complex multifactorial process. The mechanisms by which caffeine and adenosine act against hair loss have been extensively researched, but little is known about their effects on the microbiome and lipidome of the scalp. Hair loss may be associated with the status of scalp microbiota and lipids. Further investigation is warranted to determine whether caffeine and adenosine can regulate scalp microbiota and lipids and thus help to prevent hair loss. The objective of this study was to assess the effect of shampoo containing caffeine and adenosine on the scalp microbiome and lipidome in subjects experiencing hair loss who were aged between 18 and 60 years. The study was a randomized, single-blind and parallel comparison trial involving full scalp treatment, which was conducted among 30 subjects experiencing hair loss. Samples were collected from subjects at baseline and at 12 weeks (±3 days). Microbiomes were analysed via 16S rDNA and ITS1 sequencing. Lipidome analysis was carried out using ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). At 12 weeks, significant clinical characteristics indicating an anti-hair loss effect were evident. Abundances of Pseudomonas, Escherichia-Shigella and Malassezia all decreased in the experimental group, whereas those of Talaromyces and Cutibacterium increased. In addition, levels of triglyceride (TG), diglyceride (DG), ceramide (Cer) and ceramide-1-phosphate (CerP) were all significantly impacted in the experimental group. Furthermore, abundances of lipid metabolites were tightly correlated with those of Escherichia-Shigella and Talaromyces. Caffeine and adenosine may enhance the anti-hair loss process through their effects on the lipidome and microbiome of the scalp.
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Affiliation(s)
- Fengzhu Li
- College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China
| | - Shulin Liu
- College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China
| | - Zhaoying Han
- College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China
| | - Yingtian Li
- College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China
| | - Haowei Chen
- Dingmageili Biotechnology Ltd., Beijing, China
| | - Qingying Shi
- College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China
| | - Jie Tan
- Dingmageili Biotechnology Ltd., Beijing, China
| | - Xihong He
- College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China
- Dingmageili Biotechnology Ltd., Beijing, China
| | - Xinyan Liu
- College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China
| | - Huabing Zhao
- College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin University of Science and Technology, Tianjin, China
| | - Fang Wang
- Dingmageili Biotechnology Ltd., Beijing, China
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Yamada C, Akkaoui J, Morozov A, Movila A. Role of Canonical and Non-Canonical Sphingolipids and their Metabolic Enzymes in Bone Health. Curr Osteoporos Rep 2025; 23:21. [PMID: 40266422 PMCID: PMC12018623 DOI: 10.1007/s11914-025-00908-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/21/2025] [Indexed: 04/24/2025]
Abstract
PURPOSE OF REVIEW This review summarizes the recently published scientific evidence regarding the role of enzymes engaged in de novo anabolic biosynthesis, catabolic, and salvage pathways of ceramide bioactive sphingolipids in bone dynamics and skeletal health. RECENT FINDINGS Ceramides are precursors for bioactive sphingolipids, including sphingosine, sphingosine-1-phosphate, and others. Studies of bone metabolism and bone-related cells demonstrated that ceramide and sphingosine-1-phosphate control levels of bone remodeling and resorption generated by osteoblasts and osteoclasts. Multiple published studies demonstrated the critical role of enzymes in regulating the ceramide/sphingosine-1-phosphate ratio relative to bone physiology and the promotion of inflammatory osteolysis. Accordingly, emerging evidence suggests that targeting sphingolipid metabolism has the potential to alleviate inflammatory osteolysis and accelerate bone regeneration. Therefore, this study aimed to discuss current knowledge about crosstalk between sphingolipids and their metabolic enzymes within osteoclast and osteoblast coupling in bone remodeling and pathogenic osteolysis. This review highlights the complexity of de novo sphingolipid biosynthesis and knowledge gaps in bone physiology and pathology. We also discuss the importance of canonical and non-canonical mammalian and bacterial-derived sphingolipids relative to bone health.
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Affiliation(s)
- Chiaki Yamada
- Department of Biomedical Sciences and Comprehensive Care, Indiana University School of Dentistry, Indianapolis, IN, USA
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA
- Richard L. Roudebush Veterans' Administration Medical Center, Indianapolis, IN, USA
| | - Juliet Akkaoui
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
| | - Alexandr Morozov
- Institute of Zoology, Moldova State University, Chisinau, Republic of Moldova
- Medpark International Hospital, Chisinau, Republic of Moldova
| | - Alexandru Movila
- Department of Biomedical Sciences and Comprehensive Care, Indiana University School of Dentistry, Indianapolis, IN, USA.
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA.
- Richard L. Roudebush Veterans' Administration Medical Center, Indianapolis, IN, USA.
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3
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Xiao Y, Zhang Y, Deng S, Yang X, Yao X. Immune and Non-immune Interactions in the Pathogenesis of Androgenetic Alopecia. Clin Rev Allergy Immunol 2025; 68:22. [PMID: 40024940 DOI: 10.1007/s12016-025-09034-5] [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] [Accepted: 02/17/2025] [Indexed: 03/04/2025]
Abstract
Androgenetic alopecia (AGA), a leading cause of progressive hair loss, affects up to 50% of males aged 50 years, causing significant psychological burden. Current treatments, such as anti-androgen drugs and minoxidil, show heterogeneous effects, even with long-term application. Meanwhile, the large-scale adoption of other adjuvant therapies has been slow, partly due to insufficient mechanistic evidence. A major barrier to developing better treatment for AGA is the incomplete understanding of its pathogenesis. The predominant academic consensus is that AGA is caused by abnormal expression of androgens and their receptors in individuals with a genetic predisposition. Emerging evidence suggests the contributing role of factors such as immune responses, oxidative stress, and microbiome changes, which were not previously given due consideration. Immune-mediated inflammation and oxidative stress disrupt hair follicles' function and damage the perifollicular niche, while scalp dysbiosis influences local metabolism and destabilizes the local microenvironment. These interconnected mechanisms collectively contribute to AGA pathogenesis. These additional aspects enhance our current understanding and confound the conventional paradigm, bridging the gap in developing holistic solutions for AGA. In this review, we gather existing evidence to discuss various etiopathogenetic factors involved in AGA and their possible interconnections, aiming to lay the groundwork for the future identification of therapeutic targets and drug development. Additionally, we summarize the advantages and disadvantages of AGA research models, ranging from cells and tissues to animals, to provide a solid basis for more effective mechanistic studies.
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Affiliation(s)
- Yu Xiao
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, 210042, Jiangsu, China
| | - Yi Zhang
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, 210042, Jiangsu, China
| | - Shuting Deng
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, 210042, Jiangsu, China
| | - Xueyuan Yang
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, 210042, Jiangsu, China
| | - Xu Yao
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, 210042, Jiangsu, China.
- Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, 210042, Jiangsu, China.
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4
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Brandes N, Hahn H, Uhmann A. CD4 expression controls epidermal stem cell balance. Sci Rep 2025; 15:4185. [PMID: 39905055 PMCID: PMC11794708 DOI: 10.1038/s41598-025-87915-7] [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: 09/23/2024] [Accepted: 01/22/2025] [Indexed: 02/06/2025] Open
Abstract
The balance of stem cell populations is essential for the maintenance, renewal, and repair of the mammalian epidermis. Here, we report that CD4, which is a typical marker of helper T cells, monocytes, macrophages, and dendritic cells, is also expressed on murine K5+ keratinocytes. Lineage tracing of CD4+ cells reveals that their epidermal progeny has self-renewal abilities and clonogenic potential. The progeny of CD4+ epidermal cells contributes to epidermal renewal and progressively colonizes the interfollicular epidermis and hair follicles with age, thereby developing to all epidermal lineages. Wound healing studies furthermore show that the progeny of CD4+ epidermal cells accumulates at wound sites. Finally, using CD4 knockout mice we demonstrate that CD4 expression is essential for maintaining fast-cycling epidermal stem cells during homeostasis and that CD4 loss mitigates the age-related decline in wound repair capacity. Collectively, our data support the conclusion that CD4 expression is required for long-term maintenance of the epidermal stem cell balance.
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Affiliation(s)
- Nadine Brandes
- Institute of Human Genetics, Tumor Genetics Group, Universitätsmedizin Göttingen, Heinrich-Düker-Weg 12, 37073, Göttingen, Germany
| | - Heidi Hahn
- Institute of Human Genetics, Tumor Genetics Group, Universitätsmedizin Göttingen, Heinrich-Düker-Weg 12, 37073, Göttingen, Germany
| | - Anja Uhmann
- Institute of Human Genetics, Tumor Genetics Group, Universitätsmedizin Göttingen, Heinrich-Düker-Weg 12, 37073, Göttingen, Germany.
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Chu S, Jia L, Li Y, Xiong J, Sun Y, Zhou Q, Du D, Li Z, Huang X, Jiang H, Wu B, Li Y. Exosome-derived long non-coding RNA AC010789.1 modified by FTO and hnRNPA2B1 accelerates growth of hair follicle stem cells against androgen alopecia by activating S100A8/Wnt/β-catenin signalling. Clin Transl Med 2025; 15:e70152. [PMID: 39748192 PMCID: PMC11695201 DOI: 10.1002/ctm2.70152] [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: 09/09/2024] [Revised: 12/10/2024] [Accepted: 12/15/2024] [Indexed: 01/04/2025] Open
Abstract
BACKGROUND The increased incidence of androgenic alopecia (AGA) causes adverse physiological and psychological effects on people of all genders. The hair follicle stem cells (HFSCs) have displayed clinical improvements on AGA. However, the molecular mechanism of HFSCs against AGA remains elusive. METHODS The expression and prognosis of lncRNA AC010789.1 in AGA hair follicle tissues were assessed by qRT-PCR analysis. CCK-8, EdU and Transwell analysis were utilized to assess cell growth. The specific binding between AC010789.1 and FTO mediated m6A modification or the effect of AC010789.1 on hnRNPA2B1, S100A8 and Wnt/β-catenin signaling expression was confirmed by bioinformatic analysis, RIP, RNA pull-down and Western blot assay. The effects of Exosome-loaded AC010789.1 prompted HFSCs proliferation and hair follicle regeneration were confirmed in hairless mice. RESULTS We herein found that the mRNA levels of lncRNA AC010789.1 were decreased in AGA tissue samples but increased in HFSCs of surrounding normal tissue samples. Overexpression (OE) of AC010789.1 promoted HFSC proliferation, DNA synthesis and migration as well as K6HF and Lgr5 upregulation, whereas knockdown of AC010789.1 showed the opposite effects. The total or AC010789.1 m6A levels were reduced and FTO demethylase was upregulated in AGA tissue samples, but these indicated the reverse results in HFSCs of surrounding normal tissue samples. FTO OE decreased AC010789.1 m6A levels and its mRNA levels in HFSCs and abolished AC010789.1-induced HFSCs proliferation. In addition, AC010789.1 was identified to bind to m6A reader hnRNPA2B1, which was downregulated in AGA but upregulated in HFSCs of surrounding normal tissue samples. hnRNPA2B1 OE attenuated AC010789.1 knockdown-induced inhibition of HFSCs proliferation. Moreover, AC010789.1 could bind to and enhance downstream S100A8 protein expression, which mediated Wnt/β-catenin signaling to accelerate HFSCs proliferation. Exosome-loaded AC010789.1 prompted HFSCs proliferation and hair follicle regeneration in mice. CONCLUSIONS Our findings demonstrated that exosome-derived lncRNA AC010789.1 modified by FTO and hnRNPA2B1 facilitated the proliferation of human HFSCs against AGA by activating S100A8/Wnt/β-catenin signaling. KEY POINTS Long non-coding RNA (lncRNA) AC010789.1 was downregulated in hair follicle tissues from androgenic alopecia (AGA) and upregulated in hair follicle stem cells (HFSCs). LncRNA AC010789.1 promoted the proliferation and migration of HFSCs. FTO/hnRNPA2B1-mediated m6A modification of lncRNA AC010789.1 promoted HFSCs growth by activating S100A8/Wnt/β-catenin signalling. Exosome-derived AC010789.1 accelerated HFSCs proliferation.
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Affiliation(s)
- Shaojun Chu
- Department of Plastic SurgeryShanghai East Hospital, School of Medicine, Tongji UniversityShanghaiChina
| | - Lingling Jia
- Department of Plastic SurgeryShanghai East Hospital, School of Medicine, Tongji UniversityShanghaiChina
| | - Yulong Li
- Department of Military Medical PsychologyAir Force Medical UniversityXi'anChina
| | - Jiachao Xiong
- Department of Plastic SurgeryShanghai East Hospital, School of Medicine, Tongji UniversityShanghaiChina
| | - Yulin Sun
- Department of Plastic SurgeryShanghai East Hospital, School of Medicine, Tongji UniversityShanghaiChina
| | - Qin Zhou
- Department of Plastic SurgeryShanghai East Hospital, School of Medicine, Tongji UniversityShanghaiChina
| | - Dexiang Du
- Department of Plastic SurgeryShanghai East Hospital, School of Medicine, Tongji UniversityShanghaiChina
| | - Zihan Li
- St Hugh's CollegeUniversity of OxfordOxfordUK
| | - Xin Huang
- Department of DermatologyHair Medical Center of Shanghai Tongji Hospital, Tongji Hospital, School of Medicine, Tongji UniversityShanghaiChina
| | - Hua Jiang
- Department of Plastic SurgeryShanghai East Hospital, School of Medicine, Tongji UniversityShanghaiChina
| | - Baojin Wu
- Department of Plastic SurgeryHuashan HospitalFudan UniversityShanghaiChina
| | - Yufei Li
- Department of Plastic SurgeryShanghai East Hospital, School of Medicine, Tongji UniversityShanghaiChina
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6
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Liu Z, Yang X, Chen S, Jia W, Qian Y, Zhang M, Fang T, Liu H, Yang H. Tumor suppressor ACER1 correlates with prognosis and Immune Infiltration in head and neck squamous cell carcinoma. Sci Rep 2024; 14:28039. [PMID: 39543336 PMCID: PMC11564793 DOI: 10.1038/s41598-024-78663-1] [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: 08/08/2023] [Accepted: 11/04/2024] [Indexed: 11/17/2024] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is notorious for poor prognoses, and effective biomarkers are urgently needed for early diagnosis of HNSCC patients. We investigate the role of alkaline ceramidase 1 (ACER1) and its relationship with immune infiltration in HNSCC. The differential expression and clinical prognostic significance of ACER1 in HNSCC patients are explored using bioinformatics methods and verified in human HNSCC samples. Genetic mutation, DNA methylation and drug sensitivity linked with ACER1 are examined. The potential biological function of ACER1 co-expression genes is assessed, and a series of functional assays are performed on ACER1in vitro. The results comprehensively reveal a relationship between ACER1 and immune infiltration in HNSCC patients. ACER1 expression is significantly downregulated in HNSCC tissues and closely correlated with better prognoses for HNSCC patients, and this prognostic significance is determined by distinct clinical characteristics. Genetic alteration and promoter hypomethylation of ACER1 are involved in progression of HNSCC, and ACER1 expression is significantly related to several drug sensitivities. Functional analysis shows that ACER1 co-expression genes are mainly enriched in the sphingolipid signaling pathway associated with inhibition of tumorigenesis, leading to better prognoses for HNSCC patients. In vitro, ACER1 overexpression inhibits proliferation and migration, induces apoptosis, and promotes adhesion of Fadu and SCC9 cells. In addition, high ACER1 expression is closely linked with infiltration levels of immune cells, and strongly associated with biomarkers of immune cells in HNSCC, suggesting the important role of ACER1 in regulating tumor immunity in HNSCC patients. In summary, ACER1 may be a useful indicator for diagnosis and prognosis, and may regulate immune infiltration in HNSCC patients, thus promising targeted immunotherapy for HNSCC.
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Affiliation(s)
- Zhixin Liu
- Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong, China
- Department of Otorhinolaryngology, Qilu Hospital of Shandong University, National Health Commission Key Laboratory of Otorhinolaryngology, Jinan, Shandong, China
| | - Xiaoqi Yang
- Department of Otorhinolaryngology, Qilu Hospital of Shandong University, National Health Commission Key Laboratory of Otorhinolaryngology, Jinan, Shandong, China
| | - Shuai Chen
- Department of Otorhinolaryngology, Qilu Hospital of Shandong University, National Health Commission Key Laboratory of Otorhinolaryngology, Jinan, Shandong, China
| | - Wenming Jia
- Department of Otorhinolaryngology, Qilu Hospital of Shandong University, National Health Commission Key Laboratory of Otorhinolaryngology, Jinan, Shandong, China
| | - Ye Qian
- Department of Otorhinolaryngology, Qilu Hospital of Shandong University, National Health Commission Key Laboratory of Otorhinolaryngology, Jinan, Shandong, China
| | - Minfa Zhang
- Department of Otorhinolaryngology, Qilu Hospital of Shandong University, National Health Commission Key Laboratory of Otorhinolaryngology, Jinan, Shandong, China
- Department of Otolaryngology/Head and Neck Surgery, Institute of Otolaryngology, Affiliated Hospital of Binzhou Medical University,, Binzhou, Shandong, China
| | - Tianhe Fang
- School of Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Heng Liu
- Department of Otorhinolaryngology, Qilu Hospital of Shandong University, National Health Commission Key Laboratory of Otorhinolaryngology, Jinan, Shandong, China.
| | - Hui Yang
- Department of Radiology, Qilu Hospital of Shandong University, Jinan,Shandong, China.
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7
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Dingjan T, Futerman AH. Fine-tuned protein-lipid interactions in biological membranes: exploration and implications of the ORMDL-ceramide negative feedback loop in the endoplasmic reticulum. Front Cell Dev Biol 2024; 12:1457209. [PMID: 39170919 PMCID: PMC11335536 DOI: 10.3389/fcell.2024.1457209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Accepted: 07/26/2024] [Indexed: 08/23/2024] Open
Abstract
Biological membranes consist of a lipid bilayer in which integral membrane proteins are embedded. Based on the compositional complexity of the lipid species found in membranes, and on their specific and selective interactions with membrane proteins, we recently suggested that membrane bilayers can be best described as "finely-tuned molecular machines." We now discuss one such set of lipid-protein interactions by describing a negative feedback mechanism operating in the de novo sphingolipid biosynthetic pathway, which occurs in the membrane of the endoplasmic reticulum, and describe the atomic interactions between the first enzyme in the pathway, namely serine palmitoyl transferase, and the product of the fourth enzyme in the pathway, ceramide. We explore how hydrogen-bonding and hydrophobic interactions formed between Asn13 and Phe63 in the serine palmitoyl transferase complex and ceramide can influence the ceramide content of the endoplasmic reticulum. This example of finely-tuned biochemical interactions raises intriguing mechanistic questions about how sphingolipids and their biosynthetic enzymes could have evolved, particularly in light of their metabolic co-dependence.
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Affiliation(s)
- Tamir Dingjan
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
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8
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Dermitzakis I, Kampitsi DD, Manthou ME, Evangelidis P, Vakirlis E, Meditskou S, Theotokis P. Ontogeny of Skin Stem Cells and Molecular Underpinnings. Curr Issues Mol Biol 2024; 46:8118-8147. [PMID: 39194698 DOI: 10.3390/cimb46080481] [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: 06/27/2024] [Revised: 07/21/2024] [Accepted: 07/25/2024] [Indexed: 08/29/2024] Open
Abstract
Skin stem cells (SCs) play a pivotal role in supporting tissue homeostasis. Several types of SCs are responsible for maintaining and regenerating skin tissue. These include bulge SCs and others residing in the interfollicular epidermis, infundibulum, isthmus, sebaceous glands, and sweat glands. The emergence of skin SCs commences during embryogenesis, where multipotent SCs arise from various precursor populations. These early events set the foundation for the diverse pool of SCs that will reside in the adult skin, ready to respond to tissue repair and regeneration demands. A network of molecular cues regulates skin SC behavior, balancing quiescence, self-renewal, and differentiation. The disruption of this delicate equilibrium can lead to SC exhaustion, impaired wound healing, and pathological conditions such as skin cancer. The present review explores the intricate mechanisms governing the development, activation, and differentiation of skin SCs, shedding light on the molecular signaling pathways that drive their fate decisions and skin homeostasis. Unraveling the complexities of these molecular drivers not only enhances our fundamental knowledge of skin biology but also holds promise for developing novel strategies to modulate skin SC fate for regenerative medicine applications, ultimately benefiting patients with skin disorders and injuries.
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Affiliation(s)
- Iasonas Dermitzakis
- Department of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Despoina Dimitria Kampitsi
- Department of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Maria Eleni Manthou
- Department of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Paschalis Evangelidis
- Hematology Unit-Hemophilia Centre, 2nd Propedeutic Department of Internal Medicine, Hippocration Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
| | - Efstratios Vakirlis
- First Department of Dermatology and Venereology, School of Medicine, Aristotle University of Thessaloniki, 54643 Thessaloniki, Greece
| | - Soultana Meditskou
- Department of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Paschalis Theotokis
- Department of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
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9
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Jamjoum R, Majumder S, Issleny B, Stiban J. Mysterious sphingolipids: metabolic interrelationships at the center of pathophysiology. Front Physiol 2024; 14:1229108. [PMID: 38235387 PMCID: PMC10791800 DOI: 10.3389/fphys.2023.1229108] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 11/27/2023] [Indexed: 01/19/2024] Open
Abstract
Metabolic pathways are complex and intertwined. Deficiencies in one or more enzymes in a given pathway are directly linked with genetic diseases, most of them having devastating manifestations. The metabolic pathways undertaken by sphingolipids are diverse and elaborate with ceramide species serving as the hubs of sphingolipid intermediary metabolism and function. Sphingolipids are bioactive lipids that serve a multitude of cellular functions. Being pleiotropic in function, deficiency or overproduction of certain sphingolipids is associated with many genetic and chronic diseases. In this up-to-date review article, we strive to gather recent scientific evidence about sphingolipid metabolism, its enzymes, and regulation. We shed light on the importance of sphingolipid metabolism in a variety of genetic diseases and in nervous and immune system ailments. This is a comprehensive review of the state of the field of sphingolipid biochemistry.
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Affiliation(s)
- Rama Jamjoum
- Department of Pharmacy, Birzeit University, West Bank, Palestine
| | - Saurav Majumder
- National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Rockville, MD, United States
| | - Batoul Issleny
- Department of Pharmacy, Birzeit University, West Bank, Palestine
| | - Johnny Stiban
- Department of Biology and Biochemistry, Birzeit University, West Bank, Palestine
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10
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Zhang X, Gong Z, Shen Y, Cai Z, Yang L, Zhang T, Li W, Zhao Y, Zhu S, Liu C, Wang J, Wang X, Qi R, Liu J, Lei X, Wang W, Jiang C, Fu Y, Kong W. Alkaline ceramidase 1-mediated platelet ceramide catabolism mitigates vascular inflammation and abdominal aortic aneurysm formation. NATURE CARDIOVASCULAR RESEARCH 2023; 2:1173-1189. [PMID: 39196139 DOI: 10.1038/s44161-023-00364-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 10/12/2023] [Indexed: 08/29/2024]
Abstract
Abdominal aortic aneurysm (AAA) is a highly lethal vascular disease. The role of platelets in AAA remains incompletely understood. Here we show that platelet ceramides, rather than other phospholipids, were elevated in an angiotensin II (AngII)-induced AAA murine model and in patients with AAA by using targeted lipidomic analysis. Among key ceramide metabolism enzymes, alkaline ceramidase 1 (Acer1) hydrolyzing ceramides were exclusively downregulated in AAA platelets. Platelet-specific Acer1 knockout mice were more susceptible to AAA upon AngII infusion without affecting hemostasis and thrombosis. Mechanistically, Acer1 deficiency in platelets facilitated platelet pro-inflammatory cytokine secretion as well as P-selectin-mediated circulating platelet-leukocyte aggregation and infiltration in aortic walls via the ceramide-p38 MAPK signaling axis. Of note, AngII repressed Acer1 expression in platelets by decreasing HuR-dependent mRNA stability. In conclusion, Acer1-mediated ceramide degradation in platelets exhibited anti-inflammatory effects and ameliorated AAA formation, potentially serving as a therapeutic target for AAA and other inflammatory vascular diseases.
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Affiliation(s)
- Xu Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Ze Gong
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Yicong Shen
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Zeyu Cai
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Liu Yang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Tao Zhang
- Department of Vascular Surgery, Peking University People's Hospital, Beijing, China
| | - Weihao Li
- Department of Vascular Surgery, Peking University People's Hospital, Beijing, China
| | - Yang Zhao
- Department of Laboratory Medicine, Peking University Third Hospital, Beijing, China
| | - Shirong Zhu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Cihang Liu
- Department of Biochemistry and Molecular Biology, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Jin Wang
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Xian Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Ruomei Qi
- Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, China
| | - Junling Liu
- Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoguang Lei
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Wengong Wang
- Department of Biochemistry and Molecular Biology, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Changtao Jiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
| | - Yi Fu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
| | - Wei Kong
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
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11
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Xu Y, Zhang Y, Qin Y, Gu M, Chen R, Sun Y, Wu Y, Li Q, Qiao Y, Wang X, Zhang Q, Kong L, Li S, Wang Z. Multi-omics analysis of functional substances and expression verification in cashmere fineness. BMC Genomics 2023; 24:720. [PMID: 38017403 PMCID: PMC10685610 DOI: 10.1186/s12864-023-09825-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Accepted: 11/21/2023] [Indexed: 11/30/2023] Open
Abstract
BACKGROUND Numerous factors influence the growth and development of cashmere. Existing research on cashmere has predominantly emphasized a single omics level. Integrating multi-omics analyses can offer a more comprehensive understanding by encompassing the entire spectrum. This study more accurately and comprehensively identified the key factors influencing cashmere fineness using multi-omics analysis. METHODS This study used skin tissues of coarse cashmere type (CT_LCG) and fine cashmere type Liaoning cashmere goats (FT_LCG) for the analysis. This study employed an integrated approach involving transcriptomics, translatomics, proteomics, and metabolomics to identify substances associated with cashmere fineness. The findings were validated using parallel reaction monitoring (PRM) and multiple reaction monitoring (MRM) techniques. RESULTS The GO functional enrichment analysis identified three common terms: multicellular organismal process, immune system process, and extracellular region. Furthermore, the KEGG enrichment analysis uncovered the involvement of the arachidonic acid metabolic pathway. Protein expression trends were verified using PRM technology. The expression trends of KRT79, as confirmed by PRM, were consistent with those observed in TMT proteomics and exhibited a positive regulatory effect on cashmere fineness. Metabolite expression trends were confirmed using MRM technology. The expression trends of 9 out of 15 validated metabolites were in agreement with those identified in the non-targeted metabolomics analysis. CONCLUSIONS This study employed multi-omics analysis to identify key regulators of cashmere fineness, including PLA2G12A, KRT79, and prostaglandin B2. The findings of this study offer valuable data and establish a theoretical foundation for conducting comprehensive investigations into the molecular regulatory mechanisms and functional aspects of cashmere fineness.
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Affiliation(s)
- Yanan Xu
- College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
| | - Yu Zhang
- College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
| | - Yuting Qin
- College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
| | - Ming Gu
- College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
| | - Rui Chen
- College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
| | - Yinggang Sun
- College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
| | - Yanzhi Wu
- College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
| | - Qian Li
- College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
| | - Yanjun Qiao
- College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
| | - Xiaowei Wang
- College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
| | - Qiu Zhang
- College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
| | - Lingchao Kong
- College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
| | - Shuaitong Li
- College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
| | - Zeying Wang
- College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China.
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12
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Sun J, Zhou Z, Zhou Y, Liu T, Li Y, Gong Z, Jin Y, Zheng L, Huang Y. Anti-Rheumatoid Arthritis Pharmacodynamic Substances Screening of Periploca forrestii Schltr.: Component Analyses In Vitro and In Vivo Combined with Multi-Technical Metabolomics. Int J Mol Sci 2023; 24:13695. [PMID: 37761998 PMCID: PMC10530683 DOI: 10.3390/ijms241813695] [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: 08/05/2023] [Revised: 08/31/2023] [Accepted: 09/02/2023] [Indexed: 09/29/2023] Open
Abstract
The purpose of this study was to elucidate the metabolic action patterns of P. forrestii against rheumatoid arthritis (RA) using metabolomics, and to obtain its potential effective substances for treating RA. First, the therapeutic effects of P. forrestii against RA were confirmed; second, the chemical composition of P. forrestii was analyzed, and 17 prototypes were absorbed into blood; subsequently, plasma metabolomics studies using UPLC-Triple-TOF-MS/MS and GC-MS were performed to disclose the metabolomics alterations in groups, which revealed 38 altered metabolites after drug intervention. These metabolites were all associated with the arthritis pathophysiology process (-log(p) > 1.6). Among them, sorted by variable important in projection (VIP), the metabolites affected (VIP ≥ 1.72) belonged to lipid metabolites. Finally, Pearson's analysis between endogenous metabolites and exogenous compounds was conducted to obtain potential pharmacological substances for the P. forrestii treatment of RA, which showed a high correlation between five blood-absorbed components and P. forrestii-regulated metabolites. This information provides a basis for the selection of metabolic action modes for P. forrestii clinical application dosage, and potential pharmacological substances that exerted anti-RA effects of P. forrestii were discovered. The study provided an experimental basis for further research on pharmacoequivalence, molecular mechanism validation, and even the development of new dosage forms in the future.
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Affiliation(s)
- Jia Sun
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang 550004, China; (J.S.); (Z.Z.); (Y.Z.); (T.L.); (Y.L.); (Z.G.); (Y.J.)
| | - Zuying Zhou
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang 550004, China; (J.S.); (Z.Z.); (Y.Z.); (T.L.); (Y.L.); (Z.G.); (Y.J.)
- School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550004, China
| | - Yang Zhou
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang 550004, China; (J.S.); (Z.Z.); (Y.Z.); (T.L.); (Y.L.); (Z.G.); (Y.J.)
- School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550004, China
| | - Ting Liu
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang 550004, China; (J.S.); (Z.Z.); (Y.Z.); (T.L.); (Y.L.); (Z.G.); (Y.J.)
| | - Yueting Li
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang 550004, China; (J.S.); (Z.Z.); (Y.Z.); (T.L.); (Y.L.); (Z.G.); (Y.J.)
| | - Zipeng Gong
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang 550004, China; (J.S.); (Z.Z.); (Y.Z.); (T.L.); (Y.L.); (Z.G.); (Y.J.)
| | - Yang Jin
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang 550004, China; (J.S.); (Z.Z.); (Y.Z.); (T.L.); (Y.L.); (Z.G.); (Y.J.)
| | - Lin Zheng
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang 550004, China; (J.S.); (Z.Z.); (Y.Z.); (T.L.); (Y.L.); (Z.G.); (Y.J.)
- School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550004, China
- National Engineering Research Center of Miao′s Medicines, Guiyang 550004, China
| | - Yong Huang
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang 550004, China; (J.S.); (Z.Z.); (Y.Z.); (T.L.); (Y.L.); (Z.G.); (Y.J.)
- School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550004, China
- National Engineering Research Center of Miao′s Medicines, Guiyang 550004, China
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Zhu JY, Ni XS, Han XY, Liu S, Ji YK, Yao J, Yan B. Metabolomic profiling of a neurodegenerative retina following optic nerve transection. Mol Med Rep 2023; 28:178. [PMID: 37539744 PMCID: PMC10433715 DOI: 10.3892/mmr.2023.13065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 07/19/2023] [Indexed: 08/05/2023] Open
Abstract
The degeneration of retinal ganglion cells (RGCs) often causes irreversible vision impairment. Prevention of RGC degeneration can prevent or delay the deterioration of visual function. The present study aimed to investigate retinal metabolic profiles following optic nerve transection (ONT) injury and identify the potential metabolic targets for the prevention of RGC degeneration. Retinal samples were dissected from ONT group and non‑ONT group. The untargeted metabolomics were carried out using liquid chromatography‑tandem mass spectrometry. The involved pathways and biomarkers were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and MetaboAnalyst 5.0. In the ONT group, 689 disparate metabolites were detected, including lipids and lipid‑like molecules. A total of 122 metabolites were successfully annotated and enriched in 50 KEGG pathways. Among them, 'sphingolipid metabolism' and 'primary bile acid biosynthesis' were identified involved in RGC degeneration. A total of five metabolites were selected as the candidate biomarkers for detecting RGC degeneration with an AUC value of 1. The present study revealed that lipid‑related metabolism was involved in the pathogenesis of retinal neurodegeneration. Taurine, taurochenodesoxycholic acid, taurocholic acid (TCA), sphingosine, and galabiosylceramide are shown as the promising biomarkers for the diagnosis of RGC degeneration.
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Affiliation(s)
- Jun-Ya Zhu
- Department of Ophthalmology and Optometry, The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
- Eye Institute and Department of Ophthalmology, Eye and Ear, Nose and Throat Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200030, P.R. China
| | - Xi-Sen Ni
- Department of Ophthalmology and Optometry, The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
- Department of Ophthalmology and Optometry, The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Xiao-Yan Han
- Eye Institute and Department of Ophthalmology, Eye and Ear, Nose and Throat Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200030, P.R. China
| | - Sha Liu
- Department of Ophthalmology and Optometry, The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
- Department of Ophthalmology and Optometry, The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Yu-Ke Ji
- Department of Ophthalmology and Optometry, The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
- Department of Ophthalmology and Optometry, The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Jin Yao
- Department of Ophthalmology and Optometry, The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
- Department of Ophthalmology and Optometry, The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Biao Yan
- Eye Institute and Department of Ophthalmology, Eye and Ear, Nose and Throat Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200030, P.R. China
- National Health Commission Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai 200030, P.R. China
- Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai 200030, P.R. China
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Fatty Acid 2-Hydroxylase and 2-Hydroxylated Sphingolipids: Metabolism and Function in Health and Diseases. Int J Mol Sci 2023; 24:ijms24054908. [PMID: 36902339 PMCID: PMC10002949 DOI: 10.3390/ijms24054908] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 02/28/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023] Open
Abstract
Sphingolipids containing acyl residues that are hydroxylated at C-2 are found in most, if not all, eukaryotes and certain bacteria. 2-hydroxylated sphingolipids are present in many organs and cell types, though they are especially abundant in myelin and skin. The enzyme fatty acid 2-hydroxylase (FA2H) is involved in the synthesis of many but not all 2-hydroxylated sphingolipids. Deficiency in FA2H causes a neurodegenerative disease known as hereditary spastic paraplegia 35 (HSP35/SPG35) or fatty acid hydroxylase-associated neurodegeneration (FAHN). FA2H likely also plays a role in other diseases. A low expression level of FA2H correlates with a poor prognosis in many cancers. This review presents an updated overview of the metabolism and function of 2-hydroxylated sphingolipids and the FA2H enzyme under physiological conditions and in diseases.
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Abstract
Ceramides are a class of sphingolipid that is the backbone structure for all sphingolipids, such as glycosphingolipids and phosphosphingolipids. While being a minor constituent of cellular membranes, ceramides are the major lipid component (along with cholesterol, free fatty acid, and other minor components) of the intercellular spaces of stratum corneum that forms the epidermal permeability barrier. These stratum corneum ceramides consist of unique heterogenous molecular species that have only been identified in terrestrial mammals. Alterations of ceramide molecular profiles are characterized in skin diseases associated with compromised permeability barrier functions, such as atopic dermatitis, psoriasis and xerosis. In addition, hereditary abnormalities of some ichthyoses are associated with an epidermal unique ceramide species, omega-O-acylceramide. Ceramides also serve as lipid modulators to regulate cellular functions, including cell cycle arrest, differentiation, and apoptosis, and it has been demonstrated that changes in ceramide metabolism also cause certain diseases. In addition, ceramide metabolites, sphingoid bases, sphingoid base-1-phosphate and ceramide-1-phosphate are also lipid mediators that regulate cellular functions. In this review article, we describe diverse physiological and pathological roles of ceramides and their metabolites in epidermal permeability barrier function, epidermal cell proliferation and differentiation, immunity, and cutaneous diseases. Finally, we summarize the utilization of ceramides as therapy to treat cutaneous disease.
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16
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Lee SA, Li KN, Tumbar T. Stem cell-intrinsic mechanisms regulating adult hair follicle homeostasis. Exp Dermatol 2020; 30:430-447. [PMID: 33278851 DOI: 10.1111/exd.14251] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 11/23/2020] [Accepted: 11/24/2020] [Indexed: 12/12/2022]
Abstract
Adult hair follicle stem cells (HFSCs) undergo dynamic and periodic molecular changes in their cellular states throughout the hair homeostatic cycle. These states are tightly regulated by cell-intrinsic mechanisms and by extrinsic signals from the microenvironment. HFSCs are essential not only for fuelling hair growth, but also for skin wound healing. Increasing evidence suggests an important role of HFSCs in organizing multiple skin components around the hair follicle, thus functioning as an organizing centre during adult skin homeostasis. Here, we focus on recent findings on cell-intrinsic mechanisms of HFSC homeostasis, which include transcription factors, histone modifications, DNA regulatory elements, non-coding RNAs, cell metabolism, cell polarity and post-transcriptional mRNA processing. Several transcription factors are now known to participate in well-known signalling pathways that control hair follicle homeostasis, as well as in super-enhancer activities to modulate HFSC and progenitor lineage progression. Interestingly, HFSCs have been shown to secrete molecules that are important in guiding the organization of several skin components around the hair follicle, including nerves, arrector pili muscle and vasculature. Finally, we discuss recent technological advances in the field such as single-cell RNA sequencing and live imaging, which revealed HFSC and progenitor heterogeneity and brought new light to understanding crosstalking between HFSCs and the microenvironment. The field is well on its way to generate a comprehensive map of molecular interactions that should serve as a solid theoretical platform for application in hair and skin disease and ageing.
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Affiliation(s)
- Seon A Lee
- Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA
| | - Kefei Nina Li
- Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA
| | - Tudorita Tumbar
- Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA
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17
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Alkaline ceramidase family: The first two decades. Cell Signal 2020; 78:109860. [PMID: 33271224 DOI: 10.1016/j.cellsig.2020.109860] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 11/22/2020] [Accepted: 11/24/2020] [Indexed: 11/21/2022]
Abstract
Ceramidases are a group of enzymes that catalyze the hydrolysis of ceramide, dihydroceramide, and phytoceramide into sphingosine (SPH), dihydrosphingosine (DHS), and phytosphingosine (PHS), respectively, along with a free fatty acid. Ceramidases are classified into the acid, neutral, and alkaline ceramidase subtypes according to the pH optima for their catalytic activity. YPC1 and YDC1 were the first alkaline ceramidase genes to be identified and cloned from the yeast Saccharomyces cerevisiae two decades ago. Subsequently, alkaline ceramidase genes were identified from other species, including one Drosophila melanogaster ACER gene (Dacer), one Arabidopsis thaliana ACER gene (AtACER), three Mus musculus ACER genes (Acer1, Acer2, and Acer3), and three Homo sapiens ACER genes (ACER1, ACER2, and ACER3). The protein products of these genes constitute a large protein family, termed the alkaline ceramidase (ACER) family. All the biochemically characterized members of the ACER family are integral membrane proteins with seven transmembrane segments in the Golgi complex or endoplasmic reticulum, and they each have unique substrate specificity. An increasing number of studies suggest that the ACER family has diverse roles in regulating sphingolipid metabolism and biological processes. Here we discuss the discovery of the ACER family, the biochemical properties, structures, and catalytic mechanisms of its members, and its role in regulating sphingolipid metabolism and biological processes in yeast, insects, plants, and mammals.
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18
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Luo M, Li JF, Yang Q, Zhang K, Wang ZW, Zheng S, Zhou JJ. Stem cell quiescence and its clinical relevance. World J Stem Cells 2020; 12:1307-1326. [PMID: 33312400 PMCID: PMC7705463 DOI: 10.4252/wjsc.v12.i11.1307] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 08/28/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023] Open
Abstract
Quiescent state has been observed in stem cells (SCs), including in adult SCs and in cancer SCs (CSCs). Quiescent status of SCs contributes to SC self-renewal and conduces to averting SC death from harsh external stimuli. In this review, we provide an overview of intrinsic mechanisms and extrinsic factors that regulate adult SC quiescence. The intrinsic mechanisms discussed here include the cell cycle, mitogenic signaling, Notch signaling, epigenetic modification, and metabolism and transcriptional regulation, while the extrinsic factors summarized here include microenvironment cells, extracellular factors, and immune response and inflammation in microenvironment. Quiescent state of CSCs has been known to contribute immensely to therapeutic resistance in multiple cancers. The characteristics and the regulation mechanisms of quiescent CSCs are discussed in detail. Importantly, we also outline the recent advances and controversies in therapeutic strategies targeting CSC quiescence.
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Affiliation(s)
- Meng Luo
- Department of Breast Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Jin-Fan Li
- Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Qi Yang
- Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Kun Zhang
- Department of Breast Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Zhan-Wei Wang
- Department of Breast Surgery, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou 313003, Zhejiang Province, China
| | - Shu Zheng
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Jiao-Jiao Zhou
- Department of Breast Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
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Ren X, Xia W, Xu P, Shen H, Dai X, Liu M, Shi Y, Ye X, Dang Y. Lgr4 Deletion Delays the Hair Cycle and Inhibits the Activation of Hair Follicle Stem Cells. J Invest Dermatol 2020; 140:1706-1712.e4. [PMID: 32035093 PMCID: PMC8507220 DOI: 10.1016/j.jid.2019.12.034] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 12/10/2019] [Accepted: 12/17/2019] [Indexed: 12/23/2022]
Abstract
It is known that LGR4 plays an important role in hair follicle (HF) development, but the impact of LGR4 on the hair cycle is still unclear. In this study, we have found that K14-Cre-mediated skin epithelia-specific deletion of Lgr4 results in delayed anagen entry during the physiological hair cycle and compromised HF regeneration upon transplantation. We show that, although Lgr4 deletion does not appear to affect the number of quiescent HF stem cells, it leads to reduced numbers of LGR5+ and actively proliferating stem cells in the HFs. Moreover, LGR4-deficient HFs show molecular changes consistent with decreased mTOR and Wnt signaling but upregulated BMP signaling. Importantly, the reactivation of the protein kinase B pathway by injecting the protein kinase B activator SC79 in Lgr4-/- mice can effectively reverse the hair cycle delay. Together, these data suggest that LGR4 promotes the normal hair cycle by activating HF stem cells and by influencing the activities of multiple signaling pathways that are known to regulate HF stem cells. Our study also implicates LGR4 as a potential target for treating hair disorder in the future.
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Affiliation(s)
- Xiaolin Ren
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Weili Xia
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Peng Xu
- Department of Dermatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hongyang Shen
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Xing Dai
- Department of Biological Chemistry, School of Medicine, University of California, Irvine, California, USA
| | - Mingyao Liu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Yuling Shi
- Department of Dermatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
| | - Xiyun Ye
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
| | - Yongyan Dang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
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Duarte C, Akkaoui J, Yamada C, Ho A, Mao C, Movila A. Elusive Roles of the Different Ceramidases in Human Health, Pathophysiology, and Tissue Regeneration. Cells 2020; 9:cells9061379. [PMID: 32498325 PMCID: PMC7349419 DOI: 10.3390/cells9061379] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 05/25/2020] [Accepted: 05/27/2020] [Indexed: 12/29/2022] Open
Abstract
Ceramide and sphingosine are important interconvertible sphingolipid metabolites which govern various signaling pathways related to different aspects of cell survival and senescence. The conversion of ceramide into sphingosine is mediated by ceramidases. Altogether, five human ceramidases—named acid ceramidase, neutral ceramidase, alkaline ceramidase 1, alkaline ceramidase 2, and alkaline ceramidase 3—have been identified as having maximal activities in acidic, neutral, and alkaline environments, respectively. All five ceramidases have received increased attention for their implications in various diseases, including cancer, Alzheimer’s disease, and Farber disease. Furthermore, the potential anti-inflammatory and anti-apoptotic effects of ceramidases in host cells exposed to pathogenic bacteria and viruses have also been demonstrated. While ceramidases have been a subject of study in recent decades, our knowledge of their pathophysiology remains limited. Thus, this review provides a critical evaluation and interpretive analysis of existing literature on the role of acid, neutral, and alkaline ceramidases in relation to human health and various diseases, including cancer, neurodegenerative diseases, and infectious diseases. In addition, the essential impact of ceramidases on tissue regeneration, as well as their usefulness in enzyme replacement therapy, is also discussed.
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Affiliation(s)
- Carolina Duarte
- Department of Periodontology, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33324, USA; (J.A.); (C.Y.); (A.H.)
- Correspondence: (C.D.); (A.M.); Tel.: +1-954-262-7306 (A.M.)
| | - Juliet Akkaoui
- Department of Periodontology, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33324, USA; (J.A.); (C.Y.); (A.H.)
| | - Chiaki Yamada
- Department of Periodontology, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33324, USA; (J.A.); (C.Y.); (A.H.)
| | - Anny Ho
- Department of Periodontology, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33324, USA; (J.A.); (C.Y.); (A.H.)
| | - Cungui Mao
- Department of Medicine, The State University of New York at Stony Brook, Stony Brook, NY 11794, USA;
- Cancer Center, The State University of New York at Stony Brook, Stony Brook, NY 11794, USA
| | - Alexandru Movila
- Department of Periodontology, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33324, USA; (J.A.); (C.Y.); (A.H.)
- Institute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, FL 33324, USA
- Correspondence: (C.D.); (A.M.); Tel.: +1-954-262-7306 (A.M.)
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He H, An F, Huang Q, Kong Y, He D, Chen L, Song H. Metabolic effect of AOS-iron in rats with iron deficiency anemia using LC-MS/MS based metabolomics. Food Res Int 2020; 130:108913. [DOI: 10.1016/j.foodres.2019.108913] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 12/02/2019] [Accepted: 12/15/2019] [Indexed: 12/17/2022]
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22
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Druggable Sphingolipid Pathways: Experimental Models and Clinical Opportunities. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1274:101-135. [PMID: 32894509 DOI: 10.1007/978-3-030-50621-6_6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Intensive research in the field of sphingolipids has revealed diverse roles in cell biological responses and human health and disease. This immense molecular family is primarily represented by the bioactive molecules ceramide, sphingosine, and sphingosine 1-phosphate (S1P). The flux of sphingolipid metabolism at both the subcellular and extracellular levels provides multiple opportunities for pharmacological intervention. The caveat is that perturbation of any single node of this highly regulated flux may have effects that propagate throughout the metabolic network in a dramatic and sometimes unexpected manner. Beginning with S1P, the receptors for which have thus far been the most clinically tractable pharmacological targets, this review will describe recent advances in therapeutic modulators targeting sphingolipids, their chaperones, transporters, and metabolic enzymes.
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23
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Casasampere M, Bielsa N, Riba D, Bassas L, Xu R, Mao C, Fabriàs G, Abad JL, Delgado A, Casas J. New fluorogenic probes for neutral and alkaline ceramidases. J Lipid Res 2019; 60:1174-1181. [PMID: 30926626 DOI: 10.1194/jlr.d092759] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 03/27/2019] [Indexed: 12/20/2022] Open
Abstract
New fluorogenic ceramidase substrates derived from the N-acyl modification of our previously reported probes (RBM14) are reported. While none of the new probes were superior to the known RBM14C12 as acid ceramidase substrates, the corresponding nervonic acid amide (RBM14C24:1) is an efficient and selective substrate for the recombinant human neutral ceramidase, both in cell lysates and in intact cells. A second generation of substrates, incorporating the natural 2-(N-acylamino)-1,3-diol-4-ene framework (compounds RBM15) is also reported. Among them, the corresponding fatty acyl amides with an unsaturated N-acyl chain can be used as substrates to determine alkaline ceramidase (ACER)1 and ACER2 activities. In particular, compound RBM15C18:1 has emerged as the best fluorogenic probe reported so far to measure ACER1 and ACER2 activities in a 96-well plate format.
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Affiliation(s)
- Mireia Casasampere
- Spanish National Research Council (CSIC), Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Department of Biological Chemistry, Research Unit on Bioactive Molecules (RUBAM), 08034 Barcelona, Spain.,Faculty of Pharmacy and Food Sciences Department of Pharmacology, Toxicology, and Medicinal Chemistry, Unit of Pharmaceutical Chemistry (Associated Unit to CSIC), University of Barcelona, 08028 Barcelona, Spain
| | - Núria Bielsa
- Spanish National Research Council (CSIC), Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Department of Biological Chemistry, Research Unit on Bioactive Molecules (RUBAM), 08034 Barcelona, Spain.,Faculty of Pharmacy and Food Sciences Department of Pharmacology, Toxicology, and Medicinal Chemistry, Unit of Pharmaceutical Chemistry (Associated Unit to CSIC), University of Barcelona, 08028 Barcelona, Spain
| | - Daniel Riba
- Spanish National Research Council (CSIC), Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Department of Biological Chemistry, Research Unit on Bioactive Molecules (RUBAM), 08034 Barcelona, Spain
| | - Laura Bassas
- Spanish National Research Council (CSIC), Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Department of Biological Chemistry, Research Unit on Bioactive Molecules (RUBAM), 08034 Barcelona, Spain
| | - Ruijuan Xu
- Department of Medicine State University of New York at Stony Brook, Stony Brook, NY 11794-8155
| | - Cungui Mao
- Department of Medicine State University of New York at Stony Brook, Stony Brook, NY 11794-8155
| | - Gemma Fabriàs
- Spanish National Research Council (CSIC), Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Department of Biological Chemistry, Research Unit on Bioactive Molecules (RUBAM), 08034 Barcelona, Spain.,Centro de Investigación Biomédica en Red (CIBEREHD), 28029 Madrid, Spain
| | - José-Luis Abad
- Spanish National Research Council (CSIC), Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Department of Biological Chemistry, Research Unit on Bioactive Molecules (RUBAM), 08034 Barcelona, Spain
| | - Antonio Delgado
- Spanish National Research Council (CSIC), Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Department of Biological Chemistry, Research Unit on Bioactive Molecules (RUBAM), 08034 Barcelona, Spain .,Faculty of Pharmacy and Food Sciences Department of Pharmacology, Toxicology, and Medicinal Chemistry, Unit of Pharmaceutical Chemistry (Associated Unit to CSIC), University of Barcelona, 08028 Barcelona, Spain
| | - Josefina Casas
- Spanish National Research Council (CSIC), Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Department of Biological Chemistry, Research Unit on Bioactive Molecules (RUBAM), 08034 Barcelona, Spain .,Centro de Investigación Biomédica en Red (CIBEREHD), 28029 Madrid, Spain
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24
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Lidgerwood GE, Pitson SM, Bonder C, Pébay A. Roles of lysophosphatidic acid and sphingosine-1-phosphate in stem cell biology. Prog Lipid Res 2018; 72:42-54. [PMID: 30196008 DOI: 10.1016/j.plipres.2018.09.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 08/15/2018] [Accepted: 09/05/2018] [Indexed: 02/06/2023]
Abstract
Stem cells are unique in their ability to self-renew and differentiate into various cell types. Because of these features, stem cells are key to the formation of organisms and play fundamental roles in tissue regeneration and repair. Mechanisms controlling their fate are thus fundamental to the development and homeostasis of tissues and organs. Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are bioactive phospholipids that play a wide range of roles in multiple cell types, during developmental and pathophysiological events. Considerable evidence now demonstrates the potent roles of LPA and S1P in the biology of pluripotent and adult stem cells, from maintenance to repair. Here we review their roles for each main category of stem cells and explore how those effects impact development and physiopathology.
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Affiliation(s)
- Grace E Lidgerwood
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia; Ophthalmology, Department of Surgery, the University of Melbourne, Melbourne, Australia
| | - Stuart M Pitson
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia
| | - Claudine Bonder
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia
| | - Alice Pébay
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia; Ophthalmology, Department of Surgery, the University of Melbourne, Melbourne, Australia.
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25
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Insights into Male Androgenetic Alopecia: Differential Gene Expression Profiling of Plucked Hair Follicles and Integration with Genetic Data. J Invest Dermatol 2018; 139:235-238. [PMID: 30009830 DOI: 10.1016/j.jid.2018.06.182] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 06/07/2018] [Accepted: 06/25/2018] [Indexed: 12/13/2022]
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26
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Li F, Xu R, Low BE, Lin CL, Garcia-Barros M, Schrandt J, Mileva I, Snider A, Luo CK, Jiang XC, Li MS, Hannun YA, Obeid LM, Wiles MV, Mao C. Alkaline ceramidase 2 is essential for the homeostasis of plasma sphingoid bases and their phosphates. FASEB J 2018; 32:3058-3069. [PMID: 29401619 DOI: 10.1096/fj.201700445rr] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Sphingosine-1-phosphate (S1P) plays important roles in cardiovascular development and immunity. S1P is abundant in plasma because erythrocytes-the major source of S1P-lack any S1P-degrading activity; however, much remains unclear about the source of the plasma S1P precursor, sphingosine (SPH), derived mainly from the hydrolysis of ceramides by the action of ceramidases that are encoded by 5 distinct genes, acid ceramidase 1 ( ASAH1)/ Asah1, ASAH2/ Asah2, alkaline ceramidase 1 ( ACER1)/ Acer1, ACER2/ Acer2, and ACER3/ Acer3, in humans/mice. Previous studies have reported that knocking out Asah1 or Asah2 failed to reduce plasma SPH and S1P levels in mice. In this study, we show that knocking out Acer1 or Acer3 also failed to reduce the blood levels of SPH or S1P in mice. In contrast, knocking out Acer2 from either whole-body or the hematopoietic lineage markedly decreased the blood levels of SPH and S1P in mice. Of interest, knocking out Acer2 from whole-body or the hematopoietic lineage also markedly decreased the levels of dihydrosphingosine (dhSPH) and dihydrosphingosine-1-phosphate (dhS1P) in blood. Taken together, these results suggest that ACER2 plays a key role in the maintenance of high plasma levels of sphingoid base-1-phosphates-S1P and dhS1P-by controlling the generation of sphingoid bases-SPH and dhSPH-in hematopoietic cells.-Li, F., Xu, R., Low, B. E., Lin, C.-L., Garcia-Barros, M., Schrandt, J., Mileva, I., Snider, A., Luo, C. K., Jiang, X.-C., Li, M.-S., Hannun, Y. A., Obeid, L. M., Wiles, M. V., Mao, C. Alkaline ceramidase 2 is essential for the homeostasis of plasma sphingoid bases and their phosphates.
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Affiliation(s)
- Fang Li
- Department of Medicine, State University of New York at Stony Brook, Stony Brook, New York, USA.,Cancer Center, State University of New York at Stony Brook, Stony Brook, New York, USA.,Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ruijuan Xu
- Department of Medicine, State University of New York at Stony Brook, Stony Brook, New York, USA.,Cancer Center, State University of New York at Stony Brook, Stony Brook, New York, USA
| | - Benjamin E Low
- Technology Evaluation and Development, The Jackson Laboratory, Bar Harbor, Maine, USA
| | - Chih-Li Lin
- Department of Medicine, State University of New York at Stony Brook, Stony Brook, New York, USA.,Cancer Center, State University of New York at Stony Brook, Stony Brook, New York, USA
| | - Monica Garcia-Barros
- Department of Medicine, State University of New York at Stony Brook, Stony Brook, New York, USA.,Cancer Center, State University of New York at Stony Brook, Stony Brook, New York, USA
| | - Jennifer Schrandt
- Department of Medicine, State University of New York at Stony Brook, Stony Brook, New York, USA.,Cancer Center, State University of New York at Stony Brook, Stony Brook, New York, USA
| | - Izolda Mileva
- Department of Medicine, State University of New York at Stony Brook, Stony Brook, New York, USA.,Cancer Center, State University of New York at Stony Brook, Stony Brook, New York, USA
| | - Ashley Snider
- Department of Medicine, State University of New York at Stony Brook, Stony Brook, New York, USA.,Cancer Center, State University of New York at Stony Brook, Stony Brook, New York, USA.,Northport Veterans Administration Medical Center, Northport, New York, USA
| | - Catherine K Luo
- Cancer Center, State University of New York at Stony Brook, Stony Brook, New York, USA
| | - Xian-Cheng Jiang
- Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York, USA
| | - Ming-Song Li
- Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yusuf A Hannun
- Department of Medicine, State University of New York at Stony Brook, Stony Brook, New York, USA.,Cancer Center, State University of New York at Stony Brook, Stony Brook, New York, USA
| | - Lina M Obeid
- Department of Medicine, State University of New York at Stony Brook, Stony Brook, New York, USA.,Cancer Center, State University of New York at Stony Brook, Stony Brook, New York, USA.,Northport Veterans Administration Medical Center, Northport, New York, USA
| | - Michael V Wiles
- Technology Evaluation and Development, The Jackson Laboratory, Bar Harbor, Maine, USA
| | - Cungui Mao
- Department of Medicine, State University of New York at Stony Brook, Stony Brook, New York, USA.,Cancer Center, State University of New York at Stony Brook, Stony Brook, New York, USA
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