|
1
|
Beale HC, Tse V, Lee JY, Akutagawa J, Mavura Y, Saint-John B, Cheney A, Mulligan DR, Chacaltana G, Gutierrez M, Tenney J, Shieh JT, Martin PM, Yip T, Hodoglugil U, Fay AJ, Brooks AN, Van Ziffle J, Stone MD, Risch N, Sanford JR, Devine P, Saba JD, Vaske OM, Slavotinek A. A novel splice site variant in DEGS1 leads to aberrant splicing and loss of DEGS1 enzyme activity, a VUS resolved. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.04.04.25325118. [PMID: 40297416 PMCID: PMC12036379 DOI: 10.1101/2025.04.04.25325118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
Purpose Pathogenic DEGS1 variants have been reported in individuals with autosomal recessive hypomyelinating leukodystrophy 18 (HLD18; MIM# 618404). We sought to resolve a 5' +4/+5 splice site variant of uncertain significance found in three individuals with HLD features. Methods We used next-generation DNA and transcriptome sequencing, cell-based splicing assays, and tandem mass spectrometry to detect and characterize the splice site variant. We then performed RNA structure probing and conventional antisense oligonucleotide screening to investigate molecular mechanisms for potential therapeutic intervention. Results A homozygous, DEGS1 5' splice site variant, c.825+4_825+5delAGinsTT (NM_003676.4) was identified in all three participants. Although the gene has been associated with autosomal recessive hypomyelinating leukodystrophy, the variant has not been previously reported in any available databases or literature. We show that the splice site variant: 1) was sufficient to induce exon two skipping in most detected transcripts; 2) resulted in structural changes to the 5' and 3' splice site regions using RNA structure probing; and 3) corresponds to plasma sphingolipid profiles consistent with loss of sphingolipid delta(4)-desaturase activity. Discussion Our RNA and lipidomic evidence proved that the DEGS1 variant c.825+4_825+5delAGinsTT is pathogenic and suggested a mechanistic model to explain how exon two skipping is induced.
Collapse
Affiliation(s)
- Holly C. Beale
- Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA, 95064, USA
- Genomics Institute, University of California Santa Cruz, Santa Cruz, CA, 95060, USA
| | - Victor Tse
- Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA, 95064, USA
- Center for Molecular Biology of RNA, University of California Santa Cruz, Santa Cruz, CA, 95064, USA
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Joanna Y. Lee
- Department of Pediatrics, University of California San Francisco, San Francisco, CA, 94143, USA
- Division of Hematology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Jon Akutagawa
- Genomics Institute, University of California Santa Cruz, Santa Cruz, CA, 95060, USA
- Department of Pediatrics, University of California San Francisco, San Francisco, CA, 94143, USA
- Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA, 95064, USA
| | - Yusuph Mavura
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, 94143, USA
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, 94158, USA
| | - Brandon Saint-John
- Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA, 95064, USA
- Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA
| | - Allison Cheney
- Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA, 95064, USA
- Genomics Institute, University of California Santa Cruz, Santa Cruz, CA, 95060, USA
| | - Dennis R. Mulligan
- Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA, 95064, USA
| | - Guillermo Chacaltana
- Center for Molecular Biology of RNA, University of California Santa Cruz, Santa Cruz, CA, 95064, USA
- Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA, 95064, USA
| | - Martin Gutierrez
- Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA, 95064, USA
- Center for Molecular Biology of RNA, University of California Santa Cruz, Santa Cruz, CA, 95064, USA
| | - Jessica Tenney
- Department of Pediatrics, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Joseph T. Shieh
- Department of Pediatrics, University of California San Francisco, San Francisco, CA, 94143, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, 94143, USA
- Division of Medical Genetics, University of California San Francisco, San Francisco, CA, 94158, USA
| | - Pierre-Marie Martin
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, 94143, USA
- Genomic Medicine Laboratory, University of California San Francisco, San Francisco, CA, 94158, USA
| | - Tiffany Yip
- Department of Pediatrics, University of California San Francisco, San Francisco, CA, 94143, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Ugur Hodoglugil
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, 94143, USA
- Genomic Medicine Laboratory, University of California San Francisco, San Francisco, CA, 94158, USA
| | - Alex J. Fay
- Department of Neurology, University of California San Francisco, San Francisco, CA, 94143, USA
- Division of Child Neurology, University of California San Francisco Benioff Children’s Hospital, San Francisco, CA, 94158, USA
| | - Angela N. Brooks
- Genomics Institute, University of California Santa Cruz, Santa Cruz, CA, 95060, USA
- Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA, 95064, USA
| | - Jessica Van Ziffle
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, 94143, USA
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
- Genetics and Genomics Services, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Michael D. Stone
- Center for Molecular Biology of RNA, University of California Santa Cruz, Santa Cruz, CA, 95064, USA
- Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA, 95064, USA
| | - Neil Risch
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, 94143, USA
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, 94158, USA
| | - Jeremy R. Sanford
- Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA, 95064, USA
- Genomics Institute, University of California Santa Cruz, Santa Cruz, CA, 95060, USA
- Center for Molecular Biology of RNA, University of California Santa Cruz, Santa Cruz, CA, 95064, USA
| | - Patrick Devine
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, 94143, USA
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
- Genetics and Genomics Services, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Julie D. Saba
- Department of Pediatrics, University of California San Francisco, San Francisco, CA, 94143, USA
- Division of Hematology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Olena M. Vaske
- Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA, 95064, USA
- Genomics Institute, University of California Santa Cruz, Santa Cruz, CA, 95060, USA
| | - Anne Slavotinek
- Department of Pediatrics, University of California San Francisco, San Francisco, CA, 94143, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, 94143, USA
| |
Collapse
|
|
2
|
Kitsou K, Kokkotis G, Rivera-Nieves J, Bamias G. Targeting the Sphingosine-1-Phosphate Pathway: New Opportunities in Inflammatory Bowel Disease Management. Drugs 2024; 84:1179-1197. [PMID: 39322927 PMCID: PMC12057646 DOI: 10.1007/s40265-024-02094-5] [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] [Accepted: 09/03/2024] [Indexed: 09/27/2024]
Abstract
Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC) are chronic immune-mediated diseases which primarily target the intestines. In recent years, the development and regulatory approval of various immunotherapies, both biological agents and small molecules, that target specific pathways of the IBD-associated inflammatory cascade have revolutionized the treatment of IBD. Small molecules offer the advantages of oral administration and short wash-out times. Sphingosine-1-phosphate (S1P) is a bioactive metabolite of ceramide, which exerts its functions after binding to five G-protein-coupled receptors (S1PR1-S1PR5). Concerning IBD, S1P participates in the egress of lymphocytes from the secondary lymphoid tissue and their re-circulation to sites of inflammation, mainly through S1PR1 binding. In addition, this system facilitates the differentiation of T-helper cells towards proinflammatory immunophenotypes. Recently, S1P modulators have offered a valuable addition to the IBD treatment armamentarium. They exert their anti-inflammatory function via sequestration of T cell subsets in the lymphoid tissues and prevention of gut homing. In this review, we revisit the role of the S1P/S1PR axis in the pathogenesis of IBD and discuss efficacy and safety data from clinical trials and real-world reports on the two S1PR modulators, ozanimod and etrasimod, that are currently approved for IBD treatment, and comment on their potential positioning in the IBD day-to-day management. We also present recent data on emerging S1P modulators. Finally, based on the successes and failures of S1PR modulators in IBD, we discuss future avenues of IBD treatments targeting the S1P/S1PR axis.
Collapse
Affiliation(s)
| | - Georgios Kokkotis
- GI-Unit, 3rd Department of Internal Medicine, Sotiria Hospital, 152 Mesogeion Av., 11528, Athens, Greece
| | - Jesús Rivera-Nieves
- San Diego VA Medical Center (SDVAMC), San Diego, CA, USA
- Division of Gastroenterology, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA, USA
| | - Giorgos Bamias
- GI-Unit, 3rd Department of Internal Medicine, Sotiria Hospital, 152 Mesogeion Av., 11528, Athens, Greece.
| |
Collapse
|
|
3
|
Spathakis M, Dovrolis N, Filidou E, Kandilogiannakis L, Tarapatzi G, Valatas V, Drygiannakis I, Paspaliaris V, Arvanitidis K, Manolopoulos VG, Kolios G, Vradelis S. Exploring Microbial Metabolite Receptors in Inflammatory Bowel Disease: An In Silico Analysis of Their Potential Role in Inflammation and Fibrosis. Pharmaceuticals (Basel) 2024; 17:492. [PMID: 38675452 PMCID: PMC11054721 DOI: 10.3390/ph17040492] [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: 03/06/2024] [Revised: 04/09/2024] [Accepted: 04/10/2024] [Indexed: 04/28/2024] Open
Abstract
Metabolites produced by dysbiotic intestinal microbiota can influence disease pathophysiology by participating in ligand-receptor interactions. Our aim was to investigate the differential expression of metabolite receptor (MR) genes between inflammatory bowel disease (IBD), healthy individuals (HIs), and disease controls in order to identify possible interactions with inflammatory and fibrotic pathways in the intestine. RNA-sequencing datasets containing 643 Crohn's disease (CD) patients, 467 ulcerative colitis (UC) patients and 295 HIs, and 4 Campylobacter jejuni-infected individuals were retrieved from the Sequence Read Archive, and differential expression was performed using the RaNA-seq online platform. The identified differentially expressed MR genes were used for correlation analysis with up- and downregulated genes in IBD, as well as functional enrichment analysis using a R based pipeline. Overall, 15 MR genes exhibited dysregulated expression in IBD. In inflamed CD, the hydroxycarboxylic acid receptors 2 and 3 (HCAR2, HCAR3) were upregulated and were associated with the recruitment of innate immune cells, while, in the non-inflamed CD ileum, the cannabinoid receptor 1 (CNR1) and the sphingosine-1-phospate receptor 4 (S1PR4) were downregulated and were involved in the regulation of B-cell activation. In inflamed UC, the upregulated receptors HCAR2 and HCAR3 were more closely associated with the process of TH-17 cell differentiation, while the pregnane X receptor (NR1I2) and the transient receptor potential vanilloid 1 (TRPV1) were downregulated and were involved in epithelial barrier maintenance. Our results elucidate the landscape of metabolite receptor expression in IBD, highlighting associations with disease-related functions that could guide the development of new targeted therapies.
Collapse
Affiliation(s)
- Michail Spathakis
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (M.S.); (E.F.); (L.K.); (G.T.); (V.V.); (K.A.); (V.G.M.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | - Nikolas Dovrolis
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (M.S.); (E.F.); (L.K.); (G.T.); (V.V.); (K.A.); (V.G.M.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | - Eirini Filidou
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (M.S.); (E.F.); (L.K.); (G.T.); (V.V.); (K.A.); (V.G.M.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | - Leonidas Kandilogiannakis
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (M.S.); (E.F.); (L.K.); (G.T.); (V.V.); (K.A.); (V.G.M.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | - Gesthimani Tarapatzi
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (M.S.); (E.F.); (L.K.); (G.T.); (V.V.); (K.A.); (V.G.M.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | - Vassilis Valatas
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (M.S.); (E.F.); (L.K.); (G.T.); (V.V.); (K.A.); (V.G.M.); (G.K.)
- Gastroenterology and Hepatology Research Laboratory, Medical School, University of Crete, 71003 Heraklion, Greece;
| | - Ioannis Drygiannakis
- Gastroenterology and Hepatology Research Laboratory, Medical School, University of Crete, 71003 Heraklion, Greece;
| | | | - Konstantinos Arvanitidis
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (M.S.); (E.F.); (L.K.); (G.T.); (V.V.); (K.A.); (V.G.M.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | - Vangelis G. Manolopoulos
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (M.S.); (E.F.); (L.K.); (G.T.); (V.V.); (K.A.); (V.G.M.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | - George Kolios
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (M.S.); (E.F.); (L.K.); (G.T.); (V.V.); (K.A.); (V.G.M.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | - Stergios Vradelis
- Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, 68100 Alexandroupolis, Greece;
| |
Collapse
|
|
4
|
Sharma J, Khan S, Singh NC, Sahu S, Raj D, Prakash S, Bandyopadhyay P, Sarkar K, Bhosale V, Chandra T, Kumaravelu J, Barthwal MK, Gupta SK, Srivastava M, Guha R, Ammanathan V, Ghoshal UC, Mitra K, Lahiri A. ORMDL3 regulates NLRP3 inflammasome activation by maintaining ER-mitochondria contacts in human macrophages and dictates ulcerative colitis patient outcome. J Biol Chem 2024; 300:107120. [PMID: 38417794 PMCID: PMC11065740 DOI: 10.1016/j.jbc.2024.107120] [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: 08/27/2023] [Revised: 02/06/2024] [Accepted: 02/20/2024] [Indexed: 03/01/2024] Open
Abstract
Genome-wide association studies in inflammatory bowel disease have identified risk loci in the orosomucoid-like protein 3/ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) gene to confer susceptibility to ulcerative colitis (UC), but the underlying functional relevance remains unexplored. Here, we found that a subpopulation of the UC patients who had higher disease activity shows enhanced expression of ORMDL3 compared to the patients with lower disease activity and the non-UC controls. We also found that the patients showing high ORMDL3 mRNA expression have elevated interleukin-1β cytokine levels indicating positive correlation. Further, knockdown of ORMDL3 in the human monocyte-derived macrophages resulted in significantly reduced interleukin-1β release. Mechanistically, we report for the first time that ORMDL3 contributes to a mounting inflammatory response via modulating mitochondrial morphology and activation of the NLRP3 inflammasome. Specifically, we observed an increased fragmentation of mitochondria and enhanced contacts with the endoplasmic reticulum (ER) during ORMDL3 over-expression, enabling efficient NLRP3 inflammasome activation. We show that ORMDL3 that was previously known to be localized in the ER also becomes localized to mitochondria-associated membranes and mitochondria during inflammatory conditions. Additionally, ORMDL3 interacts with mitochondrial dynamic regulating protein Fis-1 present in the mitochondria-associated membrane. Accordingly, knockdown of ORMDL3 in a dextran sodium sulfate -induced colitis mouse model showed reduced colitis severity. Taken together, we have uncovered a functional role for ORMDL3 in mounting inflammation during UC pathogenesis by modulating ER-mitochondrial contact and dynamics.
Collapse
Affiliation(s)
- Jyotsna Sharma
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Shaziya Khan
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Nishakumari C Singh
- Sophisticated Analytical Instrument Facility and Research Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Shikha Sahu
- Department of Gastroenterology, Sanjay Gandhi postgraduate institute of medical sciences, Lucknow, India
| | - Desh Raj
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Shakti Prakash
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | | | - Kabita Sarkar
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Vivek Bhosale
- Toxicology and Experimental Medicine Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Tulika Chandra
- Department of Transfusion Medicine, Kings George Medical University, Lucknow, India
| | - Jagavelu Kumaravelu
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Manoj Kumar Barthwal
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Shashi Kumar Gupta
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Mrigank Srivastava
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India; Molecular Parasitology and Immunology Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Rajdeep Guha
- Lab Animal Facility, CSIR-Central Drug Research Institute, Lucknow, India
| | - Veena Ammanathan
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Uday C Ghoshal
- Department of Gastroenterology, Sanjay Gandhi postgraduate institute of medical sciences, Lucknow, India
| | - Kalyan Mitra
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India; Sophisticated Analytical Instrument Facility and Research Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Amit Lahiri
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
| |
Collapse
|
|
5
|
Wang S, Li L, Chen Y, Liu Q, Zhou S, Li N, Wu Y, Yuan J. Houttuynia cordata thunb. alleviates inflammatory bowel disease by modulating intestinal microenvironment: a research review. Front Immunol 2023; 14:1306375. [PMID: 38077358 PMCID: PMC10702737 DOI: 10.3389/fimmu.2023.1306375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 11/06/2023] [Indexed: 12/18/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a complex group of chronic intestinal diseases, the cause of which has not yet been clarified, but it is widely believed that the disorder of the intestinal microenvironment and its related functional changes are key factors in the development of the disease. Houttuynia cordata thunb. is a traditional plant with abundant resources and long history of utilization in China, which has attracted widespread attention in recent years due to its potential in the treatment of IBD. However, its development and utilization are limited owing to the aristolochic acid alkaloids contained in it. Therefore, based on the relationship between the intestinal microenvironment and IBD, this article summarizes the potential mechanisms by which the main active ingredients of Houttuynia cordata thunb., such as volatile oils, polysaccharides, and flavonoids, and related traditional Chinese medicine preparations, such as Xiezhuo Jiedu Formula, alleviate IBD by regulating the intestinal microenvironment. At the same time, combined with current reports, the medicinal and edible safety of Houttuynia cordata thunb. is explained for providing ideas for further research and development of Houttuynia chordate thunb. in IBD disease, more treatment options for IBD patients, and more insights into the therapeutic potential of plants with homology of medicine and food in intestinal diseases, and even more diseases.
Collapse
Affiliation(s)
- Si Wang
- First Clinical School of Medicine, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
| | - Lei Li
- College of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
| | - Yuhan Chen
- College of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
| | - Qian Liu
- College of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
| | - Shengyu Zhou
- College of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
| | - Ning Li
- First Clinical School of Medicine, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
| | - Yueying Wu
- College of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
- Yunnan Provincial Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
| | - Jiali Yuan
- College of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
- Yunnan Provincial Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
| |
Collapse
|
|
6
|
Fohmann I, Weinmann A, Schumacher F, Peters S, Prell A, Weigel C, Spiegel S, Kleuser B, Schubert-Unkmeir A. Sphingosine kinase 1/S1P receptor signaling axis is essential for cellular uptake of Neisseria meningitidis in brain endothelial cells. PLoS Pathog 2023; 19:e1011842. [PMID: 38033162 PMCID: PMC10715668 DOI: 10.1371/journal.ppat.1011842] [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] [Received: 07/29/2023] [Revised: 12/12/2023] [Accepted: 11/18/2023] [Indexed: 12/02/2023] Open
Abstract
Invasion of brain endothelial cells (BECs) is central to the pathogenicity of Neisseria meningitidis infection. Here, we established a key role for the bioactive sphingolipid sphingosine-1-phosphate (S1P) and S1P receptor (S1PR) 2 in the uptake process. Quantitative sphingolipidome analyses of BECs infected with N. meningitidis revealed elevated S1P levels, which could be attributed to enhanced expression of the enzyme sphingosine kinase 1 and its activity. Increased activity was dependent on the interaction of meningococcal type IV pilus with the endothelial receptor CD147. Concurrently, infection led to increased expression of the S1PR2. Blocking S1PR2 signaling impaired epidermal growth factor receptor (EGFR) phosphorylation, which has been shown to be involved in cytoskeletal remodeling and bacterial endocytosis. Strikingly, targeting S1PR1 or S1PR3 also interfered with bacterial uptake. Collectively, our data support a critical role of the SphK/S1P/S1PR axis in the invasion of N. meningitidis into BECs, defining a potential target for adjuvant therapy.
Collapse
Affiliation(s)
- Ingo Fohmann
- Institute for Hygiene and Microbiology, University of Würzburg, Würzburg, Germany
| | - Alina Weinmann
- Institute for Hygiene and Microbiology, University of Würzburg, Würzburg, Germany
| | - Fabian Schumacher
- Institute of Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, Berlin, Germany
| | - Simon Peters
- Institute for Hygiene and Microbiology, University of Würzburg, Würzburg, Germany
| | - Agata Prell
- Institute of Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, Berlin, Germany
| | - Cynthia Weigel
- Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America
| | - Sarah Spiegel
- Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America
| | - Burkhard Kleuser
- Institute of Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, Berlin, Germany
| | | |
Collapse
|
|
7
|
Pirttiniemi A, Adeshara K, Happonen N, Einarsdottir E, Katayama S, Salmenkari H, Hörkkö S, Kere J, Groop PH, Lehto M. Long-chain polyphosphates inhibit type I interferon signaling and augment LPS-induced cytokine secretion in human leukocytes. J Leukoc Biol 2023; 114:250-265. [PMID: 37224571 DOI: 10.1093/jleuko/qiad058] [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: 06/23/2022] [Revised: 04/20/2023] [Accepted: 05/12/2023] [Indexed: 05/26/2023] Open
Abstract
Inorganic polyphosphates are evolutionarily conserved bioactive phosphate polymers found as various chain lengths in all living organisms. In mammals, polyphosphates play a vital role in the regulation of cellular metabolism, coagulation, and inflammation. Long-chain polyphosphates are found along with endotoxins in pathogenic gram-negative bacteria and can participate in bacterial virulence. We aimed to investigate whether exogenously administered polyphosphates modulate human leukocyte function in vitro by treating the cells with 3 different chain lengths of polyphosphates (P14, P100, and P700). The long-chain polyphosphates, P700, had a remarkable capacity to downregulate type I interferon signaling dose dependently in THP1-Dual cells while only a slight elevation could be observed in the NF-κB pathway with the highest dose of P700. P700 treatment decreased lipopolysaccharide-induced IFNβ transcription and secretion, reduced STAT1 phosphorylation, and downregulated subsequent interferon-stimulated gene expression in primary human peripheral blood mononuclear cells. P700 also augmented lipopolysaccharide-induced secretion of IL-1α, IL-1β, IL-4, IL-5, IL-10, and IFNγ. Furthermore, P700 has previously been reported to increase the phosphorylation of several intracellular signaling mediators, such as AKT, mTOR, ERK, p38, GSK3α/β, HSP27, and JNK pathway components, which was supported by our findings. Taken together, these observations demonstrate the extensive modulatory effects P700 has on cytokine signaling and the inhibitory effects specifically targeted to type I interferon signaling in human leukocytes.
Collapse
Affiliation(s)
- Anniina Pirttiniemi
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum, Haartmaninkatu 8, 00290 Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 4, 00290 Helsinki, Finland
- Clinical and Molecular Metabolism, Faculty of Medicine Research Programs, University of Helsinki, Biomedicum, Haartmaninkatu 8, 00290 Helsinki, Finland
| | - Krishna Adeshara
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum, Haartmaninkatu 8, 00290 Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 4, 00290 Helsinki, Finland
- Clinical and Molecular Metabolism, Faculty of Medicine Research Programs, University of Helsinki, Biomedicum, Haartmaninkatu 8, 00290 Helsinki, Finland
| | - Natalie Happonen
- Medical Microbiology and Immunology, Research Unit of Biomedicine, University of Oulu, Aapistie 5A, 90220 Oulu, Finland
- Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Aapistie 5A, 90220 Oulu, Finland
- Nordlab, Oulu University Hospital, Kajaanintie 50, 90220 Oulu, Finland
| | - Elisabet Einarsdottir
- Science for Life Laboratory, Department of Gene Technology, KTH-Royal Institute of Technology, Tomtebodavägen 23A, 17165 Solna, Sweden
| | - Shintaro Katayama
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum, Haartmaninkatu 8, 00290 Helsinki, Finland
- Stem Cells and Metabolism Research Program, University of Helsinki, Biomedicum, Haartmaninkatu 8, 00290 Helsinki, Finland
- Department of Biosciences and Nutrition, Karolinska Institutet, Neo, Blickagången 16, Flemingsberg, SE-14183 Huddinge, Sweden
| | - Hanne Salmenkari
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum, Haartmaninkatu 8, 00290 Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 4, 00290 Helsinki, Finland
- Clinical and Molecular Metabolism, Faculty of Medicine Research Programs, University of Helsinki, Biomedicum, Haartmaninkatu 8, 00290 Helsinki, Finland
| | - Sohvi Hörkkö
- Medical Microbiology and Immunology, Research Unit of Biomedicine, University of Oulu, Aapistie 5A, 90220 Oulu, Finland
- Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Aapistie 5A, 90220 Oulu, Finland
| | - Juha Kere
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum, Haartmaninkatu 8, 00290 Helsinki, Finland
- Stem Cells and Metabolism Research Program, University of Helsinki, Biomedicum, Haartmaninkatu 8, 00290 Helsinki, Finland
- Department of Biosciences and Nutrition, Karolinska Institutet, Neo, Blickagången 16, Flemingsberg, SE-14183 Huddinge, Sweden
| | - Per-Henrik Groop
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum, Haartmaninkatu 8, 00290 Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 4, 00290 Helsinki, Finland
- Clinical and Molecular Metabolism, Faculty of Medicine Research Programs, University of Helsinki, Biomedicum, Haartmaninkatu 8, 00290 Helsinki, Finland
- Department of Diabetes, Central Clinical School, Monash University, Alfred Centre, 99 Commercial Road, Melbourne 3004, VIC, Australia
| | - Markku Lehto
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum, Haartmaninkatu 8, 00290 Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 4, 00290 Helsinki, Finland
- Clinical and Molecular Metabolism, Faculty of Medicine Research Programs, University of Helsinki, Biomedicum, Haartmaninkatu 8, 00290 Helsinki, Finland
| |
Collapse
|
|
8
|
Xu Z, Zhang Q, Ding C, Wen F, Sun F, Liu Y, Tao C, Yao J. Beneficial Effects of Hordenine on a Model of Ulcerative Colitis. Molecules 2023; 28:molecules28062834. [PMID: 36985809 PMCID: PMC10054341 DOI: 10.3390/molecules28062834] [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: 01/03/2023] [Revised: 03/09/2023] [Accepted: 03/13/2023] [Indexed: 03/30/2023] Open
Abstract
Hordenine, a phenethylamine alkaloid, is found in a variety of plants and exhibits a broad array of biological activities and pharmacological properties, including anti-inflammatory and anti-fibrotic effects. However, the efficacy and underlying mechanisms of hordenine in treating ulcerative colitis (UC) remain unclear. To address this, we examined the therapeutic effects of hordenine on dextran sodium sulphate (DSS)-induced UC by comparing disease activity index (DAI), colon length, secretion of inflammatory factors, and degree of colonic histological lesions across diseased mice that were and were not treated with hordenine. We found that hordenine significantly reduced DAI and levels of pro-inflammatory factors, including interleukin (IL)-6, IL-1β, and tumor necrosis factor alpha (TNF-α), and also alleviated colon tissue oedema, colonic lesions, inflammatory cells infiltration and decreased the number of goblet cells. Moreover, in vitro experiments showed that hordenine protected intestinal epithelial barrier function by increasing the expression of tight junction proteins including ZO-1 and occludin, while also promoting the healing of intestinal mucosa. Using immunohistochemistry and western blotting, we demonstrated that hordenine reduced the expression of sphingosine kinase 1 (SPHK1), sphingosine-1-phosphate receptor 1 (S1PR1), and ras-related C3 botulinum toxin substrate 1 (Rac1), and it inhibited the expression of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in colon tissues. Thus, hordenine appears to be effective in UC treatment owing to pharmacological mechanisms that favor mucosal healing and the inhibition of SPHK-1/S1PR1/STAT3 signaling.
Collapse
Affiliation(s)
- Zhengguang Xu
- School of Basic Medicine, Jining Medical University, Jining 272067, China
| | - Qilian Zhang
- School of Basic Medicine, Jining Medical University, Jining 272067, China
- School of Basic Medicine, Weifang Medical University, Weifang 261000, China
| | - Ce Ding
- School of Basic Medicine, Jining Medical University, Jining 272067, China
| | - Feifei Wen
- School of Basic Medicine, Jining Medical University, Jining 272067, China
| | - Fang Sun
- School of Basic Medicine, Jining Medical University, Jining 272067, China
- Jining Key Laboratory of Pharmacology, Jining Medical University, Jining 272067, China
| | - Yanzhan Liu
- School of Basic Medicine, Jining Medical University, Jining 272067, China
| | - Chunxue Tao
- School of Basic Medicine, Jining Medical University, Jining 272067, China
| | - Jing Yao
- School of Basic Medicine, Jining Medical University, Jining 272067, China
- Jining Key Laboratory of Pharmacology, Jining Medical University, Jining 272067, China
| |
Collapse
|
|
9
|
Zhang P, Zhang Q, Shao Z. Silence of S1PR4 Represses the Activation of Fibroblast-like Synoviocytes by Regulating IL-17/STAT3 Signaling Pathway. Inflammation 2023; 46:234-243. [PMID: 36068391 DOI: 10.1007/s10753-022-01728-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 08/04/2022] [Accepted: 08/04/2022] [Indexed: 11/26/2022]
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease with persistent inflammation and progressive joint damage. However, the underlying pathological mechanisms of RA are still unclear. Fibroblast‑like synoviocytes (FLSs) play an important role in the pathogenesis of RA by the regulation of proliferation and apoptosis, and the release of multiple pro-inflammatory factors. The lipid mediator sphingosine-1-phosphate receptor 4 (S1PR4) is one of the sphingolipid sphingosine-1-phosphate (S1P) receptors, which affects the function of immune cells. However, the role of S1PR4 in the activation of FLSs and the development of RA is unknown. In this study, we found that the expression of S1PR4 was significantly increased in RA-FLSs. The silence of S1PR4 decreases the proliferation, migration, proinflammation, and promotes the apoptosis of RA-FLSs, accompanied with repressing interleukin-17 (IL-17)/signal transducer and activator of transcription 3 (STAT3) signal pathway. However, the regulatory effects of S1PR4 silencing on RA-FLSs were partly abolished by additional recombinant human (rh) IL-17A treatment. Therefore, our study demonstrated that S1PR4 silencing might inhibit proliferation, migration, proinflammation, and promote apoptosis of RA-FLSs partly by repressing IL-17, which suggests that inhibitors for S1PR4 might be a potentially promising strategy for the treatment of RA.
Collapse
Affiliation(s)
- Pengyu Zhang
- Department of Nephropathy and Rheumatism, Tongde Hospital of Zhejiang Province, Hangzhou, 310007, Zhejiang, China
| | - Qiang Zhang
- Department of Rheumatology and Immunology, The 962Nd Hospital of The PLA Joint Logistic Support Force, Harbin, Heilongjiang, 150080, China
| | - Zhenxia Shao
- Department of Gynaecology, Shaoxing Second Hospital, No. 123 Yan'an Road, Shaoxing, 312000, Zhejiang, China.
| |
Collapse
|
|
10
|
Tourkochristou E, Mouzaki A, Triantos C. Unveiling the biological role of sphingosine-1-phosphate receptor modulators in inflammatory bowel diseases. World J Gastroenterol 2023; 29:110-125. [PMID: 36683721 PMCID: PMC9850947 DOI: 10.3748/wjg.v29.i1.110] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/16/2022] [Accepted: 12/14/2022] [Indexed: 01/04/2023] Open
Abstract
Inflammatory bowel disease (IBD) is chronic inflammation of the gastrointestinal tract that has a high epidemiological prevalence worldwide. The increasing disease burden worldwide, lack of response to current biologic therapeutics, and treatment-related immunogenicity have led to major concerns regarding the clinical management of IBD patients and treatment efficacy. Understanding disease pathogenesis and disease-related molecular mechanisms is the most important goal in developing new and effective therapeutics. Sphingosine-1-phosphate (S1P) receptor (S1PR) modulators form a class of oral small molecule drugs currently in clinical development for IBD have shown promising effects on disease improvement. S1P is a sphingosine-derived phospholipid that acts by binding to its receptor S1PR and is involved in the regulation of several biological processes including cell survival, differentiation, migration, proliferation, immune response, and lymphocyte trafficking. T lymphocytes play an important role in regulating inflammatory responses. In inflamed IBD tissue, an imbalance between T helper (Th) and regulatory T lymphocytes and Th cytokine levels was found. The S1P/S1PR signaling axis and metabolism have been linked to inflammatory responses in IBD. S1P modulators targeting S1PRs and S1P metabolism have been developed and shown to regulate inflammatory responses by affecting lymphocyte trafficking, lymphocyte number, lymphocyte activity, cytokine production, and contributing to gut barrier function.
Collapse
Affiliation(s)
- Evanthia Tourkochristou
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| |
Collapse
|
|
11
|
Deng Y, Chen H, Huang Y, Zhang Y, Ren H, Fang M, Wang Q, Chen W, Hale RC, Galloway TS, Chen D. Long-Term Exposure to Environmentally Relevant Doses of Large Polystyrene Microplastics Disturbs Lipid Homeostasis via Bowel Function Interference. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2022; 56:15805-15817. [PMID: 36282942 DOI: 10.1021/acs.est.1c07933] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
The question of whether long-term chronic exposure to microplastics (MPs) could induce dose- and size-dependent adverse effects in mammals remains controversial and poorly understood. Our study explored potential health risks from dietary exposure to environmentally relevant doses of polystyrene (PS) MPs, through a mouse model and integrated analyses of the interruptions of fecal microbial metagenomes and plasma lipidomes. After 21 weeks of exposure to the MPs (40-100 μm), mice mainly exhibited gut microbiota dysbiosis, tissue inflammation, and plasma lipid metabolism disorder, although no notable accumulation of MPs was observed in the gut or liver. The change of the relative abundance of microbiota was strongly associated with the exposure dose and size of MPs while less significant effects were observed in gut damage and abnormal lipid metabolism. Moreover, multiomics data suggested that the host abnormal lipid metabolism was closely related to bowel function disruptions, including gut microbiota dysbiosis, increased gut permeability, and inflammation induced by MPs. We revealed for the first time that even without notable accumulation in mouse tissues, long-term exposure to MPs at environmentally relevant doses could still induce widespread health risks. This raises concern on the health risks from the exposure of humans and other mammals to environmentally relevant dose MPs.
Collapse
Affiliation(s)
- Yongfeng Deng
- School of Environment and Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou 510632, China
| | - Hexia Chen
- School of Environment and Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou 510632, China
| | - Yichao Huang
- School of Environment and Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou 510632, China
| | - Yan Zhang
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, Jiangsu 210023, China
| | - Hongqiang Ren
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, Jiangsu 210023, China
| | - Mingliang Fang
- School of Civil and Environmental Engineering, Nanyang Technological University, 50 Nanyang Avenue, 639798, Singapore
| | - Qing Wang
- Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Wen Chen
- Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Robert C Hale
- Virginia Institute of Marine Science, William & Mary, P.O. Box 1346, Gloucester Point, Virginia 23062, United States
| | - Tamara S Galloway
- Biosciences, College of Life and Environmental Sciences, Geoffrey Pope Building, University of Exeter, Stocker Road, Exeter, Devon EX4 4QD, United Kingdom
| | - Da Chen
- School of Environment and Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou 510632, China
| |
Collapse
|
|
12
|
Miao RR, Zhan S, Cui SX, Qu XJ. Intestinal aberrant sphingolipid metabolism shaped-gut microbiome and bile acids metabolome in the development of hepatic steatosis. FASEB J 2022; 36:e22398. [PMID: 35792869 DOI: 10.1096/fj.202200148rr] [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: 02/09/2022] [Revised: 05/17/2022] [Accepted: 05/24/2022] [Indexed: 11/11/2022]
Abstract
Conjugated bile acids (CBAs) play major roles in hepatic gene regulation via nuclear S1P-inhibited histone deacetylase (HDACs). Gut microbiota modifies bile acid pool to generate CBAs and then CBAs returned to liver to regulate hepatic genes, fatty liver, and non-alcoholic fatty liver disease (NAFLD). However, it is not yet known how the gut microbiota was modified under the environment of inflammatory bowel disease (IBD). Here, we revealed that aberrant intestinal sphingosine kinases (SphKs), a major risk factor of IBD, modified gut microbiota by increasing the proportions of Firmicutes and Verrucomicrobia, which were associated with the increase in CBAs. When exposed to a high-fat diet (HFD), sphingosine kinases 2 knockout (SphK2KO) mice developed more severity of intestinal inflammation and hepatic steatosis than their wild-type (WT) littermates. Due to knockdown of nuclear SphK2, Sphk2KO mice exhibited an increase in sphingosine kinases 1 (SphK1) and sphingosine-1-phosphate (S1P) in intestinal epithelial cells. Therefore, the microbiota was modified in the environment of the SphK1/S1P-induced IBD. 16S rDNA amplicon sequencing of cecal contents indicated an increase of Firmicutes and Verrucomicrobia. Ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) measured an increase in CBAs, including taurocholic acid (TCA), taurodeoxycholic acid (TDCA), and glycocholic acid (GCA), in cecal contents and liver tissues of Sphk2KO mice. These CBAs accumulated in the liver promoted hepatic steatosis through downregulating the acetylation of H3K9, H3K14, H3K18 and H3K27 due to the CBAs-S1PR2-nuclear SphK2-S1P signaling pathway was blocked in HFD-SphK2KO mice. In summary, intestinal aberrant sphingolipid metabolism developed hepatic steatosis through the increase in CBAs associated with an increase in Firmicutes and Verrucomicrobia.
Collapse
Affiliation(s)
- Rong-Rong Miao
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Sheng Zhan
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Shu-Xiang Cui
- Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, China
| | - Xian-Jun Qu
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| |
Collapse
|
|
13
|
Chen T, Gu K, Lin R, Liu Y, Shan Y. The function of Sphingosine-1-phosphate receptor 2 (S1PR2) in maintaining intestinal barrier and inducing ulcerative colitis. Bioengineered 2022; 13:13703-13717. [PMID: 35707833 PMCID: PMC9276026 DOI: 10.1080/21655979.2022.2076500] [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] [Indexed: 11/05/2022] Open
Abstract
Sphingosine-1-phosphate receptor 2 (S1PR2) was highly expressed in intestinal epithelial cells (IECs) and facilitated the proliferation of IECs. However, the specific function of S1PR2 in intestinal diseases, such as ulcerative colitis (UC), remains unclear. Accordingly, the current study set out to investigate the function of S1PR2 in maintaining intestinal barrier and inducing UC. S1PR2-overexpressed and knockdown Caco-2 cells were established to explore the function of S1PR2 on the permeability of IECs barrier. The UC-like mouse model in which UC is induced by dextran sulfate sodium (DSS) was established and utilized to investigate the role for S1PR2. The results showed that S1PR2 functioned as a maintainer of IECs permeability and a pathogenic factor for UC. A series of in vitro and in vivo experiments were conducted, and it was found that S1PR2 played an important role in intestinal epithelial cell proliferation and maintenance of intestinal epithelial cell barrier, possibly by the regulation on the expression level of SphK2, HDAC1, HDAC2, and ERK1/2 signaling pathway. The expression of S1PR2 was upregulated in UC mice and the colonic pathological damage in UC mice could be alleviated by the inhibition of S1PR2. Collectively, these results suggest that S1PR2 functions as a maintainer of IECs permeability and a pathogenic factor for UC. The research suggests S1PR2 may be an effective target for developing therapeutic strategies against UC. Abbreviations: S1PR2, Sphingosine-1-phosphate receptor 2; UC, ulcerative colitis; IECs, intestinal epithelial cells; DSS, dextran sulfate sodium; IBD, inflammation bowel disease; CD, Crohn’s disease; S1P, sphingosin-1-phosphate; SphK, sphingosine kinase; HIECs, human IECs; siRNA, small interfering RNA; CCK-8, cell counting kit-8; TEER, transepithelial electrical resistance; TEM, transmission electron microscope; RT-PCR, real-time reverse transcriptase polymerase-chain reaction; ELISA, enzyme-linked immunosorbent assay; HE, hematoxylin and eosin.
Collapse
Affiliation(s)
- Tanzhou Chen
- The Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Kaier Gu
- The Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Ruoyang Lin
- The Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Yang Liu
- The Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Yunfeng Shan
- Surgery, The First Affiliated Hospital of Wenzhou Medical UniversityThe Department of Hepato-Pancreato-Biliary, Wenzhou, People's Republic of China
| |
Collapse
|
|
14
|
Zheng L, Wen XL, Duan SL. Role of metabolites derived from gut microbiota in inflammatory bowel disease. World J Clin Cases 2022; 10:2660-2677. [PMID: 35434116 PMCID: PMC8968818 DOI: 10.12998/wjcc.v10.i9.2660] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 12/12/2021] [Accepted: 02/27/2022] [Indexed: 02/06/2023] Open
Abstract
Over the past two decades, it is improved gut microbiota plays an important role in the health and disease pathogenesis. Metabolites, small molecules produced as intermediate or end products of microbial metabolism, is considered as one of the major interaction way for gut microbiota with the host. Bacterial metabolisms of dietary substrates, modification of host molecules or bacteria are the major source of metabolites. Signals from microbial metabolites affect immune maturation and homeostasis, host energy metabolism as well as mucosal integrity maintenance. Based on many researches, the composition and function of the microbiota can be changed, which is also seen in the metabolite profiles of patients with inflammatory bowel disease (IBD). Additionally, some specific classes of metabolites also can trigger IBD. In this paper, definition of the key classes of microbial-derived metabolites which are changed in IBD, description of the pathophysiological basis of association and identification of the precision therapeutic modulation in the future are the major contents.
Collapse
Affiliation(s)
- Lie Zheng
- Department of Gastroenterology, Shaanxi Hospital of Traditional Chinese Medicine, Xi’an 710003, Shaanxi Province, China
| | - Xin-Li Wen
- Department of Gastroenterology, Shaanxi Hospital of Traditional Chinese Medicine, Xi’an 710003, Shaanxi Province, China
| | - Sheng-Lei Duan
- Department of Gastroenterology, Shaanxi Hospital of Traditional Chinese Medicine, Xi’an 710003, Shaanxi Province, China
| |
Collapse
|
|
15
|
Zheng L, Wen XL, Duan SL. Role of metabolites derived from gut microbiota in inflammatory bowel disease. World J Clin Cases 2022; 10:2658-2675. [DOI: 10.12998/wjcc.v10.i9.2658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Over the past two decades, it is improved gut microbiota plays an important role in the health and disease pathogenesis. Metabolites, small molecules produced as intermediate or end products of microbial metabolism, is considered as one of the major interaction way for gut microbiota with the host. Bacterial metabolisms of dietary substrates, modification of host molecules or bacteria are the major source of metabolites. Signals from microbial metabolites affect immune maturation and homeostasis, host energy metabolism as well as mucosal integrity maintenance. Based on many researches, the composition and function of the microbiota can be changed, which is also seen in the metabolite profiles of patients with inflammatory bowel disease (IBD). Additionally, some specific classes of metabolites also can trigger IBD. In this paper, definition of the key classes of microbial-derived metabolites which are changed in IBD, description of the pathophysiological basis of association and identification of the precision therapeutic modulation in the future are the major contents.
Collapse
Affiliation(s)
- Lie Zheng
- Department of Gastroenterology, Shaanxi Hospital of Traditional Chinese Medicine, Xi’an 710003, Shaanxi Province, China
| | - Xin-Li Wen
- Department of Gastroenterology, Shaanxi Hospital of Traditional Chinese Medicine, Xi’an 710003, Shaanxi Province, China
| | - Sheng-Lei Duan
- Department of Gastroenterology, Shaanxi Hospital of Traditional Chinese Medicine, Xi’an 710003, Shaanxi Province, China
| |
Collapse
|
|
16
|
Liu J, Zhao W, Li C, Wu T, Han L, Hu Z, Li X, Zhou J, Chen X. Terazosin Stimulates Pgk1 to Remedy Gastrointestinal Disorders. Int J Mol Sci 2021; 23:416. [PMID: 35008842 PMCID: PMC8745693 DOI: 10.3390/ijms23010416] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 12/28/2021] [Accepted: 12/28/2021] [Indexed: 12/19/2022] Open
Abstract
Gastrointestinal disease is the most common health concern that occurs due to environmental, infectious, immunological, psychological, and genetic stress. Among them, the most frequent diseases are gastric ulcer (GU) and ulcerative colitis (UC). DSS-induced UC and ethanol-stimulated GU models resemble the pathophysiology of human gastrointestinal disease. The current study was designed to explore the anti-oxidation, anti-inflammation, anti-cell death properties of terazosin, an α-adrenergic receptor antagonist, in vivo and in vitro. Our results indicate that terazosin dramatically activates Pgk1, and upregulates glycose metabolism, evidenced by the enhanced ATP production and higher LDH enzymatic activity. Also, terazosin significantly enhances p-AKT expression and inhibits NF-κB p65 activation through abrogating the phosphorylation of IKBα, as well as lowers Caspase-1 and GSDMD expression. The findings in this study demonstrate that terazosin exhibits anti-inflammatory effects by downregulating NF-κB-GSDMD signal pathway, along with enhancing glycolysis for gastrointestinal disease treatment. Meanwhile, we also find terazosin ameliorates ethanol-induced gastric mucosal damage in mice. Collectively, as a clinical drug, terazosin should be translated into therapeutics for gastrointestinal disease soon.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | - Xinping Chen
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China; (J.L.); (W.Z.); (C.L.); (T.W.); (L.H.); (Z.H.); (X.L.); (J.Z.)
| |
Collapse
|
|
17
|
Lizhong Decoction () Ameliorates Ulcerative Colitis in Mice via Regulation of Plasma and Urine Metabolic Profiling. Chin J Integr Med 2021; 28:1015-1022. [PMID: 34586559 DOI: 10.1007/s11655-021-3299-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/04/2020] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To elucidate the mechanism of Lizhong Decoction (LZD, ) in treating dextran sodium sulfate (DSS)-induced colitis in mice based on metabonomics. METHODS Thirty-six mice were randomly divided into 6 groups, including normal, model, low- (1.365 g/kg), medium- (4.095 g/kg) and high dose (12.285 g/kg) LZD and salazosulfadimidine (SASP) groups, 6 mice in each group. Colitis model mice were induced by DSS admistration for 7 days, and treated with low, medium and high dose LZD extract and positive drug SASP. Metabolic comparison of DSS-induced colitis and normal mice was investigated by using ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass (UPLC-Q-TOF/MS) combined with Metabolynx™ software. RESULTS The metabolic profiles of plasma and urine in colitis mice were distinctly ameliorated after LZD treatment (P<0.05). Potential biomarkers (9 in serum and 4 in urine) were screened and tentatively identified. The endogenous metabolites were mainly involved in primary bile acid, sphingolipid, linoleic acid, arachidonic acid, amino acids (alanine, aspartate, and glutamate), butanoate and glycerophospholipid metabolism in plasma, and terpenoid backbone biosynthesis, glycerophospholipid and tryptophan metabolism in urine. After LZD treatment, these markers notably restored to normal levels. CONCLUSIONS The study revealed the underlying mechanism of LZD on amelioration of ulcerative colitis based on metabonomics, which laid a foundation for further exploring the pathological and physiological mechanism, early diagnosis, and corresponding drug development of colitis.
Collapse
|
|
18
|
Zhao P, Tassew GB, Lee JY, Oskouian B, Muñoz DP, Hodgin JB, Watson GL, Tang F, Wang JY, Luo J, Yang Y, King S, Krauss RM, Keller N, Saba JD. Efficacy of AAV9-mediated SGPL1 gene transfer in a mouse model of S1P lyase insufficiency syndrome. JCI Insight 2021; 6:145936. [PMID: 33755599 PMCID: PMC8119223 DOI: 10.1172/jci.insight.145936] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 03/17/2021] [Indexed: 12/26/2022] Open
Abstract
Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a rare metabolic disorder caused by inactivating mutations in sphingosine-1-phosphate lyase 1 (SGPL1), which is required for the final step of sphingolipid metabolism. SPLIS features include steroid-resistant nephrotic syndrome and impairment of neurological, endocrine, and hematopoietic systems. Many affected individuals die within the first 2 years. No targeted therapy for SPLIS is available. We hypothesized that SGPL1 gene replacement would address the root cause of SPLIS, thereby serving as a universal treatment for the condition. As proof of concept, we evaluated the efficacy of adeno-associated virus 9–mediated transfer of human SGPL1 (AAV-SPL) given to newborn Sgpl1-KO mice that model SPLIS and die in the first weeks of life. Treatment dramatically prolonged survival and prevented nephrosis, neurodevelopmental delay, anemia, and hypercholesterolemia. STAT3 pathway activation and elevated proinflammatory and profibrogenic cytokines observed in KO kidneys were attenuated by treatment. Plasma and tissue sphingolipids were reduced in treated compared with untreated KO pups. SGPL1 expression and activity were measurable for at least 40 weeks. In summary, early AAV-SPL treatment prevents nephrosis, lipidosis, and neurological impairment in a mouse model of SPLIS. Our results suggest that SGPL1 gene replacement holds promise as a durable and universal targeted treatment for SPLIS.
Collapse
Affiliation(s)
- Piming Zhao
- Department of Pediatrics, UCSF, San Francisco, California, USA.,Cure Genetics, Suzhou, China
| | | | - Joanna Y Lee
- Department of Pediatrics, UCSF, San Francisco, California, USA
| | - Babak Oskouian
- Department of Pediatrics, UCSF, San Francisco, California, USA
| | - Denise P Muñoz
- Department of Pediatrics, UCSF, San Francisco, California, USA
| | - Jeffrey B Hodgin
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Gordon L Watson
- Department of Pediatrics, UCSF, San Francisco, California, USA
| | - Felicia Tang
- Department of Pediatrics, UCSF, San Francisco, California, USA
| | - Jen-Yeu Wang
- Department of Pediatrics, UCSF, San Francisco, California, USA
| | - Jinghui Luo
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Yingbao Yang
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Sarah King
- Department of Pediatrics, UCSF, San Francisco, California, USA
| | - Ronald M Krauss
- Department of Pediatrics, UCSF, San Francisco, California, USA
| | - Nancy Keller
- Department of Pediatrics, UCSF, San Francisco, California, USA
| | - Julie D Saba
- Department of Pediatrics, UCSF, San Francisco, California, USA
| |
Collapse
|
|
19
|
Wang H, Wang Z, Liu Z, Wang K, Xu W. Membrane disruption of Fusarium oxysporum f. sp. niveum induced by myriocin from Bacillus amyloliquefaciens LZN01. Microb Biotechnol 2021; 14:517-534. [PMID: 32954686 PMCID: PMC7936314 DOI: 10.1111/1751-7915.13659] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 08/10/2020] [Accepted: 08/14/2020] [Indexed: 12/28/2022] Open
Abstract
Myriocin, which is produced by Bacillus amyloliquefaciens LZN01, can inhibit the growth of Fusarium oxysporum f. sp. niveum (Fon). In the present study, the antifungal mechanism of myriocin against Fon was investigated with a focus on the effects of myriocin on the cell membrane. Myriocin decreased the membrane fluidity and destroyed the membrane integrity of Fon. Significant microscopic morphological changes, including conidial shrinkage, the appearance of larger vacuoles and inhomogeneity of electron density, were observed in myriocin-treated cells. A membrane-targeted mechanism of action was also supported by transcriptomic and proteomic analyses; a total of 560 common differentially expressed genes (DEGs) and 285 common differentially expressed proteins (DEPs) were identified. The DEGs were further verified by using RT-qPCR. The combined analysis between the transcriptome and proteome revealed that the expression of some membrane-related genes and proteins, mainly those related to sphingolipid metabolism, glycerophospholipid metabolism, steroid biosynthesis, ABC transporters and protein processing in the endoplasmic reticulum, was disordered. Myriocin affected the serine palmitoyl transferase (SPT) activity as evidenced through molecular docking. Our results indicate that myriocin has significant antifungal activity owing to its ability to induce membrane damage in Fon.
Collapse
Affiliation(s)
- Hengxu Wang
- College of Life Science and AgroforestryQiqihar UniversityQiqihar161006China
- Key Laboratory of Urban AgricultureMinistry of Agriculture and Rural AffairsShanghai200240China
- Heilongjiang Provincial Technology Innovation Center of Agromicrobial Preparation IndustrializationQiqihar161006China
| | - Zhigang Wang
- College of Life Science and AgroforestryQiqihar UniversityQiqihar161006China
- Key Laboratory of Urban AgricultureMinistry of Agriculture and Rural AffairsShanghai200240China
- Heilongjiang Provincial Technology Innovation Center of Agromicrobial Preparation IndustrializationQiqihar161006China
| | - Zeping Liu
- College of Life Science and AgroforestryQiqihar UniversityQiqihar161006China
- Heilongjiang Provincial Technology Innovation Center of Agromicrobial Preparation IndustrializationQiqihar161006China
| | - Kexin Wang
- College of Life Science and AgroforestryQiqihar UniversityQiqihar161006China
- Heilongjiang Provincial Technology Innovation Center of Agromicrobial Preparation IndustrializationQiqihar161006China
| | - Weihui Xu
- College of Life Science and AgroforestryQiqihar UniversityQiqihar161006China
- Key Laboratory of Urban AgricultureMinistry of Agriculture and Rural AffairsShanghai200240China
- Heilongjiang Provincial Technology Innovation Center of Agromicrobial Preparation IndustrializationQiqihar161006China
| |
Collapse
|
|
20
|
Wang X, Chen S, Xiang H, Liang Z, Lu H. Role of sphingosine-1-phosphate receptors in vascular injury of inflammatory bowel disease. J Cell Mol Med 2021; 25:2740-2749. [PMID: 33595873 PMCID: PMC7957208 DOI: 10.1111/jcmm.16333] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 01/12/2021] [Accepted: 01/18/2021] [Indexed: 12/14/2022] Open
Abstract
Sphingosine‐1‐phosphate receptors (S1PRs) have an impact on the intestinal inflammation of inflammatory bowel disease (IBD) by regulating lymphocyte migration and differentiation. S1PR modulators as an emerging therapeutic approach are being investigated for the treatment of IBD. However, the role of S1PRs in intestinal vessels has not drawn much attention. Intestinal vascular damage is one of the major pathophysiological features of IBD, characterized by increased vascular density and impaired barrier function. S1PRs have pleiotropic effects on vascular endothelial cells, including proliferation, migration, angiogenesis and barrier homeostasis. Mounting evidence shows that S1PRs are abnormally expressed on intestinal vascular endothelial cells in IBD. Unexpectedly, S1PR modulators may damage intestinal vasculature, for example increase intestinal bleeding; therefore, S1PRs are thought to be involved in the regulation of intestinal vascular function in IBD. However, little is understood about how S1PRs regulate intestinal vascular function and participate in the initiation and progression of IBD. In this review, we summarize the pathogenic role of S1PRs in and the underlying mechanisms behind the intestinal vascular injury in IBD in order for improving IBD practice including S1PR‐targeted therapies.
Collapse
Affiliation(s)
- Xuewen Wang
- Center for Experimental Medicine, the Third Xiangya Hospital of Central South University, Changsha, China.,Department of Cardiology, the Third Xiangya Hospital of Central South University, Changsha, China
| | - Shuhua Chen
- Department of Biochemistry, School of Life Sciences of Central South University, Changsha, China
| | - Hong Xiang
- Center for Experimental Medicine, the Third Xiangya Hospital of Central South University, Changsha, China
| | - Ziwei Liang
- Department of Clinical laboratory, Yueyang Hospital Affiliated to Hunan Normal University, Yueyang, China
| | - Hongwei Lu
- Center for Experimental Medicine, the Third Xiangya Hospital of Central South University, Changsha, China.,Department of Cardiology, the Third Xiangya Hospital of Central South University, Changsha, China
| |
Collapse
|
|
21
|
Bauset C, Gisbert-Ferrándiz L, Cosín-Roger J. Metabolomics as a Promising Resource Identifying Potential Biomarkers for Inflammatory Bowel Disease. J Clin Med 2021; 10:jcm10040622. [PMID: 33562024 PMCID: PMC7915257 DOI: 10.3390/jcm10040622] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 02/02/2021] [Accepted: 02/02/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a relapsing chronic disorder of the gastrointestinal tract characterized by disruption of epithelial barrier function and excessive immune response to gut microbiota. The lack of biomarkers providing early diagnosis or defining the status of the pathology difficulties an accurate assessment of the disease. Given the different metabolomic profiles observed in IBD patients, metabolomics may reveal prime candidates to be studied, which may help in understanding the pathology and identifying novel therapeutic targets. In this review, we summarize the most current advances describing the promising metabolites such as lipids or amino acids found through untargeted metabolomics from serum, faecal, urine and biopsy samples.
Collapse
Affiliation(s)
- Cristina Bauset
- Department of Pharmacology and CIBER, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain; (C.B.); (L.G.-F.)
| | - Laura Gisbert-Ferrándiz
- Department of Pharmacology and CIBER, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain; (C.B.); (L.G.-F.)
| | - Jesús Cosín-Roger
- Hospital Dr. Peset, Fundación para la Investigación Sanitaria y Biomédica de la Comunitat Valenciana, FISABIO, 46017 Valencia, Spain
- Correspondence: ; Tel.: +34-963851234
| |
Collapse
|
|
22
|
Sandborn WJ, Feagan BG, Hanauer S, Vermeire S, Ghosh S, Liu WJ, Petersen A, Charles L, Huang V, Usiskin K, Wolf DC, D’Haens G. Long-Term Efficacy and Safety of Ozanimod in Moderately to Severely Active Ulcerative Colitis: Results From the Open-Label Extension of the Randomized, Phase 2 TOUCHSTONE Study. J Crohns Colitis 2021; 15:1120-1129. [PMID: 33438008 PMCID: PMC8256627 DOI: 10.1093/ecco-jcc/jjab012] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS This analysis examined the long-term safety and efficacy of ozanimod in patients with moderately to severely active ulcerative colitis [UC] with ≥ 4 years of follow-up in the phase 2 TOUCHSTONE open-label extension [OLE]. METHODS Patients receiving placebo or ozanimod HCl 0.5 mg or 1 mg during the double-blind period could enter the OLE [ozanimod HCl 1 mg daily]. Partial Mayo score [pMS] clinical response and remission were assessed through OLE week 200 and summarized descriptively using observed cases [OC] and non-responder imputation [NRI]. Endoscopy was required at OLE week 56 and the end of treatment. Parameters associated with endoscopy were summarized at weeks 56 and 104 [OC], and week 56 [NRI]. C-reactive protein and faecal calprotectin were assessed. Adverse events were monitored throughout the study. RESULTS Of 197 patients receiving double-blind treatment, 170 entered the OLE. Discontinuation rates were 28% at year 1 and 15-18% annually through year 4. Partial Mayo measures indicated clinical response and remission rates at OLE week 200 of 93.3% and 82.7%, respectively, using OC and 41% and 37% with the more conservative NRI analysis. At weeks 56 and 104, respectively, histological remission rates were 46.3% and 38.5%, and endoscopic improvement rates were 46.4% and 46.5% [OC]. No new safety signals were identified during ≥ 4 years of follow-up. CONCLUSIONS There was a high rate of continued study participation and long-term benefit with ozanimod HCl 1 mg daily based on clinical, histological and biomarker measures in patients with moderately to severely active UC in the TOUCHSTONE OLE. [NCT02531126].
Collapse
Affiliation(s)
- William J Sandborn
- Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA,Corresponding author: W. Sandborn, MD, UC San Diego Health System, 9500 Gilman Drive, MC 0956, La Jolla, CA 92093, USA. Tel: 858-657-5331;
| | | | | | | | | | | | | | | | | | | | - Douglas C Wolf
- Center for Crohn’s Disease & Ulcerative Colitis, Atlanta Gastroenterology Associates, Atlanta, GA, USA
| | - Geert D’Haens
- Inflammatory Bowel Disease Center, Amsterdam University Medical Center, Amsterdam, the Netherlands
| |
Collapse
|
|
23
|
Yao J, Liu T, Chen RJ, Liang J, Li J, Wang CG. Sphingosine-1-phosphate signal transducer and activator of transcription 3 signaling pathway contributes to baicalein-mediated inhibition of dextran sulfate sodium-induced experimental colitis in mice. Chin Med J (Engl) 2020; 133:292-300. [PMID: 31904729 PMCID: PMC7004614 DOI: 10.1097/cm9.0000000000000627] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Background: Baicalein has been shown to have anti-inflammatory and anti-tumor activities. However, the mechanisms underlying its anti-inflammatory effect on colitis remain unclear. Methods: A dextran sodium sulfate (DSS)-induced model of acute colitis was established in BALB/c mice (6–8 weeks old, weighing 18–22 g). Six groups of mice received: (1) water for 10 days (control), n = 6; (2) DSS 4% solution in the drinking water for 7 days, followed by normal water for 3 days, n = 7; (3), (4), and (5) as for group 2 plus baicalein (10, 20, 40 mg/kg) administered once daily starting on day 1, n = 6; and (6) as for (2) plus 5-aminosalicylic acid (50 mg/kg) administered once daily starting on day 1, n = 6. Body weights, stool consistency, and hematochezia were recorded, and the severity of colitis was evaluated using a disease activity index. On day 11, the mice were euthanized, and organs and blood were collected for analysis. Serum inflammatory factors were detected by enzyme-linked immunosorbent assay; CD11b-positive cells were analyzed by immunofluorescence microscopy; expression of retinoic-acid-receptor-related orphan nuclear receptor gamma, sphingosine kinase 1 (SPHK1), and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) was detected by immunohistochemistry; and expression of nucleotide-binding oligomerization domain 2 (NOD2), SPHK1, sphingosine 1-phosphate receptor 1 (S1PR1), total STAT3, and p-STAT3 were detected by western blotting analysis. Inter-group differences were compared using Student's t test. Results: Baicalein treatment dose-dependently reduced DSS-induced weight loss (P < 0.01 or P < 0.05), splenomegaly (P < 0.01), and colonic damage, as reflected by amelioration of diarrhea, rectal bleeding, and colonic ulceration, congestion, edema (shown as colon length, P < 0.05 or P < 0.01), and inflammatory cell infiltration. Baicalein also significantly decreased the levels of inflammatory mediators in the serum (P < 0.01) and colon, and significantly inhibited expression of NOD2 SPHK1, S1PR1, and p-STAT3 in the colon (P < 0.05). Conclusions: Baicalein treatment ameliorated colitis in mice by inhibiting S1P-STAT3 signaling, suggesting that this flavonoid might be beneficial in the treatment of colitis.
Collapse
Affiliation(s)
- Jing Yao
- Department of Pharmacology, School of Basic Medicine, Jining Medical University, Jining, Shandong 272000, China
| | - Tao Liu
- Department of Otorhinolaryngology, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, China
| | - Rui-Jiao Chen
- Department of Chemistry, School of Basic Medicine, Jining Medical University, Jining, Shandong 272000, China
| | - Jing Liang
- School of Life Sciences, Qufu Normal University, Qufu, Shandong 273100, China
| | - Jun Li
- Department of Pharmacology, School of Basic Medicine, Jining Medical University, Jining, Shandong 272000, China
| | - Chuan-Gong Wang
- Department of Pharmacology, School of Basic Medicine, Jining Medical University, Jining, Shandong 272000, China
| |
Collapse
|
|
24
|
Alhouayek M, Ameraoui H, Muccioli GG. Bioactive lipids in inflammatory bowel diseases - From pathophysiological alterations to therapeutic opportunities. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1866:158854. [PMID: 33157277 DOI: 10.1016/j.bbalip.2020.158854] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 10/16/2020] [Accepted: 10/27/2020] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel diseases (IBDs), such as Crohn's disease and ulcerative colitis, are lifelong diseases that remain challenging to treat. IBDs are characterized by alterations in intestinal barrier function and dysregulation of the innate and adaptive immunity. An increasing number of lipids are found to be important regulators of inflammation and immunity as well as gut physiology. Therefore, the study of lipid mediators in IBDs is expected to improve our understanding of disease pathogenesis and lead to novel therapeutic opportunities. Here, through selected examples - such as fatty acids, specialized proresolving mediators, lysophospholipids, endocannabinoids, and oxysterols - we discuss how lipid signaling is involved in IBD physiopathology and how modulating lipid signaling pathways could affect IBDs.
Collapse
Affiliation(s)
- Mireille Alhouayek
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, 1200 Bruxelles, Belgium.
| | - Hafsa Ameraoui
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, 1200 Bruxelles, Belgium
| | - Giulio G Muccioli
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, 1200 Bruxelles, Belgium.
| |
Collapse
|
|
25
|
Zhao P, Liu ID, Hodgin JB, Benke PI, Selva J, Torta F, Wenk MR, Endrizzi JA, West O, Ou W, Tang E, Goh DLM, Tay SKH, Yap HK, Loh A, Weaver N, Sullivan B, Larson A, Cooper MA, Alhasan K, Alangari AA, Salim S, Gumus E, Chen K, Zenker M, Hildebrandt F, Saba JD. Responsiveness of sphingosine phosphate lyase insufficiency syndrome to vitamin B6 cofactor supplementation. J Inherit Metab Dis 2020; 43:1131-1142. [PMID: 32233035 PMCID: PMC8072405 DOI: 10.1002/jimd.12238] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 03/25/2020] [Accepted: 03/26/2020] [Indexed: 12/26/2022]
Abstract
Sphingosine-1-phosphate (S1P) lyase is a vitamin B6-dependent enzyme that degrades sphingosine-1-phosphate in the final step of sphingolipid metabolism. In 2017, a new inherited disorder was described caused by mutations in SGPL1, which encodes sphingosine phosphate lyase (SPL). This condition is referred to as SPL insufficiency syndrome (SPLIS) or alternatively as nephrotic syndrome type 14 (NPHS14). Patients with SPLIS exhibit lymphopenia, nephrosis, adrenal insufficiency, and/or neurological defects. No targeted therapy for SPLIS has been reported. Vitamin B6 supplementation has therapeutic activity in some genetic diseases involving B6-dependent enzymes, a finding ascribed largely to the vitamin's chaperone function. We investigated whether B6 supplementation might have activity in SPLIS patients. We retrospectively monitored responses of disease biomarkers in patients supplemented with B6 and measured SPL activity and sphingolipids in B6-treated patient-derived fibroblasts. In two patients, disease biomarkers responded to B6 supplementation. S1P abundance and activity levels increased and sphingolipids decreased in response to B6. One responsive patient is homozygous for an SPL R222Q variant present in almost 30% of SPLIS patients. Molecular modeling suggests the variant distorts the dimer interface which could be overcome by cofactor supplementation. We demonstrate the first potential targeted therapy for SPLIS and suggest that 30% of SPLIS patients might respond to cofactor supplementation.
Collapse
Affiliation(s)
- Piming Zhao
- Department of Pediatrics, Division of Hematology/Oncology, University of California, San Francisco, California
| | - Isaac D. Liu
- Department of Pediatrics, Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore
| | - Jeffrey B. Hodgin
- Department of Pathology, University of Michigan Hospitals and Health Center, Ann Arbor, Michigan
| | - Peter I. Benke
- SLING, Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Jeremy Selva
- SLING, Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Federico Torta
- SLING, Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Markus R. Wenk
- SLING, Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - James A. Endrizzi
- Department of Pediatrics, Division of Hematology/Oncology, University of California, San Francisco, California
| | - Olivia West
- Department of Pediatrics, Division of Hematology/Oncology, University of California, San Francisco, California
| | - Weixing Ou
- Department of Pediatrics, Division of Hematology/Oncology, University of California, San Francisco, California
| | - Emily Tang
- Department of Pediatrics, Division of Hematology/Oncology, University of California, San Francisco, California
| | - Denise Li-Meng Goh
- Department of Pediatrics, Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore
| | - Stacey Kiat-Hong Tay
- Department of Pediatrics, Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore
| | - Hui-Kim Yap
- Department of Pediatrics, Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore
| | - Alwin Loh
- Department of Pediatrics, Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore
| | - Nicole Weaver
- Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
| | - Bonnie Sullivan
- Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
- Division of Clinical Genetics, Children’s Mercy Kansas City, Kansas City, Missouri
- Department of Pediatrics, University of Missouri, Kansas City, Missouri
| | - Austin Larson
- Department of Pediatrics, University of Colorado School of Medicine, Denver, Colorado
| | - Megan A. Cooper
- Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
| | - Khalid Alhasan
- Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Abdullah A. Alangari
- Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Suha Salim
- Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Evren Gumus
- Department of Medicine, Harran University, Sanliurfa, Turkey
| | - Karin Chen
- Department of Pediatrics, Division of Allergy and Immunology, University of Utah School of Medicine, Salt Lake City, Utah
| | - Martin Zenker
- Institute of Human Genetics, Otto von Guericke University, Magdeburg, Germany
| | | | - Julie D. Saba
- Department of Pediatrics, Division of Hematology/Oncology, University of California, San Francisco, California
| |
Collapse
|
|
26
|
Yang T, Wang X, Yuan Z, Miao Y, Wu Z, Chai Y, Yu Q, Wang H, Sun L, Huang X, Zhang L, Jiang Z. Sphingosine 1-phosphate receptor-1 specific agonist SEW2871 ameliorates ANIT-induced dysregulation of bile acid homeostasis in mice plasma and liver. Toxicol Lett 2020; 331:242-253. [PMID: 32579994 DOI: 10.1016/j.toxlet.2020.06.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 06/15/2020] [Accepted: 06/18/2020] [Indexed: 12/12/2022]
Abstract
Dysregulated bile acid (BA) homeostasis is an extremely significant pathological phenomenon of intrahepatic cholestasis, and the accumulated BA could further trigger hepatocyte injury. Here, we showed that the expression of sphingosine-1-phosphate receptor 1 (S1PR1) was down-regulated by α-naphthylisothiocyanate (ANIT) in vivo and in vitro. The up-regulated S1PR1 induced by SEW2871 (a specific agonist of S1PR1) could improve ANIT-induced deficiency of hepatocyte tight junctions (TJs), cholestatic liver injury and the disrupted BA homeostasis in mice. BA metabolic profiles showed that SEW2871 not only reversed the disruption of plasma BA homeostasis, but also alleviated BA accumulation in the liver of ANIT-treated mice. Further quantitative analysis of 19 BAs showed that ANIT increased almost all BAs in mice plasma and liver, all of which were restored by SEW2871. Our data demonstrated that the top performing BAs were taurine conjugated bile acids (T-), especially taurocholic acid (TCA). Molecular mechanism studies indicated that BA transporters, synthetase, and BAs nuclear receptors (NRs) might be the important factors that maintained BA homeostasis by SEW2871 in ANIT-induced cholestasis. In conclusion, these results demonstrated that S1PR1 selective agonists might be the novel and potential effective agents for the treatment of intrahepatic cholestasis by recovering dysregulated BA homeostasis.
Collapse
Affiliation(s)
- Tingting Yang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Xue Wang
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Zihang Yuan
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Yingying Miao
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Ziteng Wu
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Yuanyuan Chai
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Qiongna Yu
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Haiyan Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Lixin Sun
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Xin Huang
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
| | - Luyong Zhang
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Zhenzhou Jiang
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China.
| |
Collapse
|
|
27
|
Sitkin S, Demyanova E, Vakhitov T, Pokrotnieks J. Altered Sphingolipid Metabolism and its Interaction With the Intestinal Microbiome Is Another Key to the Pathogenesis of Inflammatory Bowel Disease. Inflamm Bowel Dis 2019; 25:e157-e158. [PMID: 31560761 DOI: 10.1093/ibd/izz228] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Affiliation(s)
- Stanislav Sitkin
- Department of Internal Diseases, Gastroenterology and Dietetics, North-Western State Medical University named after I.I. Mechnikov, St. Petersburg, Russia
- Department of Microbiology, State Research Institute of Highly Pure Biopreparations, St. Petersburg, Russia
- Institute of Perinatology and Pediatrics, Almazov National Medical Research Centre, St. Petersburg, Russia
| | - Elena Demyanova
- Department of Microbiology, State Research Institute of Highly Pure Biopreparations, St. Petersburg, Russia
| | - Timur Vakhitov
- Department of Microbiology, State Research Institute of Highly Pure Biopreparations, St. Petersburg, Russia
| | - Juris Pokrotnieks
- Department of Internal Diseases, Rīga Stradiņš University, Riga, Latvia
- Centre of Gastroenterology, Hepatology and Nutrition, Pauls Stradiņš Clinical University Hospital, Riga, Latvia
| |
Collapse
|
|
28
|
Diab J, Hansen T, Goll R, Stenlund H, Ahnlund M, Jensen E, Moritz T, Florholmen J, Forsdahl G. Lipidomics in Ulcerative Colitis Reveal Alteration in Mucosal Lipid Composition Associated With the Disease State. Inflamm Bowel Dis 2019; 25:1780-1787. [PMID: 31077307 DOI: 10.1093/ibd/izz098] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND The onset of ulcerative colitis (UC) is associated with alterations in lipid metabolism and a disruption of the balance between pro- and anti-inflammatory molecules. Only a few studies describe the mucosal lipid biosignatures during active UC. Moreover, the dynamics of lipid metabolism in the remission state is poorly defined. Therefore, this study aims to characterize mucosal lipid profiles in treatment-naïve UC patients and deep remission UC patients compared with healthy subjects. METHODS Treatment-naïve UC patients (n = 21), UC patients in deep remission (n = 12), and healthy volunteers (n = 14) were recruited. The state of deep remission was defined by histological and immunological remission defined by a normalized TNF-α gene expression. Mucosa biopsies were collected by colonoscopy. Lipid analysis was performed by means of ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS-MS). In total, 220 lipids from 11 lipid classes were identified. RESULTS The relative concentration of 122 and 36 lipids was altered in UC treatment-naïve patients and UC remission patients, respectively, compared with healthy controls. The highest number of significant variations was in the phosphatidylcholine (PC), ceramide (Cer), and sphingomyelin (SM) composition. Multivariate analysis revealed discrimination among the study groups based on the lipid profile. Furthermore, changes in phosphatidylethanolamine(38:3), Cer(d18:1/24:0), and Cer(d18:1/24:2) were most distinctive between the groups. CONCLUSION This study revealed a discriminant mucosal lipid composition pattern between treatment-naïve UC patients, deep remission UC patients, and healthy controls. We report several distinctive lipids, which might be involved in the inflammatory response in UC, and could reflect the disease state.
Collapse
Affiliation(s)
- Joseph Diab
- Natural Products and Medicinal Chemistry Research Group, Department of Pharmacy Faculty of Health Sciences, University of Tromsø-The Arctic University of Norway, Tromsø, Norway
| | - Terkel Hansen
- Natural Products and Medicinal Chemistry Research Group, Department of Pharmacy Faculty of Health Sciences, University of Tromsø-The Arctic University of Norway, Tromsø, Norway
| | - Rasmus Goll
- Research Group of Gastroenterology and Nutrition, Department of Clinical Medicine, Faculty of Health Sciences, University of Tromsø-The Arctic University of Norway, Tromsø, Norway.,Department of Medical Gastroenterology, University Hospital of North Norway, Tromsø, Norway
| | - Hans Stenlund
- Swedish Metabolomics Center, Swedish University of Agricultural Sciences, Umeå, Sweden
| | - Maria Ahnlund
- Swedish Metabolomics Center, Swedish University of Agricultural Sciences, Umeå, Sweden
| | - Einar Jensen
- Natural Products and Medicinal Chemistry Research Group, Department of Pharmacy Faculty of Health Sciences, University of Tromsø-The Arctic University of Norway, Tromsø, Norway
| | - Thomas Moritz
- Department of Medical Gastroenterology, University Hospital of North Norway, Tromsø, Norway
| | - Jon Florholmen
- Research Group of Gastroenterology and Nutrition, Department of Clinical Medicine, Faculty of Health Sciences, University of Tromsø-The Arctic University of Norway, Tromsø, Norway.,Department of Medical Gastroenterology, University Hospital of North Norway, Tromsø, Norway
| | - Guro Forsdahl
- Natural Products and Medicinal Chemistry Research Group, Department of Pharmacy Faculty of Health Sciences, University of Tromsø-The Arctic University of Norway, Tromsø, Norway
| |
Collapse
|
|
29
|
The Lipid Status in Patients with Ulcerative Colitis: Sphingolipids are Disease-Dependent Regulated. J Clin Med 2019; 8:jcm8070971. [PMID: 31277430 PMCID: PMC6678307 DOI: 10.3390/jcm8070971] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 06/13/2019] [Accepted: 07/02/2019] [Indexed: 02/06/2023] Open
Abstract
The factors that contribute to the development of ulcerative colitis (UC), are still not fully identified. Disruption of the colon barrier is one of the first events leading to invasion of bacteria and activation of the immune system. The colon barrier is strongly influenced by sphingolipids. Sphingolipids impact cell-cell contacts and function as second messengers. We collected blood and colon tissue samples from UC patients and healthy controls and investigated the sphingolipids and other lipids by LC-MS/MS or LC-QTOFMS. The expression of enzymes of the sphingolipid pathway were determined by RT-PCR and immunohistochemistry. In inflamed colon tissue, the de novo-synthesis of sphingolipids is reduced, whereas lactosylceramides are increased. Reduction of dihydroceramides was due to posttranslational inhibition rather than altered serine palmitoyl transferase or ceramide synthase expression in inflamed colon tissue. Furthermore, in human plasma from UC-patients, several sphinglipids change significantly in comparison to healthy controls. Beside sphingolipids free fatty acids, lysophosphatidylcholines and triglycerides changed significantly in the blood of colitis patients dependent on the disease severity. Our data indicate that detraction of the sphingolipid de novo synthesis in colon tissue might be an important trigger for UC. Several lipids changed significantly in the blood, which might be used as biomarkers for disease control; however, diet-related variabilities need to be considered.
Collapse
|
|
30
|
Plöhn S, Edelmann B, Japtok L, He X, Hose M, Hansen W, Schuchman EH, Eckstein A, Berchner-Pfannschmidt U. CD40 Enhances Sphingolipids in Orbital Fibroblasts: Potential Role of Sphingosine-1-Phosphate in Inflammatory T-Cell Migration in Graves' Orbitopathy. Invest Ophthalmol Vis Sci 2019; 59:5391-5397. [PMID: 30452592 DOI: 10.1167/iovs.18-25466] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose Graves' orbitopathy (GO) is an autoimmune orbital disorder associated with Graves' disease caused by thyrotropin receptor autoantibodies. Orbital fibroblasts (OFs) and CD40 play a key role in disease pathogenesis. The bioactive lipid sphingosine-1-phosphate (S1P) has been implicated in promoting adipogenesis, fibrosis, and inflammation in OFs. We investigated the role of CD40 signaling in inducing S1P activity in orbital inflammation. Methods OFs and T cells were derived from GO patients and healthy control (Ctl) persons. S1P abundance in orbital tissues was evaluated by immunofluorescence. OFs were stimulated with CD40 ligand and S1P levels were determined by ELISA. Further, activities of acid sphingomyelinase (ASM), acid ceramidase, and sphingosine kinase were measured by ultraperformance liquid chromatography. Sphingosine and ceramide contents were analyzed by mass spectrometry. Finally, the role for S1P in T-cell attraction was investigated by T-cell migration assays. Results GO orbital tissue showed elevated amounts of S1P as compared to control samples. Stimulation of CD40 induced S1P expression in GO-derived OFs, while Ctl-OFs remained unaffected. A significant increase of ASM and sphingosine kinase activities, as well as lipid formation, was observed in GO-derived OFs. Migration assay of T cells in the presence of SphK inhibitor revealed that S1P released by GO-OFs attracted T cells for migration. Conclusions The results demonstrated that CD40 ligand stimulates GO fibroblast to produce S1P, which is a driving force for T-cell migration. The results support the use of S1P receptor signaling modulators in GO management.
Collapse
Affiliation(s)
- Svenja Plöhn
- Molecular Ophthalmology, Department of Ophthalmology, University of Duisburg-Essen, Essen, Germany.,Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States
| | - Bärbel Edelmann
- Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.,Department for Haematology and Oncology, Otto-von-Guericke University, Magdeburg, Germany
| | - Lukasz Japtok
- Department of Toxicology, Institute of Nutritional Science, University of Potsdam, Potsdam, Germany
| | - Xingxuan He
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States
| | - Matthias Hose
- Institute of Medical Microbiology, University of Duisburg-Essen, Essen, Germany
| | - Wiebke Hansen
- Institute of Medical Microbiology, University of Duisburg-Essen, Essen, Germany
| | - Edward H Schuchman
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States
| | - Anja Eckstein
- Molecular Ophthalmology, Department of Ophthalmology, University of Duisburg-Essen, Essen, Germany
| | | |
Collapse
|
|
31
|
Abstract
The liver is the central organ involved in lipid metabolism and the gastrointestinal (GI) tract is responsible for nutrient absorption and partitioning. Obesity, dyslipidemia and metabolic disorders are of increasing public health concern worldwide, and novel therapeutics that target both the liver and the GI tract (gut-liver axis) are much needed. In addition to aiding fat digestion, bile acids act as important signaling molecules that regulate lipid, glucose and energy metabolism via activating nuclear receptor, G protein-coupled receptors (GPCRs), Takeda G protein receptor 5 (TGR5) and sphingosine-1-phosphate receptor 2 (S1PR2). Sphingosine-1-phosphate (S1P) is synthesized by two sphingosine kinase isoforms and is a potent signaling molecule that plays a critical role in various diseases such as fatty liver, inflammatory bowel disease (IBD) and colorectal cancer. In this review, we will focus on recent findings related to the role of S1P-mediated signaling pathways in the gut-liver axis.
Collapse
Affiliation(s)
- Eric K. Kwong
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA,McGuire VA Medical Center, Richmond, VA, USA
| | - Huiping Zhou
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA,McGuire VA Medical Center, Richmond, VA, USA,Corresponding author. Department of Microbiology and Immunology, Virginia Commonwealth University, McGuire Veterans Affairs Medical Center, Richmond, VA, USA. (H. Zhou)
| |
Collapse
|
|
32
|
Lai Y, Xue J, Liu CW, Gao B, Chi L, Tu P, Lu K, Ru H. Serum Metabolomics Identifies Altered Bioenergetics, Signaling Cascades in Parallel with Exposome Markers in Crohn's Disease. Molecules 2019; 24:E449. [PMID: 30691236 PMCID: PMC6385106 DOI: 10.3390/molecules24030449] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 01/15/2019] [Accepted: 01/22/2019] [Indexed: 02/08/2023] Open
Abstract
: Inflammatory bowel disease (IBD) has stimulated much interest due to its surging incidences and health impacts in the U.S. and worldwide. However, the exact cause of IBD remains incompletely understood, and biomarker is lacking towards early diagnostics and effective therapy assessment. To tackle these, the emerging high-resolution mass spectrometry (HRMS)-based metabolomics shows promise. Here, we conducted a pilot untargeted LC/MS metabolomic profiling in Crohn's disease, for which serum samples of both active and inactive cases were collected, extracted, and profiled by a state-of-the-art compound identification workflow. Results show a distinct metabolic profile of Crohn's from control, with most metabolites downregulated. The identified compounds are structurally diverse, pointing to important pathway perturbations ranging from energy metabolism (e.g., β-oxidation of fatty acids) to signaling cascades of lipids (e.g., DHA) and amino acid (e.g., L-tryptophan). Importantly, an integral role of gut microbiota in the pathogenesis of Crohn's disease is highlighted. Xenobiotics and their biotransformants were widely detected, calling for massive exposomic profiling for future cohort studies as such. This study endorses the analytical capacity of untargeted metabolomics for biomarker development, cohort stratification, and mechanistic interpretation; the findings might be valuable for advancing biomarker research and etiologic inquiry in IBD.
Collapse
Affiliation(s)
- Yunjia Lai
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, CB #7431, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | - Jingchuan Xue
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, CB #7431, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | - Chih-Wei Liu
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, CB #7431, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | - Bei Gao
- NIH West Coast Metabolomics Center, University of California at Davis, Davis, CA 95616, USA.
| | - Liang Chi
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, CB #7431, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | - Pengcheng Tu
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, CB #7431, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | - Kun Lu
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, CB #7431, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | - Hongyu Ru
- Department of Population Health and Pathobiology, North Carolina State University, Raleigh, NC 27695, USA.
| |
Collapse
|