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Guan J, Wu F, Wu S, Ren Y, Wang J, Zhu H. FTY720 alleviates D-GalN/LPS-induced acute liver failure by regulating the JNK/MAPK pathway. Int Immunopharmacol 2025; 157:114726. [PMID: 40311319 DOI: 10.1016/j.intimp.2025.114726] [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: 01/13/2025] [Revised: 04/20/2025] [Accepted: 04/22/2025] [Indexed: 05/03/2025]
Abstract
Acute liver failure (ALF) poses a considerable health and economic burden worldwide and has limited treatment options. Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive phospholipid that participates in various cellular processes by through S1P receptors (S1PRs). Previous studies have showed that the hepatic S1P levels were increased. Notably, deletion or inhibition of sphingosine kinase 1 (SphK1), the key enzyme responsible for S1P biosynthesis, could alleviate D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced ALF in mice. However, the role of the S1P receptor modulator FTY720 in ALF remains unclear. In this study, we investigated the effects of FTY720 on D-GalN/LPS-induced ALF model. Our results demonstrated that FTY720 pretreatment significantly alleviated liver injury, decreased the serum levels of alanine aminotransferase and aspartate aminotransferase, and mitigated histopathological damage in ALF model mice. Mechanistically, FTY720 could inhibit the inflammatory response and reduced apoptosis. The protective effect of FTY720 was mediated by c-Jun N-terminal kinase (JNK)/mitogen-activated protein kinase (MAPK) signalling. A pharmacological JNK activator (anisomycin) partially counteracted these protective effects. FTY720, targeting S1PRs, is expected to be an effective therapeutic strategy for ALF.
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Affiliation(s)
- Jun Guan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Fengtian Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Shanshan Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Yanli Ren
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Jing Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Haihong Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
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Kim HJ, Yang D, Hong JH. Various Cellular Components and Its Signaling Cascades Through the Involvement of Signaling Messengers in Keratinocyte Differentiation. Antioxidants (Basel) 2025; 14:426. [PMID: 40298779 PMCID: PMC12023943 DOI: 10.3390/antiox14040426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2025] [Revised: 03/28/2025] [Accepted: 03/30/2025] [Indexed: 04/30/2025] Open
Abstract
Skin is a highly differentiated tissue, in which various signaling molecules play critical roles in the differentiation and proliferation of keratinocytes. Among these, the second messenger calcium and its gradient across skin layers are pivotal in regulating keratinocyte differentiation. Additionally, a diverse array of cellular signaling molecules has been identified as essential for promoting keratinocyte differentiation, thereby maintaining skin integrity and barrier function. The barrier function of the skin provides essential protection against exogenous stimuli and pathogens while maintaining structural stability. The homeostatic processes of skin differentiation are modulated by these second messengers and various signaling molecules. Thus, this review highlights the components associated with keratinocyte differentiation and their biological and pathophysiological roles, as well as redox-sensitive differentiation factors in the modulation of skin homeostasis. This review aims to enhance our understanding of skin physiology and provide insights that may facilitate the development of novel therapeutic strategies for skin diseases.
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Affiliation(s)
| | - Dongki Yang
- Department of Physiology, Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, 155 Getbeolro, Yeonsu-gu, Incheon 21999, Republic of Korea;
| | - Jeong Hee Hong
- Department of Physiology, Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, 155 Getbeolro, Yeonsu-gu, Incheon 21999, Republic of Korea;
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Esmaeili Y, Toiserkani F, Qazanfarzadeh Z, Ghasemlou M, Naebe M, Barrow CJ, Timms W, Jafarzadeh S. Unlocking the potential of green-engineered carbon quantum dots for sustainable packaging biomedical applications and water purification. Adv Colloid Interface Sci 2025; 338:103414. [PMID: 39889506 DOI: 10.1016/j.cis.2025.103414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Revised: 01/20/2025] [Accepted: 01/22/2025] [Indexed: 02/03/2025]
Abstract
Carbon quantum dots (CQDs) with well-defined architectures offer highly fascinating properties such as excellent water-solubility, exceptional luminescence, large specific surface area, non-toxicity, biocompatibility and tuneable morphological, structural, and chemical features. This review comprehensively overviews recent breakthroughs and critical milestones in the green synthesis of CQDs from renewable sources and provides guidance for their sustainable development towards fulfilling the goals of green chemistry. It also discusses the interaction of CQDs with various biopolymers to improve the material performance and functionality. This paper also highlights the latest technological applications of CQDs in numerous fields, including sustainable packaging, biosensing, bioimaging, cancer therapy, drug delivery as well as water purification. Finally, it summarizes the main challenges and provides an outlook on the future directions of CQDs in packaging and biomedical fields. This review can act as a roadmap to guide researchers for tailoring the properties of CQDs for important composite and biomedical fields.
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Affiliation(s)
- Yasaman Esmaeili
- School of Engineering, Deakin University, Geelong Waurn Ponds Campus, Victoria 3216, Australia
| | - Farzad Toiserkani
- School of Polymer Science and Polymer Engineering, University of Akron, OH 44325, United States
| | - Zeinab Qazanfarzadeh
- Division of Industrial Biotechnology, Department of Life Sciences, Chalmers University of Technology, 412 96 Gothenburg, Sweden
| | - Mehran Ghasemlou
- Centre for Sustainable Bioproducts, Deakin University, Geelong Waurn Ponds Campus, Victoria 3216, Australia; School of Science, STEM College, RMIT University, Melbourne, VIC 3001, Australia
| | - Minoo Naebe
- Institute for Frontier Materials (IFM), Deakin University, Geelong Waurn Ponds Campus, Victoria 3216, Australia; Centre for Sustainable Bioproducts, Deakin University, Geelong Waurn Ponds Campus, Victoria 3216, Australia
| | - Colin J Barrow
- Centre for Sustainable Bioproducts, Deakin University, Geelong Waurn Ponds Campus, Victoria 3216, Australia
| | - Wendy Timms
- School of Engineering, Deakin University, Geelong Waurn Ponds Campus, Victoria 3216, Australia; Centre for Sustainable Bioproducts, Deakin University, Geelong Waurn Ponds Campus, Victoria 3216, Australia.
| | - Shima Jafarzadeh
- School of Engineering, Deakin University, Geelong Waurn Ponds Campus, Victoria 3216, Australia; Centre for Sustainable Bioproducts, Deakin University, Geelong Waurn Ponds Campus, Victoria 3216, Australia.
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Serafini S, O’Flaherty C. Sphingolipids modulate redox signalling during human sperm capacitation. Hum Reprod 2025; 40:210-225. [PMID: 39658334 PMCID: PMC11788196 DOI: 10.1093/humrep/deae268] [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: 07/02/2024] [Revised: 10/30/2024] [Indexed: 12/12/2024] Open
Abstract
STUDY QUESTION What role do sphingolipids have in mediating human sperm capacitation? SUMMARY ANSWER Sphingosine 1-phosphate (S1P) mediates the acquisition of fertilizing competency in human spermatozoa by engaging with its Gi-coupled receptor S1PR1 and promoting production of reactive oxygen species such as nitric oxide and superoxide anion. WHAT IS KNOWN ALREADY Bioactive sphingolipids, such as S1P, are fundamental for regulating numerous physiological domains and processes, such as cell membranes and signalling, cell death and proliferation, cell migration and invasiveness, inflammation, and central nervous system development. STUDY DESIGN, SIZE, DURATION Semen samples were obtained from a cohort of 10 healthy non-smoking volunteers (18-30 years old) to investigate the role of S1P in sperm. PARTICIPANTS/MATERIALS, SETTING, METHODS Percoll-selected human spermatozoa were incubated at 37°C for 3.5 h in BWW media with or without foetal cord serum ultrafiltrate (FCSu), sphingosine (Sph), or ceramide (Cer). Spermatozoa were also incubated with or without pharmacological inhibitors of sphingolipid metabolism. Protein tyrosine phosphorylation was determined by immunoblotting. The acrosome reaction was determined by PSA-FTIC labelling of the acrosome and analysed using fluorescence microscopy. Intracellular nitric oxide (NO•) production was determined using a DAF-2DA probe. Immunocytochemistry was performed to localize and assess the functional relationship of key components of lipid signalling in spermatozoa. Sperm viability and motility of the samples were evaluated by the hypo-osmotic swelling (HOS) test and computer-aided sperm analysis (CASA). Statistical differences between groups were determined using ANOVA and Tukey's test. Normal distribution of the data and variance homogeneity were assessed using Shapiro-Wilk and Levene's test, respectively. A difference was considered significant when the P-value was ≤0.05. MAIN RESULTS AND THE ROLE OF CHANCE S1P mediates the acquisition of fertilizing competency in human spermatozoa by engaging with its Gi-coupled receptor S1PR1. We found that S1PR1 redistributes to the post-acrosomal region upon induction of capacitation. S1P signalling promotes the activation of the PI3K-AKT pathway, leading to NO• production during sperm capacitation. L-NAME, an nitric oxide synthase inhibitor, impaired the Sph- and Cer-dependent capacitation. Additionally, Sph and Cer promote superoxide anion (O2•-) production, and the extracellular addition of superoxide dismutase (SOD) prevented Sph- and Cer-dependent capacitation, suggesting that Sph and Cer stimulate O2•- production during sperm capacitation. Protein kinase type R (PKR), ceramide kinase (CERK), and protein kinase C (PKC) are responsible for translocating and activating sphingosine kinase 1 (SphK1), which is necessary to promote S1P production for sperm capacitation. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION The utilization and actions of sphingolipids may differ in spermatozoa of different species. WIDER IMPLICATIONS OF THE FINDINGS Sphingolipid metabolites such as Sph, Cer, S1P, and ceramide 1-phosphate (C1P) play a crucial role in inducing human sperm capacitation. Our research has provided new insights into fundamental sphingolipid processes in human sperm, including the importance of C1P in translocating and activating SphK1 as well as the S1P signalling to regulate the PI3K/AKT/NOS pathway to generate NO• for sperm capacitation. We are the first to identify the presence of PKR in human spermatozoa and its role in the phosphorylation activities of SphK1 with the subsequent activation of S1P signalling. Furthermore, our study has identified that S1PR1 and S1PR3 are involved in capacitation and the acrosome reaction, respectively. These findings shed light on a novel mechanism by which sphingolipids drive capacitation in human sperm and pave the way for further exploration of the role of bioactive sphingolipid metabolites in this process. Lastly, our studies lay the foundation for examining the lipid profile of infertile males, as potential discrepancies can affect the functional capacity of spermatozoa to reach fertilizing potential. STUDY FUNDING/COMPETING INTEREST(S) This research was funded by the Canadian Institutes of Health Research (CIHR), grant number PJT-165962 to C.O.F. S.S. was awarded a Research Institute-MUHC Desjardins Studentship. There are no competing interests to report.
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Affiliation(s)
- Steven Serafini
- Experimental Medicine Division, Department of Medicine, McGill University, Montréal, QC, Canada
- Urology Division, Department of Surgery, McGill University, Montréal, QC, Canada
- The Research Institute, McGill University Health Centre, Montréal, QC, Canada
| | - Cristian O’Flaherty
- Experimental Medicine Division, Department of Medicine, McGill University, Montréal, QC, Canada
- Urology Division, Department of Surgery, McGill University, Montréal, QC, Canada
- The Research Institute, McGill University Health Centre, Montréal, QC, Canada
- Department of Anatomy and Cell Biology, McGill University, Montréal, QC, Canada
- Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada
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Pandian K, van Zonneveld AJ, Harms A, Hankemeier T. Metabolic alterations of endothelial cells under transient and persistent hypoxia: study using a 3D microvessels-on-chip model. Tissue Barriers 2024:2431416. [PMID: 39584359 DOI: 10.1080/21688370.2024.2431416] [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: 09/25/2024] [Revised: 11/08/2024] [Accepted: 11/12/2024] [Indexed: 11/26/2024] Open
Abstract
Numerous signaling pathways are activated during hypoxia to facilitate angiogenesis, promoting interactions among endothelial cells and initiating downstream signaling cascades. Although the pivotal role of the nitric oxide (NO) response pathway is well-established, the involvement of arginine-specific metabolism and bioactive lipid mechanisms in 3D flow-activated in vitro models remains less understood. In this study, we explored the levels of arginine-specific metabolites and bioactive lipids in human coronary artery endothelial cells (HCAECs) under both transient and persistent hypoxia. We compared targeted metabolite levels between a 2D static culture model and a 3D microvessels-on-chip model. Notably, we observed robust regulation of NO metabolites in both transient and persistent hypoxic conditions. In the 2D model under transient hypoxia, metabolic readouts of bioactive lipids revealed increased oxidative stress markers, a phenomenon not observed in the 3D microvessels. Furthermore, we made a novel discovery that the responses of bioactive lipids were regulated by hypoxia inducible factor-1α (HIF-1α) in the 2D cell culture model and partially by HIF-1α and flow-induced shear stress in the 3D microvessels. Immunostaining confirmed the HIF-1α-induced regulation under both hypoxic conditions. Real-time oxygen measurements in the 3D microvessels using an oxygen probe validated that oxygen levels were maintained in the 3D model. Overall, our findings underscore the critical regulatory roles of HIF-1α and shear stress in NO metabolites and bioactive lipids in both 2D and 3D cell culture models.
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Affiliation(s)
- Kanchana Pandian
- Division of Systems Biomedicine and Pharmacology, LACDR, Leiden University, Leiden, The Netherlands
| | - Anton Jan van Zonneveld
- Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - Amy Harms
- Division of Systems Biomedicine and Pharmacology, LACDR, Leiden University, Leiden, The Netherlands
| | - Thomas Hankemeier
- Division of Systems Biomedicine and Pharmacology, LACDR, Leiden University, Leiden, The Netherlands
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6
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Limbu KR, Chhetri RB, Kim S, Shrestha J, Oh YS, Baek DJ, Park EY. Targeting sphingosine 1-phosphate and sphingosine kinases in pancreatic cancer: mechanisms and therapeutic potential. Cancer Cell Int 2024; 24:353. [PMID: 39462385 PMCID: PMC11514880 DOI: 10.1186/s12935-024-03535-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 10/15/2024] [Indexed: 10/29/2024] Open
Abstract
Pancreatic cancer is known to be the most lethal cancer. Fewer new treatments are being developed for pancreatic cancer as compared to other cancers. The bioactive lipid S1P, which is mainly regulated by sphingosine kinase 1 (SK1) and sphingosine kinase 2 (SK2) enzymes, plays significant roles in pancreatic cancer initiation and exacerbation. S1P controls many signaling pathways to modulate the progression of pancreatic cancer through the G-coupled receptor S1PR1-5. Several papers reporting amelioration of pancreatic cancer via modulation of S1P levels or downstream signaling pathways have previously been published. In this paper, for the first time, we have reviewed the results of previous studies to understand how S1P and its receptors contribute to the development of pancreatic cancer, and whether S1P can be a therapeutic target. In addition, we have also reviewed papers dealing with the effects of SK1 and SK2, which are kinases that regulate the level of S1P, on the pathogenesis of pancreatic cancer. We have also listed available drugs that particularly focus on S1P, S1PRs, SK1, and SK2 for the treatment of pancreatic cancer. Through this review, we would like to suggest that the SK/S1P/S1PR signaling system can be an important target for treating pancreatic cancer, where a new treatment target is desperately warranted.
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Affiliation(s)
- Khem Raj Limbu
- College of Pharmacy, Mokpo National University, Joennam, 58554, South Korea
| | | | - Subin Kim
- College of Pharmacy, Mokpo National University, Joennam, 58554, South Korea
| | - Jitendra Shrestha
- Massachusetts General Hospital Cancer Center, Boston, MA, 02114, USA
| | - Yoon Sin Oh
- Department of Food and Nutrition, Eulji University, Seongnam, 13135, South Korea
| | - Dong Jae Baek
- College of Pharmacy, Mokpo National University, Joennam, 58554, South Korea.
| | - Eun-Young Park
- College of Pharmacy, Mokpo National University, Joennam, 58554, South Korea.
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Foster DJ, Dunnavant K, Shrader CW, LoPresti M, Seay S, Kharel Y, Brown AM, Huang T, Lynch KR, Santos WL. Discovery of Potent, Orally Bioavailable Sphingosine-1-Phosphate Transporter (Spns2) Inhibitors. J Med Chem 2024; 67:11273-11295. [PMID: 38952222 PMCID: PMC11247503 DOI: 10.1021/acs.jmedchem.4c00879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/03/2024]
Abstract
Targeting the S1P pathway has resulted in the development of S1P1 receptor modulators for the treatment of multiple sclerosis and ulcerative colitis. We hypothesize that targeting an upstream node of the S1P pathway may provide an improved adverse event profile. In this report, we performed a structure-activity relationship study focusing on the benzoxazole scaffold in SLB1122168, which lead to the discovery of 11i (SLF80821178) as a potent inhibitor of S1P release from HeLa cells (IC50: 51 ± 3 nM). Administration of SLF80821178 to mice induced ∼50% reduction in circulating lymphocyte counts, recapitulating the lymphopenia characteristic of Spns2 null animals. Molecular modeling studies suggest that SLF80821178 binds Spns2 in its occluded inward-facing state and forms hydrogen bonds with Asn112 and Ser211 and π stacking with Phe234. Taken together, SLF80821178 can serve as a scaffold for future inhibitor development and represents a chemical tool to study the therapeutic implication of inhibiting Spns2.
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Affiliation(s)
- Daniel J Foster
- Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States
| | - Kyle Dunnavant
- Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States
| | - Christopher W Shrader
- Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States
| | - Marion LoPresti
- Department of Biochemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States
| | - Sarah Seay
- Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States
| | - Yugesh Kharel
- Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, United States
| | - Anne M Brown
- Department of Biochemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States
| | - Tao Huang
- Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, United States
| | - Kevin R Lynch
- Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, United States
| | - Webster L Santos
- Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States
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Lee J, Mani A, Shin MJ, Krauss RM. Leveraging altered lipid metabolism in treating B cell malignancies. Prog Lipid Res 2024; 95:101288. [PMID: 38964473 PMCID: PMC11347096 DOI: 10.1016/j.plipres.2024.101288] [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: 02/19/2024] [Revised: 06/12/2024] [Accepted: 07/01/2024] [Indexed: 07/06/2024]
Abstract
B cell malignancies, comprising over 80 heterogeneous blood cancers, pose significant prognostic challenges due to intricate oncogenic signaling. Emerging evidence emphasizes the pivotal role of disrupted lipid metabolism in the development of these malignancies. Variations in lipid species, such as phospholipids, cholesterol, sphingolipids, and fatty acids, are widespread across B cell malignancies, contributing to uncontrolled cell proliferation and survival. Phospholipids play a crucial role in initial signaling cascades leading to B cell activation and malignant transformation through constitutive B cell receptor (BCR) signaling. Dysregulated cholesterol and sphingolipid homeostasis support lipid raft integrity, crucial for propagating oncogenic signals. Sphingolipids impact malignant B cell stemness, proliferation, and survival, while glycosphingolipids in lipid rafts modulate BCR activation. Additionally, cancer cells enhance fatty acid-related processes to meet heightened metabolic demands. In obese individuals, the obesity-derived lipids and adipokines surrounding adipocytes rewire lipid metabolism in malignant B cells, evading cytotoxic therapies. Genetic drivers such as MYC translocations also intrinsically alter lipid metabolism in malignant B cells. In summary, intrinsic and extrinsic factors converge to reprogram lipid metabolism, fostering aggressive phenotypes in B cell malignancies. Therefore, targeting altered lipid metabolism has translational potential for improving risk stratification and clinical management of diverse B cell malignancy subtypes.
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Affiliation(s)
- Jaewoong Lee
- School of Biosystems and Biomedical Sciences, College of Health Science, Korea University, Seoul 02841, Republic of Korea; Department of Integrated Biomedical and Life Science, Korea University, Seoul 02841, Republic of Korea; Interdisciplinary Program in Precision Public Health, Korea University, Seoul 02841, Republic of Korea; Center of Molecular and Cellular Oncology, Yale University, New Haven, CT 06511, USA.
| | - Arya Mani
- Department of Internal Medicine, Section of Cardiovascular Medicine, Yale University, New Haven, CT 06511, USA; Department of Genetics, Yale University, New Haven, CT 06511, USA
| | - Min-Jeong Shin
- School of Biosystems and Biomedical Sciences, College of Health Science, Korea University, Seoul 02841, Republic of Korea; Department of Integrated Biomedical and Life Science, Korea University, Seoul 02841, Republic of Korea; Interdisciplinary Program in Precision Public Health, Korea University, Seoul 02841, Republic of Korea
| | - Ronald M Krauss
- Department of Pediatrics and Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
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Polenz CK, Scipione CA, Hyduk SJ, Althagafi MG, Ibrahim HM, Cybulsky MI. Plasma S1P Orchestrates the Reverse Transendothelial Migration of Aortic Intimal Myeloid Cells in Mice. Arterioscler Thromb Vasc Biol 2024; 44:883-897. [PMID: 38328936 DOI: 10.1161/atvbaha.123.320227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 01/24/2024] [Indexed: 02/09/2024]
Abstract
BACKGROUND Myeloid cells (MCs) reside in the aortic intima at regions predisposed to atherosclerosis. Systemic inflammation triggers reverse transendothelial migration (RTM) of intimal MCs into the arterial blood, which orchestrates a protective immune response that clears intracellular pathogens from the arterial intima. Molecular pathways that regulate RTM remain poorly understood. S1P (sphingosine-1-phosphate) is a lipid mediator that regulates immune cell trafficking by signaling via 5 G-protein-coupled receptors (S1PRs [S1P receptors]). We investigated the role of S1P in the RTM of aortic intimal MCs. METHODS Intravenous injection of lipopolysaccharide was used to model a systemic inflammatory stimulus that triggers RTM. CD11c+ intimal MCs in the lesser curvature of the ascending aortic arch were enumerated by en face confocal microscopy. Local gene expression was evaluated by transcriptomic analysis of microdissected intimal cells. RESULTS In wild-type C57BL/6 mice, lipopolysaccharide induced intimal cell expression of S1pr1, S1pr3, and Sphk1 (a kinase responsible for S1P production). Pharmacological modulation of multiple S1PRs blocked lipopolysaccharide-induced RTM and modulation of S1PR1 and S1PR3 reduced RTM in an additive manner. Cre-mediated deletion of S1pr1 in MCs blocked lipopolysaccharide-induced RTM, confirming a role for myeloid-specific S1PR1 signaling. Global or hematopoietic deficiency of Sphk1 reduced plasma S1P levels, the abundance of CD11c+ MCs in the aortic intima, and blunted lipopolysaccharide-induced RTM. In contrast, plasma S1P levels, the abundance of intimal MCs, and lipopolysaccharide-induced RTM were rescued in Sphk1-/- mice transplanted with Sphk1+/+ or mixed Sphk1+/+ and Sphk1-/- bone marrow. Stimulation with lipopolysaccharide increased endothelial permeability and intimal MC exposure to circulating factors such as S1P. CONCLUSIONS Functional and expression studies support a novel role for S1P signaling in the regulation of lipopolysaccharide-induced RTM and the homeostatic maintenance of aortic intimal MCs. Our data provide insight into how circulating plasma mediators help orchestrate intimal MC dynamics.
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Affiliation(s)
- Chanele K Polenz
- Departments of Laboratory Medicine and Pathobiology (C.K.P., C.A.S., M.G.A., H.M.I., M.I.C.), University of Toronto, Canada
- Toronto General Hospital Research Institute, University Health Network, Canada (C.K.P., C.A.S., S.J.H., M.G.A., H.M.I., M.I.C.)
| | - Corey A Scipione
- Departments of Laboratory Medicine and Pathobiology (C.K.P., C.A.S., M.G.A., H.M.I., M.I.C.), University of Toronto, Canada
- Immunology (C.A.S., M.I.C.), University of Toronto, Canada
- Toronto General Hospital Research Institute, University Health Network, Canada (C.K.P., C.A.S., S.J.H., M.G.A., H.M.I., M.I.C.)
| | - Sharon J Hyduk
- Toronto General Hospital Research Institute, University Health Network, Canada (C.K.P., C.A.S., S.J.H., M.G.A., H.M.I., M.I.C.)
| | - Marwan G Althagafi
- Departments of Laboratory Medicine and Pathobiology (C.K.P., C.A.S., M.G.A., H.M.I., M.I.C.), University of Toronto, Canada
- Toronto General Hospital Research Institute, University Health Network, Canada (C.K.P., C.A.S., S.J.H., M.G.A., H.M.I., M.I.C.)
| | - Hisham M Ibrahim
- Departments of Laboratory Medicine and Pathobiology (C.K.P., C.A.S., M.G.A., H.M.I., M.I.C.), University of Toronto, Canada
- Toronto General Hospital Research Institute, University Health Network, Canada (C.K.P., C.A.S., S.J.H., M.G.A., H.M.I., M.I.C.)
| | - Myron I Cybulsky
- Departments of Laboratory Medicine and Pathobiology (C.K.P., C.A.S., M.G.A., H.M.I., M.I.C.), University of Toronto, Canada
- Immunology (C.A.S., M.I.C.), University of Toronto, Canada
- Toronto General Hospital Research Institute, University Health Network, Canada (C.K.P., C.A.S., S.J.H., M.G.A., H.M.I., M.I.C.)
- Peter Munk Cardiac Centre, University Health Network, Toronto, Canada (M.I.C.)
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Gao Y, Zhai W, Sun L, Du X, Wang X, Mulholland MW, Yin Y, Zhang W. Hepatic LGR4 aggravates cholestasis-induced liver injury in mice. Am J Physiol Gastrointest Liver Physiol 2024; 326:G460-G472. [PMID: 38440827 PMCID: PMC11213478 DOI: 10.1152/ajpgi.00127.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 02/20/2024] [Accepted: 02/26/2024] [Indexed: 03/06/2024]
Abstract
Current therapy for hepatic injury induced by the accumulation of bile acids is limited. Leucine-rich repeat G protein-coupled receptor 4 (LGR4), also known as GPR48, is critical for cytoprotection and cell proliferation. Here, we reported a novel function for the LGR4 in cholestatic liver injury. In the bile duct ligation (BDL)-induced liver injury model, hepatic LGR4 expression was significantly downregulated. Deficiency of LGR4 in hepatocytes (Lgr4LKO) notably decreased BDL-induced liver injury measured by hepatic necrosis, fibrosis, and circulating liver enzymes and total bilirubin. Levels of total bile acids in plasma and liver were markedly reduced in these mice. However, deficiency of LGR4 in macrophages (Lyz2-Lgr4MKO) demonstrated no significant effect on liver injury induced by BDL. Deficiency of LGR4 in hepatocytes significantly attenuated S1PR2 and the phosphorylation of protein kinase B (AKT) induced by BDL. Recombinant Rspo1 and Rspo3 potentiated the taurocholic acid (TCA)-induced upregulation in S1PR2 and phosphorylation of AKT in hepatocytes. Inhibition of S1PR2-AKT signaling by specific AKT or S1PR2 inhibitors blocked the increase of bile acid secretion induced by Rspo1/3 in hepatocytes. Our studies indicate that the R-spondins (Rspos)-LGR4 signaling in hepatocytes aggravates the cholestatic liver injury by potentiating the production of bile acids in a S1PR2-AKT-dependent manner.NEW & NOTEWORTHY Deficiency of LGR4 in hepatocytes alleviates BDL-induced liver injury. LGR4 in macrophages demonstrates no effect on BDL-induced liver injury. Rspos-LGR4 increases bile acid synthesis and transport via potentiating S1PR2-AKT signaling in hepatocytes.
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Affiliation(s)
- Yuan Gao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, People's Republic of China
| | - Wenbo Zhai
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, People's Republic of China
| | - Lijun Sun
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, People's Republic of China
| | - Xueqian Du
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, People's Republic of China
| | - Xianfeng Wang
- Department of Pharmacology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, People's Republic of China
| | - Michael W Mulholland
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan, United States
| | - Yue Yin
- Department of Pharmacology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, People's Republic of China
| | - Weizhen Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, People's Republic of China
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan, United States
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11
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Aikawa S, Hirota Y. Roles of lipid mediators in early pregnancy events. Reprod Med Biol 2024; 23:e12597. [PMID: 39010880 PMCID: PMC11247399 DOI: 10.1002/rmb2.12597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 06/24/2024] [Indexed: 07/17/2024] Open
Abstract
Background Early pregnancy events, including embryo implantation, are critical for maintaining a healthy pregnancy and facilitating childbirth. Despite numerous signaling pathways implicated in establishing early pregnancy, a comprehensive understanding of implantation remains elusive. Methods This paper provides a comprehensive review of the current research on lipids in the context of early pregnancy, with a particular focus on feto-maternal communications. Main Findings Embryo implantation entails direct interaction between uterine tissues and embryos. Introducing embryos triggers significant changes in uterine epithelial morphology and stromal differentiation, facilitating embryo implantation through communication with uterine tissue. Studies employing genetic models and chemical compounds targeting enzymes and receptors have elucidated the crucial roles of lipid mediators-prostaglandins, lysophosphatidic acid, sphingosine-1-phosphate, and cannabinoids-in early pregnancy events. Conclusion Given the high conservation of lipid synthases and receptors across species, lipid mediators likely play pivotal roles in rodents and humans. Further investigations into lipids hold promise for developing novel diagnostic and therapeutic approaches for infertility in humans.
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Affiliation(s)
- Shizu Aikawa
- Department of Obstetrics and Gynecology Graduate School of Medicine, The University of Tokyo Tokyo Japan
| | - Yasushi Hirota
- Department of Obstetrics and Gynecology Graduate School of Medicine, The University of Tokyo Tokyo Japan
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12
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Kleuser B, Schumacher F, Gulbins E. New Therapeutic Options in Pulmonal Diseases: Sphingolipids and Modulation of Sphingolipid Metabolism. Handb Exp Pharmacol 2024; 284:289-312. [PMID: 37922034 DOI: 10.1007/164_2023_700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2023]
Abstract
Sphingolipids are crucial molecules in the respiratory airways. As in most other tissues and organs, in the lung sphingolipids play an essential role as structural constituents as they regulate barrier function and fluidity of cell membranes. A lung-specific feature is the occurrence of sphingolipids as minor structural components in the surfactant. However, sphingolipids are also key signaling molecules involved in airway cell signaling and their dynamical formation and metabolism are important for normal lung physiology. Dysregulation of sphingolipid metabolism and signaling is involved in altering lung tissue and initiates inflammatory processes promoting the pathogenesis of pulmonal diseases including cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), and asthma.In the present review, the important role of specific sphingolipid species in pulmonal diseases will be discussed. Only such an understanding opens up the possibility of developing new therapeutic strategies with the aim of correcting the imbalance in sphingolipid metabolism and signaling. Such delivery strategies have already been studied in animal models of these lung diseases, demonstrating that targeting the sphingolipid profile represents new therapeutic opportunities for lung disorders.
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Affiliation(s)
- Burkhard Kleuser
- Institute of Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, Berlin, Germany.
| | - Fabian Schumacher
- Institute of Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, Berlin, Germany
| | - Erich Gulbins
- Institute of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
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13
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Wang D, Han S, Lv G, Hu Y, Zhuo W, Zeng Z, Tang J, Huang Y, Wang F, Wang J, Zhao Y, Zhao G. Pancreatic Acinar Cells-Derived Sphingosine-1-Phosphate Contributes to Fibrosis of Chronic Pancreatitis via Inducing Autophagy and Activation of Pancreatic Stellate Cells. Gastroenterology 2023; 165:1488-1504.e20. [PMID: 37634735 DOI: 10.1053/j.gastro.2023.08.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 07/22/2023] [Accepted: 08/11/2023] [Indexed: 08/29/2023]
Abstract
BACKGROUND & AIMS Studies have demonstrated that activated pancreatic stellate cells (PSCs) play a crucial role in pancreatic fibrogenesis in chronic pancreatitis (CP); however, the precise mechanism for PSCs activation has not been fully elucidated. We analyzed the role of injured pancreatic acinar cells (iPACs) in the activation of PSCs of CP. METHODS Sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) signaling was evaluated in experimental CP induced by cerulein injection or pancreatic duct ligation, as well as in PACs injured by cholecystokinin. The activation of PSCs and pancreatic fibrosis in CP samples was evaluated by immunohistochemical and immunofluorescence analyses. In vitro coculture assay of iPACs and PSCs was created to evaluate the effect of the SPHK1/S1P pathway and S1P receptor 2 (SIPR2) on autophagy and activation of PSCs. The pathogenesis of CP was assessed in SPHK1-/- mice or PACs-specific SPHK1-knockdown mice with recombinant adeno-associated virus serotypes 9-SPHK1-knockdown, as well as in mice treated with inhibitor of SPHK1 and S1P receptor 2 (S1PR2). RESULTS SPHK1/S1P was remarkably increased in iPACs and acinar cells in pancreatic tissues of CP mice. Meanwhile, the pathogenesis, fibrosis, and PSCs activation of CP was significantly prevented in SPHK1-/- mice and recombinant adeno-associated virus serotypes 9-SPHK1-knockdown mice. Meanwhile, iPACs obviously activated PSCs, which was prevented by SPHK1 knockdown in iPACs. Moreover, iPACs-derived S1P specifically combined to S1PR2 of PSCs, by which modulated 5' adenosine monophosphate-activated protein kinase/mechanistic target of rapamycin pathway and consequently induced autophagy and activation of PSCs. Furthermore, hypoxia-inducible factor 1-α and -2α promoted SPHK1 transcription of PACs under hypoxia conditions, which is a distinct characteristic of the CP microenvironment. Coincidently, inhibition of SPHK1 and S1PR2 activity with inhibitor PF-543 and JTE-013 obviously impeded pancreatic fibrogenesis of CP mice. CONCLUSIONS The activated SPHK1/S1P pathway in iPACs induces autophagy and activation of PSCs by regulating the S1PR2/5' adenosine monophosphate-activated protein kinase/mammalian target of rapamycin pathway, which promotes fibrogenesis of CP. The hypoxia microenvironment might contribute to the cross talk between PACs and PSCs in pathogenesis of CP.
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Affiliation(s)
- Decai Wang
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan China
| | - Shengbo Han
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan China
| | - Guozheng Lv
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan China
| | - Yuhang Hu
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan China
| | - Wenfeng Zhuo
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan China
| | - Zhu Zeng
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan China
| | - Jiang Tang
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan China
| | - Yan Huang
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan China
| | - Fan Wang
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan China
| | - Jie Wang
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan China
| | - Yong Zhao
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan China
| | - Gang Zhao
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan China.
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14
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Jamil M, Cowart LA. Sphingolipids in mitochondria-from function to disease. Front Cell Dev Biol 2023; 11:1302472. [PMID: 38078003 PMCID: PMC10702779 DOI: 10.3389/fcell.2023.1302472] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 11/03/2023] [Indexed: 02/12/2024] Open
Abstract
Sphingolipids are not only structural components of cellular membranes but also play vital roles in cell signaling and modulation of cellular processes. Within mitochondria, sphingolipids exert diverse effects on mitochondrial dynamics, energy metabolism, oxidative stress, and cell death pathways. In this review, we summarize literature addressing the crucial role of sphingolipids in mitochondria, highlighting their impact on mitochondrial dynamics, cellular bioenergetics, and important cell processes including apoptosis and mitophagy.
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Affiliation(s)
- Maryam Jamil
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United States
- Department of Biochemistry and Molecular Biology, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States
| | - Lauren Ashley Cowart
- Department of Biochemistry and Molecular Biology, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States
- Richmond Veteran’s Affairs Medical Center, Richmond, VA, United States
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15
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Wang Z, Xu J, Zou S, Chen Z, Dong S, Wang K. Prognostic significance of plasma S1P in acute intracerebral hemorrhage: A prospective cohort study. Clin Chim Acta 2023; 551:117585. [PMID: 37813327 DOI: 10.1016/j.cca.2023.117585] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Revised: 09/29/2023] [Accepted: 10/06/2023] [Indexed: 10/11/2023]
Abstract
OBJECTIVE Sphingosine-1-phosphate (S1P) may regulate neuroinflammatory immunity and blood-brain barrier integrity. This study was designed to assess the prognostic role of plasma S1P in intracerebral hemorrhage (ICH). METHODS In this prospective cohort study, plasma S1P levels were measured in 51 controls, at admission in 114 ICH patients and at days 1, 3, 5 and 7 in 51 of all patients. Univariate analysis and multivariate analysis were sequentially used to investigate severity correlation and prognosis association. RESULTS Plasma S1P levels were significantly elevated at admission, peaked at day 5, and declined at day 7, which were significantly higher during 7 days than those of controls (all P < 0.001). Areas under receiver operating characteristic curve (AUCs) of plasma S1P levels insignificant differed among all time points (all P > 0.05). Admission plasma S1P levels, in close correlation with National Institutes of Health Stroke Scale (NIHSS) scores [β, 7.661; 95 % confidence interval (CI), 4.893-10.399; P < 0.001] and hematoma volume (β, 1.285; 95 % CI, 0.348-2.230; P < 0.001), independently predicted 3-month poor prognosis (modified Rankin Scale scores of 3-6) (odds ratio, 3.184; 95 % CI, 1.057-9.597; P = 0.040). Admission plasma S1P levels had AUC of 0.799 (95 % CI, 0.713-0.868) for prognosis prediction. The levels > 240.4 ng/ml distinguished risk of poor prognosis with the maximum Youden index of 0.518. Prediction model integrating NIHSS scores, hematoma volume and admission plasma S1P levels had substantially higher prognostic predictive ability than NIHSS scores (P = 0.023), but not than hematoma volume (P = 0.061). CONCLUSION There is a significant elevation of plasma S1P levels during early period after ICH, which were independently related to severity and poor prognosis. Thus, plasma S1P may be a potential prognostic biomarker of ICH.
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Affiliation(s)
- Zefan Wang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou 310053, China
| | - Jian Xu
- Graduate School, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou 310053, China
| | - Shengdong Zou
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou 310053, China
| | - Ziyin Chen
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou 310053, China
| | - Shuangyong Dong
- Emergency Department, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, No. 261 Huansha Road, Hangzhou 310006, China
| | - Keyi Wang
- Central Laboratory, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, No. 261 Huansha Road, Hangzhou 310006, China.
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16
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Hegewisch-Solloa E, Nalin AP, Freud AG, Mace EM. Deciphering the localization and trajectory of human natural killer cell development. J Leukoc Biol 2023; 114:487-506. [PMID: 36869821 DOI: 10.1093/jleuko/qiad027] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 02/07/2023] [Accepted: 02/12/2023] [Indexed: 03/05/2023] Open
Abstract
Innate immune cells represent the first line of cellular immunity, comprised of both circulating and tissue-resident natural killer cells and innate lymphoid cells. These innate lymphocytes arise from a common CD34+ progenitor that differentiates into mature natural killer cells and innate lymphoid cells. The successive stages in natural killer cell maturation are characterized by increased lineage restriction and changes to phenotype and function. Mechanisms of human natural killer cell development have not been fully elucidated, especially the role of signals that drive the spatial localization and maturation of natural killer cells. Cytokines, extracellular matrix components, and chemokines provide maturation signals and influence the trafficking of natural killer cell progenitors to peripheral sites of differentiation. Here we present the latest advances in our understanding of natural killer and innate lymphoid cell development in peripheral sites, including secondary lymphoid tissues (i.e. tonsil). Recent work in the field has provided a model for the spatial distribution of natural killer cell and innate lymphoid cell developmental intermediates in tissue and generated further insights into the developmental niche. In support of this model, future studies using multifaceted approaches seek to fully map the developmental trajectory of human natural killer cells and innate lymphoid cells in secondary lymphoid tissues.
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Affiliation(s)
- Everardo Hegewisch-Solloa
- Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, 630 W 168th St. New York, NY 10032, USA
| | - Ansel P Nalin
- Biomedical Sciences Graduate Program, Medical Scientist Training Program, Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, The Ohio State University, 460 W 10th Ave. Columbus, OH 43210, USA
| | - Aharon G Freud
- Department of Pathology, Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, The Ohio State University, 460 W 12th Ave. Columbus, OH 43210, USA
| | - Emily M Mace
- Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, 630 W 168th St. New York, NY 10032, USA
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17
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Masuda-Kuroki K, Alimohammadi S, Di Nardo A. S. epidermidis Rescues Allergic Contact Dermatitis in Sphingosine 1-Phosphate Receptor 2-Deficient Skin. Int J Mol Sci 2023; 24:13190. [PMID: 37685997 PMCID: PMC10487941 DOI: 10.3390/ijms241713190] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 08/19/2023] [Accepted: 08/23/2023] [Indexed: 09/10/2023] Open
Abstract
Recent studies have identified a subtype of the S1P-receptor family called sphingosine-1-phosphate receptor 2 (S1PR2), which plays a crucial role in maintaining the skin barrier. It has been observed that S1PR2 and Staphylococcus epidermidis (S. epidermidis) work together to regulate the skin barrier. However, the interaction between these two factors is still unclear. To investigate this, a study was conducted on healthy skin and allergic contact dermatitis (ACD) using 3,4-Dibutoxy-3-cyclobutene-1,2-dione (SADBE) on the ears of S1pr2fl/fl and S1pr2fl/flK14-Cre mice and using 1 × 106 CFU of S. epidermidis to examine its effects on the skin. The results showed that in S. epidermidis-conditioned ACD, the ear thickness of S1pr2fl/flK14-Cre mice was lower than that of S1pr2fl/fl mice, and mRNA expressions of Il-1β and Cxcl2 of S1pr2fl/flK14-Cre mice were lower than that of S1pr2fl/fl mice in ACD with S. epidermidis. Furthermore, the gene expression of Claudin-1 and Occludin in S1pr2fl/flK14-Cre mice was higher than that of S1pr2fl/fl mice in ACD with S. epidermidis. The study concludes that S. epidermidis colonization improves the skin barrier and prevents ACD even when S1P signaling malfunctions.
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Affiliation(s)
| | | | - Anna Di Nardo
- Department of Dermatology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; (K.M.-K.); (S.A.)
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18
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Martín-Hernández D, Muñoz-López M, Tendilla-Beltrán H, Caso JR, García-Bueno B, Menchén L, Leza JC. Immune System and Brain/Intestinal Barrier Functions in Psychiatric Diseases: Is Sphingosine-1-Phosphate at the Helm? Int J Mol Sci 2023; 24:12634. [PMID: 37628815 PMCID: PMC10454107 DOI: 10.3390/ijms241612634] [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: 07/27/2023] [Revised: 08/07/2023] [Accepted: 08/08/2023] [Indexed: 08/27/2023] Open
Abstract
Over the past few decades, extensive research has shed light on immune alterations and the significance of dysfunctional biological barriers in psychiatric disorders. The leaky gut phenomenon, intimately linked to the integrity of both brain and intestinal barriers, may play a crucial role in the origin of peripheral and central inflammation in these pathologies. Sphingosine-1-phosphate (S1P) is a bioactive lipid that regulates both the immune response and the permeability of biological barriers. Notably, S1P-based drugs, such as fingolimod and ozanimod, have received approval for treating multiple sclerosis, an autoimmune disease of the central nervous system (CNS), and ulcerative colitis, an inflammatory condition of the colon, respectively. Although the precise mechanisms of action are still under investigation, the effectiveness of S1P-based drugs in treating these pathologies sparks a debate on extending their use in psychiatry. This comprehensive review aims to delve into the molecular mechanisms through which S1P modulates the immune system and brain/intestinal barrier functions. Furthermore, it will specifically focus on psychiatric diseases, with the primary objective of uncovering the potential of innovative therapies based on S1P signaling.
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Affiliation(s)
- David Martín-Hernández
- Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Instituto de Investigación Hospital 12 de Octubre (i+12), Instituto Universitario de Investigación en Neuroquímica (IUIN), 28040 Madrid, Spain; (M.M.-L.); (J.R.C.); (B.G.-B.); (J.C.L.)
- Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III (CIBERSAM, ISCIII), 28029 Madrid, Spain
| | - Marina Muñoz-López
- Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Instituto de Investigación Hospital 12 de Octubre (i+12), Instituto Universitario de Investigación en Neuroquímica (IUIN), 28040 Madrid, Spain; (M.M.-L.); (J.R.C.); (B.G.-B.); (J.C.L.)
- Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III (CIBERSAM, ISCIII), 28029 Madrid, Spain
| | - Hiram Tendilla-Beltrán
- Laboratorio de Neuropsiquiatría, Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla (BUAP), 72570 Puebla, Mexico;
| | - Javier R. Caso
- Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Instituto de Investigación Hospital 12 de Octubre (i+12), Instituto Universitario de Investigación en Neuroquímica (IUIN), 28040 Madrid, Spain; (M.M.-L.); (J.R.C.); (B.G.-B.); (J.C.L.)
- Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III (CIBERSAM, ISCIII), 28029 Madrid, Spain
| | - Borja García-Bueno
- Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Instituto de Investigación Hospital 12 de Octubre (i+12), Instituto Universitario de Investigación en Neuroquímica (IUIN), 28040 Madrid, Spain; (M.M.-L.); (J.R.C.); (B.G.-B.); (J.C.L.)
- Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III (CIBERSAM, ISCIII), 28029 Madrid, Spain
| | - Luis Menchén
- Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, Departamento de Medicina, Universidad Complutense, Instituto de Investigación Sanitaria Gregorio Marañón, 28007 Madrid, Spain;
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III (CIBEREHD, ISCIII), 28029 Madrid, Spain
| | - Juan C. Leza
- Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Instituto de Investigación Hospital 12 de Octubre (i+12), Instituto Universitario de Investigación en Neuroquímica (IUIN), 28040 Madrid, Spain; (M.M.-L.); (J.R.C.); (B.G.-B.); (J.C.L.)
- Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III (CIBERSAM, ISCIII), 28029 Madrid, Spain
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19
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Jayant G, Kuperberg S, Somnay K, Wadgaonkar R. The Role of Sphingolipids in Regulating Vascular Permeability in Idiopathic Pulmonary Fibrosis. Biomedicines 2023; 11:1728. [PMID: 37371823 DOI: 10.3390/biomedicines11061728] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 05/29/2023] [Accepted: 06/05/2023] [Indexed: 06/29/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a disease that causes scarring and fibrotic transformation of the lung parenchyma, resulting in the progressive loss of respiratory function and, often, death. Current treatments that target profibrotic factors can slow the rate of progression but are unable to ultimately stop it. In the past decade, many studies have shown that increased vascular permeability may be both a predictive and perpetuating factor in fibrogenesis. Consequently, there is a search for therapeutic targets to try and modulate vascular permeability in fibrotic lungs. One such class of targets that show great promise is sphingolipids. Sphingolipids are common in cell membranes and are increasingly recognized as critical to many cell signaling pathways, including those that affect the integrity of the vascular endothelial barrier. In this focused review we look at sphingolipids, particularly the sphingosine-1-phosphate (S1P) axis and its effects on vascular permeability, and how those effects may affect the pathogenesis of IPF. We further examine existing S1P modulators and their potential efficacy as therapeutics for IPF.
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Affiliation(s)
- Girish Jayant
- SUNY Downstate College of Medicine, Brooklyn, NY 11203, USA
| | | | - Kaumudi Somnay
- NY Presbyterian Hospital Queens, New York, NY 11355, USA
| | - Raj Wadgaonkar
- SUNY Downstate College of Medicine, Brooklyn, NY 11203, USA
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20
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Li Y, Li B, Chen WD, Wang YD. Role of G-protein coupled receptors in cardiovascular diseases. Front Cardiovasc Med 2023; 10:1130312. [PMID: 37342437 PMCID: PMC10277692 DOI: 10.3389/fcvm.2023.1130312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 05/09/2023] [Indexed: 06/22/2023] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of death globally, with CVDs accounting for nearly 30% of deaths worldwide each year. G-protein-coupled receptors (GPCRs) are the most prominent family of receptors on the cell surface, and play an essential regulating cellular physiology and pathology. Some GPCR antagonists, such as β-blockers, are standard therapy for the treatment of CVDs. In addition, nearly one-third of the drugs used to treat CVDs target GPCRs. All the evidence demonstrates the crucial role of GPCRs in CVDs. Over the past decades, studies on the structure and function of GPCRs have identified many targets for the treatment of CVDs. In this review, we summarize and discuss the role of GPCRs in the function of the cardiovascular system from both vascular and heart perspectives, then analyze the complex ways in which multiple GPCRs exert regulatory functions in vascular and heart diseases. We hope to provide new ideas for the treatment of CVDs and the development of novel drugs.
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Affiliation(s)
- Yuanqiang Li
- State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Boyu Li
- Department of Gastroenterology and Hematology, The People's Hospital of Hebi, Henan, China
| | - Wei-Dong Chen
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot, China
- Key Laboratory of Receptors-Mediated Gene Regulation, School of Medicine, The People’s Hospital of Hebi, Henan University, Kaifeng, China
| | - Yan-Dong Wang
- State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
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21
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Levesque MV, Hla T. Signal Transduction and Gene Regulation in the Endothelium. Cold Spring Harb Perspect Med 2023; 13:a041153. [PMID: 35667710 PMCID: PMC9722983 DOI: 10.1101/cshperspect.a041153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Extracellular signals act on G-protein-coupled receptors (GPCRs) to regulate homeostasis and adapt to stress. This involves rapid intracellular post-translational responses and long-lasting gene-expression changes that ultimately determine cellular phenotype and fate changes. The lipid mediator sphingosine 1-phosphate (S1P) and its receptors (S1PRs) are examples of well-studied GPCR signaling axis essential for vascular development, homeostasis, and diseases. The biochemical cascades involved in rapid S1P signaling are well understood. However, gene-expression regulation by S1PRs are less understood. In this review, we focus our attention to how S1PRs regulate nuclear chromatin changes and gene transcription to modulate vascular and lymphatic endothelial phenotypic changes during embryonic development and adult homeostasis. Because S1PR-targeted drugs approved for use in the treatment of autoimmune diseases cause substantial vascular-related adverse events, these findings are critical not only for general understanding of stimulus-evoked gene regulation in the vascular endothelium, but also for therapeutic development of drugs for autoimmune and perhaps vascular diseases.
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Affiliation(s)
- Michel V Levesque
- Vascular Biology Program, Boston Children's Hospital and Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Timothy Hla
- Vascular Biology Program, Boston Children's Hospital and Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115, USA
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22
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Raza Y, Atallah J, Luberto C. Advancements on the Multifaceted Roles of Sphingolipids in Hematological Malignancies. Int J Mol Sci 2022; 23:12745. [PMID: 36361536 PMCID: PMC9654982 DOI: 10.3390/ijms232112745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 10/07/2022] [Accepted: 10/17/2022] [Indexed: 09/19/2023] Open
Abstract
Dysregulation of sphingolipid metabolism plays a complex role in hematological malignancies, beginning with the first historical link between sphingolipids and apoptosis discovered in HL-60 leukemic cells. Numerous manuscripts have reviewed the field including the early discoveries that jumpstarted the studies. Many studies discussed here support a role for sphingolipids, such as ceramide, in combinatorial therapeutic regimens to enhance anti-leukemic effects and reduce resistance to standard therapies. Additionally, inhibitors of specific nodes of the sphingolipid pathway, such as sphingosine kinase inhibitors, significantly reduce leukemic cell survival in various types of leukemias. Acid ceramidase inhibitors have also shown promising results in acute myeloid leukemia. As the field moves rapidly, here we aim to expand the body of literature discussed in previously published reviews by focusing on advances reported in the latter part of the last decade.
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Affiliation(s)
- Yasharah Raza
- Department of Pharmacological Sciences, Molecular and Cellular Pharmacology, Stony Brook University, Stony Brook, NY 11794, USA
- Stony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USA
| | - Jane Atallah
- Stony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USA
- Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794, USA
| | - Chiara Luberto
- Stony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USA
- Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794, USA
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Yang J, Tang X, Li B, Shi J. Sphingosine 1-phosphate receptor 2 mediated early stages of pancreatic and systemic inflammatory responses via NF-kappa B activation in acute pancreatitis. Cell Commun Signal 2022; 20:157. [PMID: 36229875 PMCID: PMC9564071 DOI: 10.1186/s12964-022-00971-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 09/17/2022] [Indexed: 11/10/2022] Open
Abstract
In acute pancreatitis, activation of inflammatory signaling, including the nuclear factor-kappa B (NF-κB) pathway, within acinar cells is known to be an early intracellular event occurring in parallel with pathologic trypsinogen activation. Sphingosine 1-phosphate receptor 2 (S1PR2) plays a critical role in endothelial inflammation, and our previous studies reported that S1PR2 deficiency significantly reduced the inflammatory response in liver injury under cholestasis conditions. However, the role of S1PR2 in inflammatory signaling activation within acinar cells and inflammatory responses during acute pancreatitis has not been elucidated. Here we report that S1PR2 was upregulated in the whole pancreas during acute pancreatitis. Blockade of S1PR2 by pharmacologic inhibition of S1PR2 by JTE-013 or AAV-mediated knockdown of S1PR2 improved the severity of pancreatic injury, as indicated by a significant reduction in inflammation and acinar cells death in acute pancreatitis mice. Moreover, S1PR2 is the predominant S1PRs expressed in pancreatic acinar cells and mediates NF-κB activation and the early inflammatory response within acinar cells under acute pancreatitis conditions via ROCK signaling pathways, not extracellular signal-regulated kinase pathways or p38 mitogen-activated protein kinase pathways. In addition, S1PR2 mediated macrophage NF-κB activation, migration and polarization toward the M1 phenotype. Therefore, these results demonstrated that the S1PR2-mediated early inflammatory response in acinar cells promotes the progression of acute pancreatitis, successfully linking local events to the systematic inflammatory response and leading to a novel therapeutic target for acute pancreatitis aimed at halting the progression of the inflammatory response.
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