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Zhao Q, Wei C, Dou J, Sun Y, Zeng Q, Bao Z. Molecular and Physiological Responses of Litopenaeus vannamei to Nitrogen and Phosphorus Stress. Antioxidants (Basel) 2025; 14:194. [PMID: 40002380 PMCID: PMC11851905 DOI: 10.3390/antiox14020194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 01/31/2025] [Accepted: 02/05/2025] [Indexed: 02/27/2025] Open
Abstract
Environmental stressors such as nitrogen and phosphorus play a critical role in regulating the growth and physiological functions of Litopenaeus vannamei, a key species in aquaculture. This study investigates the effects of nitrogen and phosphorus stress on shrimp growth, oxidative stress, tissue damage, and molecular mechanisms. Exposure to increasing concentrations of nitrogen and phosphorus significantly reduced growth rates. Oxidative stress markers, including superoxide dismutase (SOD), catalase (CAT), total antioxidant capacity (T-AOC), and malondialdehyde (MDA), indicated heightened oxidative damage under both stress conditions, with nitrogen stress causing more severe responses than phosphorus stress. Histopathological analysis revealed substantial damage to the gills and hepatopancreas, organs essential for respiration and metabolism. Transcriptomic analysis identified differentially expressed genes (DEGs) enriched in apoptosis, lysosome, sphingolipid metabolism, and phagosome pathways, suggesting shared molecular responses to nitrogen and phosphorus stress. The results demonstrate that L. vannamei initiates oxidative and immune responses to cope with environmental stressors, but the adaptive capacity remains limited. These findings provide a foundation for understanding the stress tolerance mechanisms in shrimp and inform future strategies for breeding high-resistance strains in aquaculture.
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Affiliation(s)
- Qianqian Zhao
- MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences/Key Laboratory of Tropical Aquatic Germplasm of Hainan Province, Sanya Oceanographic Institution, Ocean University of China, Qingdao, Shandong/Sanya, Hainan 266100/572025, China; (Q.Z.); (C.W.)
| | - Cun Wei
- MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences/Key Laboratory of Tropical Aquatic Germplasm of Hainan Province, Sanya Oceanographic Institution, Ocean University of China, Qingdao, Shandong/Sanya, Hainan 266100/572025, China; (Q.Z.); (C.W.)
- Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou 511458, China
- Hainan Seed Industry Laboratory, Sanya 572025, China
| | - Jiangling Dou
- MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences/Key Laboratory of Tropical Aquatic Germplasm of Hainan Province, Sanya Oceanographic Institution, Ocean University of China, Qingdao, Shandong/Sanya, Hainan 266100/572025, China; (Q.Z.); (C.W.)
| | - Yue Sun
- MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences/Key Laboratory of Tropical Aquatic Germplasm of Hainan Province, Sanya Oceanographic Institution, Ocean University of China, Qingdao, Shandong/Sanya, Hainan 266100/572025, China; (Q.Z.); (C.W.)
- Hainan Seed Industry Laboratory, Sanya 572025, China
| | - Qifan Zeng
- MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences/Key Laboratory of Tropical Aquatic Germplasm of Hainan Province, Sanya Oceanographic Institution, Ocean University of China, Qingdao, Shandong/Sanya, Hainan 266100/572025, China; (Q.Z.); (C.W.)
- Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou 511458, China
- Hainan Seed Industry Laboratory, Sanya 572025, China
| | - Zhenmin Bao
- MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences/Key Laboratory of Tropical Aquatic Germplasm of Hainan Province, Sanya Oceanographic Institution, Ocean University of China, Qingdao, Shandong/Sanya, Hainan 266100/572025, China; (Q.Z.); (C.W.)
- Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou 511458, China
- Hainan Seed Industry Laboratory, Sanya 572025, China
- Hebei Xinhai Aquatic Biotechnology Co., Ltd., Cangzhou 061101, China
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Zhao F, Shao M, Li M, Li T, Zheng Y, Sun W, Ni C, Li L. Sphingolipid metabolites involved in the pathogenesis of atherosclerosis: perspectives on sphingolipids in atherosclerosis. Cell Mol Biol Lett 2025; 30:18. [PMID: 39920588 PMCID: PMC11804087 DOI: 10.1186/s11658-024-00679-2] [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: 07/29/2024] [Accepted: 12/17/2024] [Indexed: 02/09/2025] Open
Abstract
Atherosclerosis, with its complex pathogenesis, is a leading underlying cause of many cardiovascular diseases, which are increasingly prevalent in the population. Sphingolipids play an important role in the development of atherosclerosis. Key metabolites and enzymes in sphingolipid metabolism influence the pathogenesis of atherosclerosis in a variety of ways, including inflammatory responses and oxidative stress. Thus, an investigation of sphingolipid metabolism-related metabolites and key enzymes may provide novel insights and treatment targets for atherosclerosis. This review discusses various mechanisms and research progress on the relationship between various sphingolipid metabolites, related enzymes, and atherosclerosis. Finally, we look into the future research direction of phytosphingolipids.
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Affiliation(s)
- Fufangyu Zhao
- National Institute of Traditional Chinese Medicine Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Mingyan Shao
- National Institute of Traditional Chinese Medicine Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Mingrui Li
- National Institute of Traditional Chinese Medicine Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Tianxing Li
- National Institute of Traditional Chinese Medicine Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Yanfei Zheng
- National Institute of Traditional Chinese Medicine Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Wenlong Sun
- Institute of Biomedical Research, School of Life Sciences, Shandong University of Technology, Zibo, 255000, Shandong, China.
| | - Cheng Ni
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - Lingru Li
- National Institute of Traditional Chinese Medicine Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
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Inskeep KA, Crase B, Dayarathna T, Stottmann RW. SMPD4-mediated sphingolipid metabolism regulates brain and primary cilia development. Development 2024; 151:dev202645. [PMID: 39470011 PMCID: PMC11586524 DOI: 10.1242/dev.202645] [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: 12/20/2023] [Accepted: 10/18/2024] [Indexed: 10/30/2024]
Abstract
Genetic variants in multiple sphingolipid biosynthesis genes cause human brain disorders. A recent study looked at people from 12 unrelated families with variants in the gene SMPD4, a neutral sphingomyelinase that metabolizes sphingomyelin into ceramide at an early stage of the biosynthesis pathway. These individuals have severe developmental brain malformations, including microcephaly and cerebellar hypoplasia. The disease mechanism of SMPD4 was not known and so we pursued a new mouse model. We hypothesized that the role of SMPD4 in producing ceramide is important for making primary cilia, a crucial organelle mediating cellular signaling. We found that the mouse model has cerebellar hypoplasia due to failure of Purkinje cell development. Human induced pluripotent stem cells lacking SMPD4 exhibit neural progenitor cell death and have shortened primary cilia, which is rescued by adding exogenous ceramide. SMPD4 production of ceramide is crucial for human brain development.
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Affiliation(s)
- Katherine A. Inskeep
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
- Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH 43205, USA
| | - Bryan Crase
- Department of Neuroscience, The Ohio State University College of Arts and Sciences, Columbus, OH 43210, USA
| | - Thamara Dayarathna
- Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH 43205, USA
| | - Rolf W. Stottmann
- Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH 43205, USA
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA
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Duret T, Elmallah M, Rollin J, Gatault P, Jiang LH, Roger S. Role of purinoreceptors in the release of extracellular vesicles and consequences on immune response and cancer progression. Biomed J 2024:100805. [PMID: 39510381 DOI: 10.1016/j.bj.2024.100805] [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: 09/04/2024] [Revised: 10/24/2024] [Accepted: 11/02/2024] [Indexed: 11/15/2024] Open
Abstract
Cell-to-cell communication is a major process for accommodating cell functioning to changes in the environments and to preserve tissue and organism homeostasis. It is achieved by different mechanisms characterized by the origin of the message, the molecular nature of the messenger, its speed of action and its reach. Purinergic signalling is a powerful mechanism initiated by extracellular nucleotides, such as ATP, acting on plasma membrane purinoreceptors. Purinergic signalling is tightly controlled in time and space by the action of ectonucleotidases. Recent studies have highlighted the critical role of purinergic signalling in controlling the generation, release and fate of extracellular vesicles and, in this way, mediating long-distance responses. Most of these discoveries have been made in immune and cancer cells. This review is aimed at establishing the current knowledge on the way which purinoreceptors control extracellular vesicle-mediated communications and consequences for recipient cells.
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Affiliation(s)
- Thomat Duret
- Université de Tours, Inserm UMR1327 ISCHEMIA « Membrane Signalling and Inflammation in Reperfusion Injuries », Tours, France; Fédération Hospitalo-Universitaire Survival optimization in organ Transplantation (FHU SUPORT), Tours, France
| | - Mohammed Elmallah
- Université de Tours, Inserm UMR1327 ISCHEMIA « Membrane Signalling and Inflammation in Reperfusion Injuries », Tours, France
| | - Jérôme Rollin
- Université de Tours, Inserm UMR1327 ISCHEMIA « Membrane Signalling and Inflammation in Reperfusion Injuries », Tours, France; Service d'Hématologie-Hémostase, CHRU de Tours, Tours, France
| | - Philippe Gatault
- Université de Tours, Inserm UMR1327 ISCHEMIA « Membrane Signalling and Inflammation in Reperfusion Injuries », Tours, France; Service de Néphrologie, Hypertension, Dialyse et Transplantation Rénale, CHRU Tours, Tours, France; Fédération Hospitalo-Universitaire Survival optimization in organ Transplantation (FHU SUPORT), Tours, France
| | - Lin-Hua Jiang
- Université de Tours, Inserm UMR1327 ISCHEMIA « Membrane Signalling and Inflammation in Reperfusion Injuries », Tours, France; School of Basic Medical Sciences, Xinxiang Medical University, China; School of Biomedical Sciences, University of Leeds, Leeds, United Kingdom
| | - Sébastien Roger
- Université de Tours, Inserm UMR1327 ISCHEMIA « Membrane Signalling and Inflammation in Reperfusion Injuries », Tours, France; Fédération Hospitalo-Universitaire Survival optimization in organ Transplantation (FHU SUPORT), Tours, France.
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Li L, Fei X, Wang H, Chen S, Xu X, Ke H, Zhou Y, Hu Y, He C, Xie C, Lu N, Liu J, Zhu Y, Li N. Genome-wide DNA methylation profiling reveals a novel hypermethylated biomarker PRKCB in gastric cancer. Sci Rep 2024; 14:26605. [PMID: 39496833 PMCID: PMC11535215 DOI: 10.1038/s41598-024-78135-6] [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: 07/19/2024] [Accepted: 10/29/2024] [Indexed: 11/06/2024] Open
Abstract
Globally, gastric cancer (GC) ranks among the most prevalent forms of malignancy, posing a significant health burden. Epigenetic modifications, predominantly characterized by alterations in DNA methylation patterns, have been linked to a diverse array of neoplastic processes. Here, we undertake a comprehensive analysis of the DNA methylation signature in GC, with the aim to discover the potential diagnostic epigenetic biomarkers. Utilizing the Illumina 935 K BeadChip, we conducted a genome-wide exploration of DNA methylation patterns in four paired samples of GC tissues and adjacent non-cancerous counterparts. The bisulfite-pyrosequencing (n = 7) was employed to the quantification for methylated gene. The pubic databases including GWAS Catalog, TCGA and GEO were used. The immunohistochemistry and qRT-PCR analysis were performed. In contrast to adjacent tissues, GC tissues manifested pronounced hypermethylation patterns specifically within the promoter cytosine-phosphate-guanine (CpG) islands, indicating localized epigenetic alterations. DNA methylome analysis further revealed 4432 differentially-methylated probes (DMPs), with the gene PRKCB exhibited the most prominent average DNA methylation disparity (mean Δβ = 0.353). Pyrosequencing validation confirmed three DMPs within the PRKCB promoter (cg08406370, cg00735962, and cg18526361). Notably, the mean methylation levels of PRKCB were inversely correlated with mRNA expression levels in the GWAS Catalog. Furthermore, both mRNA and protein expression levels of PRKCB were significantly reduced in GCs when compared to their adjacent non-cancerous counterparts, verified by TCGA and GEO database. Our study reveals significant DNA methylation alterations in GC and emphasizes the pivotal role of PRKCB gene hypermethylation in conferring GC risk, which offers fresh perspectives for advancing diagnostic approaches and therapeutic strategies for GC.
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Affiliation(s)
- Leyan Li
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Xiao Fei
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Huan Wang
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
- Postdoctoral Innovation Practice Base, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Sihai Chen
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Xinbo Xu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Huajing Ke
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yanan Zhou
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yi Hu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Cong He
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Chuan Xie
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Nonghua Lu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Jianping Liu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yin Zhu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
| | - Nianshuang Li
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
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Burgelman M, Dujardin P, Willems A, Hochepied T, Van Imschoot G, Van Wonterghem E, Van Hoecke L, Vandendriessche C, Vandenbroucke RE. Challenging the conventional wisdom: Re-evaluating Smpd3's role in extracellular vesicle biogenesis. JOURNAL OF EXTRACELLULAR BIOLOGY 2024; 3:e70015. [PMID: 39525277 PMCID: PMC11544639 DOI: 10.1002/jex2.70015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 07/27/2024] [Accepted: 09/28/2024] [Indexed: 11/16/2024]
Abstract
Extracellular vesicles (EVs) are pivotal in intercellular communication, impacting diverse physiological and pathological processes. Current in vitro EV biogenesis studies often utilize pharmacological inhibitors, inducing off-target effects and overlooking cell-specific production nuances. Addressing these limitations, we utilized CRISPR/Cas9 to generate heterozygous full-body and conditional sphingomyelin phosphodiesterase 3 (Smpd3) knockout (KO) transgenic mice. Smpd3, also known as neutral sphingomyelinase 2 (nSMase2), triggers membrane curvature through sphingomyelin hydrolysis to ceramide, thereby influencing exosome release. Intriguingly, Smpd3 deficiency demonstrated no impact on EV release both in vitro and in vivo, underscoring its potential cell-type-specific role in EV biogenesis. Notably, bone marrow derived macrophages (BMDMs) did exhibit reduced EV release upon Alix deletion. Our findings open avenues for subsequent inquiries, enriching our knowledge of EV biogenesis and illuminating intercellular communication in health and disease.
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Affiliation(s)
- Marlies Burgelman
- VIB Center for Inflammation ResearchGhentBelgium
- Department of Biomedical Molecular BiologyGhent UniversityGhentBelgium
| | - Pieter Dujardin
- VIB Center for Inflammation ResearchGhentBelgium
- Department of Biomedical Molecular BiologyGhent UniversityGhentBelgium
| | - Anthony Willems
- VIB Center for Inflammation ResearchGhentBelgium
- Department of Biomedical Molecular BiologyGhent UniversityGhentBelgium
| | - Tino Hochepied
- VIB Center for Inflammation ResearchGhentBelgium
- Department of Biomedical Molecular BiologyGhent UniversityGhentBelgium
| | - Griet Van Imschoot
- VIB Center for Inflammation ResearchGhentBelgium
- Department of Biomedical Molecular BiologyGhent UniversityGhentBelgium
| | - Elien Van Wonterghem
- VIB Center for Inflammation ResearchGhentBelgium
- Department of Biomedical Molecular BiologyGhent UniversityGhentBelgium
| | - Lien Van Hoecke
- VIB Center for Inflammation ResearchGhentBelgium
- Department of Biomedical Molecular BiologyGhent UniversityGhentBelgium
| | - Charysse Vandendriessche
- VIB Center for Inflammation ResearchGhentBelgium
- Department of Biomedical Molecular BiologyGhent UniversityGhentBelgium
| | - Roosmarijn E. Vandenbroucke
- VIB Center for Inflammation ResearchGhentBelgium
- Department of Biomedical Molecular BiologyGhent UniversityGhentBelgium
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Huang M, Stremlau M, Zavras J, Zivko C, Thomas AG, Pietri P, Machairaki V, Slusher BS. Neutral sphingomyelinase 2: A promising drug target for CNS disease. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2024; 102:65-101. [PMID: 39929585 DOI: 10.1016/bs.apha.2024.10.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2025]
Abstract
Neutral sphingomyelinase 2 (nSMase2), encoded by the SMPD3 gene, is a pivotal enzyme in sphingolipid metabolism, hydrolyzing sphingomyelin to produce ceramide, a bioactive lipid involved in apoptosis, inflammation, membrane structure, and extracellular vesicle (EV) biogenesis. nSMase2 is abundantly expressed in the central nervous system (CNS), particularly in neurons, and its dysregulation is implicated in pathologies such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), prion diseases, and neuroviral diseases. In this review, we discuss the critical role of nSMase2 in the CNS and its involvement in neurological as well as non-neurological diseases. We explore the enzyme's functions in sphingolipid metabolism, its regulatory mechanisms, and the implications of its dysregulation in disease pathogenesis. The chapter highlights the therapeutic potential of pharmacologically targeting nSMase2 with small molecule inhibitors and emphasizes the need for further research to optimize inhibitor specificity and efficacy for clinical applications. By understanding the multifaceted roles of nSMase2, we aim to provide insights into novel therapeutic strategies for treating complex diseases associated with its dysregulation.
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Affiliation(s)
- Meixiang Huang
- Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States
| | - Matthew Stremlau
- Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States
| | - Jason Zavras
- Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, United States
| | - Cristina Zivko
- Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States; The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease, Johns Hopkins University School of Medicine, Baltimore, United States
| | - Ajit G Thomas
- Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States
| | - Peter Pietri
- Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States
| | - Vasiliki Machairaki
- Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States; The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease, Johns Hopkins University School of Medicine, Baltimore, United States
| | - Barbara S Slusher
- Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States; Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, United States; Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States.
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Suhaiman L, Belmonte SA. Lipid remodeling in acrosome exocytosis: unraveling key players in the human sperm. Front Cell Dev Biol 2024; 12:1457638. [PMID: 39376630 PMCID: PMC11456524 DOI: 10.3389/fcell.2024.1457638] [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: 07/01/2024] [Accepted: 09/03/2024] [Indexed: 10/09/2024] Open
Abstract
It has long been thought that exocytosis was driven exclusively by well-studied fusion proteins. Some decades ago, the role of lipids became evident and escalated interest in the field. Our laboratory chose a particular cell to face this issue: the human sperm. What makes this cell special? Sperm, as terminal cells, are characterized by their scarcity of organelles and the complete absence of transcriptional and translational activities. They are specialized for a singular membrane fusion occurrence: the exocytosis of the acrosome. This unique trait makes them invaluable for the study of exocytosis in isolation. We will discuss the lipids' role in human sperm acrosome exocytosis from various perspectives, with a primary emphasis on our contributions to the field. Sperm cells have a unique lipid composition, very rare and not observed in many cell types, comprising a high content of plasmalogens, long-chain, and very-long-chain polyunsaturated fatty acids that are particular constituents of some sphingolipids. This review endeavors to unravel the impact of membrane lipid composition on the proper functioning of the exocytic pathway in human sperm and how this lipid dynamic influences its fertilizing capability. Evidence from our and other laboratories allowed unveiling the role and importance of multiple lipids that drive exocytosis. This review highlights the role of cholesterol, diacylglycerol, and particular phospholipids like phosphatidic acid, phosphatidylinositol 4,5-bisphosphate, and sphingolipids in driving sperm acrosome exocytosis. Furthermore, we provide a comprehensive overview of the factors and enzymes that regulate lipid turnover during the exocytic course. A more thorough grasp of the role played by lipids transferred from sperm can provide insights into certain causes of male infertility. It may lead to enhancements in diagnosing infertility and techniques like assisted reproductive technology (ART).
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Affiliation(s)
- Laila Suhaiman
- Instituto de Medicina y Biología Experimental de Cuyo (IMBECU)-CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Argentina
- Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina
| | - Silvia A. Belmonte
- Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina
- Instituto de Histología y Embriología de Mendoza (IHEM) “Dr. Mario H. Burgos”, CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Universidad Nacional de Cuyo, Mendoza, Argentina
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Mondal K, Del Mar NA, Gary AA, Grambergs RC, Yousuf M, Tahia F, Stephenson B, Stephenson DJ, Chalfant CE, Reiner A, Mandal N. Sphingolipid changes in mouse brain and plasma after mild traumatic brain injury at the acute phases. Lipids Health Dis 2024; 23:200. [PMID: 38937745 PMCID: PMC11209960 DOI: 10.1186/s12944-024-02186-x] [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: 02/21/2024] [Accepted: 06/14/2024] [Indexed: 06/29/2024] Open
Abstract
BACKGROUND Traumatic brain injury (TBI) causes neuroinflammation and can lead to long-term neurological dysfunction, even in cases of mild TBI (mTBI). Despite the substantial burden of this disease, the management of TBI is precluded by an incomplete understanding of its cellular mechanisms. Sphingolipids (SPL) and their metabolites have emerged as key orchestrators of biological processes related to tissue injury, neuroinflammation, and inflammation resolution. No study so far has investigated comprehensive sphingolipid profile changes immediately following TBI in animal models or human cases. In this study, sphingolipid metabolite composition was examined during the acute phases in brain tissue and plasma of mice following mTBI. METHODS Wildtype mice were exposed to air-blast-mediated mTBI, with blast exposure set at 50-psi on the left cranium and 0-psi designated as Sham. Sphingolipid profile was analyzed in brain tissue and plasma during the acute phases of 1, 3, and 7 days post-TBI via liquid-chromatography-mass spectrometry. Simultaneously, gene expression of sphingolipid metabolic markers within brain tissue was analyzed using quantitative reverse transcription-polymerase chain reaction. Significance (P-values) was determined by non-parametric t-test (Mann-Whitney test) and by Tukey's correction for multiple comparisons. RESULTS In post-TBI brain tissue, there was a significant elevation of 1) acid sphingomyelinase (aSMase) at 1- and 3-days, 2) neutral sphingomyelinase (nSMase) at 7-days, 3) ceramide-1-phosphate levels at 1 day, and 4) monohexosylceramide (MHC) and sphingosine at 7-days. Among individual species, the study found an increase in C18:0 and a decrease in C24:1 ceramides (Cer) at 1 day; an increase in C20:0 MHC at 3 days; decrease in MHC C18:0 and increase in MHC C24:1, sphingomyelins (SM) C18:0, and C24:0 at 7 days. Moreover, many sphingolipid metabolic genes were elevated at 1 day, followed by a reduction at 3 days and an absence at 7-days post-TBI. In post-TBI plasma, there was 1) a significant reduction in Cer and MHC C22:0, and an increase in MHC C16:0 at 1 day; 2) a very significant increase in long-chain Cer C24:1 accompanied by significant decreases in Cer C24:0 and C22:0 in MHC and SM at 3 days; and 3) a significant increase of C22:0 in all classes of SPL (Cer, MHC and SM) as well as a decrease in Cer C24:1, MHC C24:1 and MHC C24:0 at 7 days. CONCLUSIONS Alterations in sphingolipid metabolite composition, particularly sphingomyelinases and short-chain ceramides, may contribute to the induction and regulation of neuroinflammatory events in the early stages of TBI, suggesting potential targets for novel diagnostic, prognostic, and therapeutic strategies in the future.
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Affiliation(s)
- Koushik Mondal
- Department of Ophthalmology, The University of Tennessee Health Science Centre, Memphis, TN, 38163, USA
- Molecular Diagnostics Laboratory, Department of Basic & Translational Research, Saroj Gupta Cancer Centre & Research Institute, Kolkata, WB, 700 063, India
| | - Nobel A Del Mar
- Department of Ophthalmology, The University of Tennessee Health Science Centre, Memphis, TN, 38163, USA
| | - Ashlyn A Gary
- Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Richard C Grambergs
- Department of Ophthalmology, The University of Tennessee Health Science Centre, Memphis, TN, 38163, USA
| | - Mohd Yousuf
- Department of Ophthalmology, The University of Tennessee Health Science Centre, Memphis, TN, 38163, USA
| | - Faiza Tahia
- Department of Ophthalmology, The University of Tennessee Health Science Centre, Memphis, TN, 38163, USA
| | - Benjamin Stephenson
- Departments of Medicine and Cell Biology, University of Virginia School of Medicine, Charlottesville, VA, 22903, USA
| | - Daniel J Stephenson
- Departments of Medicine and Cell Biology, University of Virginia School of Medicine, Charlottesville, VA, 22903, USA
| | - Charles E Chalfant
- Departments of Medicine and Cell Biology, University of Virginia School of Medicine, Charlottesville, VA, 22903, USA
- Research Service, Richmond VA Medical Center, Richmond, VA, 23298, USA
| | - Anton Reiner
- Department of Ophthalmology, The University of Tennessee Health Science Centre, Memphis, TN, 38163, USA
- Department of Anatomy and Neurobiology, The University of Tennessee Health Science Centre, Memphis, TN, 38163, USA
| | - Nawajes Mandal
- Department of Ophthalmology, The University of Tennessee Health Science Centre, Memphis, TN, 38163, USA.
- Department of Anatomy and Neurobiology, The University of Tennessee Health Science Centre, Memphis, TN, 38163, USA.
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Centre, Memphis, TN, 38163, USA.
- Memphis VA Medical Center, Memphis, TN, 38104, USA.
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10
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Zeng Q, Gong Y, Zhu N, Shi Y, Zhang C, Qin L. Lipids and lipid metabolism in cellular senescence: Emerging targets for age-related diseases. Ageing Res Rev 2024; 97:102294. [PMID: 38583577 DOI: 10.1016/j.arr.2024.102294] [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: 02/10/2024] [Revised: 03/27/2024] [Accepted: 04/03/2024] [Indexed: 04/09/2024]
Abstract
Cellular senescence is a kind of cellular state triggered by endogenous or exogenous stimuli, which is mainly characterized by stable cell cycle arrest and complex senescence-associated secretory phenotype (SASP). Once senescent cells accumulate in tissues, they may eventually accelerate the progression of age-related diseases, such as atherosclerosis, osteoarthritis, chronic lung diseases, cancers, etc. Recent studies have shown that the disorders of lipid metabolism are not only related to age-related diseases, but also regulate the cellular senescence process. Based on existing research evidences, the changes in lipid metabolism in senescent cells are mainly concentrated in the metabolic processes of phospholipids, fatty acids and cholesterol. Obviously, the changes in lipid-metabolizing enzymes and proteins involved in these pathways play a critical role in senescence. However, the link between cellular senescence, changes in lipid metabolism and age-related disease remains to be elucidated. Herein, we summarize the lipid metabolism changes in senescent cells, especially the senescent cells that promote age-related diseases, as well as focusing on the role of lipid-related enzymes or proteins in senescence. Finally, we explore the prospect of lipids in cellular senescence and their potential as drug targets for preventing and delaying age-related diseases.
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Affiliation(s)
- Qing Zeng
- Laboratory of Stem Cell Regulation with Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
| | - Yongzhen Gong
- Laboratory of Stem Cell Regulation with Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
| | - Neng Zhu
- The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410021, China
| | - Yaning Shi
- Laboratory of Stem Cell Regulation with Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Science and Technology Innovation Center, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
| | - Chanjuan Zhang
- Laboratory of Stem Cell Regulation with Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
| | - Li Qin
- Laboratory of Stem Cell Regulation with Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Institutional Key Laboratory of Vascular Biology and Translational Medicine in Hunan Province, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China.
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11
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Mohammadi A, Shabani R, Bashiri Z, Rafiei S, Asgari H, Koruji M. Therapeutic potential of exosomes in spermatogenesis regulation and male infertility. Biol Cell 2024; 116:e2300127. [PMID: 38593304 DOI: 10.1111/boc.202300127] [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: 01/21/2024] [Revised: 02/19/2024] [Accepted: 02/22/2024] [Indexed: 04/11/2024]
Abstract
BACKGROUND Spermatogenesis is a fundamental process crucial for male reproductive health and fertility. Exosomes, small membranous vesicles released by various cell types, have recently garnered attention for their role in intercellular communication. OBJECTIVE This review aims to comprehensively explore the role of exosomes in regulating spermatogenesis, focusing on their involvement in testicular development and cell-to-cell communication. METHODS A systematic examination of literature was conducted to gather relevant studies elucidating the biogenesis, composition, and functions of exosomes in the context of spermatogenesis. RESULTS Exosomes play a pivotal role in orchestrating the complex signaling networks required for proper spermatogenesis. They facilitate the transfer of key regulatory molecules between different cell populations within the testes, including Sertoli cells, Leydig cells, and germ cells. CONCLUSION The emerging understanding of exosome-mediated communication sheds light on novel mechanisms underlying spermatogenesis regulation. Further research in this area holds promise for insights into male reproductive health and potential therapeutic interventions.
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Affiliation(s)
- Amirhossein Mohammadi
- Stem Cell and Regenerative Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ronak Shabani
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Reproductive Sciences and Technology Research Center, Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Bashiri
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Endometrium and Endometriosis Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Omid Fertility & Infertility Clinic, Hamedan, Iran
| | - Sara Rafiei
- Department of Botany and Plant Sciences, Faculty of Biological Sciences, Alzahra University, Tehran, Iran
| | - Hamidreza Asgari
- Stem Cell and Regenerative Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Morteza Koruji
- Stem Cell and Regenerative Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
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12
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Ríos-Medina Y, Rico-Chávez P, Martínez-Vieyra I, Durán-Álvarez JC, Rodriguez-Varela M, Rincón-Heredia R, Reyes-López C, Cerecedo D. Altered Plasma Membrane Lipid Composition in Hypertensive Neutrophils Impacts Epithelial Sodium Channel (ENaC) Endocytosis. Int J Mol Sci 2024; 25:4939. [PMID: 38732158 PMCID: PMC11084340 DOI: 10.3390/ijms25094939] [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: 03/28/2024] [Revised: 04/22/2024] [Accepted: 04/24/2024] [Indexed: 05/13/2024] Open
Abstract
Biological membranes are composed of a lipid bilayer with embedded proteins, including ion channels like the epithelial sodium channel (ENaC), which are critical for sodium homeostasis and implicated in arterial hypertension (HTN). Changes in the lipid composition of the plasma membrane can significantly impact cellular processes related to physiological functions. We hypothesized that the observed overexpression of ENaC in neutrophils from HTN patients might result from alterations in the structuring domains within the plasma membrane, disrupting the endocytic processes responsible for ENaC retrieval. This study assessed the structural lipid composition of neutrophil plasma membranes from HTN patients along with the expression patterns of key elements regulating ENaC at the plasma membrane. Our findings suggest alterations in microdomain structure and SGK1 kinase activity, which could prolong ENaC presence on the plasma membrane. Additionally, we propose that the proteasomal and lysosomal degradation pathways are insufficient to diminish ENaC presence at the plasma membrane in HTN. These results highlight the importance of understanding ENaC retrieval mechanisms and suggest that targeting these mechanisms could provide insights for developing drugs to prevent and treat HTN.
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Affiliation(s)
- Yolanda Ríos-Medina
- Laboratorio de Hematobiología, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional, Mexico City 07230, Mexico; (Y.R.-M.); (P.R.-C.); (I.M.-V.)
| | - Pedro Rico-Chávez
- Laboratorio de Hematobiología, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional, Mexico City 07230, Mexico; (Y.R.-M.); (P.R.-C.); (I.M.-V.)
| | - Ivette Martínez-Vieyra
- Laboratorio de Hematobiología, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional, Mexico City 07230, Mexico; (Y.R.-M.); (P.R.-C.); (I.M.-V.)
| | - Juan C. Durán-Álvarez
- Instituto de Ciencias Aplicadas y Tecnología, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico; (J.C.D.-Á.); (M.R.-V.)
| | - Mario Rodriguez-Varela
- Instituto de Ciencias Aplicadas y Tecnología, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico; (J.C.D.-Á.); (M.R.-V.)
| | - Ruth Rincón-Heredia
- Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico;
| | - César Reyes-López
- Laboratorio de Bioquímica Estructural, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional, Mexico City 07230, Mexico;
| | - Doris Cerecedo
- Laboratorio de Hematobiología, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional, Mexico City 07230, Mexico; (Y.R.-M.); (P.R.-C.); (I.M.-V.)
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Madhan S, Dhar R, Devi A. Plant-derived exosomes: a green approach for cancer drug delivery. J Mater Chem B 2024; 12:2236-2252. [PMID: 38351750 DOI: 10.1039/d3tb02752j] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/29/2024]
Abstract
Plant-derived exosomes (PDEs) are natural extracellular vesicles (EVs). In the current decade, they have been highlighted for cancer therapeutic development. Cancer is a global health crisis and it requires an effective, affordable, and less side effect-based treatment. Emerging research based on PDEs suggests that they have immense potential to be considered as a therapeutic option. Research evidences indicate that PDEs' internal molecular cargos show impressive cancer prevention activity with less toxicity. PDEs-based drug delivery systems overcome several limitations of traditional drug delivery tools. Extraction of PDEs from plant sources employ diverse methodologies, encompassing ultracentrifugation, immunoaffinity, size-based isolation, and precipitation, each with distinct advantages and limitations. The core constituents of PDEs comprise of lipids, proteins, DNA, and RNA. Worldwide, a few clinical trials on plant-derived exosomes are underway, and regulatory affairs for their use as therapeutic agents are still not understood with clarity. This review aims to comprehensively analyze the current state of research on plant-derived exosomes as a promising avenue for drug delivery, highlighting anticancer activity, challenges, and future orientation in effective cancer therapeutic development.
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Affiliation(s)
- Shrishti Madhan
- Cancer and Stem Cell Biology Laboratory, Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu District - 603 203, Tamil Nadu, India.
| | - Rajib Dhar
- Cancer and Stem Cell Biology Laboratory, Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu District - 603 203, Tamil Nadu, India.
| | - Arikketh Devi
- Cancer and Stem Cell Biology Laboratory, Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu District - 603 203, Tamil Nadu, India.
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14
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Akbari-Gharalari N, Khodakarimi S, Nezhadshahmohammad F, Karimipour M, Ebrahimi-Kalan A, Wu J. Exosomes in neuron-glia communication: A review on neurodegeneration. BIOIMPACTS : BI 2024; 14:30153. [PMID: 39296798 PMCID: PMC11406431 DOI: 10.34172/bi.2023.30153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 12/03/2023] [Accepted: 01/02/2024] [Indexed: 09/21/2024]
Abstract
Introduction Exosomes, a subset of extracellular vesicles (EVs), are crucial for intercellular communication in various contexts. Despite their small size, they carry diverse cargo, including RNA, proteins, and lipids. Internalization by recipient cells raises concerns about potential disruptions to cellular functions. Notably, the ability of exosomes to traverse the blood-brain barrier (BBB) has significant implications. Methods To conduct a thorough investigation into the existing academic literature on exosomes within the framework of neuron-glia communication, a comprehensive search strategy was implemented across the PubMed, Google Scholar, and Science Direct databases. Multiple iterations of the keywords "exosome," "neuron-glia communication," and "neurological disorders" were employed to systematically identify relevant publications. Furthermore, an exploration of the Clinicaltrials.gov database was undertaken to identify clinical trials related to cellular signaling, utilizing analogous terminology. Results Although the immediate practical applications of exosomes are somewhat limited, their potential as carriers of pathogenic attributes offers promising opportunities for the development of precisely targeted therapeutic strategies for neurological disorders. This review presents a comprehensive overview of contemporary insights into the pivotal roles played by exosomes as agents mediating communication between neurons and glial cells within the central nervous system (CNS). Conclusion By delving into the intricate dynamics of exosomal communication in the CNS, this review contributes to a deeper understanding of the roles of exosomes in both physiological and pathological processes, thereby paving the way for potential therapeutic advancements in the field of neurological disorders.
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Affiliation(s)
- Naeimeh Akbari-Gharalari
- Department of Neurosciences and Cognition, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sina Khodakarimi
- Department of Neurosciences and Cognition, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mohammad Karimipour
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abbas Ebrahimi-Kalan
- Department of Neurosciences and Cognition, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jiagian Wu
- The Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- Center for Stem Cell and Regenerative Medicine, UT Brown Foundation Institute of Molecular Medicine, Houston, TX 77030, USA
- MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
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15
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Inskeep KA, Crase B, Stottmann RW. SMPD4 mediated sphingolipid metabolism regulates brain and primary cilia development. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.15.571873. [PMID: 38168190 PMCID: PMC10760124 DOI: 10.1101/2023.12.15.571873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
Genetic variants in multiple sphingolipid biosynthesis genes cause human brain disorders. A recent study collected patients from twelve unrelated families with variants in the gene SMPD4 , a neutral sphingomyelinase which metabolizes sphingomyelin into ceramide at an early stage of the biosynthesis pathway. These patients have severe developmental brain malformations including microcephaly and cerebellar hypoplasia. However, the mechanism of SMPD4 was not known and we pursued a new mouse model. We hypothesized that the role of SMPD4 in producing ceramide is important for making primary cilia, a crucial organelle mediating cellular signaling. We found that the mouse model has cerebellar hypoplasia due to failure of Purkinje cell development. Human induced pluripotent stem cells exhibit neural progenitor cell death and have shortened primary cilia which is rescued by adding exogenous ceramide. SMPD4 production of ceramide is crucial for human brain development.
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16
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Hurwitz SN, Jung SK, Kobulsky DR, Fazelinia H, Spruce LA, Pérez EB, Groen N, Mesaros C, Kurre P. Neutral sphingomyelinase blockade enhances hematopoietic stem cell fitness through an integrated stress response. Blood 2023; 142:1708-1723. [PMID: 37699202 PMCID: PMC10667352 DOI: 10.1182/blood.2023022147] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 09/06/2023] [Accepted: 09/07/2023] [Indexed: 09/14/2023] Open
Abstract
Hematopoietic stem and progenitor cell (HSPC) transplantation serves as a curative therapy for many benign and malignant hematopoietic disorders and as a platform for gene therapy. However, growing needs for ex vivo manipulation of HSPC-graft products are limited by barriers in maintaining critical self-renewal and quiescence properties. The role of sphingolipid metabolism in safeguarding these essential cellular properties has been recently recognized, but not yet widely explored. Here, we demonstrate that pharmacologic and genetic inhibition of neutral sphingomyelinase 2 (nSMase-2) leads to sustained improvements in long-term competitive transplantation efficiency after ex vivo culture. Mechanistically, nSMase-2 blockade activates a canonical integrated stress response (ISR) and promotes metabolic quiescence in human and murine HSPCs. These adaptations result in part from disruption in sphingolipid metabolism that impairs the release of nSMase-2-dependent extracellular vesicles (EVs). The aggregate findings link EV trafficking and the ISR as a regulatory dyad guarding HSPC homeostasis and long-term fitness. Translationally, transient nSMase-2 inhibition enables ex vivo graft manipulation with enhanced HSPC potency.
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Affiliation(s)
- Stephanie N. Hurwitz
- Comprehensive Bone Marrow Failure Center, Children's Hospital of Philadelphia, Philadelphia, PA
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
| | - Seul K. Jung
- Comprehensive Bone Marrow Failure Center, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Danielle R. Kobulsky
- Comprehensive Bone Marrow Failure Center, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Hossein Fazelinia
- Proteomics Core Facility, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Lynn A. Spruce
- Proteomics Core Facility, Children's Hospital of Philadelphia, Philadelphia, PA
| | | | | | - Clementina Mesaros
- Center of Excellence in Environmental Toxicology, Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA
| | - Peter Kurre
- Comprehensive Bone Marrow Failure Center, Children's Hospital of Philadelphia, Philadelphia, PA
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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17
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Liu M, Shen J, Zhu X, Ju T, Willing BP, Wu X, Lu Q, Liu R. Peanut skin procyanidins reduce intestinal glucose transport protein expression, regulate serum metabolites and ameliorate hyperglycemia in diabetic mice. Food Res Int 2023; 173:113471. [PMID: 37803795 DOI: 10.1016/j.foodres.2023.113471] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 09/05/2023] [Accepted: 09/10/2023] [Indexed: 10/08/2023]
Abstract
One of diabetic characteristics is the postprandial hyperglycemia. Inhibiting glucose uptake may be beneficial for controlling postprandial blood glucose levels and regulating the glucose metabolism Peanut skin procyanidins (PSP) have shown a potential for lowering blood glucose; however, the underlying mechanism through which PSP regulate glucose metabolism remains unknown. In the current study, we investigated the effect of PSP on intestinal glucose transporters and serum metabolites using a mouse model of diabetic mice. Results showed that PSP improved glucose tolerance and systemic insulin sensitivity, which coincided with decreased expression of sodium-glucose cotransporter 1 and glucose transporter 2 in the intestinal epithelium induced by an activation of the phospholipase C β2/protein kinase C signaling pathway. Moreover, untargeted metabolomic analysis of serum samples revealed that PSP altered arachidonic acid, sphingolipid, glycerophospholipid, bile acids, and arginine metabolic pathways. The study provides new insight into the anti-diabetic mechanism of PSP and a basis for further research.
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Affiliation(s)
- Min Liu
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430000, China; Wuhan Engineering Research Center of Bee Products on Quality and Safety Control, Wuhan 430000, China
| | - Jinxin Shen
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430000, China; Wuhan Engineering Research Center of Bee Products on Quality and Safety Control, Wuhan 430000, China
| | - Xiaoling Zhu
- Hubei Provincial Institute for Food Supervision and Test, Wuhan 430070, China
| | - Tingting Ju
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2P5, Canada
| | - Benjamin P Willing
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2P5, Canada
| | - Xin Wu
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430000, China; Wuhan Engineering Research Center of Bee Products on Quality and Safety Control, Wuhan 430000, China
| | - Qun Lu
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430000, China; Wuhan Engineering Research Center of Bee Products on Quality and Safety Control, Wuhan 430000, China; Key Laboratory of Environment Correlative Dietology, Ministry of Education, Wuhan 430000, China
| | - Rui Liu
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430000, China; Wuhan Engineering Research Center of Bee Products on Quality and Safety Control, Wuhan 430000, China; Key Laboratory of Environment Correlative Dietology, Ministry of Education, Wuhan 430000, China; Key Laboratory of Urban Agriculture in Central China, Ministry of Agriculture and Rural Affairs, China.
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18
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Wandrey M, Jablonska J, Stauber RH, Gül D. Exosomes in Cancer Progression and Therapy Resistance: Molecular Insights and Therapeutic Opportunities. Life (Basel) 2023; 13:2033. [PMID: 37895415 PMCID: PMC10608050 DOI: 10.3390/life13102033] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 10/04/2023] [Accepted: 10/05/2023] [Indexed: 10/29/2023] Open
Abstract
The development of therapy resistance still represents a major hurdle in treating cancers, leading to impaired treatment success and increased patient morbidity. The establishment of minimally invasive liquid biopsies is a promising approach to improving the early diagnosis, as well as therapy monitoring, of solid tumors. Because of their manifold functions in the tumor microenvironment, tumor-associated small extracellular vesicles, referred to as exosomes, have become a subject of intense research. Besides their important roles in cancer progression, metastasis, and the immune response, it has been proposed that exosomes also contribute to the acquisition and transfer of therapy resistance, mainly by delivering functional proteins and RNAs, as well as facilitating the export of active drugs or functioning as extracellular decoys. Extensive research has focused on understanding the molecular mechanisms underlying the occurrence of resistance and translating these into strategies for early detection. With this review, we want to provide an overview of the current knowledge about the (patho-)biology of exosomes, as well as state-of-the-art methods of isolation and analysis. Furthermore, we highlight the role of exosomes in tumorigenesis and cancer treatment, where they can function as therapeutic agents, biomarkers, and/or targets. By focusing on their roles in therapy resistance, we will reveal new paths of exploiting exosomes for cancer diagnosis and treatment.
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Affiliation(s)
- Madita Wandrey
- Nanobiomedicine/ENT Department, University Medical Center Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (M.W.); (R.H.S.)
| | - Jadwiga Jablonska
- Translational Oncology/ENT Department, University Hospital Essen, Hufelandstraße 55, 45147 Essen, Germany;
- German Cancer Consortium (DKTK) Partner Site Düsseldorf/Essen, 45147 Essen, Germany
| | - Roland H. Stauber
- Nanobiomedicine/ENT Department, University Medical Center Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (M.W.); (R.H.S.)
| | - Désirée Gül
- Nanobiomedicine/ENT Department, University Medical Center Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (M.W.); (R.H.S.)
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El-Amouri S, Karakashian A, Bieberich E, Nikolova-Karakashian M. Regulated translocation of neutral sphingomyelinase-2 to the plasma membrane drives insulin resistance in steatotic hepatocytes. J Lipid Res 2023; 64:100435. [PMID: 37640282 PMCID: PMC10550728 DOI: 10.1016/j.jlr.2023.100435] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 08/11/2023] [Accepted: 08/14/2023] [Indexed: 08/31/2023] Open
Abstract
Obesity-associated diabetes is linked to the accumulation of ceramide in various organs, including the liver. The exact mechanisms by which ceramide contributes to diabetic pathology are unclear, but one proposed scenario is that ceramide accumulation may inhibit insulin signaling pathways. It is unknown however whether the excess ceramide is generated proximal to the insulin receptor, that is, at the plasma membrane (PM), where it could affect the insulin signaling pathway directly, or the onset of insulin resistance is due to ceramide-induced mitochondrial dysfunction and/or lipotoxicity. Using hepatic cell lines and primary cultures, gain- and loss- of function approach, and state-of-the art lipid imaging, this study shows that PM-associated neutral sphingomyelinase 2 (nSMase2) regulates ceramide homeostasis in fat-loaded hepatocytes and drives the onset of insulin resistance. Our results provide evidence of a regulated translocation of nSMase2 to the PM which leads to local generation of ceramide and insulin resistance in cells treated with palmitic acid (PAL), a type of fat commonly found in diabetogenic diets. Oleic acid, which also causes accumulation of lipid droplets, does not induce nSMase2 translocation and insulin resistance. Experiments using the acyl-biotin exchange method to quantify protein palmitoylation show that cellular PAL abundance regulates the rate of nSMase2 palmitoylation. Furthermore, while inhibition of nSMase2 with GW4869 prevents PAL-induced insulin resistance, the overexpression of wild type nSMase2 but not palmitoylation-defective mutant protein potentiates the suppressive effect of PAL on insulin signaling. Overall, this study identifies nSMase2 as a novel component of the mechanism of insulin resistance onset in fat-loaded hepatocytes, that is, cell-autonomous and driven by PAL.
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Affiliation(s)
- S El-Amouri
- Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA
| | - A Karakashian
- Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA
| | - E Bieberich
- Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA
| | - M Nikolova-Karakashian
- Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA.
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20
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Wei Q, Yu Z, Zhou X, Gong R, Jiang R, Xu G, Liu W. Metabolomic Profiling of Aqueous Humor from Pathological Myopia Patients with Choroidal Neovascularization. Metabolites 2023; 13:900. [PMID: 37623844 PMCID: PMC10456621 DOI: 10.3390/metabo13080900] [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: 06/05/2023] [Revised: 07/27/2023] [Accepted: 07/28/2023] [Indexed: 08/26/2023] Open
Abstract
Choroidal neovascularization (CNV) is a severe complication observed in individuals with pathological myopia (PM). Our hypothesis is that specific metabolic alterations occur during the development of CNV in patients with PM. To investigate this, an untargeted metabolomics analysis was conducted using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) on aqueous humor (AH) samples obtained from meticulously matched PM patients, including those with CNV (n = 11) and without CNV (n = 11). The analysis aimed to identify differentially expressed metabolites between the two groups. Furthermore, the discriminative ability of each metabolite was evaluated using the area under the receiver operating characteristic curve (AUC). Enriched metabolic pathways were determined using the KEGG and MetaboAnalyst databases. Our results revealed the detection of 272 metabolites using GC-MS and 1457 metabolites using LC-MS in AH samples. Among them, 97 metabolites exhibited significant differential expression between the CNV and non-CNV groups. Noteworthy candidates, including D-citramalic acid, biphenyl, and isoleucylproline, demonstrated high AUC values ranging from 0.801 to 1, indicating their potential as disease biomarkers. Additionally, all three metabolites showed a strong association with retinal cystoid edema in CNV patients. Furthermore, the study identified 12 altered metabolic pathways, with five of them related to carbohydrate metabolism, suggesting their involvement in the occurrence of myopic CNV. These findings provide possible disease-specific biomarkers of CNV in PM and suggest the role of disturbed carbohydrate metabolism in its pathogenesis. Larger studies are needed to validate these findings.
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Affiliation(s)
- Qiaoling Wei
- Department of Ophthalmology, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200031, China
- Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai 200031, China
- NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai 200031, China
- Ocular Trauma Center, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200031, China
| | - Zhiqiang Yu
- Department of Ophthalmology, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200031, China
- Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai 200031, China
- NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai 200031, China
| | - Xianjin Zhou
- Department of Ophthalmology, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200031, China
- Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai 200031, China
- NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai 200031, China
| | - Ruowen Gong
- Department of Ophthalmology, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200031, China
- Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai 200031, China
- NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai 200031, China
| | - Rui Jiang
- Department of Ophthalmology, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200031, China
- Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai 200031, China
- NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai 200031, China
- Ocular Trauma Center, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200031, China
| | - Gezhi Xu
- Department of Ophthalmology, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200031, China
- Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai 200031, China
- NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai 200031, China
| | - Wei Liu
- Department of Ophthalmology, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200031, China
- Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai 200031, China
- NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai 200031, China
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21
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Yoo SW, Waheed AA, Deme P, Tohumeken S, Rais R, Smith MD, DeMarino C, Calabresi PA, Kashanchi F, Freed EO, Slusher BS, Haughey NJ. Inhibition of neutral sphingomyelinase 2 impairs HIV-1 envelope formation and substantially delays or eliminates viral rebound. Proc Natl Acad Sci U S A 2023; 120:e2219543120. [PMID: 37406092 PMCID: PMC10334757 DOI: 10.1073/pnas.2219543120] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 04/03/2023] [Indexed: 07/07/2023] Open
Abstract
Although HIV-1 Gag is known to drive viral assembly and budding, the precise mechanisms by which the lipid composition of the plasma membrane is remodeled during assembly are incompletely understood. Here, we provide evidence that the sphingomyelin hydrolase neutral sphingomyelinase 2 (nSMase2) interacts with HIV-1 Gag and through the hydrolysis of sphingomyelin creates ceramide that is necessary for proper formation of the viral envelope and viral maturation. Inhibition or depletion of nSMase2 resulted in the production of noninfectious HIV-1 virions with incomplete Gag lattices lacking condensed conical cores. Inhibition of nSMase2 in HIV-1-infected humanized mouse models with a potent and selective inhibitor of nSMase2 termed PDDC [phenyl(R)-(1-(3-(3,4-dimethoxyphenyl)-2, 6-dimethylimidazo[1,2-b]pyridazin-8-yl) pyrrolidin-3-yl)-carbamate] produced a linear reduction in levels of HIV-1 in plasma. If undetectable plasma levels of HIV-1 were achieved with PDDC treatment, viral rebound did not occur for up to 4 wk when PDDC was discontinued. In vivo and tissue culture results suggest that PDDC selectively kills cells with actively replicating HIV-1. Collectively, this work demonstrates that nSMase2 is a critical regulator of HIV-1 replication and suggests that nSMase2 could be an important therapeutic target with the potential to kill HIV-1-infected cells.
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Affiliation(s)
- Seung-Wan Yoo
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD21210
| | - Abdul A. Waheed
- Virus-Cell Interaction Section, HIV-1 Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD21702
| | - Pragney Deme
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD21210
| | - Sehmus Tohumeken
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD21210
| | - Rana Rais
- Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD21205
| | - Matthew D. Smith
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD21210
| | - Catherine DeMarino
- Laboratory of Molecular Virology, George Mason University, Manassas, VA20110
| | - Peter A. Calabresi
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD21210
| | - Fatah Kashanchi
- Laboratory of Molecular Virology, George Mason University, Manassas, VA20110
| | - Eric O. Freed
- Virus-Cell Interaction Section, HIV-1 Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD21702
| | - Barbara S. Slusher
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD21210
- Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD21205
- Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD21210
- Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD21210
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD21224
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD21205
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD21210
| | - Norman J. Haughey
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD21210
- Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD21210
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22
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Peche VS, Pietka TA, Jacome-Sosa M, Samovski D, Palacios H, Chatterjee-Basu G, Dudley AC, Beatty W, Meyer GA, Goldberg IJ, Abumrad NA. Endothelial cell CD36 regulates membrane ceramide formation, exosome fatty acid transfer and circulating fatty acid levels. Nat Commun 2023; 14:4029. [PMID: 37419919 PMCID: PMC10329018 DOI: 10.1038/s41467-023-39752-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 06/28/2023] [Indexed: 07/09/2023] Open
Abstract
Endothelial cell (EC) CD36 controls tissue fatty acid (FA) uptake. Here we examine how ECs transfer FAs. FA interaction with apical membrane CD36 induces Src phosphorylation of caveolin-1 tyrosine-14 (Cav-1Y14) and ceramide generation in caveolae. Ensuing fission of caveolae yields vesicles containing FAs, CD36 and ceramide that are secreted basolaterally as small (80-100 nm) exosome-like extracellular vesicles (sEVs). We visualize in transwells EC transfer of FAs in sEVs to underlying myotubes. In mice with EC-expression of the exosome marker emeraldGFP-CD63, muscle fibers accumulate circulating FAs in emGFP-labeled puncta. The FA-sEV pathway is mapped through its suppression by CD36 depletion, blocking actin-remodeling, Src inhibition, Cav-1Y14 mutation, and neutral sphingomyelinase 2 inhibition. Suppression of sEV formation in mice reduces muscle FA uptake, raises circulating FAs, which remain in blood vessels, and lowers glucose, mimicking prominent Cd36-/- mice phenotypes. The findings show that FA uptake influences membrane ceramide, endocytosis, and EC communication with parenchymal cells.
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Affiliation(s)
- V S Peche
- Department of Medicine, Division of Nutritional Sciences, Washington University School of Medicine, St. Louis, MO, 63110, USA.
| | - T A Pietka
- Department of Medicine, Division of Nutritional Sciences, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - M Jacome-Sosa
- Department of Medicine, Division of Nutritional Sciences, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - D Samovski
- Department of Medicine, Division of Nutritional Sciences, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - H Palacios
- Department of Medicine, Division of Nutritional Sciences, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - G Chatterjee-Basu
- Department of Medicine, Division of Nutritional Sciences, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - A C Dudley
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, 22908, USA
| | - W Beatty
- Department of Microbiology, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - G A Meyer
- Departments of Physical Therapy, Neurology and Orthopedic Surgery, Washington University School of Medicine, St. Louis, 63110, USA
| | - I J Goldberg
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - N A Abumrad
- Department of Medicine, Division of Nutritional Sciences, Washington University School of Medicine, St. Louis, MO, 63110, USA.
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
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23
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Gamal M, Tallima H, Azzazy HME, Abdelnaser A. Impact of HepG2 Cells Glutathione Depletion on Neutral Sphingomyelinases mRNA Levels and Activity. Curr Issues Mol Biol 2023; 45:5005-5017. [PMID: 37367067 DOI: 10.3390/cimb45060318] [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: 01/09/2023] [Revised: 02/28/2023] [Accepted: 03/28/2023] [Indexed: 06/28/2023] Open
Abstract
Liver cancer is a prevalent form of cancer worldwide. While research has shown that increasing sphingomyelin (SM) hydrolysis by activating the cell surface membrane-associated neutral sphingomyelinase 2 (nSMase2) can control cell proliferation and apoptosis, the role of total glutathione depletion in inducing tumor cell apoptosis via nSMase2 activation is still under investigation. Conversely, glutathione-mediated inhibition of reactive oxygen species (ROS) accumulation is necessary for the enzymatic activity of nSMase1 and nSMase3, increased ceramide levels, and cell apoptosis. This study evaluated the effects of depleting total glutathione in HepG2 cells using buthionine sulfoximine (BSO). The study assessed nSMases RNA levels and activities, intracellular ceramide levels, and cell proliferation using RT-qPCR, Amplex red neutral sphingomyelinase fluorescence assay, and colorimetric assays, respectively. The results indicated a lack of nSMase2 mRNA expression in treated and untreated HepG2 cells. Depletion of total glutathione resulted in a significant increase in mRNA levels but a dramatic reduction in the enzymatic activity of nSMase1 and nSMase3, a rise in ROS levels, a decrease in intracellular levels of ceramide, and an increase in cell proliferation. These findings suggest that total glutathione depletion may exacerbate liver cancer (HCC) and not support using total glutathione-depleting agents in HCC management. It is important to note that these results are limited to HepG2 cells, and further studies are necessary to determine if these effects will also occur in other cell lines. Additional research is necessary to explore the role of total glutathione depletion in inducing tumor cell apoptosis.
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Affiliation(s)
- Marie Gamal
- Department of Chemistry, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt
| | - Hatem Tallima
- Department of Chemistry, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt
| | - Hassan M E Azzazy
- Department of Chemistry, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt
| | - Anwar Abdelnaser
- Institute of Global Health and Human Ecology, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt
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24
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Otsuka M, Kotani A. Recent advances in extracellular vesicles in gastrointestinal cancer and lymphoma. Cancer Sci 2023; 114:2230-2237. [PMID: 36851868 PMCID: PMC10236630 DOI: 10.1111/cas.15771] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 02/14/2023] [Accepted: 02/20/2023] [Indexed: 03/01/2023] Open
Abstract
Extracellular vesicles (EVs) are intercellular communication agents that transfer microRNAs (miRNAs), other non-coding RNAs (ncRNAs), messenger RNAs (mRNAs), proteins, lipids, metabolites, and other molecules from donor cells (e.g., cancer cells) to recipient cells (e.g., stromal cells). In 2007, miRNAs were reported to be abundant among the ncRNAs present in EVs. Since then, many studies have investigated the functions of miRNAs and have attempted to apply these molecules to aid in the diagnosis and treatment of cancer. Research on EVs has expanded, particularly in the field of cancer, because cancer cells heavily secrete EVs. The cargo of these EVs, especially those in small EVs, such as exosomes, is assumed to work cooperatively and significantly in the tumor microenvironment and to promote metastasis. In this review, we first summarize recent studies on EVs in gastrointestinal cancer and highlight studies on human satellite II RNAs, which are a type of ncRNA found in EVs that possess repetitive sequences. Second, since several recent studies have revealed that phospholipids, which are components of EV membranes, play important roles in intercellular communication and the generation of lipid mediators in the tumor microenvironment, we review the reported roles of these molecules and discuss their potential use in the design of new cancer treatments.
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Affiliation(s)
- Motoyuki Otsuka
- Department of Gastroenterology and HepatologyAcademic Field of Medicine, Density and Pharmaceutical SciencesOkayama UniversityOkayamaJapan
| | - Ai Kotani
- Department of Innovative Medical ScienceTokai University School of MedicineIseharaJapan
- Division of Hematological MalignancyInstitute of Medical SciencesTokai UniversityIseharaJapan
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25
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Dwivedi M, Ghosh D, Saha A, Hasan S, Jindal D, Yadav H, Yadava A, Dwivedi M. Biochemistry of exosomes and their theranostic potential in human diseases. Life Sci 2023; 315:121369. [PMID: 36639052 DOI: 10.1016/j.lfs.2023.121369] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 12/22/2022] [Accepted: 01/01/2023] [Indexed: 01/11/2023]
Abstract
Exosomes are classified as special extracellular vesicles in the eukaryotic system having diameters ranging from 30 to 120 nm. These vesicles carry various endogenous molecules including DNA, mRNA, microRNA, circular RNA, and proteins, crucial for numerous metabolic reactions and can be proposed as therapeutic or diagnostic targets for several disorders. The donor exosomes release their content to recipient cells and further establish the significant intercellular communication showing biological effects by triggering environmental alterations. Exosomes derived from mesenchymal and dendritic cells have demonstrated their therapeutic potential against organ injury. Yet, various intricacies are involved in exosomal transport and its inclusion in cancer and other disease pathogenesis needs to be explored. The exosomes represent profound potential as diagnostic biomarkers and therapeutic carriers in various pathophysiological conditions such as neurodegenerative diseases, chronic cancers, infectious diseases, female reproductive diseases and cardiovascular diseases. In the current study, we demonstrate the advancements in the implication of exosomes as one of the irrefutable prognostic biological targets in human health and diseases.
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Affiliation(s)
- Manish Dwivedi
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, India.
| | - Diya Ghosh
- Department of Biotechnology, Heritage Institute of Technology, Kolkata, West Bengal, India
| | - Anwesha Saha
- Department of Biotechnology, Heritage Institute of Technology, Kolkata, West Bengal, India
| | - Saba Hasan
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, India
| | - Divya Jindal
- Center for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, Noida, India
| | - Hitendra Yadav
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, India
| | - Anuradha Yadava
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, India
| | - Medha Dwivedi
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, India
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26
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Wang A, Zhang H, Liu J, Yan Z, Sun Y, Su W, Yu JG, Mi J, Zhao L. Targeted Lipidomics and Inflammation Response to Six Weeks of Sprint Interval Training in Male Adolescents. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2023; 20:3329. [PMID: 36834025 PMCID: PMC9963480 DOI: 10.3390/ijerph20043329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 02/06/2023] [Accepted: 02/09/2023] [Indexed: 06/18/2023]
Abstract
Lipids play an important role in coordinating and regulating metabolic and inflammatory processes. Sprint interval training (SIT) is widely used to improve sports performance and health outcomes, but the current understanding of SIT-induced lipid metabolism and the corresponding systemic inflammatory status modification remains controversial and limited, especially in male adolescents. To answer these questions, twelve untrained male adolescents were recruited and underwent 6 weeks of SIT. The pre- and post-training testing included analyses of peak oxygen consumption (VO2peak), biometric data (weight and body composition), serum biochemical parameters (fasting blood glucose, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triacylglycerol, testosterone, and cortisol), inflammatory markers, and targeted lipidomics. After the 6-week SIT, the serum C-reactive protein (CRP), interleukin (IL)-1β, IL-2, IL-4, IL-10, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β significantly decreased (p < 0.05), whereas IL-6 and IL-10/TNF-α significantly increased (p < 0.05). In addition, the targeted lipidomics revealed changes in 296 lipids, of which 33 changed significantly (p < 0.05, fold change > 1.2 or <1/1.2). The correlation analysis revealed that the changes in the inflammatory markers were closely correlated with the changes in some of the lipids, such as LPC, HexCer, and FFA. In conclusion, the 6-week SIT induced significant changes in the inflammatory markers and circulating lipid composition, offering health benefits to the population.
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Affiliation(s)
- Aozhe Wang
- Department of Exercise Physiology, Beijing Sport University, Beijing 100084, China
| | - Haifeng Zhang
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing 100020, China
| | - Jianming Liu
- School of Competitive Sports, Beijing Sport University, Beijing 100084, China
| | - Zhiyi Yan
- Department of Exercise Physiology, Beijing Sport University, Beijing 100084, China
| | - Yaqi Sun
- Department of Exercise Physiology, Beijing Sport University, Beijing 100084, China
| | - Wantang Su
- Department of Exercise Physiology, Beijing Sport University, Beijing 100084, China
| | - Ji-Guo Yu
- Department of Community Medicine and Rehabilitation, Faculty of Medicine, Umeå University, 901 87 Umeå, Sweden
| | - Jing Mi
- School of Competitive Sports, Beijing Sport University, Beijing 100084, China
| | - Li Zhao
- Department of Exercise Physiology, Beijing Sport University, Beijing 100084, China
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27
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Mühle C, Kornhuber J. Characterization of a Neutral Sphingomyelinase Activity in Human Serum and Plasma. Int J Mol Sci 2023; 24:ijms24032467. [PMID: 36768790 PMCID: PMC9916453 DOI: 10.3390/ijms24032467] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/21/2023] [Accepted: 01/24/2023] [Indexed: 01/31/2023] Open
Abstract
Alterations of sphingolipids and their metabolizing enzymes play a role in various diseases. However, peripheral biomarkers for such changes are limited. Particularly, in the increasingly reported involvement of neutral sphingomyelinase (NSM) with four described isoforms in tissues or cells, a peripheral marker is lacking. We here describe the detection of an NSM activity in human serum and plasma samples which hydrolyses fluorescently labeled sphingomyelin to ceramide in a time- and volume-dependent manner. Reaction rates were linear up to 10 days, and serum volumes above 2 vol-% were inhibitory. Biochemical properties were different from acid sphingomyelinase (ASM) with respect to detergent specificity (sodium deoxycholate), pH profile (pH 7-9), and cation dependence: Serum NSM activity was inhibited by EDTA ≥ 1 µM and restored in EDTA-anticoagulated plasma with the addition of ≥ 100 µM Co2+. It was independent of Mg2+, the typical cofactor of cellular NSM species, and even inhibited by [Mg2+] ≥ 20 mM. Serum NSM activity was not correlated with ASM activity and was independent of sex and age in 24 healthy adults. Since human peripheral NSM activity is very low and activities in rodents are even lower or undetectable, future research should aim to increase the reaction rate and determine the source of this enzymatic activity. The established activity could serve as a future biomarker or therapeutic target in diseases affected by sphingolipid derangements.
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Affiliation(s)
- Christiane Mühle
- Correspondence: ; Tel.: +49-9131-85-44738; Fax: +49-9131-85-36381
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28
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Kar R, Dhar R, Mukherjee S, Nag S, Gorai S, Mukerjee N, Mukherjee D, Vatsa R, Chandrakanth Jadhav M, Ghosh A, Devi A, Krishnan A, Thorat ND. Exosome-Based Smart Drug Delivery Tool for Cancer Theranostics. ACS Biomater Sci Eng 2023; 9:577-594. [PMID: 36621949 PMCID: PMC9930096 DOI: 10.1021/acsbiomaterials.2c01329] [Citation(s) in RCA: 112] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Exosomes are the phospholipid-membrane-bound subpopulation of extracellular vesicles derived from the plasma membrane. The main activity of exosomes is cellular communication. In cancer, exosomes play an important rolefrom two distinct perspectives, one related to carcinogenesis and the other as theragnostic and drug delivery tools. The outer phospholipid membrane of Exosome improves drug targeting efficiency. . Some of the vital features of exosomes such as biocompatibility, low toxicity, and low immunogenicity make it a more exciting drug delivery system. Exosome-based drug delivery is a new innovative approach to cancer treatment. Exosome-associated biomarker analysis heralded a new era of cancer diagnostics in a more specific way. This Review focuses on exosome biogenesis, sources, isolation, interrelationship with cancer and exosome-related cancer biomarkers, drug loading methods, exosome-based biomolecule delivery, advances and limitations of exosome-based drug delivery, and exosome-based drug delivery in clinical settings studies. The exosome-based understanding of cancer will change the diagnostic and therapeutic approach in the future.
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Affiliation(s)
- Rishav Kar
- Department
of Medical Biotechnology, Ramakrishna Mission
Vivekananda Educational and Research Institute, Howrah, West Bengal 711202, India
| | - Rajib Dhar
- Cancer
and Stem Cell Biology Laboratory, Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Sayantanee Mukherjee
- Centre
for Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
| | - Sagnik Nag
- Department
of Biotechnology, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu 632014, India
| | - Sukhamoy Gorai
- Rush
University Medical Center, 1620 W Harrison St, Chicago, Illinois 60612, United
States
| | - Nobendu Mukerjee
- Department
of Microbiology, West Bengal State University, Kolkata, West Bengal 700126, India,Department
of Health Sciences, Novel Global Community
Educational Foundation, https://www.ngcef.net/
| | - Dattatreya Mukherjee
- Raiganj
Government Medical College and Hospital, Raiganj, West Bengal 733134, India
| | - Rishabh Vatsa
- Department
of Microbiology, Vels Institute of Science,
Technology and Advanced Studies, Pallavaram, Chennai 600117, Tamilnadu, India
| | | | - Arabinda Ghosh
- Microbiology
Division, Department of Botany, Gauhati
University, Guwahati, Assam 781014, India
| | - Arikketh Devi
- Cancer
and Stem Cell Biology Laboratory, Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Anand Krishnan
- Department
of Chemical Pathology, School of Pathology, Faculty of Health Sciences, University of the Free State, Bloemfontein, Free State 9300, South Africa
| | - Nanasaheb D. Thorat
- Nuffield
Department of Women’s and Reproductive Health, Division of
Medical Sciences, John Radcliffe Hospital, University of Oxford, Oxford OX1 2JD, United Kingdom,Department
of Physics, Bernal Institute and Limerick Digital Cancer Research
Centre (LDCRC) University of Limerick, Castletroy, Limerick V94T9PX, Ireland,,
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29
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Kalinichenko LS, Mühle C, Jia T, Anderheiden F, Datz M, Eberle AL, Eulenburg V, Granzow J, Hofer M, Hohenschild J, Huber SE, Kämpf S, Kogias G, Lacatusu L, Lugmair C, Taku SM, Meixner D, Sembritzki NK, Praetner M, Rhein C, Sauer C, Scholz J, Ulrich F, Valenta F, Weigand E, Werner M, Tay N, Mc Veigh CJ, Haase J, Wang AL, Abdel-Hafiz L, Huston JP, Smaga I, Frankowska M, Filip M, Lourdusamy A, Kirchner P, Ekici AB, Marx LM, Suresh NP, Frischknecht R, Fejtova A, Saied EM, Arenz C, Bozec A, Wank I, Kreitz S, Hess A, Bäuerle T, Ledesma MD, Mitroi DN, Miranda AM, Oliveira TG, Lenz B, Schumann G, Kornhuber J, Müller CP. Adult alcohol drinking and emotional tone are mediated by neutral sphingomyelinase during development in males. Cereb Cortex 2023; 33:844-864. [PMID: 35296883 DOI: 10.1093/cercor/bhac106] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 02/21/2022] [Accepted: 02/24/2022] [Indexed: 02/03/2023] Open
Abstract
Alcohol use, abuse, and addiction, and resulting health hazards are highly sex-dependent with unknown mechanisms. Previously, strong links between the SMPD3 gene and its coded protein neutral sphingomyelinase 2 (NSM) and alcohol abuse, emotional behavior, and bone defects were discovered and multiple mechanisms were identified for females. Here we report strong sex-dimorphisms for central, but not for peripheral mechanisms of NSM action in mouse models. Reduced NSM activity resulted in enhanced alcohol consumption in males, but delayed conditioned rewarding effects. It enhanced the acute dopamine response to alcohol, but decreased monoaminergic systems adaptations to chronic alcohol. Reduced NSM activity increased depression- and anxiety-like behavior, but was not involved in alcohol use for the self-management of the emotional state. Constitutively reduced NSM activity impaired structural development in the brain and enhanced lipidomic sensitivity to chronic alcohol. While the central effects were mostly opposite to NSM function in females, similar roles in bone-mediated osteocalcin release and its effects on alcohol drinking and emotional behavior were observed. These findings support the view that the NSM and multiple downstream mechanism may be a source of the sex-differences in alcohol use and emotional behavior.
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Affiliation(s)
- Liubov S Kalinichenko
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
| | - Christiane Mühle
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
| | - Tianye Jia
- The Centre for Population Neuroscience and Stratified Medicine (PONS), ISTBI, Fudan University, Shanghai 200433, China.,PONS Centre and SGDP Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AB, UK
| | - Felix Anderheiden
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
| | - Maria Datz
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
| | - Anna-Lisa Eberle
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
| | - Volker Eulenburg
- Department for Anesthesiology and Intensive Care, Faculty of Medicine, University of Leipzig, Leipzig 04103, Germany
| | - Jonas Granzow
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
| | - Martin Hofer
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
| | - Julia Hohenschild
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
| | - Sabine E Huber
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
| | - Stefanie Kämpf
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
| | - Georgios Kogias
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
| | - Laura Lacatusu
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
| | - Charlotte Lugmair
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
| | - Stephen Mbu Taku
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
| | - Doris Meixner
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
| | - Nina-Kristin Sembritzki
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
| | - Marc Praetner
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany.,Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich 82152, Germany
| | - Cosima Rhein
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany.,Department of Psychosomatic Medicine and Psychotherapy, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen 91054, Germany
| | - Christina Sauer
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
| | - Jessica Scholz
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
| | - Franziska Ulrich
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
| | - Florian Valenta
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
| | - Esther Weigand
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
| | - Markus Werner
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
| | - Nicole Tay
- The Centre for Population Neuroscience and Stratified Medicine (PONS), ISTBI, Fudan University, Shanghai 200433, China
| | - Conor J Mc Veigh
- School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin 4, Ireland
| | - Jana Haase
- School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin 4, Ireland
| | - An-Li Wang
- Center for Behavioral Neuroscience, Institute of Experimental Psychology, University of Düsseldorf, Düsseldorf 40225, Germany
| | - Laila Abdel-Hafiz
- Center for Behavioral Neuroscience, Institute of Experimental Psychology, University of Düsseldorf, Düsseldorf 40225, Germany
| | - Joseph P Huston
- Center for Behavioral Neuroscience, Institute of Experimental Psychology, University of Düsseldorf, Düsseldorf 40225, Germany
| | - Irena Smaga
- Department of Drug Addiction Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, Kraków 31-343, Poland
| | - Malgorzata Frankowska
- Department of Drug Addiction Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, Kraków 31-343, Poland
| | - Malgorzata Filip
- Department of Drug Addiction Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, Kraków 31-343, Poland
| | - Anbarasu Lourdusamy
- Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK
| | - Philipp Kirchner
- Institute of Human Genetics, Friedrich Alexander University of Erlangen-Nuremberg (FAU), Erlangen 91054, Germany
| | - Arif B Ekici
- Institute of Human Genetics, Friedrich Alexander University of Erlangen-Nuremberg (FAU), Erlangen 91054, Germany
| | - Lena M Marx
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
| | - Neeraja Puliparambil Suresh
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
| | - Renato Frischknecht
- Department of Biology, Animal Physiology, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen 91058, Germany
| | - Anna Fejtova
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
| | - Essa M Saied
- Institute for Chemistry, Humboldt University, Berlin 12489, Germany.,Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt
| | - Christoph Arenz
- Institute for Chemistry, Humboldt University, Berlin 12489, Germany
| | - Aline Bozec
- Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen 91054, Germany.,Deutsches Zentrum für Immuntherapie (DZI), Erlangen 91054, Germany
| | - Isabel Wank
- Department of Experimental and Clinical Pharmacology and Toxicology, Emil Fischer Center, Friedrich-Alexander-University of Erlangen-Nuremberg (FAU), Erlangen, Germany
| | - Silke Kreitz
- Department of Experimental and Clinical Pharmacology and Toxicology, Emil Fischer Center, Friedrich-Alexander-University of Erlangen-Nuremberg (FAU), Erlangen, Germany
| | - Andreas Hess
- Department of Experimental and Clinical Pharmacology and Toxicology, Emil Fischer Center, Friedrich-Alexander-University of Erlangen-Nuremberg (FAU), Erlangen, Germany
| | - Tobias Bäuerle
- Preclinical Imaging Platform Erlangen, Institute of Radiology, University Hospital Erlangen, Erlangen 91054, Germany
| | | | - Daniel N Mitroi
- Centro Biologia Molecular Severo Ochoa (CSIC-UAM), Madrid 28040, Spain
| | - André M Miranda
- School of Medicine, Life and Health Sciences Research Institute (ICVS), University of Minho, Campus Gualtar, Braga 4710-057, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães 4710-057, Portugal
| | - Tiago Gil Oliveira
- School of Medicine, Life and Health Sciences Research Institute (ICVS), University of Minho, Campus Gualtar, Braga 4710-057, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães 4710-057, Portugal
| | - Bernd Lenz
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany.,Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health (CIMH), Medical Faculty Mannheim, Heidelberg University, J5, Mannheim 68159, Germany
| | - Gunter Schumann
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany.,The Centre for Population Neuroscience and Stratified Medicine (PONS), ISTBI, Fudan University, Shanghai 200433, China.,Department of Psychiatry and Psychotherapie, CCM, PONS Centre, Charite Mental Health, Charite Universitaetsmedizin Berlin, Berlin 10117, Germany
| | - Johannes Kornhuber
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
| | - Christian P Müller
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany.,Centre for Drug Research, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia
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30
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Gurunathan S, Kim JH. Graphene Oxide Enhances Biogenesis and Release of Exosomes in Human Ovarian Cancer Cells. Int J Nanomedicine 2022; 17:5697-5731. [PMID: 36466784 PMCID: PMC9717435 DOI: 10.2147/ijn.s385113] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 11/04/2022] [Indexed: 07/20/2023] Open
Abstract
BACKGROUND Exosomes, which are nanovesicles secreted by almost all the cells, mediate intercellular communication and are involved in various physiological and pathological processes. We aimed to investigate the effects of graphene oxide (GO) on the biogenesis and release of exosomes in human ovarian cancer (SKOV3) cells. METHODS Exosomes were isolated using ultracentrifugation and ExoQuick and characterized by various analytical techniques. The expression levels of exosome markers were analyzed via quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS Graphene oxide (10-50 μg/mL), cisplatin (2-10 μg/mL), and C6-ceramide (5-25 μM) inhibited the cell viability, proliferation, and cytotoxicity in a dose-dependent manner. We observed that graphene oxide (GO), cisplatin (CIS), and C6-Ceramide (C6-Cer) stimulated acetylcholine esterase and neutral sphingomyelinase activity, total exosome protein concentration, and exosome counts associated with increased level of apoptosis, oxidative stress and endoplasmic reticulum stress. In contrast, GW4869 treatment inhibits biogenesis and release of exosomes. We observed that the human ovarian cancer cells secreted exosomes with typical cup-shaped morphology and surface protein biomarkers. The expression levels of TSG101, CD9, CD63, and CD81 were significantly higher in GO-treated cells than in control cells. Further, cytokine and chemokine levels were significantly higher in exosomes isolated from GO-treated SKOV3 cells than in those isolated from control cells. SKOV3 cells pre-treated with N-acetylcysteine or GW4869 displayed a significant reduction in GO-induced exosome biogenesis and release. Furthermore, endocytic inhibitors decrease exosome biogenesis and release by impairing endocytic pathways. CONCLUSION This study identifies GO as a potential tool for targeting the exosome pathway and stimulating exosome biogenesis and release. We believe that the knowledge acquired in this study can be potentially extended to other exosome-dominated pathologies and model systems. Furthermore, these nanoparticles can provide a promising means to enhance exosome production in SKOV3 cells.
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Affiliation(s)
- Sangiliyandi Gurunathan
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, 05029, Korea
| | - Jin Hoi Kim
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, 05029, Korea
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31
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Ho QWC, Zheng X, Ali Y. Ceramide Acyl Chain Length and Its Relevance to Intracellular Lipid Regulation. Int J Mol Sci 2022; 23:9697. [PMID: 36077094 PMCID: PMC9456274 DOI: 10.3390/ijms23179697] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 08/19/2022] [Accepted: 08/24/2022] [Indexed: 11/17/2022] Open
Abstract
Ceramides are a class of sphingolipids which are implicated in skin disorders, obesity, and other metabolic diseases. As a class with pleiotropic effects, recent efforts have centred on discerning specific ceramide species and their effects on atopic dermatitis, obesity, type 2 diabetes, and cardiovascular diseases. This delineation has allowed the identification of disease biomarkers, with long acyl chain ceramides such as C16- and C18-ceramides linked to metabolic dysfunction and cardiac function decline, while ultra-long acyl chain ceramides (>25 carbon acyl chain) were reported to be essential for maintaining a functional skin barrier. Given the intricate link between free fatty acids with ceramides, especially the de novo synthetic pathway, intracellular lipid droplet formation is increasingly viewed as an important mechanism for preventing accumulation of toxic ceramide species. Here, we review recent reports of various ceramide species involved in skin abnormalities and metabolic diseases, and we propose that promotion of lipid droplet biogenesis can be seen as a potential protective mechanism against deleterious ceramides.
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Affiliation(s)
- Qing Wei Calvin Ho
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore 308232, Singapore
| | - Xiaofeng Zheng
- Department of Endocrinology and Metabolism, Center for Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yusuf Ali
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore 308232, Singapore
- Singapore Eye Research Institute (SERI), Singapore General Hospital, Singapore 168751, Singapore
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32
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Nicholson RJ, Norris MK, Poss AM, Holland WL, Summers SA. The Lard Works in Mysterious Ways: Ceramides in Nutrition-Linked Chronic Disease. Annu Rev Nutr 2022; 42:115-144. [PMID: 35584813 PMCID: PMC9399075 DOI: 10.1146/annurev-nutr-062220-112920] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Diet influences onset, progression, and severity of several chronic diseases, including heart failure, diabetes, steatohepatitis, and a subset of cancers. The prevalence and clinical burden of these obesity-linked diseases has risen over the past two decades. These metabolic disorders are driven by ectopic lipid deposition in tissues not suited for fat storage, leading to lipotoxic disruption of cell function and survival. Sphingolipids such as ceramides are among the most deleterious and bioactive metabolites that accrue, as they participate in selective insulin resistance, dyslipidemia, oxidative stress and apoptosis. This review discusses our current understanding of biochemical pathways controlling ceramide synthesis, production and action; influences of diet on ceramide levels; application of circulating ceramides as clinical biomarkers of metabolic disease; and molecular mechanisms linking ceramides to altered metabolism and survival of cells. Development of nutritional or pharmacological strategies to lower ceramides could have therapeutic value in a wide range of prevalent diseases.
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Affiliation(s)
- Rebekah J. Nicholson
- Department of Nutrition and Integrative Physiology, University of Utah College of Health, Salt Lake City, Utah, USA,Diabetes and Metabolism Research Center, University of Utah College of Medicine, Salt Lake City, Utah, USA
| | - Marie K. Norris
- Department of Nutrition and Integrative Physiology, University of Utah College of Health, Salt Lake City, Utah, USA,Diabetes and Metabolism Research Center, University of Utah College of Medicine, Salt Lake City, Utah, USA
| | - Annelise M. Poss
- Department of Nutrition and Integrative Physiology, University of Utah College of Health, Salt Lake City, Utah, USA,Diabetes and Metabolism Research Center, University of Utah College of Medicine, Salt Lake City, Utah, USA
| | - William L. Holland
- Department of Nutrition and Integrative Physiology, University of Utah College of Health, Salt Lake City, Utah, USA,Diabetes and Metabolism Research Center, University of Utah College of Medicine, Salt Lake City, Utah, USA
| | - Scott A. Summers
- Department of Nutrition and Integrative Physiology, University of Utah College of Health, Salt Lake City, Utah, USA,Diabetes and Metabolism Research Center, University of Utah College of Medicine, Salt Lake City, Utah, USA
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33
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Fei C, Ji D, Tong H, Li Y, Su L, Qin Y, Bian Z, Zhang W, Mao C, Li L, Lu T. Therapeutic mechanism of Curcuma aromatica Salisb. rhizome against coronary heart disease based on integrated network pharmacology, pharmacological evaluation and lipidomics. Front Pharmacol 2022; 13:950749. [PMID: 36016561 PMCID: PMC9396035 DOI: 10.3389/fphar.2022.950749] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 07/14/2022] [Indexed: 11/22/2022] Open
Abstract
Curcuma aromatica Salisb. rhizome (CASR) has multifunctional characteristics worldwide and a long history of use as a botanical drug with. Currently, it is often used clinically to treat coronary heart disease (CHD) caused by blood stasis syndrome. However, the therapeutic mechanism of CASR in the treatment of CHD remains poorly understood. In study, the main chemical constituents of CASR were analyzed using UPLC-Q-TOF-MS/MS. Then, its potential therapeutic mechanism against CHD was predicted. Subsequently, pharmacological evaluation was performed using CHD rat model. Finally, a lipidomics approach was applied to explore the different lipid metabolites to verify the regulation of CASR on lipid metabolism disorders in CHD. A total of 35 compounds was identified from CASR. Seventeen active components and 51 potential targets related to CHD were screened by network pharmacology, involving 13 key pathways. In vivo experiments showed that CASR could significantly improve myocardial infarction, blood stasis, and blood lipid levels and regulate the PI3K/AKT/mTOR signaling pathway in CHD rats. Lipidomics further showed that CASR could regulate abnormal sphingolipid, glycerophospholipid, and glycerolipid metabolism in CHD rats. The therapeutic mechanism of CASR against CHD was initially elucidated and included the regulation of lipid metabolism. Its effects may be attributed to active ingredients, such as curzerene, isoprocurcumenol, and (+)-curcumenol. This study reveals the characteristics of multi-component and multi-pathway of CASR in the treatment of CHD, which provides a basis for the follow-up development and utilization of CASR.
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Affiliation(s)
- Chenghao Fei
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - De Ji
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Huangjin Tong
- Department of Pharmacy, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yu Li
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Lianlin Su
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yuwen Qin
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhenhua Bian
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Department of Pharmacy, Wuxi Affiliated Hospital of Nanjing University of Chinese Medicine, Wuxi, China
| | - Wei Zhang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
| | - Chunqin Mao
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- *Correspondence: Chunqin Mao, ; Lin Li, ; Tulin Lu,
| | - Lin Li
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- *Correspondence: Chunqin Mao, ; Lin Li, ; Tulin Lu,
| | - Tulin Lu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- *Correspondence: Chunqin Mao, ; Lin Li, ; Tulin Lu,
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34
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Ceramide and Sphingosine-1-Phosphate in Neurodegenerative Disorders and Their Potential Involvement in Therapy. Int J Mol Sci 2022; 23:ijms23147806. [PMID: 35887154 PMCID: PMC9324343 DOI: 10.3390/ijms23147806] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/08/2022] [Accepted: 07/11/2022] [Indexed: 02/04/2023] Open
Abstract
Neurodegenerative disorders (ND) are progressive diseases of the nervous system, often without resolutive therapy. They are characterized by a progressive impairment and loss of specific brain regions and neuronal populations. Cellular and animal model studies have identified several molecular mechanisms that play an important role in the pathogenesis of ND. Among them are alterations of lipids, in particular sphingolipids, that play a crucial role in neurodegeneration. Overall, during ND, ceramide-dependent pro-apoptotic signalling is promoted, whereas levels of the neuroprotective spingosine-1-phosphate are reduced. Moreover, ND are characterized by alterations of the metabolism of complex sphingolipids. The finding that altered sphingolipid metabolism has a role in ND suggests that its modulation might provide a useful strategy to identify targets for possible therapies. In this review, based on the current literature, we will discuss how bioactive sphingolipids (spingosine-1-phosphate and ceramide) are involved in some ND (Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis) and their possible involvement in therapies.
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35
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Sanchez V, Galor A, Jensen K, Mondal K, Mandal N. Relationships between ocular surface sphingomyelinases, Meibum and Tear Sphingolipids, and clinical parameters of meibomian gland dysfunction. Ocul Surf 2022; 25:101-107. [PMID: 35714913 DOI: 10.1016/j.jtos.2022.06.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 06/08/2022] [Accepted: 06/10/2022] [Indexed: 10/18/2022]
Abstract
PURPOSE Sphingolipids (SPL) are a class of lipid molecules that play important functional and structural roles in our body and are a component of meibum. Sphingomyelinases (SMases) are key enzymes in sphingolipid metabolism that hydrolyze sphingomyelin (SM) and generate ceramide (Cer). The purpose of this study was to examine relationships between ocular surface SMases, SPL composition, and parameters of Meibomian gland dysfunction (MGD). METHODS Individuals were grouped by meibum quality (n = 25 with poor-quality, MGD, and n = 25 with good-quality, control). Meibum and tears were analyzed with LC-MS to quantify SPL classes: Cer, Hexosyl-Ceramide (Hex-Cer), SM, Sphingosine (Sph), and sphingosine 1-phosphate (S1P). SMase activity in tears were quantified using a commercially available 'SMase assay'. Statistical analysis included multiple linear regression analyses to assess the impact of SMase activity on lipid composition, as well as ocular surface symptoms and signs of MGD. RESULTS Demographic characteristics were similar between the two groups. nSMase and aSMase levels were lower in the poor vs good quality group. aSMase activity in tears negatively correlated with SM in meibum and tears and positively with Sph in meibum and S1P in tears. Lower SMase activity were associated with signs of MGD, most notably Meibomian gland dropout. CONCLUSION This study suggests that individuals with MGD have reduced enzymatic activity of SMases in tears. Specifically, individuals with poor vs good meibum quality were noted to have alterations in SMase activity and SPL composition of meibum and tears which may reflect deviations from normal lipid metabolism in individuals with MGD.
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Affiliation(s)
- Victor Sanchez
- Miami Veterans Administration Medical Center, 1201 NW 16th St, Miami, FL, 33125, USA; New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - Anat Galor
- Miami Veterans Administration Medical Center, 1201 NW 16th St, Miami, FL, 33125, USA; Bascom Palmer Eye Institute, University of Miami, 900 NW 17th Street, Miami, FL, 33136, USA
| | - Katherine Jensen
- Miami Veterans Administration Medical Center, 1201 NW 16th St, Miami, FL, 33125, USA
| | - Koushik Mondal
- Department of Ophthalmology, University of Tennessee Health Sciences Center, Hamilton Eye Institute, 930 Madison Avenue, Memphis, TN, 38163, USA
| | - Nawajes Mandal
- Department of Ophthalmology, University of Tennessee Health Sciences Center, Hamilton Eye Institute, 930 Madison Avenue, Memphis, TN, 38163, USA; Departments of Anatomy and Neurobiology, Pharmaceutical Sciences, University of Tennessee Health Sciences Center, 930 Madison Avenue, Memphis, TN, 38163, USA; Memphis VA Medical Center, 1030 Jefferson Avenue, Memphis, TN, 38104, USA.
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Arya SB, Chen S, Jordan-Javed F, Parent CA. Ceramide-rich microdomains facilitate nuclear envelope budding for non-conventional exosome formation. Nat Cell Biol 2022; 24:1019-1028. [PMID: 35739317 DOI: 10.1038/s41556-022-00934-8] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 05/05/2022] [Indexed: 02/06/2023]
Abstract
Neutrophils migrating towards chemoattractant gradients amplify their recruitment range by releasing the secondary chemoattractant leukotriene B4 (LTB4) refs. 1,2. We previously demonstrated that LTB4 and its synthesizing enzymes, 5-lipoxygenase (5-LO), 5-LO activating protein (FLAP) and leukotriene A4 hydrolase, are packaged and released in exosomes3. Here we report that the biogenesis of the LTB4-containing exosomes originates at the nuclear envelope (NE) of activated neutrophils. We show that the neutral sphingomyelinase 1 (nSMase1)-mediated generation of ceramide-enriched lipid-ordered microdomains initiates the clustering of the LTB4-synthesizing enzymes on the NE. We isolated and analysed exosomes from activated neutrophils and established that the FLAP/5-LO-positive exosome population is distinct from that of the CD63-positive exosome population. Furthermore, we observed a strong co-localization between ALIX and FLAP at the periphery of nuclei and within cytosolic vesicles. We propose that the initiation of NE curvature and bud formation is mediated by nSMase1-dependent ceramide generation, which leads to FLAP and ALIX recruitment. Together, these observations elucidate the mechanism for LTB4 secretion and identify a non-conventional pathway for exosome generation.
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Affiliation(s)
- Subhash B Arya
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA.,Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
| | - Song Chen
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Fatima Jordan-Javed
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Carole A Parent
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA. .,Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA. .,Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA. .,Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
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Abdi S, Javanmehr N, Ghasemi-Kasman M, Bali HY, Pirzadeh M. Stem Cell-based Therapeutic and Diagnostic Approaches in Alzheimer's Disease. Curr Neuropharmacol 2022; 20:1093-1115. [PMID: 34970956 PMCID: PMC9886816 DOI: 10.2174/1570159x20666211231090659] [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] [Received: 05/11/2021] [Revised: 07/24/2021] [Accepted: 09/21/2021] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Alzheimer's disease (AD) is a neurodegenerative impairment mainly recognized by memory loss and cognitive deficits. However, the current therapies against AD are mostly limited to palliative medications, prompting researchers to investigate more efficient therapeutic approaches for AD, such as stem cell therapy. Recent evidence has proposed that extensive neuronal and synaptic loss and altered adult neurogenesis, which is perceived pivotal in terms of plasticity and network maintenance, occurs early in the course of AD, which exacerbates neuronal vulnerability to AD. Thus, regeneration and replenishing the depleted neuronal networks by strengthening the endogenous repair mechanisms or exogenous stem cells and their cargoes is a rational therapeutic approach. Currently, several stem cell-based therapies as well as stem cell products like exosomes, have shown promising results in the early diagnosis of AD. OBJECTIVE This review begins with a comparison between AD and normal aging pathophysiology and a discussion on open questions in the field. Next, summarizing the current stem cell-based therapeutic and diagnostic approaches, we declare the advantages and disadvantages of each method. Also, we comprehensively evaluate the human clinical trials of stem cell therapies for AD. METHODOLOGY Peer-reviewed reports were extracted through Embase, PubMed, and Google Scholar until 2021. RESULTS With several ongoing clinical trials, stem cells and their derivatives (e.g., exosomes) are an emerging and encouraging field in diagnosing and treating neurodegenerative diseases. Although stem cell therapies have been successful in animal models, numerous clinical trials in AD patients have yielded unpromising results, which we will further discuss.
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Affiliation(s)
- Sadaf Abdi
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Nima Javanmehr
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Maryam Ghasemi-Kasman
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran;,Neuroscience Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran,Address correspondence to this author at the Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, P.O. Box 4136747176, Babol, Iran; Tel/Fax: +98-11-32190557; E-mail:
| | | | - Marzieh Pirzadeh
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
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Abstract
Altered lipid metabolism is a characteristic feature and potential driving factor of acute kidney injury (AKI). Of the lipids that accumulate in injured renal tissues, ceramides are potent regulators of metabolism and cell fate. Up-regulation of ceramide synthesis is a common feature shared across several AKI etiologies in vitro and in vivo. Furthermore, ceramide accumulation is an early event in the natural history of AKI that precedes cell death and organ dysfunction. Emerging evidence suggests that inhibition of ceramide accumulation may improve renal outcomes in several models of AKI. This review examines the landscape of ceramide metabolism and regulation in the healthy and injured kidney. Furthermore, we discuss the body of literature regarding ceramides as therapeutic targets for AKI and consider potential mechanisms by which ceramides drive kidney pathogenesis.
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Affiliation(s)
- Rebekah J Nicholson
- Department of Nutrition and Integrative Physiology, Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, UT
| | - William L Holland
- Department of Nutrition and Integrative Physiology, Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, UT
| | - Scott A Summers
- Department of Nutrition and Integrative Physiology, Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, UT.
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Ca 2+-activated sphingomyelin scrambling and turnover mediate ESCRT-independent lysosomal repair. Nat Commun 2022; 13:1875. [PMID: 35388011 PMCID: PMC8986845 DOI: 10.1038/s41467-022-29481-4] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 03/11/2022] [Indexed: 12/14/2022] Open
Abstract
Lysosomes are vital organelles vulnerable to injuries from diverse materials. Failure to repair or sequester damaged lysosomes poses a threat to cell viability. Here we report that cells exploit a sphingomyelin-based lysosomal repair pathway that operates independently of ESCRT to reverse potentially lethal membrane damage. Various conditions perturbing organelle integrity trigger a rapid calcium-activated scrambling and cytosolic exposure of sphingomyelin. Subsequent metabolic conversion of sphingomyelin by neutral sphingomyelinases on the cytosolic surface of injured lysosomes promotes their repair, also when ESCRT function is compromised. Conversely, blocking turnover of cytosolic sphingomyelin renders cells more sensitive to lysosome-damaging drugs. Our data indicate that calcium-activated scramblases, sphingomyelin, and neutral sphingomyelinases are core components of a previously unrecognized membrane restoration pathway by which cells preserve the functional integrity of lysosomes.
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Revealing 2-Dimethylhydrazino-2-alkyl alkynyl sphingosine derivatives as Sphingosine Kinase 2 inhibitors: some hints on the structural basis for selective inhibition. Bioorg Chem 2022; 121:105668. [DOI: 10.1016/j.bioorg.2022.105668] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 02/02/2022] [Accepted: 02/07/2022] [Indexed: 12/29/2022]
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Exosomes in cardiovascular diseases: a blessing or a sin for the mankind. Mol Cell Biochem 2022; 477:833-847. [PMID: 35064412 DOI: 10.1007/s11010-021-04328-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 12/07/2021] [Indexed: 12/13/2022]
Abstract
Cardiovascular diseases (CVDs) comprises disorders of blood vessels and heart. Multiple cells in the heart suggests that hetero-cellular communication, which is an important aspect in heart functioning and there is a need to elucidate the way in which this inter-cellular communication occurs. Now a days, exosomal research has gained much attention. Exosomes, nano-shuttles, are EVs with diameters ranging from 40 to 160 nm (average 100 nm), secreted by body cells. These vesicles act as cell-to-cell communicators and are carriers of important biomolecules such as RNAs, miRNAs, Proteins and lipids. Exosomes can change the gene expression of the recipient cells, thereby, changes the cellular characteristics. Exosomes have known to play an essential role in protection as well as progression of various cardiovascular diseases. In the present review, role of exosomes in various CVDs have been discussed.
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Rana R, Kant R, Kaul D, Sachdev A, Ganguly NK. Integrated view of molecular diagnosis and prognosis of dengue viral infection: future prospect of exosomes biomarkers. Mol Cell Biochem 2022; 477:815-832. [PMID: 35059925 DOI: 10.1007/s11010-021-04326-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 12/03/2021] [Indexed: 10/19/2022]
Abstract
Dengue viruses (DENVs) are the viruses responsible for dengue infection which affects lungs, liver, heart and also other organs of individuals. DENVs consist of the group of four serotypically diverse dengue viruses transmitted in tropical and sub-tropical countries of world. Aedes mosquito is the principal vector which spread the infection from infected person to healthy humans. DENVs can cause different syndromes depending on serotype of virus which range from undifferentiated mild fever to dengue hemorrhagic fever resulting in vascular leakage due to release of cytokine and Dengue shock syndrome with fluid loss and hypotensive shock, or other severe manifestations such as bleeding and organ failure. Increase in dengue cases in pediatric population is a major concern. Transmission of dengue depends on various factors like temperature, rainfall, and distribution of Aedes aegypti mosquitoes. The present review describes a comprehensive overview of dengue, pathophysiology, diagnosis, treatment with an emphasis on potential of exosomes as biomarkers for early prediction of dengue in pediatrics.
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Affiliation(s)
- Rashmi Rana
- Department of Research, Sir Ganga Ram Hospital, New Delhi, 110060, India.
| | - Ravi Kant
- Department of Research, Sir Ganga Ram Hospital, New Delhi, 110060, India
| | - Dinesh Kaul
- Department of Pediatrics, Sir Ganga Ram Hospital, New Delhi, 110060, India
| | - Anil Sachdev
- Department of Pediatrics, Sir Ganga Ram Hospital, New Delhi, 110060, India
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Peters S, Fohmann I, Rudel T, Schubert-Unkmeir A. A Comprehensive Review on the Interplay between Neisseria spp. and Host Sphingolipid Metabolites. Cells 2021; 10:cells10113201. [PMID: 34831424 PMCID: PMC8623382 DOI: 10.3390/cells10113201] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/11/2021] [Accepted: 11/12/2021] [Indexed: 02/01/2023] Open
Abstract
Sphingolipids represent a class of structural related lipids involved in membrane biology and various cellular processes including cell growth, apoptosis, inflammation and migration. Over the past decade, sphingolipids have become the focus of intensive studies regarding their involvement in infectious diseases. Pathogens can manipulate the sphingolipid metabolism resulting in cell membrane reorganization and receptor recruitment to facilitate their entry. They may recruit specific host sphingolipid metabolites to establish a favorable niche for intracellular survival and proliferation. In contrast, some sphingolipid metabolites can also act as a first line defense against bacteria based on their antimicrobial activity. In this review, we will focus on the strategies employed by pathogenic Neisseria spp. to modulate the sphingolipid metabolism and hijack the sphingolipid balance in the host to promote cellular colonization, invasion and intracellular survival. Novel techniques and innovative approaches will be highlighted that allow imaging of sphingolipid derivatives in the host cell as well as in the pathogen.
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Affiliation(s)
- Simon Peters
- Institute for Hygiene and Microbiology, University of Wuerzburg, 97080 Wuerzburg, Germany; (S.P.); (I.F.)
| | - Ingo Fohmann
- Institute for Hygiene and Microbiology, University of Wuerzburg, 97080 Wuerzburg, Germany; (S.P.); (I.F.)
| | - Thomas Rudel
- Chair of Microbiology, University of Wuerzburg, 97080 Wuerzburg, Germany;
| | - Alexandra Schubert-Unkmeir
- Institute for Hygiene and Microbiology, University of Wuerzburg, 97080 Wuerzburg, Germany; (S.P.); (I.F.)
- Correspondence: ; Tel.: +49-931-31-46721; Fax: +49-931-31-46445
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da Costa VR, Araldi RP, Vigerelli H, D’Ámelio F, Mendes TB, Gonzaga V, Policíquio B, Colozza-Gama GA, Valverde CW, Kerkis I. Exosomes in the Tumor Microenvironment: From Biology to Clinical Applications. Cells 2021; 10:2617. [PMID: 34685596 PMCID: PMC8533895 DOI: 10.3390/cells10102617] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 08/25/2021] [Accepted: 08/26/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer is one of the most important health problems and the second leading cause of death worldwide. Despite the advances in oncology, cancer heterogeneity remains challenging to therapeutics. This is because the exosome-mediated crosstalk between cancer and non-cancer cells within the tumor microenvironment (TME) contributes to the acquisition of all hallmarks of cancer and leads to the formation of cancer stem cells (CSCs), which exhibit resistance to a range of anticancer drugs. Thus, this review aims to summarize the role of TME-derived exosomes in cancer biology and explore the clinical potential of mesenchymal stem-cell-derived exosomes as a cancer treatment, discussing future prospects of cell-free therapy for cancer treatment and challenges to be overcome.
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Affiliation(s)
- Vitor Rodrigues da Costa
- Programa de Pós-Graduação em Biologia Estrutural e Funcional, Escola Paulista de Medicina (EPM), Federal University of São Paulo (UNIFES), São Paulo 04039-032, Brazil; (V.R.d.C.); (T.B.M.); (G.A.C.-G.)
- Genetics Laboratory, Instituto Butantan, São Paulo 05508-010, Brazil; (H.V.); (F.D.); (V.G.); (B.P.)
| | - Rodrigo Pinheiro Araldi
- Programa de Pós-Graduação em Biologia Estrutural e Funcional, Escola Paulista de Medicina (EPM), Federal University of São Paulo (UNIFES), São Paulo 04039-032, Brazil; (V.R.d.C.); (T.B.M.); (G.A.C.-G.)
- Genetics Laboratory, Instituto Butantan, São Paulo 05508-010, Brazil; (H.V.); (F.D.); (V.G.); (B.P.)
- Cellavita Pesquisas Científicas Ltd.a., Valinhos 13271-650, Brazil;
| | - Hugo Vigerelli
- Genetics Laboratory, Instituto Butantan, São Paulo 05508-010, Brazil; (H.V.); (F.D.); (V.G.); (B.P.)
| | - Fernanda D’Ámelio
- Genetics Laboratory, Instituto Butantan, São Paulo 05508-010, Brazil; (H.V.); (F.D.); (V.G.); (B.P.)
| | - Thais Biude Mendes
- Programa de Pós-Graduação em Biologia Estrutural e Funcional, Escola Paulista de Medicina (EPM), Federal University of São Paulo (UNIFES), São Paulo 04039-032, Brazil; (V.R.d.C.); (T.B.M.); (G.A.C.-G.)
- Genetics Laboratory, Instituto Butantan, São Paulo 05508-010, Brazil; (H.V.); (F.D.); (V.G.); (B.P.)
- Cellavita Pesquisas Científicas Ltd.a., Valinhos 13271-650, Brazil;
| | - Vivian Gonzaga
- Genetics Laboratory, Instituto Butantan, São Paulo 05508-010, Brazil; (H.V.); (F.D.); (V.G.); (B.P.)
- Cellavita Pesquisas Científicas Ltd.a., Valinhos 13271-650, Brazil;
| | - Bruna Policíquio
- Genetics Laboratory, Instituto Butantan, São Paulo 05508-010, Brazil; (H.V.); (F.D.); (V.G.); (B.P.)
- Cellavita Pesquisas Científicas Ltd.a., Valinhos 13271-650, Brazil;
| | - Gabriel Avelar Colozza-Gama
- Programa de Pós-Graduação em Biologia Estrutural e Funcional, Escola Paulista de Medicina (EPM), Federal University of São Paulo (UNIFES), São Paulo 04039-032, Brazil; (V.R.d.C.); (T.B.M.); (G.A.C.-G.)
- Genetic Bases of Thyroid Tumors Laboratory, Division of Genetics, Department of Morphology and Genetics, Federal University of São Paulo (UNIFESP), São Paulo 04039-032, Brazil
| | | | - Irina Kerkis
- Programa de Pós-Graduação em Biologia Estrutural e Funcional, Escola Paulista de Medicina (EPM), Federal University of São Paulo (UNIFES), São Paulo 04039-032, Brazil; (V.R.d.C.); (T.B.M.); (G.A.C.-G.)
- Genetics Laboratory, Instituto Butantan, São Paulo 05508-010, Brazil; (H.V.); (F.D.); (V.G.); (B.P.)
- Cellavita Pesquisas Científicas Ltd.a., Valinhos 13271-650, Brazil;
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Shi J, Hyman AJ, De Vecchis D, Chong J, Lichtenstein L, Futers TS, Rouahi M, Salvayre AN, Auge N, Kalli AC, Beech DJ. Sphingomyelinase Disables Inactivation in Endogenous PIEZO1 Channels. Cell Rep 2021; 33:108225. [PMID: 33027663 PMCID: PMC7539531 DOI: 10.1016/j.celrep.2020.108225] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/30/2020] [Accepted: 09/11/2020] [Indexed: 11/29/2022] Open
Abstract
Endogenous PIEZO1 channels of native endothelium lack the hallmark inactivation often seen when these channels are overexpressed in cell lines. Because prior work showed that the force of shear stress activates sphingomyelinase in endothelium, we considered if sphingomyelinase is relevant to endogenous PIEZO1. Patch clamping was used to quantify PIEZO1-mediated signals in freshly isolated murine endothelium exposed to the mechanical forces caused by shear stress and membrane stretch. Neutral sphingomyelinase inhibitors and genetic disruption of sphingomyelin phosphodiesterase 3 (SMPD3) cause PIEZO1 to switch to profoundly inactivating behavior. Ceramide (a key product of SMPD3) rescues non-inactivating channel behavior. Its co-product, phosphoryl choline, has no effect. In contrast to ceramide, sphingomyelin (the SMPD3 substrate) does not affect inactivation but alters channel force sensitivity. The data suggest that sphingomyelinase activity, ceramide, and sphingomyelin are determinants of native PIEZO gating that enable sustained activity.
SMPD3 sphingomyelinase enables long-lasting PIEZO1 activity in response to force Ceramide, a key lipid product of SMPD3, promotes long-lasting activity Sphingomyelin, the SMPD3 substrate, does not affect the duration of activity Sphingomyelin alters PIEZO1 force sensitivity
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Affiliation(s)
- Jian Shi
- Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, UK.
| | - Adam J Hyman
- Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, UK
| | - Dario De Vecchis
- Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, UK
| | - Jiehan Chong
- Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, UK
| | - Laeticia Lichtenstein
- Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, UK
| | - T Simon Futers
- Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, UK
| | - Myriam Rouahi
- INSERM U-1048 and Université Paul Sabatier, 31432 Cedex 4 Toulouse, France
| | | | - Nathalie Auge
- INSERM U-1048 and Université Paul Sabatier, 31432 Cedex 4 Toulouse, France
| | - Antreas C Kalli
- Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, UK; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK.
| | - David J Beech
- Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, UK.
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Schneider-Schaulies S, Schumacher F, Wigger D, Schöl M, Waghmare T, Schlegel J, Seibel J, Kleuser B. Sphingolipids: Effectors and Achilles Heals in Viral Infections? Cells 2021; 10:cells10092175. [PMID: 34571822 PMCID: PMC8466362 DOI: 10.3390/cells10092175] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/16/2021] [Accepted: 08/20/2021] [Indexed: 12/26/2022] Open
Abstract
As viruses are obligatory intracellular parasites, any step during their life cycle strictly depends on successful interaction with their particular host cells. In particular, their interaction with cellular membranes is of crucial importance for most steps in the viral replication cycle. Such interactions are initiated by uptake of viral particles and subsequent trafficking to intracellular compartments to access their replication compartments which provide a spatially confined environment concentrating viral and cellular components, and subsequently, employ cellular membranes for assembly and exit of viral progeny. The ability of viruses to actively modulate lipid composition such as sphingolipids (SLs) is essential for successful completion of the viral life cycle. In addition to their structural and biophysical properties of cellular membranes, some sphingolipid (SL) species are bioactive and as such, take part in cellular signaling processes involved in regulating viral replication. It is especially due to the progress made in tools to study accumulation and dynamics of SLs, which visualize their compartmentalization and identify interaction partners at a cellular level, as well as the availability of genetic knockout systems, that the role of particular SL species in the viral replication process can be analyzed and, most importantly, be explored as targets for therapeutic intervention.
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Affiliation(s)
- Sibylle Schneider-Schaulies
- Institute for Virology and Immunobiology, University of Wuerzburg, 97078 Würzburg, Germany; (S.S.-S.); (M.S.); (T.W.)
| | - Fabian Schumacher
- Institute of Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, 14195 Berlin, Germany; (F.S.); (D.W.)
| | - Dominik Wigger
- Institute of Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, 14195 Berlin, Germany; (F.S.); (D.W.)
| | - Marie Schöl
- Institute for Virology and Immunobiology, University of Wuerzburg, 97078 Würzburg, Germany; (S.S.-S.); (M.S.); (T.W.)
| | - Trushnal Waghmare
- Institute for Virology and Immunobiology, University of Wuerzburg, 97078 Würzburg, Germany; (S.S.-S.); (M.S.); (T.W.)
| | - Jan Schlegel
- Department for Biotechnology and Biophysics, University of Wuerzburg, 97074 Würzburg, Germany;
| | - Jürgen Seibel
- Department for Organic Chemistry, University of Wuerzburg, 97074 Würzburg, Germany;
| | - Burkhard Kleuser
- Institute of Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, 14195 Berlin, Germany; (F.S.); (D.W.)
- Correspondence: ; Tel.: +49-30-8386-9823
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Sperm Lipid Markers of Male Fertility in Mammals. Int J Mol Sci 2021; 22:ijms22168767. [PMID: 34445473 PMCID: PMC8395862 DOI: 10.3390/ijms22168767] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/10/2021] [Accepted: 08/12/2021] [Indexed: 12/13/2022] Open
Abstract
Sperm plasma membrane lipids are essential for the function and integrity of mammalian spermatozoa. Various lipid types are involved in each key step within the fertilization process in their own yet coordinated way. The balance between lipid metabolism is tightly regulated to ensure physiological cellular processes, especially referring to crucial steps such as sperm motility, capacitation, acrosome reaction or fusion. At the same time, it has been shown that male reproductive function depends on the homeostasis of sperm lipids. Here, we review the effects of phospholipid, neutral lipid and glycolipid homeostasis on sperm fertilization function and male fertility in mammals.
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Sindhu S, Leung YH, Arefanian H, Madiraju SRM, Al‐Mulla F, Ahmad R, Prentki M. Neutral sphingomyelinase-2 and cardiometabolic diseases. Obes Rev 2021; 22:e13248. [PMID: 33738905 PMCID: PMC8365731 DOI: 10.1111/obr.13248] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/18/2021] [Accepted: 02/26/2021] [Indexed: 12/13/2022]
Abstract
Sphingolipids, in particular ceramides, play vital role in pathophysiological processes linked to metabolic syndrome, with implications in the development of insulin resistance, pancreatic ß-cell dysfunction, type 2 diabetes, atherosclerosis, inflammation, nonalcoholic steatohepatitis, and cancer. Ceramides are produced by the hydrolysis of sphingomyelin, catalyzed by different sphingomyelinases, including neutral sphingomyelinase 2 (nSMase2), whose dysregulation appears to underlie many of the inflammation-related pathologies. In this review, we discuss the current knowledge on the biochemistry of nSMase2 and ceramide production and its regulation by inflammatory cytokines, with particular reference to cardiometabolic diseases. nSMase2 contribution to pathogenic processes appears to involve cyclical feed-forward interaction with proinflammatory cytokines, such as TNF-α and IL-1ß, which activate nSMase2 and the production of ceramides, that in turn triggers the synthesis and release of inflammatory cytokines. We elaborate these pathogenic interactions at the molecular level and discuss the potential therapeutic benefits of inhibiting nSMase2 against inflammation-driven cardiometabolic diseases.
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Affiliation(s)
- Sardar Sindhu
- Animal and Imaging core facilityDasman Diabetes InstituteDasmanKuwait
| | - Yat Hei Leung
- Departments of Nutrition, Biochemistry and Molecular MedicineUniversity of MontrealMontréalQuebecCanada
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)Montreal Diabetes Research CenterMontréalQuebecCanada
| | - Hossein Arefanian
- Immunology and Microbiology DepartmentDasman Diabetes InstituteDasmanKuwait
| | - S. R. Murthy Madiraju
- Departments of Nutrition, Biochemistry and Molecular MedicineUniversity of MontrealMontréalQuebecCanada
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)Montreal Diabetes Research CenterMontréalQuebecCanada
| | - Fahd Al‐Mulla
- Department of Genetics and BioinformaticsDasman Diabetes InstituteDasmanKuwait
| | - Rasheed Ahmad
- Immunology and Microbiology DepartmentDasman Diabetes InstituteDasmanKuwait
| | - Marc Prentki
- Departments of Nutrition, Biochemistry and Molecular MedicineUniversity of MontrealMontréalQuebecCanada
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)Montreal Diabetes Research CenterMontréalQuebecCanada
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Suprunenko EA, Sazonova EA, Vasiliev AV. Extracellular Vesicles of Pluripotent Stem Cells. Russ J Dev Biol 2021. [DOI: 10.1134/s1062360421030073] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
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Seibel J, Schneider-Schaulies S, Kleuser B. Editorial: Sphingolipids in Infection Control. Front Cell Dev Biol 2021; 9:697290. [PMID: 34235157 PMCID: PMC8255667 DOI: 10.3389/fcell.2021.697290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 05/19/2021] [Indexed: 11/24/2022] Open
Affiliation(s)
- Jürgen Seibel
- Department for Organic Chemistry and Insitute for Virology and Immunobiology, Julius Maximilian University of Würzburg, Würzburg, Germany
| | - Sibylle Schneider-Schaulies
- Department for Organic Chemistry and Insitute for Virology and Immunobiology, Julius Maximilian University of Würzburg, Würzburg, Germany
| | - Burkhard Kleuser
- Institute of Pharmacy, Free University of Berlin, Berlin, Germany
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