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1
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Huang Y, Wang M, Yang Z, Wang X, Wang X, He F. Determination of nine prostaglandins in the arachidonic acid metabolic pathway with UHPLC-QQQ-MS/MS and application to in vitro and in vivo inflammation models. Front Pharmacol 2025; 16:1595059. [PMID: 40520189 PMCID: PMC12162277 DOI: 10.3389/fphar.2025.1595059] [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: 03/18/2025] [Accepted: 04/30/2025] [Indexed: 06/18/2025] Open
Abstract
Background Prostaglandins play a vital role as crucial metabolites and inflammatory indicators within the arachidonic acid (AA) metabolic pathway. Conventional assays typically focus on a single inflammatory indicator, while multi-index detection entails a large number of samples. Methods In this study, an ultra-high-performance liquid chromatography coupled with triple quadrupole mass spectrometry (UHPLC-QQQ-MS/MS) method was newly developed for simultaneous quantitative analysis of nine AA metabolites, including prostaglandin F2β (PGF2β), prostaglandin E2 (PGE2), prostaglandin E1 (PGE1), prostaglandin D1 (PGD1), prostaglandin D2 (PGD2), prostaglandin A2 (PGA2), prostaglandin J2 (PGJ2), prostaglandin B2 (PGB2), and prostaglandin A1 (PGA1), in the supernatant of LPS-induced RAW264.7 cells and the serum samples of adjuvant-induced arthritis (AIA) rats. Results The newly established UHPLC-QQQ-MS/MS method successfully and rapidly quantified the contents of the nine prostaglandins simultaneously. The methodology was validated. The levels of PGE2, PGD1, PGD2, PGA2, and PGJ2 in the LPS-induced RAW264.7 cells group were higher than those in blank group. At the same time, the levels of these PGs decreased significantly (p < 0.01 vs. LPS-induced group) after the positive drug (dexamethasone) intervention. On the 14th day of AIA modeling, the paw volume of the AIA rats was significantly enlarged (p < 0.01 vs. blank group), and the serum samples from the AIA group showed significantly increased levels of PGE2, PGD2, and PGA2 (p < 0.01 vs. blank group), suggesting the emergence of arthritis. The levels of other prostaglandins were below the limit of quantification. Conclusion The method established in this study for determining nine prostaglandins in the AA metabolic pathway with UHPLC-QQQ-MS/MS embodied the advantages of requiring a low amount of sample, a simple pretreatment process, and the rapid and efficient simultaneous quantification of multiple inflammatory factors. It provided a novel assay method for the pharmacological study of the AA metabolic pathway.
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Affiliation(s)
- Yufeng Huang
- Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Mengxian Wang
- Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- College of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Ziqi Yang
- Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- College of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Xiaotong Wang
- Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, China
| | - Xinxin Wang
- Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, China
| | - Fan He
- Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
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Santangelo BE, Bada M, Hunter LE, Lozupone C. Hypothesizing mechanistic links between microbes and disease using knowledge graphs. Sci Rep 2025; 15:6905. [PMID: 40011529 PMCID: PMC11865272 DOI: 10.1038/s41598-025-91230-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 02/19/2025] [Indexed: 02/28/2025] Open
Abstract
Knowledge graphs have been a useful tool for many biomedical applications because of their effective representation of biological concepts. Plentiful evidence exists linking the gut microbiome to disease in a correlative context, but uncovering the mechanistic explanation for those associations remains a challenge. Here we demonstrate the potential of knowledge graphs to hypothesize plausible mechanistic accounts of host-microbe interactions in disease. We have constructed a knowledge graph of linked microbes, genes and metabolites called MGMLink, and, using a shortest path or template-based search through the graph and a novel path-prioritization methodology based on the structure of the knowledge graph, we show that this knowledge supports inference of mechanistic hypotheses that explain observed relationships between microbes and disease phenotypes. We discuss specific applications of this methodology in inflammatory bowel disease and Parkinson's disease. This approach enables mechanistic hypotheses surrounding the complex interactions between gut microbes and disease to be generated in a scalable and comprehensive manner.
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Affiliation(s)
- Brook E Santangelo
- Department of Biomedical Informatics, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA.
| | - Michael Bada
- Department of Pediatrics, University of Chicago, Chicago, IL, USA
| | | | - Catherine Lozupone
- Department of Biomedical Informatics, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA
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Kojima F, Hioki Y, Sekiya H, Kashiwagi H, Iizuka Y, Eto K, Maehana S, Kawakami F, Kubo M, Ishibashi H, Ichikawa T. Microsomal Prostaglandin E Synthase-1 Controls Colonic Prostaglandin E 2 Production and Exerts a Protective Effect on Colitis Induced by Trinitrobenzene Sulfonic Acid in Mice. Int J Mol Sci 2024; 25:12326. [PMID: 39596393 PMCID: PMC11594388 DOI: 10.3390/ijms252212326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 11/15/2024] [Indexed: 11/28/2024] Open
Abstract
Microsomal prostaglandin E synthase-1 (mPGES-1) is an isozyme of the prostaglandin (PG) E synthase that acts downstream of cyclooxygenase and catalyzes the conversion of PGH2 to PGE2. The impact of genetic deletion of mPGES-1 on the development of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, a well-established model of inflammatory bowel disease (IBD), was investigated in this study. After administration of TNBS, mice deficient in mPGES-1 (mPGES-1-/- mice) showed more severe colitis than did wild-type (WT) mice. Histological examination revealed that mPGES-1-/- mice had markedly exacerbated symptoms of colitis. mPGES-1 expression was detectable in the colons of WT mice at both the mRNA and protein levels. Lack of mPGES-1 resulted in marked reduction of colonic PGE2 production. Our study also showed a significant increase in colonic expression of interleukin-17A (IL-17A), as well as interferon γ (IFNγ) and tumor necrosis factor α, during colitis in mPGES-1-/- mice compared with that in WT mice. Furthermore, loss of mPGES-1 increased the populations of IL-17A-producing T-helper (Th) 17 and IFNγ-producing Th1 cells in mesenteric lymph nodes. These results suggest that mPGES-1 is the main enzyme responsible for colonic PGE2 production and deficiency of mPGES-1 facilitates the development of colitis and T-cell-mediated immunity. mPGES-1 might, therefore, impact T-cell-related immune response associated with IBD.
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Affiliation(s)
- Fumiaki Kojima
- Department of Pharmacology, Kitasato University School of Allied Health Sciences, Sagamihara 252-0373, Japan
- Department of Regulation Biochemistry, Kitasato University Graduate School of Medical Sciences, Sagamihara 252-0373, Japan; (F.K.); (T.I.)
- Regenerative Medicine and Cell Design Research Facility, Sagamihara 252-0373, Japan; (Y.I.); (K.E.); (S.M.); (M.K.); (H.I.)
| | - Yuka Hioki
- Department of Pharmacology, Kitasato University School of Allied Health Sciences, Sagamihara 252-0373, Japan
- Department of Regulation Biochemistry, Kitasato University Graduate School of Medical Sciences, Sagamihara 252-0373, Japan; (F.K.); (T.I.)
| | - Hiroki Sekiya
- Department of Pharmacology, Kitasato University School of Allied Health Sciences, Sagamihara 252-0373, Japan
- Department of Regulation Biochemistry, Kitasato University Graduate School of Medical Sciences, Sagamihara 252-0373, Japan; (F.K.); (T.I.)
| | - Hitoshi Kashiwagi
- Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan;
| | - Yoshiko Iizuka
- Regenerative Medicine and Cell Design Research Facility, Sagamihara 252-0373, Japan; (Y.I.); (K.E.); (S.M.); (M.K.); (H.I.)
- Department of Public Health, Kitasato University Graduate School of Medical Sciences, Sagamihara 252-0373, Japan
| | - Kei Eto
- Regenerative Medicine and Cell Design Research Facility, Sagamihara 252-0373, Japan; (Y.I.); (K.E.); (S.M.); (M.K.); (H.I.)
- Department of Physiology, Kitasato University School of Allied Health Sciences, Sagamihara 252-0373, Japan
| | - Shotaro Maehana
- Regenerative Medicine and Cell Design Research Facility, Sagamihara 252-0373, Japan; (Y.I.); (K.E.); (S.M.); (M.K.); (H.I.)
- Department of Environmental Microbiology, Kitasato University Graduate School of Medical Sciences, Sagamihara 252-0373, Japan
| | - Fumitaka Kawakami
- Department of Regulation Biochemistry, Kitasato University Graduate School of Medical Sciences, Sagamihara 252-0373, Japan; (F.K.); (T.I.)
- Regenerative Medicine and Cell Design Research Facility, Sagamihara 252-0373, Japan; (Y.I.); (K.E.); (S.M.); (M.K.); (H.I.)
| | - Makoto Kubo
- Regenerative Medicine and Cell Design Research Facility, Sagamihara 252-0373, Japan; (Y.I.); (K.E.); (S.M.); (M.K.); (H.I.)
- Department of Environmental Microbiology, Kitasato University Graduate School of Medical Sciences, Sagamihara 252-0373, Japan
| | - Hitoshi Ishibashi
- Regenerative Medicine and Cell Design Research Facility, Sagamihara 252-0373, Japan; (Y.I.); (K.E.); (S.M.); (M.K.); (H.I.)
- Department of Physiology, Kitasato University School of Allied Health Sciences, Sagamihara 252-0373, Japan
| | - Takafumi Ichikawa
- Department of Regulation Biochemistry, Kitasato University Graduate School of Medical Sciences, Sagamihara 252-0373, Japan; (F.K.); (T.I.)
- Regenerative Medicine and Cell Design Research Facility, Sagamihara 252-0373, Japan; (Y.I.); (K.E.); (S.M.); (M.K.); (H.I.)
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Anbazhagan M, Sharma G, Murthy S, Maddipatla SC, Kolachala VL, Dodd A, Randunne A, Cutler DJ, Kugathasan S, Matthews JD. PTGER4 signaling regulates class IIa HDAC function and SPINK4 mRNA levels in rectal epithelial cells. Cell Commun Signal 2024; 22:493. [PMID: 39396982 PMCID: PMC11472582 DOI: 10.1186/s12964-024-01879-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 10/06/2024] [Indexed: 10/15/2024] Open
Abstract
BACKGROUND The prostaglandin receptor PTGER4 facilitates homeostasis in the gut. Previous reports indicate that goblet cells, marked by SPINK4 expression, might be affected by PTGER4 activity. Current evidence suggests that prostaglandin E2 (PGE2) produced by mesenchymal stromal cells (MSC) stimulates PTGER4 in epithelial cells during inflammatory conditions. Here, we investigate the subcellular mechanisms and mRNA levels downstream of PTGER4 activity in epithelial cells. METHODS Mucosal cells, organoids, and MSC were obtained from patient biopsies harvested by endoscopy. Using independent and co-cultures, we manipulated the activity of PTGER4, the downstream enzymes, and mRNA levels, by using PGE2, in combination with chemical inhibitors, L-161982, H89, LB100, DAPT, LMK-235, or with butyrate. Immunofluorescence, single cell sequencing, RNAscope, ELISA, real time PCR, and Western blotting were used to examine these samples. RESULTS SPINK4 mRNA levels were increased in organoids by co-culture with MSC or exogenous stimulation with PGE2 that could be blocked by L-161982 or LMK-235, PTGER4 or HDAC4 inhibitors, respectively. Expression of PTGER4 was co-localized with JAM-A in the basolateral surfaces in rectal epithelial cells grown as organoids. PGE2 treatment of rectal organoids decreased HDAC4, 5, and 7 phosphorylation levels that could be blocked by L-161982 treatment. Butyrate treatment, or addition of L-161982, increased the phosphorylated levels of HDAC4, 5, and 7. CONCLUSIONS These findings suggest a mechanism during mucosal injury whereby MSC production of PGE2 increases HDAC4, 5, and 7 activities in epithelial cells by upregulating PTGER4 signaling, ultimately increasing SPINK4 mRNA levels and extracellular release of SPINK4.
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Affiliation(s)
- Murugadas Anbazhagan
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Emory University, Atlanta, GA, USA
| | - Garima Sharma
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Emory University, Atlanta, GA, USA
| | - Shanta Murthy
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Emory University, Atlanta, GA, USA
| | - Sushma Chowdary Maddipatla
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Emory University, Atlanta, GA, USA
| | - Vasantha L Kolachala
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Emory University, Atlanta, GA, USA
| | - Anne Dodd
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Emory University, Atlanta, GA, USA
| | - Amanda Randunne
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Emory University, Atlanta, GA, USA
| | - David J Cutler
- Department of Human Genetics, Emory University, Atlanta, GA, USA
| | - Subra Kugathasan
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Emory University, Atlanta, GA, USA
- Department of Pediatrics and Pediatric Research Institute, Division of Pediatric Gastroenterology, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, USA
| | - Jason D Matthews
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Emory University, Atlanta, GA, USA.
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Health Science Research Building, 1760 Haygood Dr, E-246, Atlanta, GA, 30322, USA.
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5
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Sipos F, Műzes G. Colonic Tuft Cells: The Less-Recognized Therapeutic Targets in Inflammatory Bowel Disease and Colorectal Cancer. Int J Mol Sci 2024; 25:6209. [PMID: 38892399 PMCID: PMC11172904 DOI: 10.3390/ijms25116209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 06/02/2024] [Accepted: 06/03/2024] [Indexed: 06/21/2024] Open
Abstract
Tuft cells are more than guardian chemosensory elements of the digestive tract. They produce a variety of immunological effector molecules in response to stimulation; moreover, they are essential for defense against protozoa and nematodes. Beyond the description of their characteristics, this review aims to elucidate the potential pathogenic and therapeutic roles of colonic tuft cells in inflammatory bowel disease and colorectal cancer, focusing on their primarily immunomodulatory action. Regarding inflammatory bowel disease, tuft cells are implicated in both maintaining the integrity of the intestinal epithelial barrier and in tissue repair and regeneration processes. In addition to maintaining intestinal homeostasis, they display complex immune-regulatory functions. During the development of colorectal cancer, tuft cells can promote the epithelial-to-mesenchymal transition, alter the gastrointestinal microenvironment, and modulate both the anti-tumor immune response and the tumor microenvironment. A wide variety of their biological functions can be targeted for anti-inflammatory or anti-tumor therapies; however, the adverse side effects of immunomodulatory actions must be strictly considered.
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Affiliation(s)
- Ferenc Sipos
- Immunology Division, Department of Internal Medicine and Hematology, Semmelweis University, 1088 Budapest, Hungary
| | - Györgyi Műzes
- Immunology Division, Department of Internal Medicine and Hematology, Semmelweis University, 1088 Budapest, Hungary
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6
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Drew DA, Kim AE, Lin Y, Qu C, Morrison J, Lewinger JP, Kawaguchi E, Wang J, Fu Y, Zemlianskaia N, Díez-Obrero V, Bien SA, Dimou N, Albanes D, Baurley JW, Wu AH, Buchanan DD, Potter JD, Prentice RL, Harlid S, Arndt V, Barry EL, Berndt SI, Bouras E, Brenner H, Budiarto A, Burnett-Hartman A, Campbell PT, Carreras-Torres R, Casey G, Chang-Claude J, Conti DV, Devall MA, Figueiredo JC, Gruber SB, Gsur A, Gunter MJ, Harrison TA, Hidaka A, Hoffmeister M, Huyghe JR, Jenkins MA, Jordahl KM, Kundaje A, Le Marchand L, Li L, Lynch BM, Murphy N, Nassir R, Newcomb PA, Newton CC, Obón-Santacana M, Ogino S, Ose J, Pai RK, Palmer JR, Papadimitriou N, Pardamean B, Pellatt AJ, Peoples AR, Platz EA, Rennert G, Ruiz-Narvaez E, Sakoda LC, Scacheri PC, Schmit SL, Schoen RE, Stern MC, Su YR, Thomas DC, Tian Y, Tsilidis KK, Ulrich CM, Um CY, van Duijnhoven FJ, Van Guelpen B, White E, Hsu L, Moreno V, Peters U, Chan AT, Gauderman WJ. Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer. SCIENCE ADVANCES 2024; 10:eadk3121. [PMID: 38809988 PMCID: PMC11135391 DOI: 10.1126/sciadv.adk3121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 04/26/2024] [Indexed: 05/31/2024]
Abstract
Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.
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Affiliation(s)
- David A. Drew
- Clinical & Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Andre E. Kim
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Yi Lin
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Conghui Qu
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - John Morrison
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Juan Pablo Lewinger
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Eric Kawaguchi
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Jun Wang
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Yubo Fu
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Natalia Zemlianskaia
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Virginia Díez-Obrero
- Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Stephanie A. Bien
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Niki Dimou
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - James W. Baurley
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia
- BioRealm LLC, Walnut, CA, USA
| | - Anna H. Wu
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Daniel D. Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010 Australia
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010 Australia
- Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - John D. Potter
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Research Centre for Hauora and Health, Massey University, Wellington, New Zealand
| | - Ross L. Prentice
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Sophia Harlid
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden
| | - Volker Arndt
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Elizabeth L. Barry
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA
| | - Sonja I. Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Emmanouil Bouras
- Laboratory of Hygiene, Social & Preventive Medicine and Medical Statistics, Department of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Arif Budiarto
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia
| | | | - Peter T. Campbell
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Robert Carreras-Torres
- Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
- Digestive Diseases and Microbiota Group, Girona Biomedical Research Institute (IDIBGI), Salt, 17190 Girona, Spain
| | - Graham Casey
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany
| | - David V. Conti
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Matthew A.M. Devall
- Department of Family Medicine, University of Virginia, Charlottesville, VA, USA
| | - Jane C. Figueiredo
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Stephen B. Gruber
- Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA
- Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, USA
| | - Andrea Gsur
- Center for Cancer Research, Medical University Vienna, Vienna, Austria
| | - Marc J. Gunter
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
- Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, UK
| | - Tabitha A. Harrison
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Akihisa Hidaka
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jeroen R. Huyghe
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Mark A. Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
| | - Kristina M. Jordahl
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
| | - Anshul Kundaje
- Department of Genetics, Stanford University, Stanford, CA, USA
- Department of Computer Science, Stanford University, Stanford, CA, USA
| | | | - Li Li
- Department of Family Medicine, University of Virginia, Charlottesville, VA, USA
- UVA Comprehensive Cancer Center, Charlottesville, VA, USA
| | - Brigid M. Lynch
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
| | - Neil Murphy
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Rami Nassir
- Department of Pathology, School of Medicine, Umm Al-Qura’a University, Mecca, Saudi Arabia
| | - Polly A. Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- School of Public Health, University of Washington, Seattle, WA, USA
| | | | - Mireia Obón-Santacana
- Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
- Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L’Hospitalet del Llobregat, 08908 Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain
| | - Shuji Ogino
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Jennifer Ose
- Huntsman Cancer Institute, Salt Lake City, UT, USA
- Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA
| | - Rish K. Pai
- Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Julie R. Palmer
- Slone Epidemiology Center at Boston University, Boston, MA, USA
| | - Nikos Papadimitriou
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Bens Pardamean
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia
| | - Andrew J. Pellatt
- Department of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anita R. Peoples
- Huntsman Cancer Institute, Salt Lake City, UT, USA
- Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA
| | - Elizabeth A. Platz
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Gad Rennert
- Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- Clalit National Cancer Control Center, Haifa, Israel
| | - Edward Ruiz-Narvaez
- Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Lori C. Sakoda
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Peter C. Scacheri
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA
| | - Stephanie L. Schmit
- Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA
- Population and Cancer Prevention Program, Case Comprehensive Cancer Center, Cleveland, OH, USA
| | - Robert E. Schoen
- Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Mariana C. Stern
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Yu-Ru Su
- Biostatistics Division, Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA
| | - Duncan C. Thomas
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Yu Tian
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- School of Public Health, Capital Medical University, Beijing, China
| | - Konstantinos K. Tsilidis
- Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, UK
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Cornelia M. Ulrich
- Huntsman Cancer Institute, Salt Lake City, UT, USA
- Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA
| | - Caroline Y. Um
- Department of Population Science, American Cancer Society, Atlanta, GA, USA
| | | | - Bethany Van Guelpen
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden
- Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - Emily White
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
| | - Li Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Biostatistics, University of Washington, Seattle, WA, USA
| | - Victor Moreno
- Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
- Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L’Hospitalet del Llobregat, 08908 Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain
- Department of Clinical Sciences, Faculty of Medicine and Health Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), University of Barcelona (UB), L’Hospitalet de Llobregat, 08908 Barcelona, Spain
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
| | - Andrew T. Chan
- Clinical & Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - W. James Gauderman
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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Bai JDK, Saha S, Wood M, Chen B, Li J, Dow LE, Montrose DC. Serine Supports Epithelial and Immune Cell Function in Colitis. THE AMERICAN JOURNAL OF PATHOLOGY 2024:S0002-9440(24)00071-3. [PMID: 38417696 DOI: 10.1016/j.ajpath.2024.01.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 12/28/2023] [Accepted: 01/29/2024] [Indexed: 03/01/2024]
Abstract
Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders of the gastrointestinal tract that are largely driven by immune cell activity; mucosal healing is critical for remission. Serine is a nonessential amino acid that supports epithelial and immune cell metabolism and proliferation; however, whether these roles affect IBD pathogenesis is not well understood. Here, we show that serine synthesis increases selectively in the epithelial cells of colons from patients with IBD and murine models of colitis. Inhibiting serine synthesis impairs colonic mucosal healing and increases susceptibility to acute injury in mice, effects associated with impaired epithelial cell proliferation. Dietary removal of serine similarly sensitizes mice to acute chemically induced colitis but ameliorates inflammation in chronic colitis models. The anti-inflammatory effect of exogenous serine depletion in chronic colitis is associated with mitochondrial dysfunction of macrophages, resulting in impaired nucleotide production and proliferation. Collectively, these results suggest that serine plays an important role in both epithelial and immune cell biology in the colon and that modulating its availability could affect IBD pathogenesis.
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Affiliation(s)
- Ji Dong K Bai
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York
| | - Suchandrima Saha
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York
| | - Michael Wood
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York
| | - Bo Chen
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York; Stony Brook Cancer Center, Stony Brook, New York
| | - Jinyu Li
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York
| | - Lukas E Dow
- Department of Medicine, Weill Cornell Medicine, New York, New York; Department of Biochemistry, Weill Cornell Medicine, New York, New York
| | - David C Montrose
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York; Stony Brook Cancer Center, Stony Brook, New York.
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8
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Rondeau LE, Da Luz BB, Santiago A, Bermudez-Brito M, Hann A, De Palma G, Jury J, Wang X, Verdu EF, Galipeau HJ, Rolland C, Deraison C, Ruf W, Bercik P, Vergnolle N, Caminero A. Proteolytic bacteria expansion during colitis amplifies inflammation through cleavage of the external domain of PAR2. Gut Microbes 2024; 16:2387857. [PMID: 39171684 PMCID: PMC11346554 DOI: 10.1080/19490976.2024.2387857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 07/03/2024] [Accepted: 07/23/2024] [Indexed: 08/23/2024] Open
Abstract
Imbalances in proteolytic activity have been linked to the development of inflammatory bowel diseases (IBD) and experimental colitis. Proteases in the intestine play important roles in maintaining homeostasis, but exposure of mucosal tissues to excess proteolytic activity can promote pathology through protease-activated receptors (PARs). Previous research implicates microbial proteases in IBD, but the underlying pathways and specific interactions between microbes and PARs remain unclear. In this study, we investigated the role of microbial proteolytic activation of the external domain of PAR2 in intestinal injury using mice expressing PAR2 with a mutated N-terminal external domain that is resistant to canonical activation by proteolytic cleavage. Our findings demonstrate the key role of proteolytic cleavage of the PAR2 external domain in promoting intestinal permeability and inflammation during colitis. In wild-type mice expressing protease-sensitive PAR2, excessive inflammation leads to the expansion of bacterial taxa that cleave the external domain of PAR2, exacerbating colitis severity. In contrast, mice expressing mutated protease-resistant PAR2 exhibit attenuated colitis severity and do not experience the same proteolytic bacterial expansion. Colonization of wild-type mice with proteolytic PAR2-activating Enterococcus and Staphylococcus worsens colitis severity. Our study identifies a previously unknown interaction between proteolytic bacterial communities, which are shaped by inflammation, and the external domain of PAR2 in colitis. The findings should encourage new therapeutic developments for IBD by targeting excessive PAR2 cleavage by bacterial proteases.
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Affiliation(s)
- Liam Emile Rondeau
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Bruna Barbosa Da Luz
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Alba Santiago
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Miriam Bermudez-Brito
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Amber Hann
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Giada De Palma
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Jennifer Jury
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Xuanyu Wang
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Elena Francisca Verdu
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Heather Jean Galipeau
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Corinne Rolland
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France
| | - Celine Deraison
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France
| | - Wolfram Ruf
- Center for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Center, Mainz, Germany
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA
| | - Premysl Bercik
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | | | - Alberto Caminero
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
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9
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Han H, Xie Q, Shao R, Li J, Du X. Alveolar macrophage-derived gVPLA2 promotes ventilator-induced lung injury via the cPLA2/PGE2 pathway. BMC Pulm Med 2023; 23:494. [PMID: 38057837 DOI: 10.1186/s12890-023-02793-x] [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: 09/08/2023] [Accepted: 11/28/2023] [Indexed: 12/08/2023] Open
Abstract
BACKGROUND Ventilator-induced lung injury (VILI) is a clinical complication of mechanical ventilation observed in patients with acute respiratory distress syndrome. It is characterized by inflammation mediated by inflammatory cells and their secreted mediators. METHODS To investigate the mechanisms underlying VILI, a C57BL/6J mouse model was induced using high tidal volume (HTV) mechanical ventilation. Mice were pretreated with Clodronate liposomes to deplete alveolar macrophages or administered normal bone marrow-derived macrophages or Group V phospholipase A2 (gVPLA2) intratracheally to inhibit bone marrow-derived macrophages. Lung tissue and bronchoalveolar lavage fluid (BALF) were collected to assess lung injury and measure Ca2 + concentration, gVPLA2, downstream phosphorylated cytoplasmic phospholipase A2 (p-cPLA2), prostaglandin E2 (PGE2), protein expression related to mitochondrial dynamics and mitochondrial damage. Cellular experiments were performed to complement the animal studies. RESULTS Depletion of alveolar macrophages attenuated HTV-induced lung injury and reduced gVPLA2 levels in alveolar lavage fluid. Similarly, inhibition of alveolar macrophage-derived gVPLA2 had a similar effect. Activation of the cPLA2/PGE2/Ca2 + pathway in alveolar epithelial cells by gVPLA2 derived from alveolar macrophages led to disturbances in mitochondrial dynamics and mitochondrial dysfunction. The findings from cellular experiments were consistent with those of animal experiments. CONCLUSIONS HTV mechanical ventilation induces the secretion of gVPLA2 by alveolar macrophages, which activates the cPLA2/PGE2/Ca2 + pathway, resulting in mitochondrial dysfunction. These findings provide insights into the pathogenesis of VILI and may contribute to the development of therapeutic strategies for preventing or treating VILI.
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Affiliation(s)
- Hanghang Han
- Department of Anesthesiology, The Second Affiliated Hospital of Guangxi Medical University, 166 East University Road, Nanning, Guangxi, 530007, China
- Guangxi Clinical Research Center for Anesthesiology, Guangxi Engineering Research Center for Tissue & Organ Injury and Repair Medicine, Guangxi Key Laboratory for Basic Science and Prevention of Perioperative Organ Disfunction, Guangxi Medical University Cancer Hospital, Guangxi Medical University Cancer Hospital, Guangxi Medical University Cancer Hospital, Nanning, 530021, China
| | - Qiuwen Xie
- Department of Anesthesiology, The Second Affiliated Hospital of Guangxi Medical University, 166 East University Road, Nanning, Guangxi, 530007, China
- Guangxi Clinical Research Center for Anesthesiology, Guangxi Engineering Research Center for Tissue & Organ Injury and Repair Medicine, Guangxi Key Laboratory for Basic Science and Prevention of Perioperative Organ Disfunction, Guangxi Medical University Cancer Hospital, Guangxi Medical University Cancer Hospital, Guangxi Medical University Cancer Hospital, Nanning, 530021, China
| | - Rongge Shao
- Department of Anesthesiology, The Second Affiliated Hospital of Guangxi Medical University, 166 East University Road, Nanning, Guangxi, 530007, China
- Guangxi Clinical Research Center for Anesthesiology, Guangxi Engineering Research Center for Tissue & Organ Injury and Repair Medicine, Guangxi Key Laboratory for Basic Science and Prevention of Perioperative Organ Disfunction, Guangxi Medical University Cancer Hospital, Guangxi Medical University Cancer Hospital, Guangxi Medical University Cancer Hospital, Nanning, 530021, China
| | - Jinju Li
- Department of Anesthesiology, The Second Affiliated Hospital of Guangxi Medical University, 166 East University Road, Nanning, Guangxi, 530007, China
- Guangxi Clinical Research Center for Anesthesiology, Guangxi Engineering Research Center for Tissue & Organ Injury and Repair Medicine, Guangxi Key Laboratory for Basic Science and Prevention of Perioperative Organ Disfunction, Guangxi Medical University Cancer Hospital, Guangxi Medical University Cancer Hospital, Guangxi Medical University Cancer Hospital, Nanning, 530021, China
| | - Xueke Du
- Department of Anesthesiology, The Second Affiliated Hospital of Guangxi Medical University, 166 East University Road, Nanning, Guangxi, 530007, China.
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10
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Santangelo B, Bada M, Hunter L, Lozupone C. Hypothesizing mechanistic links between microbes and disease using knowledge graphs. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.01.569645. [PMID: 38106100 PMCID: PMC10723325 DOI: 10.1101/2023.12.01.569645] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2023]
Abstract
Knowledge graphs have found broad biomedical applications, providing useful representations of complex knowledge. Although plentiful evidence exists linking the gut microbiome to disease, mechanistic understanding of those relationships remains generally elusive. Here we demonstrate the potential of knowledge graphs to hypothesize plausible mechanistic accounts of host-microbe interactions in disease. To do so, we constructed a knowledge graph of linked microbes, genes and metabolites called MGMLink. Using a semantically constrained shortest path search through the graph and a novel path prioritization methodology based on cosine similarity, we show that this knowledge supports inference of mechanistic hypotheses that explain observed relationships between microbes and disease phenotypes. We discuss specific applications of this methodology in inflammatory bowel disease and Parkinson's disease. This approach enables mechanistic hypotheses surrounding the complex interactions between gut microbes and disease to be generated in a scalable and comprehensive manner.
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11
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Lobos-González L, Oróstica L, Díaz-Valdivia N, Rojas-Celis V, Campos A, Duran-Jara E, Farfán N, Leyton L, Quest AFG. Prostaglandin E2 Exposure Disrupts E-Cadherin/Caveolin-1-Mediated Tumor Suppression to Favor Caveolin-1-Enhanced Migration, Invasion, and Metastasis in Melanoma Models. Int J Mol Sci 2023; 24:16947. [PMID: 38069269 PMCID: PMC10707163 DOI: 10.3390/ijms242316947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 10/20/2023] [Accepted: 10/27/2023] [Indexed: 12/18/2023] Open
Abstract
Caveolin-1 (CAV1) is a membrane-bound protein that suppresses tumor development yet also promotes metastasis. E-cadherin is important in CAV1-dependent tumor suppression and prevents CAV1-enhanced lung metastasis. Here, we used murine B16F10 and human A375 melanoma cells with low levels of endogenous CAV1 and E-cadherin to unravel how co-expression of E-cadherin modulates CAV1 function in vitro and in vivo in WT C57BL/6 or Rag-/- immunodeficient mice and how a pro-inflammatory environment generated by treating cells with prostaglandin E2 (PGE2) alters CAV1 function in the presence of E-cadherin. CAV1 expression augmented migration, invasion, and metastasis of melanoma cells, and these effects were abolished via transient co-expression of E-cadherin. Importantly, exposure of cells to PGE2 reverted the effects of E-cadherin expression and increased CAV1 phosphorylation on tyrosine-14 and metastasis. Moreover, PGE2 administration blocked the ability of the CAV1/E-cadherin complex to prevent tumor formation. Therefore, our results support the notion that PGE2 can override the tumor suppressor potential of the E-cadherin/CAV1 complex and that CAV1 released from the complex is phosphorylated on tyrosine-14 and promotes migration/invasion/metastasis. These observations provide direct evidence showing how a pro-inflammatory environment caused here via PGE2 administration can convert a potent tumor suppressor complex into a promoter of malignant cell behavior.
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Affiliation(s)
- Lorena Lobos-González
- Centro de Medicina Regenerativa, Facultad de Medicina-Clínica Alemana, Universidad del Desarrollo, Avenida Lo Plaza 680, Las Condes 7610658, Chile; (L.L.-G.); (E.D.-J.)
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380494, Chile; (N.D.-V.); (V.R.-C.); (A.C.)
| | - Lorena Oróstica
- Laboratory of Cellular Communication, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Program of Cell and Molecular Biology, Biomedical Sciences Institute (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile;
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad Diego Portales, Santiago 8370007, Chile
| | - Natalia Díaz-Valdivia
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380494, Chile; (N.D.-V.); (V.R.-C.); (A.C.)
- Laboratory of Cellular Communication, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Program of Cell and Molecular Biology, Biomedical Sciences Institute (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile;
| | - Victoria Rojas-Celis
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380494, Chile; (N.D.-V.); (V.R.-C.); (A.C.)
- Laboratory of Cellular Communication, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Program of Cell and Molecular Biology, Biomedical Sciences Institute (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile;
| | - America Campos
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380494, Chile; (N.D.-V.); (V.R.-C.); (A.C.)
- CRUK Scotland Institute, Glasgow G61 1BD, UK
| | - Eduardo Duran-Jara
- Centro de Medicina Regenerativa, Facultad de Medicina-Clínica Alemana, Universidad del Desarrollo, Avenida Lo Plaza 680, Las Condes 7610658, Chile; (L.L.-G.); (E.D.-J.)
- Subdepartamento Genética Molecular, Instituto de Salud Pública de Chile, Santiago 7780050, Chile
| | - Nicole Farfán
- Cancer and ncRNAs Laboratory, Universidad Andres Bello, Santiago 7550611, Chile;
| | - Lisette Leyton
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380494, Chile; (N.D.-V.); (V.R.-C.); (A.C.)
- Laboratory of Cellular Communication, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Program of Cell and Molecular Biology, Biomedical Sciences Institute (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile;
| | - Andrew F. G. Quest
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380494, Chile; (N.D.-V.); (V.R.-C.); (A.C.)
- Laboratory of Cellular Communication, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Program of Cell and Molecular Biology, Biomedical Sciences Institute (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile;
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12
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Bohusné Barta B, Sipos F, Műzes G. [Characteristics of intestinal tuft cells and their role in the pathomechanism of inflammatory bowel disease and colorectal carcinoma]. Orv Hetil 2023; 164:1727-1735. [PMID: 37930381 DOI: 10.1556/650.2023.32898] [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: 07/22/2023] [Accepted: 08/20/2023] [Indexed: 11/07/2023]
Abstract
Given their fundamental physiological importance, their involvement in the immune system, and their close association with the development of intestinal diseases, the interest in intestinal epithelial cells has increased significantly over the past fifteen years. Their close association with intestinal worm and protozoan infections - a significant 2016 discovery - has further stimulated research into uncommon chemosensitive tuft epithelial cells. Although their numbers are relatively low, tuft cells are now recognized as an essential sentinel of the gastrointestinal tract, as their taste receptors for succinate, sweet, and bitter continuously monitor intestinal contents. When stimulated, tuft cells release a number of effector molecules, including immunomodulatory molecules like interleukin 25, prostaglandins E2 and D2, cysteinyl leukotriene C4, acetylcholine, thymic stromal lymphopoietin, and beta-endorphins. Tuft cells have been shown to be crucial for immunity against nematodes and protozoa. The majority of tuft cell research has used the doublecortin-like (microtubule-linked) kinase 1 protein marker on mice; however, the expression of the enzyme cyclooxygenase-1 may help identify human intestinal tuft cells. Few studies have examined the association between tuft cells and intestinal diseases in humans. This article provides an update on intestinal epithelial tuft cells, including their physiology, immunological nodal function, and role in human diseases. We conclude by discussing the potential clinical therapeutic value of tuft cells. Orv Hetil. 2023; 164(44): 1727-1735.
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Affiliation(s)
- Bettina Bohusné Barta
- 1 Semmelweis Egyetem, Általános Orvostudományi Kar, I. Sz. Patológiai és Rákkutató Intézet Budapest, Üllői út 26., 1085 Magyarország
| | - Ferenc Sipos
- 2 Semmelweis Egyetem, Általános Orvostudományi Kar, Belgyógyászati és Hematológiai Klinika Budapest Magyarország
| | - Györgyi Műzes
- 2 Semmelweis Egyetem, Általános Orvostudományi Kar, Belgyógyászati és Hematológiai Klinika Budapest Magyarország
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13
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Zhang L, Tang R, Wu Y, Liang Z, Liu J, Pi J, Zhang H. The Role and Mechanism of Retinol and Its Transformation Product, Retinoic Acid, in Modulating Oxidative Stress-Induced Damage to the Duck Intestinal Epithelial Barrier In Vitro. Animals (Basel) 2023; 13:3098. [PMID: 37835704 PMCID: PMC10572057 DOI: 10.3390/ani13193098] [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: 08/24/2023] [Revised: 09/24/2023] [Accepted: 09/28/2023] [Indexed: 10/15/2023] Open
Abstract
This study aimed to investigate the effects and mechanisms of retinol and retinoic acid on primary duck intestinal epithelial cells under oxidative stress induced by H2O2. Different ratios of retinol and retinoic acid were used for treatment. The study evaluated the cell morphology, viability, antioxidative capacity, and barrier function of cells. The expression of genes related to oxidative stress and the intestinal barrier was analyzed. The main findings demonstrated that the treated duck intestinal epithelial cells exhibited increased viability, increased antioxidative capacity, and improved intestinal barrier function compared to the control group. High retinoic acid treatment improved viability and gene expression, while high retinol increased antioxidative indicators and promoted intestinal barrier repair. Transcriptome analysis revealed the effects of treatments on cytokine interactions, retinol metabolism, PPAR signaling, and cell adhesion. In conclusion, this study highlights the potential of retinol and retinoic acid in protecting and improving intestinal cell health under oxidative stress, providing valuable insights for future research.
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Affiliation(s)
- Li Zhang
- Institute of Animal Husbandry and Veterinary Science, Hubei Academy of Agricultural Sciences, Wuhan 430064, China; (L.Z.); (R.T.); (Y.W.); (Z.L.); (J.P.)
- School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang 621010, China;
| | - Rui Tang
- Institute of Animal Husbandry and Veterinary Science, Hubei Academy of Agricultural Sciences, Wuhan 430064, China; (L.Z.); (R.T.); (Y.W.); (Z.L.); (J.P.)
- School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang 621010, China;
| | - Yan Wu
- Institute of Animal Husbandry and Veterinary Science, Hubei Academy of Agricultural Sciences, Wuhan 430064, China; (L.Z.); (R.T.); (Y.W.); (Z.L.); (J.P.)
| | - Zhenhua Liang
- Institute of Animal Husbandry and Veterinary Science, Hubei Academy of Agricultural Sciences, Wuhan 430064, China; (L.Z.); (R.T.); (Y.W.); (Z.L.); (J.P.)
| | - Jingbo Liu
- School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang 621010, China;
| | - Jinsong Pi
- Institute of Animal Husbandry and Veterinary Science, Hubei Academy of Agricultural Sciences, Wuhan 430064, China; (L.Z.); (R.T.); (Y.W.); (Z.L.); (J.P.)
| | - Hao Zhang
- Institute of Animal Husbandry and Veterinary Science, Hubei Academy of Agricultural Sciences, Wuhan 430064, China; (L.Z.); (R.T.); (Y.W.); (Z.L.); (J.P.)
- Hubei Key Laboratory of Animal Embryo Engineering and Molecular Breeding, Wuhan 430064, China
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14
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Yang H, Rothenberger E, Zhao T, Fan W, Kelly A, Attaya A, Fan D, Panigrahy D, Deng J. Regulation of inflammation in cancer by dietary eicosanoids. Pharmacol Ther 2023:108455. [PMID: 37257760 DOI: 10.1016/j.pharmthera.2023.108455] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/16/2023] [Accepted: 05/22/2023] [Indexed: 06/02/2023]
Abstract
BACKGROUND Cancer is a major burden of disease worldwide and increasing evidence shows that inflammation contributes to cancer development and progression. Eicosanoids are derived from dietary polyunsaturated fatty acids, such as arachidonic acid (AA), and are mainly produced by a series of enzymatic pathways that include cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P-450 epoxygenase (CYP). Eicosanoids consist of at least several hundred individual molecules and play important roles in the inflammatory response and inflammation-related cancers. SCOPE AND APPROACH Dietary sources of AA and biosynthesis of eicosanoids from AA through different metabolic pathways are summarized. The bioactivities of eicosanoids and their potential molecular mechanisms on inflammation and cancer are revealed. Additionally, current challenges and limitations in eicosanoid research on inflammation-related cancer are discussed. KEY FINDINGS AND CONCLUSIONS Dietary AA generates a large variety of eicosanoids, including prostaglandins, thromboxane A2, leukotrienes, cysteinyl leukotrienes, lipoxins, hydroxyeicosatetraenoic acids (HETEs), and epoxyeicosatrienoic acids (EETs). Eicosanoids exert different bioactivities and mechanisms involved in the inflammation and related cancer developments. A deeper understanding of eicosanoid biology may be advantageous in cancer treatment and help to define cellular targets for further therapeutic development.
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Affiliation(s)
- Haixia Yang
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China.
| | - Eva Rothenberger
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Tong Zhao
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Wendong Fan
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Abigail Kelly
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Ahmed Attaya
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Daidi Fan
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an 710069, China
| | - Dipak Panigrahy
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
| | - Jianjun Deng
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an 710069, China; State Key Laboratory of Vegetable Biobreeding, Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing 100081, China.
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15
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Cao Q, Mertens RT, Sivanathan KN, Cai X, Xiao P. Macrophage orchestration of epithelial and stromal cell homeostasis in the intestine. J Leukoc Biol 2022; 112:313-331. [PMID: 35593111 PMCID: PMC9543232 DOI: 10.1002/jlb.3ru0322-176r] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/29/2022] [Accepted: 05/02/2022] [Indexed: 11/06/2022] Open
Abstract
The intestinal tract is a complex ecosystem where numerous cell types of epithelial, immune, neuronal, and endothelial origin coexist in an intertwined, highly organized manner. The functional equilibrium of the intestine relies heavily on the proper crosstalk and cooperation among each cell population. Furthermore, macrophages are versatile, innate immune cells that participate widely in the modulation of inflammation and tissue remodeling. Emerging evidence suggest that macrophages are central in orchestrating tissue homeostasis. Herein, we describe how macrophages interact with epithelial cells, neurons, and other types of mesenchymal cells under the context of intestinal inflammation, followed by the therapeutic implications of cellular crosstalk pertaining to the treatment of inflammatory bowel disease.
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Affiliation(s)
- Qian Cao
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Randall Tyler Mertens
- Department of Immunology, Harvard Medical School, Boston, Massachusetts, USA.,Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Kisha Nandini Sivanathan
- Department of Immunology, Harvard Medical School, Boston, Massachusetts, USA.,Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Xuechun Cai
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Peng Xiao
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Department of Immunology, Harvard Medical School, Boston, Massachusetts, USA.,Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.,The Key Laboratory for Immunity and Inflammatory Diseases of Zhejiang Province, Hangzhou, China.,Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China
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16
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Chukwunyere U, Mercan M, Sehirli AO, Abacioglu N. Possible cytoprotective mechanisms of oxytocin against 5-fluorouracil-induced gastrointestinal mucositis. Mol Biol Rep 2022; 49:4055-4059. [PMID: 35474056 DOI: 10.1007/s11033-022-07384-3] [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: 02/03/2022] [Revised: 03/15/2022] [Accepted: 03/16/2022] [Indexed: 11/27/2022]
Abstract
Gastrointestinal mucositis is a common and dose-limiting side effect characterized by ulcerative lesions in the mucosa of the digestive tract in patients receiving anticancer drugs such as 5-fluorouracil (5-FU), a potent antineoplastic drug. Several protocols have reported the efficacy of therapeutic interventions to prevent this side effect, although complete success has not yet been achieved and mucositis remains one of the most serious complications associated with 5-FU therapy. Oxytocin, a well-known antistress agent, has been reported to have comparable effects to ranitidine. Previous studies have shown that oxytocin inhibits gastric acid secretion and the expression of proinflammatory cytokines in rats. If oxytocin can reduce stress-induced ulcers via antioxidant, antiapoptotic, and anti-inflammatory pathways, then it may have a dose-dependent effect on gastrointestinal mucositis caused by 5-FU.
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Affiliation(s)
- Ugochukwu Chukwunyere
- Department of Pharmacology, Faculty of Pharmacy, Near East University, 99138, Lefkosa, TRNC, Turkey.
| | - Merve Mercan
- Department of Pharmacology, Faculty of Pharmacy, Near East University, 99138, Lefkosa, TRNC, Turkey
| | - Ahmet Ozer Sehirli
- Department of Pharmacology, Faculty of Dentistry, Near East University, Lefkosa, TRNC, Turkey
| | - Nurettin Abacioglu
- Department of Pharmacology, Faculty of Pharmacy, Near East University, 99138, Lefkosa, TRNC, Turkey
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17
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Tsiantas K, Konteles SJ, Kritsi E, Sinanoglou VJ, Tsiaka T, Zoumpoulakis P. Effects of Non-Polar Dietary and Endogenous Lipids on Gut Microbiota Alterations: The Role of Lipidomics. Int J Mol Sci 2022; 23:ijms23084070. [PMID: 35456888 PMCID: PMC9024800 DOI: 10.3390/ijms23084070] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 02/25/2022] [Accepted: 03/31/2022] [Indexed: 02/07/2023] Open
Abstract
Advances in sequencing technologies over the past 15 years have led to a substantially greater appreciation of the importance of the gut microbiome to the health of the host. Recent outcomes indicate that aspects of nutrition, especially lipids (exogenous or endogenous), can influence the gut microbiota composition and consequently, play an important role in the metabolic health of the host. Thus, there is an increasing interest in applying holistic analytical approaches, such as lipidomics, metabolomics, (meta)transcriptomics, (meta)genomics, and (meta)proteomics, to thoroughly study the gut microbiota and any possible interplay with nutritional or endogenous components. This review firstly summarizes the general background regarding the interactions between important non-polar dietary (i.e., sterols, fat-soluble vitamins, and carotenoids) or amphoteric endogenous (i.e., eicosanoids, endocannabinoids-eCBs, and specialized pro-resolving mediators-SPMs) lipids and gut microbiota. In the second stage, through the evaluation of a vast number of dietary clinical interventions, a comprehensive effort is made to highlight the role of the above lipid categories on gut microbiota and vice versa. In addition, the present status of lipidomics in current clinical interventions as well as their strengths and limitations are also presented. Indisputably, dietary lipids and most phytochemicals, such as sterols and carotenoids, can play an important role on the development of medical foods or nutraceuticals, as they exert prebiotic-like effects. On the other hand, endogenous lipids can be considered either prognostic indicators of symbiosis or dysbiosis or even play a role as specialized mediators through dietary interventions, which seem to be regulated by gut microbiota.
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Affiliation(s)
- Konstantinos Tsiantas
- Department of Food Science and Technology, University of West Attica, Ag. Spyridonos, 12243 Egaleo, Greece; (K.T.); (S.J.K.); (E.K.); (V.J.S.)
| | - Spyridon J. Konteles
- Department of Food Science and Technology, University of West Attica, Ag. Spyridonos, 12243 Egaleo, Greece; (K.T.); (S.J.K.); (E.K.); (V.J.S.)
| | - Eftichia Kritsi
- Department of Food Science and Technology, University of West Attica, Ag. Spyridonos, 12243 Egaleo, Greece; (K.T.); (S.J.K.); (E.K.); (V.J.S.)
| | - Vassilia J. Sinanoglou
- Department of Food Science and Technology, University of West Attica, Ag. Spyridonos, 12243 Egaleo, Greece; (K.T.); (S.J.K.); (E.K.); (V.J.S.)
| | - Thalia Tsiaka
- Department of Food Science and Technology, University of West Attica, Ag. Spyridonos, 12243 Egaleo, Greece; (K.T.); (S.J.K.); (E.K.); (V.J.S.)
- Institute of Chemical Biology, National Hellenic Research Foundation, 48, Vas. Constantinou Ave., 11635 Athens, Greece
- Correspondence: (T.T.); (P.Z.)
| | - Panagiotis Zoumpoulakis
- Department of Food Science and Technology, University of West Attica, Ag. Spyridonos, 12243 Egaleo, Greece; (K.T.); (S.J.K.); (E.K.); (V.J.S.)
- Institute of Chemical Biology, National Hellenic Research Foundation, 48, Vas. Constantinou Ave., 11635 Athens, Greece
- Correspondence: (T.T.); (P.Z.)
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18
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Hendel SK, Kellermann L, Hausmann A, Bindslev N, Jensen KB, Nielsen OH. Tuft Cells and Their Role in Intestinal Diseases. Front Immunol 2022; 13:822867. [PMID: 35237268 PMCID: PMC8884241 DOI: 10.3389/fimmu.2022.822867] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 01/25/2022] [Indexed: 12/11/2022] Open
Abstract
The interests in intestinal epithelial tuft cells, their basic physiology, involvement in immune responses and relevance for gut diseases, have increased dramatically over the last fifteen years. A key discovery in 2016 of their close connection to helminthic and protozoan infection has further spurred the exploration of these rare chemosensory epithelial cells. Although very sparse in number, tuft cells are now known as important sentinels in the gastrointestinal tract as they monitor intestinal content using succinate as well as sweet and bitter taste receptors. Upon stimulation, tuft cells secrete a broad palette of effector molecules, including interleukin-25, prostaglandin E2 and D2, cysteinyl leukotriene C4, acetylcholine, thymic stromal lymphopoietin, and β-endorphins, some of which with immunomodulatory functions. Tuft cells have proven indispensable in anti-helminthic and anti-protozoan immunity. Most studies on tuft cells are based on murine experiments using double cortin-like kinase 1 (DCLK1) as a marker, while human intestinal tuft cells can be identified by their expression of the cyclooxygenase-1 enzyme. So far, only few studies have examined tuft cells in humans and their relation to gut disease. Here, we present an updated view on intestinal epithelial tuft cells, their physiology, immunological hub function, and their involvement in human disease. We close with a discussion on how tuft cells may have potential therapeutic value in a clinical context.
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Affiliation(s)
- Sebastian Kjærgaard Hendel
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Herlev, Denmark
- *Correspondence: Sebastian Kjærgaard Hendel,
| | - Lauge Kellermann
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Annika Hausmann
- Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Niels Bindslev
- Department of Biomedical Sciences , University of Copenhagen, Copenhagen, Denmark
| | - Kim Bak Jensen
- Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
| | - Ole Haagen Nielsen
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Herlev, Denmark
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19
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Kojima F, Sekiya H, Hioki Y, Kashiwagi H, Kubo M, Nakamura M, Maehana S, Imamichi Y, Yuhki KI, Ushikubi F, Kitasato H, Ichikawa T. Facilitation of colonic T cell immune responses is associated with an exacerbation of dextran sodium sulfate-induced colitis in mice lacking microsomal prostaglandin E synthase-1. Inflamm Regen 2022; 42:1. [PMID: 34983695 PMCID: PMC8725565 DOI: 10.1186/s41232-021-00188-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 12/07/2021] [Indexed: 12/24/2022] Open
Abstract
Background Microsomal prostaglandin E synthase-1 (mPGES-1) is a key enzyme that acts downstream of cyclooxygenase and plays a major role in inflammation by converting prostaglandin (PG) H2 to PGE2. The present study investigated the effect of genetic deletion of mPGES-1 on the development of immunologic responses to experimental colitis induced by dextran sodium sulfate (DSS), a well-established model of inflammatory bowel disease (IBD). Methods Colitis was induced in mice lacking mPGES-1 (mPGES-1−/− mice) and wild-type (WT) mice by administering DSS for 7 days. Colitis was assessed by body weight loss, diarrhea, fecal bleeding, and histological features. The colonic expression of mPGES-1 was determined by real-time PCR, western blotting, and immunohistochemistry. The impact of mPGES-1 deficiency on T cell immunity was determined by flow cytometry and T cell depletion in vivo. Results After administration of DSS, mPGES-1−/− mice exhibited more severe weight loss, diarrhea, and fecal bleeding than WT mice. Histological analysis further showed significant exacerbation of colonic inflammation in mPGES-1−/− mice. In WT mice, the colonic expression of mPGES-1 was highly induced on both mRNA and protein levels and colonic PGE2 increased significantly after DSS administration. Additionally, mPGES-1 protein was localized in the colonic mucosal epithelium and infiltrated inflammatory cells in underlying connective tissues and the lamina propria. The abnormalities consistent with colitis in mPGES-1−/− mice were associated with higher expression of colonic T-helper (Th)17 and Th1 cytokines, including interleukin 17A and interferon-γ. Furthermore, lack of mPGES-1 increased the numbers of Th17 and Th1 cells in the lamina propria mononuclear cells within the colon, even though the number of suppressive regulatory T cells also increased. CD4+ T cell depletion effectively reduced symptoms of colitis as well as colonic expression of Th17 and Th1 cytokines in mPGES-1−/− mice, suggesting the requirement of CD4+ T cells in the exacerbation of DSS-induced colitis under mPGES-1 deficiency. Conclusions These results demonstrate that mPGES-1 is the main enzyme responsible for colonic PGE2 production and deficiency of mPGES-1 facilitates the development of colitis by affecting the development of colonic T cell–mediated immunity. mPGES-1 might therefore impact both the intestinal inflammation and T cell–mediated immunity associated with IBD. Supplementary Information The online version contains supplementary material available at 10.1186/s41232-021-00188-1.
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Affiliation(s)
- Fumiaki Kojima
- Department of Pharmacology, Kitasato University School of Allied Health Sciences, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan. .,Department of Regulation Biochemistry, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan. .,Regenerative Medicine and Cell Design Research Facility, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan.
| | - Hiroki Sekiya
- Department of Regulation Biochemistry, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan
| | - Yuka Hioki
- Department of Pharmacology, Kitasato University School of Allied Health Sciences, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan
| | - Hitoshi Kashiwagi
- Department of Pharmacology, Asahikawa Medical University, 2-1-1-1 Midorigaoka higashi, Asahikawa, 078-8510, Japan
| | - Makoto Kubo
- Regenerative Medicine and Cell Design Research Facility, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan.,Division of Clinical Immunology, Graduate School of Medical Sciences, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0373, Japan
| | - Masaki Nakamura
- Regenerative Medicine and Cell Design Research Facility, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan.,Department of Environmental Microbiology, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan
| | - Shotaro Maehana
- Regenerative Medicine and Cell Design Research Facility, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan.,Department of Environmental Microbiology, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan
| | - Yoshitaka Imamichi
- Department of Pharmacology, Asahikawa Medical University, 2-1-1-1 Midorigaoka higashi, Asahikawa, 078-8510, Japan
| | - Koh-Ichi Yuhki
- Department of Pharmacology, Asahikawa Medical University, 2-1-1-1 Midorigaoka higashi, Asahikawa, 078-8510, Japan
| | - Fumitaka Ushikubi
- Department of Pharmacology, Asahikawa Medical University, 2-1-1-1 Midorigaoka higashi, Asahikawa, 078-8510, Japan
| | - Hidero Kitasato
- Regenerative Medicine and Cell Design Research Facility, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan.,Department of Environmental Microbiology, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan
| | - Takafumi Ichikawa
- Department of Regulation Biochemistry, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan.,Regenerative Medicine and Cell Design Research Facility, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan
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20
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Wu W, Li WX, Huang CH. Phospholipase A 2, a nonnegligible enzyme superfamily in gastrointestinal diseases. Biochimie 2021; 194:79-95. [PMID: 34974145 DOI: 10.1016/j.biochi.2021.12.014] [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: 07/03/2021] [Revised: 12/25/2021] [Accepted: 12/28/2021] [Indexed: 11/16/2022]
Abstract
Gastrointestinal tract is important for digestion, absorption, detoxification and immunity. Gastrointestinal diseases are mainly caused by the imbalance of protective and attacking factors in gastrointestinal mucosa, which can seriously harm human health. Phospholipase A2 (PLA2) is a large family closely involved in lipid metabolism and is found in almost all human cells. A growing number of studies have revealed that its metabolites are deeply implicated in various inflammatory pathways and also regulates the maintenance of numerous biological events such as dietary digestion, membrane remodeling, barrier action, and host immunity. In addition to their phospholipase activity, some members of the superfamily also have other catalytic activities. Based on the in-depth effects of phospholipase A2 on bioactive lipid metabolism and inflammatory cytokines, PLA2 and its metabolites are likely to be involved in the pathogenesis, development or prevention of gastrointestinal diseases. Therefore, this review will focus on the physiological and pathogenic roles of several important PLA2 enzymes in the gastrointestinal tract, and reveals the potential of PLA2 as a therapeutic target for gastrointestinal diseases.
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Affiliation(s)
- Wei Wu
- Queen Mary School, Medical Department, Nanchang University, Nanchang, Jiangxi, China
| | - Wen-Xuan Li
- Queen Mary School, Medical Department, Nanchang University, Nanchang, Jiangxi, China
| | - Chun-Hong Huang
- School of Basic Medical Sciences, 330006, Nanchang University, Nanchang, Jiangxi, China.
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21
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Frigerio S, Lartey DA, D’Haens GR, Grootjans J. The Role of the Immune System in IBD-Associated Colorectal Cancer: From Pro to Anti-Tumorigenic Mechanisms. Int J Mol Sci 2021; 22:12739. [PMID: 34884543 PMCID: PMC8657929 DOI: 10.3390/ijms222312739] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 11/18/2021] [Accepted: 11/23/2021] [Indexed: 12/12/2022] Open
Abstract
Patients with inflammatory bowel disease (IBD) have increased incidence of colorectal cancer (CRC). IBD-associated cancer follows a well-characterized sequence of intestinal epithelial changes, in which genetic mutations and molecular aberrations play a key role. IBD-associated cancer develops against a background of chronic inflammation and pro-inflammatory immune cells, and their products contribute to cancer development and progression. In recent years, the effect of the immunosuppressive microenvironment in cancer development and progression has gained more attention, mainly because of the unprecedented anti-tumor effects of immune checkpoint inhibitors in selected groups of patients. Even though IBD-associated cancer develops in the background of chronic inflammation which is associated with activation of endogenous anti-inflammatory or suppressive mechanisms, the potential role of an immunosuppressive microenvironment in these cancers is largely unknown. In this review, we outline the role of the immune system in promoting cancer development in chronic inflammatory diseases such as IBD, with a specific focus on the anti-inflammatory mechanisms and suppressive immune cells that may play a role in IBD-associated tumorigenesis.
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Affiliation(s)
- Sofía Frigerio
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, Location AMC, 1105 AZ Amsterdam, The Netherlands; (S.F.); (D.A.L.); (G.R.D.)
- Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, Location AMC, 1105 AZ Amsterdam, The Netherlands
| | - Dalia A. Lartey
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, Location AMC, 1105 AZ Amsterdam, The Netherlands; (S.F.); (D.A.L.); (G.R.D.)
- Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, Location AMC, 1105 AZ Amsterdam, The Netherlands
| | - Geert R. D’Haens
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, Location AMC, 1105 AZ Amsterdam, The Netherlands; (S.F.); (D.A.L.); (G.R.D.)
| | - Joep Grootjans
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, Location AMC, 1105 AZ Amsterdam, The Netherlands; (S.F.); (D.A.L.); (G.R.D.)
- Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, Location AMC, 1105 AZ Amsterdam, The Netherlands
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22
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Suman S, Kumar S, Moon BH, Angdisen J, Kallakury BVS, Datta K, Fornace AJ. Effects of dietary aspirin on high-LET radiation-induced prostaglandin E2 levels and gastrointestinal tumorigenesis in Apc 1638N/+ mice. LIFE SCIENCES IN SPACE RESEARCH 2021; 31:85-91. [PMID: 34689954 PMCID: PMC9808916 DOI: 10.1016/j.lssr.2021.09.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 08/18/2021] [Accepted: 09/03/2021] [Indexed: 05/21/2023]
Abstract
Inevitable exposure to high-LET ionizing radiation (IR) present in galactic cosmic radiation (GCR) could enhance gastrointestinal (GI) cancer incidence among astronauts undertaking deep space exploration and GI-cancer mortality has been predicted to far exceed NASA's limit of < 3% REID (Radiation exposure-induced death) from cancer. Therefore, the development of countermeasure agents against high-LET radiation-induced GI cancer is needed to safeguard astronauts during and after an outer space mission. The cyclooxygenase-2/prostaglandin E2 (COX2/PGE2) mediated activation of pro-inflammatory and oncogenic signaling has been reported to play an important role in persistent inflammation and GI-tumorigenesis after high-LET radiation exposure. Therefore, aspirin, a well-known inhibitor of the COX/PGE2 pathway, was evaluated as a potential countermeasure against 28Si-induced PGE2 and tumorigenesis in Apc1638N/+, a murine model of human GI-cancer. Animals were fed either standard or aspirin supplemented diet (75, 150, or 300 mg/day of human equivalent dose) starting at the age of 4 weeks and continued till the end of the study, while mice were exposed to 28Si-ions (300 MeV/n; 69 keV/μm) at the age of 8 weeks. Serum PGE2 level, GI tumor size (>2mm2), number, and cluster (>5 adjoining tumors) were analyzed at 150 days post-exposure. Aspirin led to a significant reduction in PGE2 in a dose-dependent manner but did not reduce 28Si-induced GI tumorigenesis even at the highest (300 mg/day) dose. In summary, this study suggests that aspirin could reduce high-LET IR-induced pro-inflammatory PGE2 levels, however, lacks the ability to reduce high-LET IR-induced GI tumorigenesis in Apc1638N/+ mice.
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Affiliation(s)
- Shubhankar Suman
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
| | - Santosh Kumar
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Bo-Hyun Moon
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Jerry Angdisen
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | | | - Kamal Datta
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA; Department of Biochemistry and Molecular & Cellular Biology and Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Albert J Fornace
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA; Department of Biochemistry and Molecular & Cellular Biology and Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA
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23
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Rosa W, da Silva Domingos O, de Oliveira Salem PP, Caldas IS, Murgu M, Lago JHG, Sartorelli P, Dias DF, Chagas-Paula DA, Soares MG. In vivo anti-inflammatory activity of Fabaceae species extracts screened by a new ex vivo assay using human whole blood. PHYTOCHEMICAL ANALYSIS : PCA 2021; 32:859-883. [PMID: 33594803 DOI: 10.1002/pca.3031] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 12/01/2020] [Accepted: 01/13/2021] [Indexed: 06/12/2023]
Abstract
INTRODUCTION Plants have been considered a promising source for discovering new compounds with pharmacological activities. The Fabaceae family comprises a large variety of species that produce substances with diverse therapeutic potential, including anti-inflammatory activity. The limitations of current anti-inflammatories generate the need to research new anti-inflammatory structures with higher efficacy as well as develop methods for screening multiple samples, reliably and ethically, to assess such therapeutic properties. OBJECTIVE Validate and apply a quantification method for prostaglandin E2 (PGE2 ) production from an ex vivo assay in human blood in order to screen anti-inflammatory activity present in many Fabaceae species extracts. METHODS Human blood was incubated with extracts from 47 Fabaceae species. After lipopolysaccharide (LPS)-induced inflammation, PGE2 was quantified in the plasma by liquid chromatography with tandem mass spectrometry (LC-MS/MS). The extracts that presented PGE2 production inhibition were further assessed through in vivo assay and then chemically characterised through an analysis of ultra-performance liquid chromatography electrospray ionisation quadrupole time-of-flight tandem mass spectrometry (UPLC-ESI-QTOF-MS2 ) data. RESULTS The new ex vivo anti-inflammatory assay showed that five out of the 47 Fabaceae species inhibited PGE2 production. Results from an in vivo assay and the metabolic profile of the active extracts supported the anti-inflammatory potential of four species. CONCLUSION The quantification method for PGE2 demonstrated fast, sensitive, precise, and accurate results. The new ex vivo anti-inflammatory assay comprised a great, reliable, and ethical approach for the screening of a large number of samples before an in vivo bioassay. Additionally, the four active extracts in both ex vivo and in vivo assays may be useful for the development of more efficient anti-inflammatory drugs.
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Affiliation(s)
- Welton Rosa
- Institute of Chemistry - Federal University of Alfenas - Unifal-MG, Alfenas, MG, Brazil
| | | | | | - Ivo Santana Caldas
- Department of Pathology and Parasitology, Federal University of Alfenas - Unifal-MG, Alfenas, MG, Brazil
| | - Michael Murgu
- Waters Corporation, Alphaville, São Paulo, SP, Brazil
| | | | - Patricia Sartorelli
- Institute of Environmental, Chemical and Pharmaceutical Sciences, Federal University of São Paulo - UNIFESP, São Paulo, SP, Brazil
| | | | | | - Marisi Gomes Soares
- Institute of Chemistry - Federal University of Alfenas - Unifal-MG, Alfenas, MG, Brazil
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24
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Polese B, Thurairajah B, Zhang H, Soo CL, McMahon CA, Fontes G, Hussain SNA, Abadie V, King IL. Prostaglandin E 2 amplifies IL-17 production by γδ T cells during barrier inflammation. Cell Rep 2021; 36:109456. [PMID: 34320346 DOI: 10.1016/j.celrep.2021.109456] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 05/21/2021] [Accepted: 07/07/2021] [Indexed: 12/21/2022] Open
Abstract
Interleukin-17 (IL-17)-producing γδ (γδ17) T cells are innate-like lymphocytes that contribute to protective anti-microbial responses but are also implicated in pathogenic inflammation at barrier sites. Understanding tissue-specific signals that regulate this subset is important to boost host defense mechanisms, but also to mitigate immunopathology. Here, we demonstrate that prostaglandin E2 (PGE2), a cyclooxygenase-dependent member of the eicosanoid family, directly enhances cytokine production by circulating and tissue-specific γδ17 T cells in vitro. Gain- and loss-of-function in vivo approaches further reveal that although provision of PGE2 amplifies psoriasiform inflammation, ablation of host mPGES1-dependent PGE2 synthesis is dispensable for cutaneous γδ17 T cell activation. By contrast, loss of endogenous PGE2 production or depletion of the gut microbiota compromises intestinal γδ17 T cell responses and increases disease severity during experimental colitis. Together, our results demonstrate how a lipid mediator can synergize with tissue-specific signals to enhance innate lymphocyte production of IL-17 during barrier inflammation.
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Affiliation(s)
- Barbara Polese
- Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Bavanitha Thurairajah
- Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montreal, QC H4A 3J1, Canada; McGill Interdisciplinary Initiative in Infection and Immunity, Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada
| | - Hualin Zhang
- Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montreal, QC H4A 3J1, Canada; McGill Interdisciplinary Initiative in Infection and Immunity, Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada
| | - Cindy Leung Soo
- McGill Interdisciplinary Initiative in Infection and Immunity, Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada
| | - Clara A McMahon
- Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montreal, QC H4A 3J1, Canada; McGill Interdisciplinary Initiative in Infection and Immunity, Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada
| | - Ghislaine Fontes
- Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montreal, QC H4A 3J1, Canada; McGill Interdisciplinary Initiative in Infection and Immunity, Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada
| | - Sabah N A Hussain
- Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Valerie Abadie
- Section of Gastroenterology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Irah L King
- Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montreal, QC H4A 3J1, Canada; McGill Interdisciplinary Initiative in Infection and Immunity, Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada.
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25
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Phospholipase Signaling in Breast Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021. [PMID: 33983572 DOI: 10.1007/978-981-32-9620-6_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/23/2023]
Abstract
Breast cancer progression results from subversion of multiple intra- or intercellular signaling pathways in normal mammary tissues and their microenvironment, which have an impact on cell differentiation, proliferation, migration, and angiogenesis. Phospholipases (PLC, PLD and PLA) are essential mediators of intra- and intercellular signaling. They hydrolyze phospholipids, which are major components of cell membrane that can generate many bioactive lipid mediators, such as diacylglycerol, phosphatidic acid, lysophosphatidic acid, and arachidonic acid. Enzymatic processing of phospholipids by phospholipases converts these molecules into lipid mediators that regulate multiple cellular processes, which in turn can promote breast cancer progression. Thus, dysregulation of phospholipases contributes to a number of human diseases, including cancer. This review describes how phospholipases regulate multiple cancer-associated cellular processes, and the interplay among different phospholipases in breast cancer. A thorough understanding of the breast cancer-associated signaling networks of phospholipases is necessary to determine whether these enzymes are potential targets for innovative therapeutic strategies.
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26
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Ye J, Erland LAE, Gill SK, Bishop SL, Verdugo-Meza A, Murch SJ, Gibson DL. Metabolomics-Guided Hypothesis Generation for Mechanisms of Intestinal Protection by Live Biotherapeutic Products. Biomolecules 2021; 11:738. [PMID: 34063522 PMCID: PMC8156236 DOI: 10.3390/biom11050738] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 05/07/2021] [Accepted: 05/10/2021] [Indexed: 12/12/2022] Open
Abstract
The use of live biotherapeutic products (LBPs), including single strains of beneficial probiotic bacteria or consortiums, is gaining traction as a viable option to treat inflammatory-mediated diseases like inflammatory bowel disease (IBD). However, LBPs' persistence in the intestine is heterogeneous since many beneficial bacteria lack mechanisms to tolerate the inflammation and the oxidative stress associated with IBD. We rationalized that optimizing LBPs with enhanced colonization and persistence in the inflamed intestine would help beneficial bacteria increase their bioavailability and sustain their beneficial responses. Our lab developed two bioengineered LBPs (SBT001/BioPersist and SBT002/BioColoniz) modified to enhance colonization or persistence in the inflamed intestine. In this study, we examined colon-derived metabolites via ultra-high performance liquid chromatography-mass spectrometry in colitic mice treated with either BioPersist or BioColoniz as compared to their unmodified parent strains (Escherichia coli Nissle 1917 [EcN] and Lactobacillus reuteri, respectively) or to each other. BioPersist administration resulted in lowered concentrations of inflammatory prostaglandins, decreased stress hormones such as adrenaline and corticosterone, increased serotonin, and decreased bile acid in comparison to EcN. In comparison to BioColoniz, BioPersist increased serotonin and antioxidant production, limited bile acid accumulation, and enhanced tissue restoration via activated purine and pyrimidine metabolism. These data generated several novel hypotheses for the beneficial roles that LBPs may play during colitis.
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Affiliation(s)
- Jiayu Ye
- Department of Biology, University of British Columbia, Syilx Okanagan Nation Territory, Kelowna, BC V1V1V7, Canada
| | - Lauren A E Erland
- Department of Chemistry, University of British Columbia, Syilx Okanagan Nation Territory, Kelowna, BC V1V1V7, Canada
| | - Sandeep K Gill
- Department of Biology, University of British Columbia, Syilx Okanagan Nation Territory, Kelowna, BC V1V1V7, Canada
| | - Stephanie L Bishop
- Department of Chemistry, University of British Columbia, Syilx Okanagan Nation Territory, Kelowna, BC V1V1V7, Canada
| | - Andrea Verdugo-Meza
- Department of Biology, University of British Columbia, Syilx Okanagan Nation Territory, Kelowna, BC V1V1V7, Canada
| | - Susan J Murch
- Department of Chemistry, University of British Columbia, Syilx Okanagan Nation Territory, Kelowna, BC V1V1V7, Canada
| | - Deanna L Gibson
- Department of Biology, University of British Columbia, Syilx Okanagan Nation Territory, Kelowna, BC V1V1V7, Canada
- Department of Medicine, University of British Columbia, Syilx Okanagan Nation Territory, Kelowna, BC V1V1V7, Canada
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Abstract
High-quality evidence indicates that regular use of aspirin is effective in reducing the risk for precancerous colorectal neoplasia and colorectal cancer (CRC). This has led to US and international guidelines recommending aspirin for the primary prevention of CRC in specific populations. In this review, we summarize key questions that require addressing prior to broader adoption of aspirin-based chemoprevention, review recent evidence related to the benefits and harms of aspirin use among specific populations, and offer a rationale for precision prevention approaches. We specifically consider the mechanistic implications of evidence showing differences in aspirin's effects according to age, the potential role of modifiable mechanistic biomarkers for personalizing prevention, and emerging evidence that the gut microbiota may offer novel aspirin-associated preventive targets to reduce high-risk neoplasia.
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Affiliation(s)
- David A Drew
- Clinical and Translational Epidemiology Unit and Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA; ,
| | - Andrew T Chan
- Clinical and Translational Epidemiology Unit and Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA; ,
- Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02114, USA
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Perisetti A, Goyal H, Tharian B, Inamdar S, Mehta JL. Aspirin for prevention of colorectal cancer in the elderly: friend or foe? Ann Gastroenterol 2021; 34:1-11. [PMID: 33414615 PMCID: PMC7774657 DOI: 10.20524/aog.2020.0556] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Accepted: 08/24/2020] [Indexed: 12/11/2022] Open
Abstract
Cancer is the leading cause of death among men and women aged 60-79 years. Colorectal cancer is the third most common cancer in males and the second most common in females, with about 0.8 million deaths worldwide per year. Individuals older than 50 years account for 20-50% of colonic adenomas. Several measures have been proposed to decrease colorectal cancer risks, such as an increase in dietary fiber, use of aspirin, and physical activity. Nonsteroidal anti-inflammatory drugs have been proposed as protective agents against the development of colorectal cancer and colorectal adenomas. Aspirin was the first pharmacological agent endorsed by the United States Preventive Services Task Force screening for colorectal cancer chemoprevention. Although studies have shown up to 40% colorectal cancer risk reduction in individuals at average risk, data regarding this benefit are inconsistent. Several recent studies show that prophylactic use of aspirin in elderly subjects may not be beneficial in preventing the occurrence of colorectal cancers. Given the risks associated with aspirin, such as non-fatal and fatal bleeding events, aspirin's role should be redefined, especially in individuals at risk of bleeding. This review provides a discussion of the recent studies on the role of aspirin use in elderly individuals at risk of colorectal cancer.
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Affiliation(s)
- Abhilash Perisetti
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR (Abhilash Perisetti, Benjamin Tharian, Sumant Inamdar)
| | - Hemant Goyal
- Department of Internal Medicine, The Wright Center for Graduate Medical Education, Scranton, PA (Hemant Goyal)
| | - Benjamin Tharian
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR (Abhilash Perisetti, Benjamin Tharian, Sumant Inamdar)
| | - Sumant Inamdar
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR (Abhilash Perisetti, Benjamin Tharian, Sumant Inamdar)
| | - Jawahar L Mehta
- Division of Cardiology, Central Arkansas Veterans Healthcare System and the University of Arkansas for Medical Sciences, Little Rock, AR (Jawahar L. Mehta), USA
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29
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Pan MH, Koh YC, Liu SY, Wu JC, Chou YC, Nagabhushanam K, Ho CT. A new metabolite: The effects of aminated tetrahydrocurcumin on inducible nitric oxide synthase and cyclooxygenase-2. JOURNAL OF CANCER RESEARCH AND PRACTICE 2021. [DOI: 10.4103/jcrp.jcrp_21_20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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30
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Kim NH, Kim KS, Shin SC, Kim EE, Yu YG. Functional expression of human prostaglandin E2 receptor 4 (EP4) in E. coli and characterization of the binding property of EP4 with G α proteins. Biochem Biophys Rep 2020; 25:100871. [PMID: 33367116 PMCID: PMC7749421 DOI: 10.1016/j.bbrep.2020.100871] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 10/15/2020] [Accepted: 11/28/2020] [Indexed: 12/05/2022] Open
Abstract
Human prostaglandin E2 receptor 4 (EP4) is one of the four subtypes of prostaglandin E2 (PGE2) receptors and belongs to the rhodopsin-type G protein-coupled receptor (GPCR) family. Particularly, EP4 is expressed in various cancer cells and is involved in cancer-cell proliferation by a G protein signaling cascade. To prepare an active form of EP4 for biochemical characterization and pharmaceutical application, this study designed a recombinant protein comprising human EP4 fused to the P9 protein (a major envelope protein of phi6 phage) and overexpressed the P9-EP4 fusion protein in the membrane fraction of E. coli. The solubilized P9-EP4 with sarkosyl (a strong anionic detergent) was purified by affinity chromatography. The purified protein was stabilized with amphiphilic polymers derived from poly-γ-glutamate. The polymer-stabilized P9-EP4 showed specific interaction with the alpha subunits of Gs or Gi proteins, and a high content of α-helical structure by a circular dichroism spectroscopy. Furthermore, the polymer-stabilized P9-EP4 showed strong heat resistance compared with P9-EP4 in detergents. The functional preparation of EP4 and its stabilization with amphiphilic polymers could facilitate both the biochemical characterization and pharmacological applications targeting EP4.
Prostaglandin E2 receptor 4 (EP4) was overexpressed as P9-fusion protein in E. coli. The APG-stabilized P9-EP4 showed specific interaction with the alpha subunits and its ligands. The APG-stabilized P9-EP4 showed strong heat resistance compared with P9-EP4 in detergents. The binding kinetics of P9-EP4 with both antagonists and agonists were analyzed.
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Affiliation(s)
- Nam Hyuk Kim
- Department of Chemistry, Kookmin University, 77, Jeongneung-ro, Seongbuk-gu, Seoul, 02707, Republic of Korea
| | - Key-Sun Kim
- Convergence research Center for Diagnosis Treatment and Care System of Dementia, Korea Institute of Science and Technology, Republic of Korea
| | - Sang Chul Shin
- Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, 02790, Republic of Korea
| | - Eunice Eunkyeong Kim
- Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, 02790, Republic of Korea
| | - Yeon Gyu Yu
- Department of Chemistry, Kookmin University, 77, Jeongneung-ro, Seongbuk-gu, Seoul, 02707, Republic of Korea
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31
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Liu D, Yu X, Sun H, Zhang W, Liu G, Zhu L. Flos lonicerae flavonoids attenuate experimental ulcerative colitis in rats via suppression of NF-κB signaling pathway. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2020; 393:2481-2494. [PMID: 32125461 DOI: 10.1007/s00210-020-01814-4] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 01/08/2020] [Indexed: 02/06/2023]
Abstract
This study sought to isolate active Flos lonicerae flavonoids and evaluate their anti-oxidative and anti-inflammatory effects as well as investigate the molecular mechanistic action of these flavonoids in the rat model of ulcerative colitis (UC). Total flavonoids and three flavonoids (hyperoside, lonicerin, and luteolin) were isolated from honeysuckle and purified via column purification. Rat model of UC was established via 2,4,6-trinitrobenzene sulfonic acid (TNBS) intoxication. The anti-oxidative and anti-inflammatory effects of the three flavonoids against TNBS-induced UC were evaluated by measuring appropriate biomarkers via assay kit. The effects of hyperoside, lonicerin, and luteolin on the regulation of nuclear factor-kappa B (NF-κB) pathway were investigated using Western blot (WB) and real-time polymerase chain reaction (RT-PCR) while their protective effects on UC were also elucidated. Pretreatment with flavonoids (hyperoside, lonicerin, and luteolin at 25-100 mg/kg) and sulfasalazine (SSZ, positive control at 100 mg/kg) substantially attenuated TBNS-induced UC. Also, the flavonoids significantly reduced the levels of respective serum oxidative and proinflammatory markers such as superoxide dismutase (SOD), myeloperoxidase (MPO), malondialdehyde (MDA), prostaglandins E2 (PGE2), tumor necrosis factor-alpha (TNF-α), interleukin-beta (IL-β), and C-reactive protein (CRP). In addition, the flavonoids remarkably inhibited the expression of NF-κB signaling pathway. F. lonicerae flavonoids (hyperoside, lonicerin, and luteolin) demonstrated potent anti-UC activities in TBNS-induced UC rat model via anti-oxidative and anti-inflammatory effects through the inhibition of NF-κB signaling pathway.
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Affiliation(s)
- Daming Liu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China.
| | - Xiao Yu
- Spleen and Stomach Diseases Department II, Longhua Hospital, Shanghai University of TCM, Shanghai, 200032, China
| | - Huiyi Sun
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Wen Zhang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Guo Liu
- BeijingUniversity of Chinese Medicine, Beijing, 100029, China
| | - Li Zhu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China.
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32
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Han H, Jayaraman A, Safe S, Chapkin RS. Targeting the aryl hydrocarbon receptor in stem cells to improve the use of food as medicine. CURRENT STEM CELL REPORTS 2020; 6:109-118. [PMID: 34395177 PMCID: PMC8362759 DOI: 10.1007/s40778-020-00184-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/04/2020] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW Intestinal stem cells, the most rapidly proliferating adult stem cells, are exquisitely sensitive to extrinsic dietary factors. Uncontrolled regulation of intestinal stem cells is closely linked to colon tumorigenesis. This review focuses on how dietary and microbial derived cues regulate intestinal stem cell functionality and colon tumorigenesis in mouse models by targeting the aryl hydrocarbon receptor (AhR). RECENT FINDINGS AhR, a ligand activated transcription factor, can integrate environmental, dietary and microbial cues to modulate intestinal stem cell proliferation, differentiation and their microenvironment, affecting colon cancer risk. Modulation of AhR activity is associated with many chronic diseases, including inflammatory bowel diseases where AhR expression is protective. SUMMARY AhR signaling controls the maintenance and differentiation of intestinal stem cells, influences local niche factors, and plays a protective role in colon tumorigenesis. Mounting evidence suggests that extrinsic nutritional/dietary cues which modulate AhR signaling may be a promising approach to colon cancer chemoprevention.
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Affiliation(s)
- Huajun Han
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX, 77843
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX, 77843
| | - Arul Jayaraman
- Department of Chemical Engineering, Texas A&M University, College Station, TX, 77843
| | - Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, 77843
| | - Robert S. Chapkin
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX, 77843
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX, 77843
- Department of Nutrition, Texas A&M University, College Station, TX, 77843
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33
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Montrose DC, Makino T, Basu S, Ito N, Dannenberg AJ. Induction of colitis-associated neoplasia in mice using azoxymethane and dextran sodium sulfate. Methods Cell Biol 2020; 163:123-135. [PMID: 33785161 DOI: 10.1016/bs.mcb.2020.09.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Long-standing inflammatory bowel diseases (IBD) increase the risk for the development of colorectal cancer (CRC). This increase is due in large part to chronic intestinal inflammation which exposes the epithelium to pro-carcinogenic factors. Moreover, enhanced mucosal proliferation associated with repetitive wound healing events following an inflammatory episode, further enhance this pro-tumorigenic environment. Although multiple factors involved in IBD pathogenesis and its associated neoplasia have been identified, more work is needed to develop and improve therapies to ameliorate disease and thus reduce CRC risk. Murine models have served as useful tools to identify factors involved in the pathogenesis of colitis-associated neoplasia and test therapies. These include both chemically-induced and genetic engineering approaches, resulting in chronic inflammation and tumor development. Here, we present a step-by-step method of inducing inflammation-associated colon neoplasia by combining administration of azoxymethane and dextran sodium sulfate in mice. A detailed description of this methodology will facilitate its use in the scientific community with the goals of further elucidating the mechanisms underlying colitis-associated tumorigenesis and developing risk reducing interventions.
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Affiliation(s)
- David C Montrose
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, United States; Stony Brook Cancer Center, Stony Brook, NY, United States.
| | - Tomoki Makino
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Srijani Basu
- Department of Medicine, Weill Cornell Medicine, New York, NY, United States
| | - Naotake Ito
- Department of Medicine, Weill Cornell Medicine, New York, NY, United States
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Huang X, Chen Z, Li M, Zhang Y, Xu S, Huang H, Wu X, Zheng X. Herbal pair Huangqin-Baishao: mechanisms underlying inflammatory bowel disease by combined system pharmacology and cell experiment approach. BMC Complement Med Ther 2020; 20:292. [PMID: 32988394 PMCID: PMC7523401 DOI: 10.1186/s12906-020-03068-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 09/01/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a severe digestive system condition, characterized by chronic and relapsing inflammation of the gastrointestinal tract. Scutellaria baicalensis Georgi (Huangqin, HQ) and Paeonia lactiflora Pall (Baishao, BS) from a typical herbal synergic pair in traditional Chinese medicine (TCM) for IBD treatments. However, the mechanisms of action for the synergy are still unclear. Therefore, this paper aimed to predict the anti-IBD targets and the main active ingredients of the HQ-BS herbal pair. METHODS A systems pharmacology approach was used to identify the bioactive compounds and to delineate the molecular targets and potential pathways of HQ-BS herbal pair. Then, the characteristics of the candidates were analyzed according to their oral bioavailability and drug-likeness indices. Finally, gene enrichment analysis with DAVID Bioinformatics Resources was performed to identify the potential pathways associated with the candidate targets. RESULTS The results showed that, a total of 38 active compounds were obtained from HQ-BS herbal pair, and 54 targets associated with IBD were identified. Gene Ontology and pathway enrichment analysis yielded the top 20 significant results with 54 targets. Furthermore, the integrated IBD pathway revealed that the HQ-BS herbal pair probably acted in patients with IBD through multiple mechanisms of regulation of the nitric oxide biosynthetic process and anti-inflammatory effects. In addition, cell experiments were carried out to verify that the HQ-BS herbal pair and their Q-markers could attenuate the levels of nitric oxide (NO), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-stimulated THP-1-derived macrophage inflammation. In particular, the crude materials exerted a much better anti-inflammatory effect than their Q-markers, which might be due to their synergistic effect. CONCLUSION This study provides novel insight into the molecular pathways involved in the mechanisms of the HQ-BS herbal pair acting on IBD.
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Affiliation(s)
- Xiaoqi Huang
- Mathematical Engineering Academy of Chinese Medicine, Guangdong Provincial Key Laboratory of New Chinese Medicinal Development and Research, Guangzhou University of Chinese Medicine, 232# Wai Huan East Road, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
- Dongguan Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Dongguan, 523808, China
| | - Zhiwei Chen
- Dongguan Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Dongguan, 523808, China
| | - Minyao Li
- Mathematical Engineering Academy of Chinese Medicine, Guangdong Provincial Key Laboratory of New Chinese Medicinal Development and Research, Guangzhou University of Chinese Medicine, 232# Wai Huan East Road, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Yaomin Zhang
- Mathematical Engineering Academy of Chinese Medicine, Guangdong Provincial Key Laboratory of New Chinese Medicinal Development and Research, Guangzhou University of Chinese Medicine, 232# Wai Huan East Road, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
- Dongguan Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Dongguan, 523808, China
| | - Shijie Xu
- Mathematical Engineering Academy of Chinese Medicine, Guangdong Provincial Key Laboratory of New Chinese Medicinal Development and Research, Guangzhou University of Chinese Medicine, 232# Wai Huan East Road, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Haiyang Huang
- Dongguan Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Dongguan, 523808, China
| | - Xiaoli Wu
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, 100# Wai Huan West Road, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China.
| | - Xuebao Zheng
- Mathematical Engineering Academy of Chinese Medicine, Guangdong Provincial Key Laboratory of New Chinese Medicinal Development and Research, Guangzhou University of Chinese Medicine, 232# Wai Huan East Road, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China.
- Dongguan Songshan Lake Yi Dao TCM Clinic, Dongguan, 523808, China.
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35
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Davis FM, Tsoi LC, Wasikowski R, denDekker A, Joshi A, Wilke C, Deng H, Wolf S, Obi A, Huang S, Billi AC, Robinson S, Lipinski J, Melvin WJ, Audu CO, Weidinger S, Kunkel SL, Smith A, Gudjonsson JE, Moore BB, Gallagher KA. Epigenetic regulation of the PGE2 pathway modulates macrophage phenotype in normal and pathologic wound repair. JCI Insight 2020; 5:138443. [PMID: 32879137 PMCID: PMC7526451 DOI: 10.1172/jci.insight.138443] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 07/29/2020] [Indexed: 12/19/2022] Open
Abstract
Macrophages are a primary immune cell involved in inflammation, and their cell plasticity allows for transition from an inflammatory to a reparative phenotype and is critical for normal tissue repair following injury. Evidence suggests that epigenetic alterations play a critical role in establishing macrophage phenotype and function during normal and pathologic wound repair. Here, we find in human and murine wound macrophages that cyclooxygenase 2/prostaglandin E2 (COX-2/PGE2) is elevated in diabetes and regulates downstream macrophage-mediated inflammation and host defense. Using single-cell RNA sequencing of human wound tissue, we identify increased NF-κB-mediated inflammation in diabetic wounds and show increased COX-2/PGE2 in diabetic macrophages. Further, we identify that COX-2/PGE2 production in wound macrophages requires epigenetic regulation of 2 key enzymes in the cytosolic phospholipase A2/COX-2/PGE2 (cPLA2/COX-2/PGE2) pathway. We demonstrate that TGF-β-induced miRNA29b increases COX-2/PGE2 production via inhibition of DNA methyltransferase 3b-mediated hypermethylation of the Cox-2 promoter. Further, we find mixed-lineage leukemia 1 (MLL1) upregulates cPLA2 expression and drives COX-2/PGE2. Inhibition of the COX-2/PGE2 pathway genetically (Cox2fl/fl Lyz2Cre+) or with a macrophage-specific nanotherapy targeting COX-2 in tissue macrophages reverses the inflammatory macrophage phenotype and improves diabetic tissue repair. Our results indicate the epigenetically regulated PGE2 pathway controls wound macrophage function, and cell-targeted manipulation of this pathway is feasible to improve diabetic wound repair.
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Affiliation(s)
- Frank M Davis
- Section of Vascular Surgery, Department of Surgery.,Department of Microbiology and Immunology
| | | | | | | | - Amrita Joshi
- Section of Vascular Surgery, Department of Surgery
| | - Carol Wilke
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Hongping Deng
- Department of Bioengineering, University of Illinois, Champaign, Illinois, USA
| | - Sonya Wolf
- Section of Vascular Surgery, Department of Surgery
| | - Andrea Obi
- Section of Vascular Surgery, Department of Surgery
| | - Steven Huang
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | | | | | - Jay Lipinski
- Section of Vascular Surgery, Department of Surgery
| | | | | | - Stephan Weidinger
- Department of Dermatology, Venereology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Steven L Kunkel
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Andrew Smith
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | | | - Bethany B Moore
- Department of Microbiology and Immunology.,Department of Dermatology, Venereology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Katherine A Gallagher
- Section of Vascular Surgery, Department of Surgery.,Department of Microbiology and Immunology
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36
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Nettleford SK, Zhao L, Qian F, Herold M, Arner B, Desai D, Amin S, Xiong N, Singh V, Carlson BA, Prabhu KS. The Essential Role of Selenoproteins in the Resolution of Citrobacter rodentium-Induced Intestinal Inflammation. Front Nutr 2020; 7:96. [PMID: 32775340 PMCID: PMC7381334 DOI: 10.3389/fnut.2020.00096] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 05/26/2020] [Indexed: 12/13/2022] Open
Abstract
Enteropathogenic Escherichia coli (EPEC) leads to adverse colonic inflammation associated with poor resolution of inflammation and loss of epithelial integrity. Micronutrient trace element selenium (Se) is incorporated into selenoproteins as the 21st amino acid, selenocysteine (Sec). Previous studies have shown that such an incorporation of Sec into the selenoproteome is key for the anti-inflammatory functions of Se in macrophages and other immune cells. An intriguing mechanism underlying the anti-inflammatory and pro-resolving effects of Se stems from the ability of selenoproteins to skew arachidonic acid metabolism from pro-inflammatory mediators, prostaglandin E2 (PGE2) toward anti-inflammatory mediators derived from PGD2, such as 15-deoxy-Δ12, 14- prostaglandin J2 (15d-PGJ2), via eicosanoid class switching of bioactive lipids. The impact of Se and such an eicosanoid-class switching mechanism was tested in an enteric infection model of gut inflammation by C. rodentium, a murine equivalent of EPEC. C57BL/6 mice deficient in Se (Se-D) experienced higher mortality when compared to those on Se adequate (0.08 ppm Se) and Se supplemented (0.4 ppm Se) diets following infection. Decreased survival was associated with decreased group 3 innate lymphoid cells (ILC3s) and T helper 17 (Th17) cells in colonic lamina propria of Se-D mice along with deceased expression of epithelial barrier protein Zo-1. Inhibition of metabolic inactivation of PGE2 by 15-prostaglandin dehydrogenase blocked the Se-dependent increase in ILC3 and Th17 cells in addition to reducing epithelial barrier integrity, as seen by increased systemic levels of FITC-dextran following oral administration; while 15d-PGJ2 administration in Se-D mice alleviated the effects by increasing ILC3 and Th17 cells. Mice lacking selenoproteins in monocyte/macrophages via the conditional deletion of the tRNA[Sec] showed increased mortality post infection. Our studies indicate a crucial role for dietary Se in the protection against inflammation following enteric infection via immune mechanisms involving epithelial barrier integrity.
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Affiliation(s)
- Shaneice K Nettleford
- Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, State College, PA, United States
| | - Luming Zhao
- Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, State College, PA, United States
| | - Fenghua Qian
- Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, State College, PA, United States
| | - Morgan Herold
- Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, State College, PA, United States
| | - Brooke Arner
- Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, State College, PA, United States
| | - Dhimant Desai
- Department of Pharmacology, Organic Synthesis Core Laboratory, Penn State Cancer Institute, Penn State College of Medicine, Hershey, PA, United States
| | - Shantu Amin
- Department of Pharmacology, Organic Synthesis Core Laboratory, Penn State Cancer Institute, Penn State College of Medicine, Hershey, PA, United States
| | - Na Xiong
- Department of Microbiology, Immunology & Molecular Genetics, Long School of Medicine, University of Texas Health San Antonio, San Antonio, TX, United States
| | - Vishal Singh
- Department of Nutritional Sciences, The Pennsylvania State University, State College, PA, United States
| | - Bradley A Carlson
- Molecular Biology of Selenium Section, Mouse Genetics Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - K Sandeep Prabhu
- Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, State College, PA, United States
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Giménez-Bastida JA, González-Sarrías A, Espín JC, Schneider C. Inhibition of 5-Lipoxygenase-Derived Leukotrienes and Hemiketals as a Novel Anti-Inflammatory Mechanism of Urolithins. Mol Nutr Food Res 2020; 64:e2000129. [PMID: 32306507 DOI: 10.1002/mnfr.202000129] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Revised: 03/27/2020] [Indexed: 12/20/2022]
Abstract
SCOPE Urolithins (Uro), gut microbial metabolites derived from ellagic acid (EA), reach significant concentrations in the human colon. Uro-A exerts anti-inflammatory activity in animal models of inflammatory bowel diseases (IBDs). It is hypothesized that Uro can modulate the biosynthesis of leukocyte-derived inflammatory eicosanoids from the 5-lipoxygenase (5-LOX), cyclooxygenase-2 (COX-2), and 5-LOX/COX-2 pathways, relevant in the onset and progression of IBDs, including 5-hydroxyeicosatetraenoic acids (5-HETEs), leukotriene-B4 (LTB4 ), prostaglandin E2 (PGE2 ), and hemiketals (HKE2 and HKD2 ). METHODS AND RESULTS Leukocytes, obtained from six healthy donors, are stimulated with lipopolysaccharide and calcium ionophore A23187. Uro, at concentrations found in the human colon (1-15 µm), decrease eicosanoid biosynthesis and COX-2 levels in the activated leukocytes. In contrast, EA and conjugated Uro (glucuronides and sulfates) are inactive. Uro-A and isourolithin-A reduce the formation of the 5-LOX/COX-2 products HKE2 and HKD2 through the COX-2 pathway (down-regulation of COX-2 and PGE2), whereas Uro-C reduces 5-HETE and LTB4 via inhibition of 5-LOX. CONCLUSIONS The results show that physiologically relevant colonic Uro target eicosanoid biosynthetic pathways. The effect on HKs and LTB4 formation is unprecedented and expands the knowledge on anti-inflammatory mechanisms of Uro against IBDs.
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Affiliation(s)
- Juan Antonio Giménez-Bastida
- Department of Pharmacology and Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical School, Nashville, TN, 37232, USA.,Laboratory of Food and Health, Research Group on Quality, Safety and Bioactivity of Plant Foods, Dept. Food Science and Technology, CEBAS-CSIC, P.O. Box 164, Murcia, Campus de Espinardo, 30100, Spain
| | - Antonio González-Sarrías
- Laboratory of Food and Health, Research Group on Quality, Safety and Bioactivity of Plant Foods, Dept. Food Science and Technology, CEBAS-CSIC, P.O. Box 164, Murcia, Campus de Espinardo, 30100, Spain
| | - Juan Carlos Espín
- Laboratory of Food and Health, Research Group on Quality, Safety and Bioactivity of Plant Foods, Dept. Food Science and Technology, CEBAS-CSIC, P.O. Box 164, Murcia, Campus de Espinardo, 30100, Spain
| | - Claus Schneider
- Department of Pharmacology and Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical School, Nashville, TN, 37232, USA
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Kjærgaard S, Damm MMB, Chang J, Riis LB, Rasmussen HB, Hytting-Andreasen R, Krug SM, Schulzke JD, Bindslev N, Hansen MB. Altered Structural Expression and Enzymatic Activity Parameters in Quiescent Ulcerative Colitis: Are These Potential Normalization Criteria? Int J Mol Sci 2020; 21:ijms21051887. [PMID: 32164249 PMCID: PMC7084207 DOI: 10.3390/ijms21051887] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 03/03/2020] [Accepted: 03/05/2020] [Indexed: 12/31/2022] Open
Abstract
Mucosal healing determined by endoscopy is currently the remission standard for ulcerative colitis (UC). However, new criteria for remission are emerging, such as histologic normalization, which appears to correlate better to the risk of relapse. Here, we study mucosal healing on a molecular and functional level in quiescent UC. We obtained endoscopic biopsies from 33 quiescent UC patients and from 17 controls. Histology was assessed using Geboes score. Protein and mRNA levels were evaluated for the tight junction proteins claudin-2, claudin-4, occludin, and tricellulin, as well as Cl−/HCO3− exchanger DRA, and cyclo-oxygenase enzymes (COX-1, COX-2). The mucosal activity of COX-1 and COX-2 enzymes was assessed in modified Ussing chambers, measuring electrogenic ion transport (short-circuit current, SCC). Chronic inflammation was present in most UC patients. The protein level of claudin-4 was reduced, while mRNA-levels of claudin-2 and claudin-4 were upregulated in UC patients. Surprisingly, the mRNA level of COX-1 was downregulated, but was unaltered for COX-2. Basal ion transport was not affected, while COX-2 inhibition induced a two-fold larger decrease in SCC in UC patients. Despite being in clinical and endoscopic remission, quiescent UC patients demonstrated abnormal mucosal barrier properties at the molecular and functional level. Further exploration of mucosal molecular signature for revision of current remission standards should be considered.
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Affiliation(s)
- Sebastian Kjærgaard
- Digestive Disease Center, Bispebjerg Hospital, 2400 Copenhagen, Denmark;
- Correspondence: (S.K.); (M.B.H.); Tel.: +45-71200271 (S.K.); +45-50603756 (M.B.H.)
| | - Morten M. B. Damm
- Digestive Disease Center, Bispebjerg Hospital, 2400 Copenhagen, Denmark;
| | - Joan Chang
- Wellcome Centre for Cell-Matrix Research, Division of Cell Matrix and Regenerative Medicine, Faculty of Biology Medicine and Health, University of Manchester, Manchester M16 8FB, UK;
| | - Lene B. Riis
- Department of Pathology, Herlev Hospital, 2730 Copenhagen, Denmark;
| | - Hanne B. Rasmussen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; (H.B.R.); (N.B.)
| | - Rasmus Hytting-Andreasen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark;
| | - Susanne M. Krug
- Institute of Clinical Physiology/Nutritional Medicine, Department of Gastroenterology, Rheumatology and Infectious Diseases, Charité—Universitätsmedizin Berlin, 12203 Berlin, Germany; (S.M.K.); (J.-D.S.)
| | - Jörg-Dieter Schulzke
- Institute of Clinical Physiology/Nutritional Medicine, Department of Gastroenterology, Rheumatology and Infectious Diseases, Charité—Universitätsmedizin Berlin, 12203 Berlin, Germany; (S.M.K.); (J.-D.S.)
| | - Niels Bindslev
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; (H.B.R.); (N.B.)
| | - Mark Berner Hansen
- Digestive Disease Center, Bispebjerg Hospital, 2400 Copenhagen, Denmark;
- Correspondence: (S.K.); (M.B.H.); Tel.: +45-71200271 (S.K.); +45-50603756 (M.B.H.)
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A review on mPGES-1 inhibitors: From preclinical studies to clinical applications. Prostaglandins Other Lipid Mediat 2019; 147:106383. [PMID: 31698145 DOI: 10.1016/j.prostaglandins.2019.106383] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 08/16/2019] [Accepted: 09/09/2019] [Indexed: 02/06/2023]
Abstract
Prostaglandin E2 (PGE2) is a lipid mediator of inflammation and cancer progression. It is mainly formed via metabolism of arachidonic acid by cyclooxygenases (COX) and the terminal enzyme microsomal prostaglandin E synthase-1 (mPGES-1). Widely used non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX activity, resulting in decreased PGE2 production and symptomatic relief. However, NSAIDs block the production of many other lipid mediators that have important physiological and resolving actions, and these drugs cause gastrointestinal bleeding and/or increase the risk for severe cardiovascular events. Selective inhibition of downstream mPGES-1 for reduction in only PGE2 biosynthesis is suggested as a safer therapeutic strategy. This review covers the recent advances in characterization of new mPGES-1 inhibitors in preclinical models and their future clinical applications.
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40
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Amberger DC, Doraneh-Gard F, Gunsilius C, Weinmann M, Möbius S, Kugler C, Rogers N, Böck C, Ködel U, Werner JO, Krämer D, Eiz-Vesper B, Rank A, Schmid C, Schmetzer HM. PGE 1-Containing Protocols Generate Mature (Leukemia-Derived) Dendritic Cells Directly from Leukemic Whole Blood. Int J Mol Sci 2019; 20:ijms20184590. [PMID: 31533251 PMCID: PMC6769744 DOI: 10.3390/ijms20184590] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 09/06/2019] [Accepted: 09/10/2019] [Indexed: 02/07/2023] Open
Abstract
Dendritic cells (DCs) and leukemia-derived DC (DCleu) are potent stimulators of various immunoreactive cells and they play a pivotal role in the (re-) activation of the immune system. As a potential treatment tool for patients with acute myeloid leukemia, we developed and analyzed two new PGE1-containing protocols (Pici-PGE1, Kit M) to generate DC/DCleu ex vivo from leukemic peripheral blood mononuclear cells (PBMCs) or directly from leukemic whole blood (WB) to simulate physiological conditions. Pici-PGE1 generated significantly higher amounts of DCs from leukemic and healthy PBMCs when compared to control and comparable amounts as the already established protocol Pici-PGE2. The proportions of sufficient DC-generation were even higher after DC/DCleu-generation with Pici-PGE1. With Kits, it was possible to generate DCs and DCleu directly from leukemic and healthy WB without induction of blast proliferation. The average amounts of generated DCs and DCleu-subgroups were comparable with all Kits. The PGE1 containing Kit M generated significantly higher amounts of mature DCs when compared to the PGE2-containing Kit K and increased the anti-leukemic-activity. In summary PGE1-containing protocols were suitable for generating DC/DCleu from PBMCs as well as from WB, which reliably (re-) activated immunoreactive cells, improved the overall ex vivo anti-leukemic activity, and influenced cytokine-release-profiles.
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Affiliation(s)
- Daniel Christoph Amberger
- Medical Department 3, Working-group: Immune-Modulation, University Hospital Munich, 81377 Munich, Germany.
| | - Fatemeh Doraneh-Gard
- Medical Department 3, Working-group: Immune-Modulation, University Hospital Munich, 81377 Munich, Germany.
| | - Carina Gunsilius
- Medical Department 3, Working-group: Immune-Modulation, University Hospital Munich, 81377 Munich, Germany.
| | - Melanie Weinmann
- Medical Department 3, Working-group: Immune-Modulation, University Hospital Munich, 81377 Munich, Germany.
| | - Sabine Möbius
- Medical Department 3, Working-group: Immune-Modulation, University Hospital Munich, 81377 Munich, Germany.
| | - Christoph Kugler
- Medical Department 3, Working-group: Immune-Modulation, University Hospital Munich, 81377 Munich, Germany.
| | - Nicole Rogers
- Medical Department 3, Working-group: Immune-Modulation, University Hospital Munich, 81377 Munich, Germany.
| | - Corinna Böck
- Medical Department 3, Working-group: Immune-Modulation, University Hospital Munich, 81377 Munich, Germany.
| | - Uwe Ködel
- Department of Neurology, Klinikum Großhadern, Ludwig-Maximilians-University, 81377 Munich, Germany.
| | - Jan-Ole Werner
- Department of Hematology and Oncology, University Hospital of Tuebingen, 72076 Tuebingen, Germany.
| | - Doris Krämer
- Department for Hematology and Oncology, University Hospital of Oldenburg, 26133 Oldenburg, Germany.
| | - Britta Eiz-Vesper
- Institute for Transfusion Medicine, Hannover Medical School, 30625 Hannover, Germany.
| | - Andreas Rank
- Department of Hematology and Oncology, University Hospital of Augsburg, 86156 Augsburg, Germany.
| | - Christoph Schmid
- Department of Hematology and Oncology, University Hospital of Augsburg, 86156 Augsburg, Germany.
| | - Helga Maria Schmetzer
- Medical Department 3, Working-group: Immune-Modulation, University Hospital Munich, 81377 Munich, Germany.
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Zackular JP, Kirk L, Trindade BC, Skaar EP, Aronoff DM. Misoprostol protects mice against severe Clostridium difficile infection and promotes recovery of the gut microbiota after antibiotic perturbation. Anaerobe 2019; 58:89-94. [PMID: 31220605 PMCID: PMC6697607 DOI: 10.1016/j.anaerobe.2019.06.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 06/15/2019] [Indexed: 01/13/2023]
Abstract
Clostridium difficile infection (CDI) is one of the most common nosocomial infections worldwide and an urgent public health threat. Epidemiological and experimental studies have demonstrated an association between nonsteroidal anti-inflammatory drug (NSAID) exposure and enhanced susceptibility to, and severity of, CDI. NSAIDs target cyclooxygenase enzymes and inhibit the production of prostaglandins (PGs), but the therapeutic potential of exogenous introduction of PGs for the treatment of CDI has not been explored. In this study, we report that treatment with the FDA-approved stable PGE1 analogue, misoprostol, protects mice against C. difficile-associated mortality, intestinal pathology, and CDI-mediated intestinal permeability. Furthermore, we report that the effect of misoprostol on the gastrointestinal tract contributes to increased recovery of the gut microbiota following antibiotic perturbation. Together, these data implicate PGs as an important host-factor associated with recovery to C. difficile-associated disease and demonstrate the potential for misoprostol in the treatment of CDI. Further studies to explore the safety and efficacy of misoprostol treatment of CDI in humans is needed.
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Affiliation(s)
- Joseph P Zackular
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, United States; Division of Protective Immunity, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, United States; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Leslie Kirk
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Bruno C Trindade
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA
| | - Eric P Skaar
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - David M Aronoff
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States.
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Kita Y, Shindou H, Shimizu T. Cytosolic phospholipase A2 and lysophospholipid acyltransferases. Biochim Biophys Acta Mol Cell Biol Lipids 2019; 1864:838-845. [DOI: 10.1016/j.bbalip.2018.08.006] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 08/06/2018] [Accepted: 08/07/2018] [Indexed: 01/01/2023]
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43
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Maseda D, Zackular JP, Trindade B, Kirk L, Roxas JL, Rogers LM, Washington MK, Du L, Koyama T, Viswanathan VK, Vedantam G, Schloss PD, Crofford LJ, Skaar EP, Aronoff DM. Nonsteroidal Anti-inflammatory Drugs Alter the Microbiota and Exacerbate Clostridium difficile Colitis while Dysregulating the Inflammatory Response. mBio 2019; 10:mBio.02282-18. [PMID: 30622186 PMCID: PMC6325247 DOI: 10.1128/mbio.02282-18] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Clostridium difficile infection (CDI) is a major public health threat worldwide. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with enhanced susceptibility to and severity of CDI; however, the mechanisms driving this phenomenon have not been elucidated. NSAIDs alter prostaglandin (PG) metabolism by inhibiting cyclooxygenase (COX) enzymes. Here, we found that treatment with the NSAID indomethacin prior to infection altered the microbiota and dramatically increased mortality and the intestinal pathology associated with CDI in mice. We demonstrated that in C. difficile-infected animals, indomethacin treatment led to PG deregulation, an altered proinflammatory transcriptional and protein profile, and perturbed epithelial cell junctions. These effects were paralleled by increased recruitment of intestinal neutrophils and CD4+ cells and also by a perturbation of the gut microbiota. Together, these data implicate NSAIDs in the disruption of protective COX-mediated PG production during CDI, resulting in altered epithelial integrity and associated immune responses.IMPORTANCEClostridium difficile infection (CDI) is a spore-forming anaerobic bacterium and leading cause of antibiotic-associated colitis. Epidemiological data suggest that use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases the risk for CDI in humans, a potentially important observation given the widespread use of NSAIDs. Prior studies in rodent models of CDI found that NSAID exposure following infection increases the severity of CDI, but mechanisms to explain this are lacking. Here we present new data from a mouse model of antibiotic-associated CDI suggesting that brief NSAID exposure prior to CDI increases the severity of the infectious colitis. These data shed new light on potential mechanisms linking NSAID use to worsened CDI, including drug-induced disturbances to the gut microbiome and colonic epithelial integrity. Studies were limited to a single NSAID (indomethacin), so future studies are needed to assess the generalizability of our findings and to establish a direct link to the human condition.
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Affiliation(s)
- Damian Maseda
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Joseph P Zackular
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Bruno Trindade
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Leslie Kirk
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Jennifer Lising Roxas
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, Arizona, USA
| | - Lisa M Rogers
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Mary K Washington
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Liping Du
- Center for Quantitative Sciences, Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Tatsuki Koyama
- Center for Quantitative Sciences, Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - V K Viswanathan
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, Arizona, USA
| | - Gayatri Vedantam
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, Arizona, USA
| | - Patrick D Schloss
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA
| | - Leslie J Crofford
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Eric P Skaar
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - David M Aronoff
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
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44
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Maseda D, Banerjee A, Johnson EM, Washington MK, Kim H, Lau KS, Crofford LJ. mPGES-1-Mediated Production of PGE 2 and EP4 Receptor Sensing Regulate T Cell Colonic Inflammation. Front Immunol 2018; 9:2954. [PMID: 30619314 PMCID: PMC6302013 DOI: 10.3389/fimmu.2018.02954] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 11/30/2018] [Indexed: 01/14/2023] Open
Abstract
PGE2 is a lipid mediator of the initiation and resolution phases of inflammation, as well as a regulator of immune system responses to inflammatory events. PGE2 is produced and sensed by T cells, and autocrine or paracrine PGE2 can affect T cell phenotype and function. In this study, we use a T cell-dependent model of colitis to evaluate the role of PGE2 on pathological outcome and T-cell phenotypes. CD4+ T effector cells either deficient in mPGES-1 or the PGE2 receptor EP4 are less colitogenic. Absence of T cell autocrine mPGES1-dependent PGE2 reduces colitogenicity in association with an increase in CD4+RORγt+ cells in the lamina propria. In contrast, recipient mice deficient in mPGES-1 exhibit more severe colitis that corresponds with a reduced capacity to generate FoxP3+ T cells, especially in mesenteric lymph nodes. Thus, our research defines how mPGES-1-driven production of PGE2 by different cell types in distinct intestinal locations impacts T cell function during colitis. We conclude that PGE2 has profound effects on T cell phenotype that are dependent on the microenvironment.
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Affiliation(s)
- Damian Maseda
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States.,Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Amrita Banerjee
- Department of Cell and Developmental Biology, Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, United States
| | - Elizabeth M Johnson
- Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Mary Kay Washington
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Hyeyon Kim
- Department of Cell and Developmental Biology, Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, United States
| | - Ken S Lau
- Department of Cell and Developmental Biology, Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, United States
| | - Leslie J Crofford
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States.,Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
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45
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Lauro G, Cantone V, Potenza M, Fischer K, Koeberle A, Werz O, Riccio R, Bifulco G. Discovery of 3-hydroxy-3-pyrrolin-2-one-based mPGES-1 inhibitors using a multi-step virtual screening protocol. MEDCHEMCOMM 2018; 9:2028-2036. [PMID: 30746063 DOI: 10.1039/c8md00497h] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Accepted: 11/17/2018] [Indexed: 12/20/2022]
Abstract
Targeting microsomal prostaglandin E2 synthase-1 (mPGES-1) represents an efficient strategy for the development of novel drugs against inflammation and cancer with potentially reduced side effects. With this aim, a virtual screening was performed on a large library of commercially available molecules using the X-ray structure of mPGES-1 co-complexed with a potent inhibitor. Combining fast ligand-based shape alignment, molecular docking experiments, and qualitative analysis of the binding poses, a small set of molecules was selected for the subsequent steps of validation of the biological activity. Compounds 2 and 3, bearing the 3-hydroxy-3-pyrrolin-2-one nucleus, showed mPGES-1-inhibitory activity in the low micromolar range. These data highlighted the applicability of the reported virtual screening protocol for the selection of new mPGES-1 inhibitors as promising anti-inflammatory/anti-cancer drugs.
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Affiliation(s)
- Gianluigi Lauro
- Department of Pharmacy , University of Salerno , via Giovanni Paolo II 132 , 84084 Fisciano , Italy . ; ; Tel: +39 (0)89 969741
| | - Vincenza Cantone
- Department of Pharmacy , University of Salerno , via Giovanni Paolo II 132 , 84084 Fisciano , Italy . ; ; Tel: +39 (0)89 969741
| | - Marianna Potenza
- Department of Pharmacy , University of Salerno , via Giovanni Paolo II 132 , 84084 Fisciano , Italy . ; ; Tel: +39 (0)89 969741
| | - Katrin Fischer
- Department of Pharmaceutical/Medicinal Chemistry , Institute of Pharmacy , Friedrich-Schiller-University Jena , Philosophenweg 14 , D-07743 Jena , Germany
| | - Andreas Koeberle
- Department of Pharmaceutical/Medicinal Chemistry , Institute of Pharmacy , Friedrich-Schiller-University Jena , Philosophenweg 14 , D-07743 Jena , Germany
| | - Oliver Werz
- Department of Pharmaceutical/Medicinal Chemistry , Institute of Pharmacy , Friedrich-Schiller-University Jena , Philosophenweg 14 , D-07743 Jena , Germany
| | - Raffaele Riccio
- Department of Pharmacy , University of Salerno , via Giovanni Paolo II 132 , 84084 Fisciano , Italy . ; ; Tel: +39 (0)89 969741
| | - Giuseppe Bifulco
- Department of Pharmacy , University of Salerno , via Giovanni Paolo II 132 , 84084 Fisciano , Italy . ; ; Tel: +39 (0)89 969741
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46
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Lin N, Shay JES, Xie H, Lee DSM, Skuli N, Tang Q, Zhou Z, Azzam A, Meng H, Wang H, FitzGerald GA, Simon MC. Myeloid Cell Hypoxia-Inducible Factors Promote Resolution of Inflammation in Experimental Colitis. Front Immunol 2018; 9:2565. [PMID: 30455703 PMCID: PMC6230677 DOI: 10.3389/fimmu.2018.02565] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2018] [Accepted: 10/17/2018] [Indexed: 12/23/2022] Open
Abstract
Colonic tissues in Inflammatory Bowel Disease (IBD) patients exhibit oxygen deprivation and activation of hypoxia-inducible factor 1α and 2α (HIF-1α and HIF-2α), which mediate cellular adaptation to hypoxic stress. Notably, macrophages and neutrophils accumulate preferentially in hypoxic regions of the inflamed colon, suggesting that myeloid cell functions in colitis are HIF-dependent. By depleting ARNT (the obligate heterodimeric binding partner for both HIFα subunits) in a murine model, we demonstrate here that myeloid HIF signaling promotes the resolution of acute colitis. Specifically, myeloid pan-HIF deficiency exacerbates infiltration of pro-inflammatory neutrophils and Ly6C+ monocytic cells into diseased tissue. Myeloid HIF ablation also hinders macrophage functional conversion to a protective, pro-resolving phenotype, and elevates gut serum amyloid A levels during the resolution phase of colitis. Therefore, myeloid cell HIF signaling is required for efficient resolution of inflammatory damage in colitis, implicating serum amyloid A in this process.
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Affiliation(s)
- Nan Lin
- Perelman School of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, United States.,Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Jessica E S Shay
- Perelman School of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, United States
| | - Hong Xie
- Perelman School of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, United States.,Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - David S M Lee
- Perelman School of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, United States.,Genomics and Computational Biology Graduate Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Nicolas Skuli
- Perelman School of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, United States
| | - Qiaosi Tang
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, United States.,Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, United States
| | - Zilu Zhou
- Genomics and Computational Biology Graduate Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Andrew Azzam
- Perelman School of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, United States
| | - Hu Meng
- Perelman School of Medicine, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, United States
| | - Haichao Wang
- Department of Emergency Medicine, North Shore University Hospital, Manhasset, NY, United States.,The Feinstein Institute for Medical Research, Manhasset, NY, United States
| | - Garret A FitzGerald
- Perelman School of Medicine, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, United States
| | - M Celeste Simon
- Perelman School of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, United States.,Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
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47
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Colonoscopic-Guided Pinch Biopsies in Mice as a Useful Model for Evaluating the Roles of Host and Luminal Factors in Colonic Inflammation. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:2811-2825. [PMID: 30273600 DOI: 10.1016/j.ajpath.2018.08.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 07/17/2018] [Accepted: 08/07/2018] [Indexed: 12/22/2022]
Abstract
Colonic inflammation, a hallmark of inflammatory bowel disease, can be influenced by host intrinsic and extrinsic factors. There continues to be a need for models of colonic inflammation that can both provide insights into disease pathogenesis and be used to investigate potential therapies. Herein, we tested the utility of colonoscopic-guided pinch biopsies in mice for studying colonic inflammation and its treatment. Gene expression profiling of colonic wound beds after injury showed marked changes, including increased expression of genes important for the inflammatory response. Interestingly, many of these gene expression changes mimicked those alterations found in inflammatory bowel disease patients. Biopsy-induced inflammation was associated with increases in neutrophils, macrophages, and natural killer cells. Injury also led to elevated levels of sphingosine-1-phosphate (S1P), a bioactive lipid that is an important mediator of inflammation mainly through its receptor, S1P1. Genetic deletion of S1P1 in the endothelium did not alter the inflammatory response but led to increased colonic bleeding. Bacteria invaded into the wound beds, raising the possibility that microbes contributed to the observed changes in mucosal gene expression. In support of this, reducing bacterial abundance markedly attenuated the inflammatory response to wounding. Taken together, this study demonstrates the utility of the pinch biopsy model of colonic injury to elucidate the molecular underpinnings of colonic inflammation and its treatment.
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48
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Jain U, Lai CW, Xiong S, Goodwin VM, Lu Q, Muegge BD, Christophi GP, VanDussen KL, Cummings BP, Young E, Hambor J, Stappenbeck TS. Temporal Regulation of the Bacterial Metabolite Deoxycholate during Colonic Repair Is Critical for Crypt Regeneration. Cell Host Microbe 2018; 24:353-363.e5. [PMID: 30122655 PMCID: PMC6555552 DOI: 10.1016/j.chom.2018.07.019] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Revised: 06/18/2018] [Accepted: 07/25/2018] [Indexed: 02/07/2023]
Abstract
Colonic wound repair is an orchestrated process, beginning with barrier re-establishment and followed by wound channel formation and crypt regeneration. Elevated levels of prostaglandin E2 (PGE2) promote barrier re-establishment; however, we found that persistently elevated PGE2 hinders subsequent repair phases. The bacterial metabolite deoxycholate (DCA) promotes transition through repair phases via PGE2 regulation. During barrier re-establishment, DCA levels are locally diminished in the wound, allowing enhanced PGE2 production and barrier re-establishment. However, during transition to the wound channel formation phase, DCA levels increase to inhibit PGE2 production and promote crypt regeneration. Altering DCA levels via antibiotic treatment enhances PGE2 levels but impairs wound repair, which is rescued with DCA treatment. DCA acts via its receptor, farnesoid X receptor, to inhibit the enzyme cPLA2 required for PGE2 synthesis. Thus, colonic wound repair requires temporally regulated signals from microbial metabolites to coordinate host-associated signaling cascades. VIDEO ABSTRACT.
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Affiliation(s)
- Umang Jain
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Chin-Wen Lai
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Shanshan Xiong
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Victoria M Goodwin
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Qiuhe Lu
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Brian D Muegge
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - George P Christophi
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110 USA
| | - Kelli L VanDussen
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Bethany P Cummings
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
| | - Erick Young
- Research Beyond Borders, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT 06877, USA
| | - John Hambor
- Research Beyond Borders, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT 06877, USA
| | - Thaddeus S Stappenbeck
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
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49
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Djuric Z, Turgeon DK, Sen A, Ren J, Herman K, Ramaswamy D, Zhao L, Ruffin MT, Normolle DP, Smith WL, Brenner DE. The Anti-inflammatory Effect of Personalized Omega-3 Fatty Acid Dosing for Reducing Prostaglandin E 2 in the Colonic Mucosa Is Attenuated in Obesity. Cancer Prev Res (Phila) 2017; 10:729-737. [PMID: 29133307 PMCID: PMC5767924 DOI: 10.1158/1940-6207.capr-17-0091] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Revised: 07/12/2017] [Accepted: 10/02/2017] [Indexed: 12/20/2022]
Abstract
This clinical trial developed a personalized dosing model for reducing prostaglandin E2 (PGE2) in colonic mucosa using ω-3 fatty acid supplementation. The model utilized serum eicosapentaenoic acid (EPA, ω-3):arachidonic acid (AA, ω-6) ratios as biomarkers of colonic mucosal PGE2 concentration. Normal human volunteers were given low and high ω-3 fatty acid test doses for 2 weeks. This established a slope and intercept of the line for dose versus serum EPA:AA ratio in each individual. The slope and intercept was utilized to calculate a personalized target dose that was given for 12 weeks. This target dose was calculated on the basis of a model, initially derived from lean rodents, showing a log-linear relationship between serum EPA:AA ratios and colonic mucosal PGE2 reduction. Bayesian methods allowed addition of human data to the rodent model as the trial progressed. The dosing model aimed to achieve a serum EPA:AA ratio that is associated with a 50% reduction in colonic PGE2 Mean colonic mucosal PGE2 concentrations were 6.55 ng/mg protein (SD, 5.78) before any supplementation and 3.59 ng/mg protein (SD, 3.29) after 12 weeks of target dosing. In secondary analyses, the decreases in PGE2 were significantly attenuated in overweight and obese participants. This occurred despite a higher target dose for the obese versus normal weight participants, as generated by the pharmacodynamic predictive model. Large decreases also were observed in 12-hydroxyicosatetraenoic acids, and PGE3 increased substantially. Future biomarker-driven dosing models for cancer prevention therefore should consider energy balance as well as overall eicosanoid homeostasis in normal tissue. Cancer Prev Res; 10(12); 729-37. ©2017 AACR.
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Affiliation(s)
- Zora Djuric
- Department of Family Medicine, University of Michigan Medical School, Ann Arbor, Michigan.
| | - D Kim Turgeon
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan
| | - Ananda Sen
- Department of Family Medicine, University of Michigan Medical School, Ann Arbor, Michigan
- Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan
| | - Jianwei Ren
- Department of Family Medicine, University of Michigan Medical School, Ann Arbor, Michigan
| | - Kirk Herman
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan
| | - Devon Ramaswamy
- Department of Family Medicine, University of Michigan Medical School, Ann Arbor, Michigan
| | - Lili Zhao
- Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan
| | - Mack T Ruffin
- Department of Family and Community Medicine, Penn State Hershey Medical Center, Hershey, Pennsylvania
| | - Daniel P Normolle
- Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania
| | - William L Smith
- Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan
| | - Dean E Brenner
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan
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50
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Grancher A, Michel P, Di Fiore F, Sefrioui D. [Aspirin and colorectal cancer]. Bull Cancer 2017; 105:171-180. [PMID: 29153543 DOI: 10.1016/j.bulcan.2017.09.013] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 08/18/2017] [Accepted: 09/08/2017] [Indexed: 12/17/2022]
Abstract
Colorectal cancer is a worldwide public health problem. Aspirin has been identified as a protective factor against the apparition of colorectal cancer. There are several mechanisms about the actions by aspirin on colorectal tumorogenesis. These are not perfectly known nowadays. On one hand, there are direct mechanisms on colorectal mucosa, on the other hand there are indirect mechanisms through platelet functions. Aspirin also plays a role by its anti-inflammatory action and the stimulation of antitumor immunity. Several studies show that long-term treatment with low-doses of aspirin decreases the incidence of adenomas and colorectal cancers. In the United States, aspirin is currently recommended for primary prevention of the risk of colorectal cancer in all patients aged 50 to 59, with a 10-year risk of cardiovascular event greater than 10 %. However, primary prevention with aspirin should not be a substitute for screening in colorectal cancer. Furthermore, aspirin seems to be beneficial when used in post-diagnosis of colorectal cancer. It could actually decrease the risk of metastasis in case of a localized colorectal cancer, and increase the survival in particular, concerning PIK3CA mutated tumors. The association of aspirin with neoadjuvant treatment of colorectal cancer by radiochimiotherapy seems to have beneficial effects. French prospective randomized study is currently being conducted to investigate postoperative aspirin in colorectal cancers with a PIK3CA mutation.
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Affiliation(s)
- Adrien Grancher
- Normandie université, UNIROUEN, hôpital universitaire de Rouen, service d'hépato-gastroenterologie, 76000 Rouen, France
| | - Pierre Michel
- Normandie université, UNIROUEN, Inserm 1245, IRON group, hôpital universitaire de Rouen, service d'hépato-gastroentérologie, 76000 Rouen, France.
| | - Frédéric Di Fiore
- Normandie université, UNIROUEN, Inserm 1245, IRON group, hôpital universitaire de Rouen, centre Henri-Becquerel, département d'oncolgie médicale, service d'hépato-gastroentérologie, 76000 Rouen, France
| | - David Sefrioui
- Normandie université, UNIROUEN, Inserm 1245, IRON group, hôpital universitaire de Rouen, service d'hépato-gastroentérologie, 76000 Rouen, France
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