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Blondeaux A, Valibouze C, Speca S, Rousseaux C, Dubuquoy C, Blanquart H, Zerbib P, Desreumaux P, Foligné B, Titécat M. Changes in HLA-B27 Transgenic Rat Fecal Microbiota Following Tofacitinib Treatment and Ileocecal Resection Surgery: Implications for Crohn's Disease Management. Int J Mol Sci 2024; 25:2164. [PMID: 38396840 PMCID: PMC10889215 DOI: 10.3390/ijms25042164] [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: 01/12/2024] [Revised: 02/02/2024] [Accepted: 02/08/2024] [Indexed: 02/25/2024] Open
Abstract
The therapeutic management of Crohn's disease (CD), a chronic relapsing-remitting inflammatory bowel disease (IBD), is highly challenging. Surgical resection is sometimes a necessary procedure even though it is often associated with postoperative recurrences (PORs). Tofacitinib, an orally active small molecule Janus kinase inhibitor, is an anti-inflammatory drug meant to limit PORs in CD. Whereas bidirectional interactions between the gut microbiota and the relevant IBD drug are crucial, little is known about the impact of tofacitinib on the gut microbiota. The HLA-B27 transgenic rat is a good preclinical model used in IBD research, including for PORs after ileocecal resection (ICR). In the present study, we used shotgun metagenomics to first delineate the baseline composition and determinants of the fecal microbiome of HLA-B27 rats and then to evaluate the distinct impact of either tofacitinib treatment, ileocecal resection or the cumulative effect of both interventions on the gut microbiota in these HLA-B27 rats. The results confirmed that the microbiome of the HLA-B27 rats was fairly different from their wild-type littermates. We demonstrated here that oral treatment with tofacitinib does not affect the gut microbial composition of HLA-B27 rats. Of note, we showed that ICR induced an intense loss of bacterial diversity together with dramatic changes in taxa relative abundances. However, the oral treatment with tofacitinib neither modified the alpha-diversity nor exacerbated significant modifications in bacterial taxa induced by ICR. Collectively, these preclinical data are rather favorable for the use of tofacitinib in combination with ICR to address Crohn's disease management when considering microbiota.
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Affiliation(s)
- Aurélie Blondeaux
- U1286—INFINITE—Institute for Translational Research in Inflammation, CHU Lille, Inserm, Univ. Lille, F-59000 Lille, France; (A.B.); (C.V.); (S.S.); (P.Z.); (P.D.); (M.T.)
- Department of Hepato-Gastroenterology, Lille University Hospital, 59037 Lille, France
| | - Caroline Valibouze
- U1286—INFINITE—Institute for Translational Research in Inflammation, CHU Lille, Inserm, Univ. Lille, F-59000 Lille, France; (A.B.); (C.V.); (S.S.); (P.Z.); (P.D.); (M.T.)
- Department of Hepato-Gastroenterology, Lille University Hospital, 59037 Lille, France
| | - Silvia Speca
- U1286—INFINITE—Institute for Translational Research in Inflammation, CHU Lille, Inserm, Univ. Lille, F-59000 Lille, France; (A.B.); (C.V.); (S.S.); (P.Z.); (P.D.); (M.T.)
| | - Christel Rousseaux
- Intestinal Biotech Development, 1 Avenue Oscar Lambret, 59045 Lille, France; (C.R.); (C.D.)
| | - Caroline Dubuquoy
- Intestinal Biotech Development, 1 Avenue Oscar Lambret, 59045 Lille, France; (C.R.); (C.D.)
| | | | - Philippe Zerbib
- U1286—INFINITE—Institute for Translational Research in Inflammation, CHU Lille, Inserm, Univ. Lille, F-59000 Lille, France; (A.B.); (C.V.); (S.S.); (P.Z.); (P.D.); (M.T.)
- Department of Hepato-Gastroenterology, Lille University Hospital, 59037 Lille, France
| | - Pierre Desreumaux
- U1286—INFINITE—Institute for Translational Research in Inflammation, CHU Lille, Inserm, Univ. Lille, F-59000 Lille, France; (A.B.); (C.V.); (S.S.); (P.Z.); (P.D.); (M.T.)
- Department of Hepato-Gastroenterology, Lille University Hospital, 59037 Lille, France
| | - Benoît Foligné
- U1286—INFINITE—Institute for Translational Research in Inflammation, CHU Lille, Inserm, Univ. Lille, F-59000 Lille, France; (A.B.); (C.V.); (S.S.); (P.Z.); (P.D.); (M.T.)
| | - Marie Titécat
- U1286—INFINITE—Institute for Translational Research in Inflammation, CHU Lille, Inserm, Univ. Lille, F-59000 Lille, France; (A.B.); (C.V.); (S.S.); (P.Z.); (P.D.); (M.T.)
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Rezazadeh F, Ramos N, Saliganan AD, Al-Hallak N, Chen K, Mohamad B, Wiesend WN, Viola NT. Detection of IL12/23p40 via PET Visualizes Inflammatory Bowel Disease. J Nucl Med 2023; 64:1806-1814. [PMID: 37474270 PMCID: PMC10626378 DOI: 10.2967/jnumed.123.265649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 06/20/2023] [Indexed: 07/22/2023] Open
Abstract
Inflammatory bowel disease (IBD), which includes both Crohn disease and ulcerative colitis, is a relapsing inflammatory disease of the gastrointestinal tract. Long-term chronic inflammatory conditions elevate the patient's risk of colorectal cancer (CRC). Currently, diagnosis requires endoscopy with biopsy. This procedure is invasive and requires a bowel-preparatory regimen, adding to patient burden. Interleukin 12 (IL12) and interleukin 23 (IL23) play key roles in inflammation, especially in the pathogenesis of IBD, and are established therapeutic targets. We propose that imaging of IL12/23 and its p40 subunit in IBD via immuno-PET potentially provides a new noninvasive diagnostic approach. Methods: Our aim was to investigate the potential of immuno-PET to image inflammation in a chemically induced mouse model of colitis using dextran sodium sulfate by targeting IL12/23p40 with a 89Zr-radiolabeled anti-IL12/23p40 antibody. Results: High uptake of the IL12/23p40 immuno-PET agent was exhibited by dextran sodium sulfate-administered mice, and this uptake correlated with increased IL12/23p40 present in the sera. Competitive binding studies confirmed the specificity of the radiotracer for IL12/23p40 in the gastrointestinal tract. Conclusion: These promising results demonstrate the utility of this radiotracer as an imaging biomarker of IBD. Moreover, IL12/23p40 immuno-PET can potentially guide treatment decisions for IBD management.
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Affiliation(s)
- Farzaneh Rezazadeh
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
| | - Nicholas Ramos
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
| | - Allen-Dexter Saliganan
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
| | - Najeeb Al-Hallak
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
| | - Kang Chen
- Departments of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan
| | - Bashar Mohamad
- Department of Gastroenterology, Wayne State University, Detroit, Michigan; and
| | - Wendy N Wiesend
- Department of Anatomic Pathology, Corewell Health William Beaumont University Hospital, Royal Oak, Michigan
| | - Nerissa T Viola
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan;
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Peixoto RD, Ferreira AR, Cleary JM, Fogacci JP, Vasconcelos JP, Jácome AA. Risk of Cancer in Inflammatory Bowel Disease and Pitfalls in Oncologic Therapy. J Gastrointest Cancer 2023; 54:357-367. [PMID: 35288863 DOI: 10.1007/s12029-022-00816-0] [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] [Accepted: 02/22/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND Inflammatory bowel disease (IBD), represented by ulcerative colitis and Crohn's disease, is an idiopathic condition caused by a dysregulated immune response to host intestinal microflora, leading to chronic relapsing intestinal inflammation. Individuals with IBD are more prone to die from several diseases, including cancer. METHODS An extensive search was conducted of PubMed using the following medical subject heading-"inflammatory bowel disease" OR "Crohn's disease" OR "ulcerative colitis" AND "cancer." RESULTS In this review article, we discuss the oncogenic mechanisms and genomics of colitis-associated colorectal cancer. Beyond this, we describe the multiple other malignancies that IBD patients are at risk for, discuss caveats in the screening and diagnosis of those cancers, and shed light on pitfalls on the management and treatment of cancer in IBD patients. CONCLUSION Patients, caregivers, and health professionals who deal with IBD must be educated on how to identify warning signs so that cancers can be diagnosed and treated as early as possible.
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Kamaludin R, Othman MHD, Kadir SHSA, Khan J, Ismail AF, Rahman MA, Jaafar J. Visible-light-driven photocatalytic dual-layer hollow fibre membrane ameliorates the changes of bisphenol A exposure in gastrointestinal tract. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:259-273. [PMID: 35902521 DOI: 10.1007/s11356-022-22121-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 07/15/2022] [Indexed: 06/15/2023]
Abstract
Various treatments of choice are available to overcome contamination of bisphenol A (BPA) in the environment including membrane technologies; however, the treatment still releases contaminants that threaten the human being. Therefore, the present study is conducted to investigate the degradation of BPA by recently developed visible-light-driven photocatalytic nitrogen-doping titanium dioxide (N-doped TiO2) dual-layer hollow fibre (DLHF) membrane and its efficiency in reducing the level of BPA in contaminated water. Fabricated with suitable polymer/photocatalyst (15/7.5 wt.%) via co-extrusion spinning method, the DLHF was characterized morphologically, evaluated for BPA degradation by using submerged photocatalytic membrane reactor under visible light irradiations followed by the investigation of intermediates formed. BPA exposure effects were accessed by immunohistochemistry staining of gastrointestinal sample obtained from animal model. BPA has been successfully degraded up to 72.5% with 2 intermediate products, B1 and B2, being identified followed by total degradation of BPA. BPA exposure leads to the high-intensity IHC staining of Claudin family which indicated the disruption of small intestinal barrier (SIB) integrity. Low IHC staining intensity of Claudin family in treated BPA group demonstrated that reducing the level of BPA by N-doped TiO2 DLHF is capable of protecting the important component of SIB. Altogether, the fabricated photocatalytic DLHF membrane is expected to have an outstanding potential in removing BPA and its health effect for household water treatment to fulfil the public focus on the safety of their household water and their need to consume clean water.
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Affiliation(s)
- Roziana Kamaludin
- Advanced Membrane Technology Research Centre (AMTEC), Universiti Teknologi Malaysia, 81310, Skudai, Johor, Malaysia
| | - Mohd Hafiz Dzarfan Othman
- Advanced Membrane Technology Research Centre (AMTEC), Universiti Teknologi Malaysia, 81310, Skudai, Johor, Malaysia.
| | - Siti Hamimah Sheikh Abdul Kadir
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA (UiTM), Jalan Hospital, Sungai Buloh Campus, 47000, Selangor, Sungai Buloh, Malaysia
| | - Jesmine Khan
- Biochemistry and Molecular Medicine Department, Faculty of Medicine, Sungai Buloh Campus, Universiti Teknologi MARA (UiTM), Jalan Hospital, 47000, Selangor, Sungai Buloh, Malaysia
| | - Ahmad Fauzi Ismail
- Advanced Membrane Technology Research Centre (AMTEC), Universiti Teknologi Malaysia, 81310, Skudai, Johor, Malaysia
| | - Mukhlis A Rahman
- Advanced Membrane Technology Research Centre (AMTEC), Universiti Teknologi Malaysia, 81310, Skudai, Johor, Malaysia
| | - Juhana Jaafar
- Advanced Membrane Technology Research Centre (AMTEC), Universiti Teknologi Malaysia, 81310, Skudai, Johor, Malaysia
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Xu L, Huang G, Cong Y, Yu Y, Li Y. Sex-related Differences in Inflammatory Bowel Diseases: The Potential Role of Sex Hormones. Inflamm Bowel Dis 2022; 28:1766-1775. [PMID: 35486387 DOI: 10.1093/ibd/izac094] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Indexed: 12/13/2022]
Abstract
Inflammatory bowel disease (IBD), characterized by chronic inflammation of the gastrointestinal tract, is a global health care problem. Compelling evidence shows sex differences regarding the prevalence, pathophysiology, clinical presentation, and treatment outcome of IBD. Sex hormones, including estrogen, progesterone, and androgen, have been proposed to have a role in the pathogenesis of sexual dimorphism in IBD. Clinical and experimental data support the modulatory effects of sex hormones on various clinical characteristics of the disease, including intestinal barrier dysfunction and mucosal immune activation. Additionally, the potential role of sex hormones in the modulation of gut microbiota is attracting increasing attention. Here, we discuss the sex dimorphic disease profile and address the potential mechanisms involved in the sex-specific pathogenesis of IBD. Improved understanding of these sex differences in the clinic could improve the knowledge of patients with IBD with heterogeneous disease profiles.
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Affiliation(s)
- Leiqi Xu
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, Shandong, P.R. China
| | - Gang Huang
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, Shandong, P.R. China
| | - Yingzi Cong
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Yanbo Yu
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, Shandong, P.R. China
| | - Yanqing Li
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, Shandong, P.R. China
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Aspalathus linearis (Rooibos) and Agmatine May Act Synergistically to Beneficially Modulate Intestinal Tight Junction Integrity and Inflammatory Profile. Pharmaceuticals (Basel) 2022; 15:ph15091097. [PMID: 36145318 PMCID: PMC9501288 DOI: 10.3390/ph15091097] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/17/2022] [Accepted: 08/28/2022] [Indexed: 11/25/2022] Open
Abstract
In order to promote gastrointestinal health, significant increases in the prevalence of gastrointestinal disorders should be paralleled by similar surges in therapeutics research. Nutraceutical interventions may play a significant role in patient management. The current study aimed to determine the potential of Aspalathus linearis (rooibos) to prevent gastrointestinal dysregulation resulting from high-dose trace-amine (TA) exposure. Considering the substantial female bias in functional gastrointestinal disorders, and the suggested phytoestrogenicity of rooibos, the study design allowed for a comparison between the effects of an ethanol extract of green rooibos and 17β-estradiol (E2). High levels of ρ-tyramine (TYR) and agmatine (AGM), but not β-phenethylamine (PEA) or tryptamine (TRP), resulted in prostaglandin E2 (PGE2) hypersecretion, increased tight-junction protein (TJP; occludin and ZO-1) secretion and (dissimilarly) disrupted the TJP cellular distribution profile. Modulating benefits of rooibos and E2 were TA-specific. Rooibos pre-treatment generally reduced IL-8 secretion across all TA conditions and prevented PGE2 hypersecretion after exposure to both TYR and AGM, but was only able to normalise TJP levels and the distribution profile in AGM-exposed cells. In contrast, E2 pre-treatment prevented only TYR-associated PGE2 hypersecretion and TJP dysregulation. Together, the data suggest that the antioxidant and anti-inflammatory effects of rooibos, rather than phytoestrogenicity, affect benefits illustrated for rooibos.
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Fischer V, Ragipoglu D, Diedrich J, Steppe L, Dudeck A, Schütze K, Kalbitz M, Gebhard F, Haffner-Luntzer M, Ignatius A. Mast Cells Trigger Disturbed Bone Healing in Osteoporotic Mice. J Bone Miner Res 2022; 37:137-151. [PMID: 34633111 DOI: 10.1002/jbmr.4455] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 09/21/2021] [Accepted: 10/03/2021] [Indexed: 12/16/2022]
Abstract
Mast cells are important tissue-resident sensor and effector immune cells but also play a major role in osteoporosis development. Mast cells are increased in numbers in the bone marrow of postmenopausal osteoporotic patients, and mast cell-deficient mice are protected from ovariectomy (OVX)-induced bone loss. In this study, we showed that mast cell-deficient Mcpt5-Cre R-DTA mice were protected from OVX-induced disturbed fracture healing, indicating a critical role for mast cells in the pathomechanisms of impaired bone repair under estrogen-deficient conditions. We revealed that mast cells trigger the fracture-induced inflammatory response by releasing inflammatory mediators, including interleukin-6, midkine (Mdk), and C-X-C motif chemokine ligand 10 (CXCL10), and promote neutrophil infiltration into the fracture site in OVX mice. Furthermore, mast cells were responsible for reduced osteoblast and increased osteoclast activities in OVX mice callus, as well as increased receptor activator of NF-κB ligand serum levels in OVX mice. Additional in vitro studies with human cells showed that mast cells stimulate osteoclastogenesis by releasing the osteoclastogenic mediators Mdk and CXCL10 in an estrogen-dependent manner, which was mediated via the estrogen receptor alpha on mast cells. In conclusion, mast cells negatively affect the healing of bone fractures under estrogen-deficient conditions. Hence, targeting mast cells might provide a therapeutic strategy to improve disturbed bone repair in postmenopausal osteoporosis. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Verena Fischer
- Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, Ulm, Germany
| | - Deniz Ragipoglu
- Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, Ulm, Germany
| | - Johanna Diedrich
- Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, Ulm, Germany
| | - Lena Steppe
- Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, Ulm, Germany
| | - Anne Dudeck
- Institute for Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Konrad Schütze
- Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, University Medical Center Ulm, Ulm, Germany
| | - Miriam Kalbitz
- Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, University Medical Center Ulm, Ulm, Germany.,Department of Trauma and Orthopedic Surgery, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen-Nürnberg, Germany
| | - Florian Gebhard
- Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, University Medical Center Ulm, Ulm, Germany
| | - Melanie Haffner-Luntzer
- Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, Ulm, Germany
| | - Anita Ignatius
- Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, Ulm, Germany
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Graham JJ, Longhi MS, Heneghan MA. T helper cell immunity in pregnancy and influence on autoimmune disease progression. J Autoimmun 2021; 121:102651. [PMID: 34020252 PMCID: PMC8221281 DOI: 10.1016/j.jaut.2021.102651] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 04/30/2021] [Accepted: 05/02/2021] [Indexed: 02/07/2023]
Abstract
Pregnancy presents the maternal immune system with a unique immunological challenge since it has to defend against pathogens while tolerating paternal allo-antigens expressed by fetal tissues. T helper (Th) cells play a central role in modulating immune responses and recent advances have defined distinct contributions of various Th cell subsets throughout each phase of human pregnancy, while dysregulation in Th responses show association with multiple obstetrical complications. In addition to localized decidual mechanisms, modulation of Th cell immunity during gestation is mediated largely by oscillations in sex hormone concentrations. Aberrant Th cell responses also underlie several autoimmune disorders while pregnancy-induced changes in the balance of Th cell immunity has been shown to exert favorable outcomes in the progression Th1 and Th17 driven autoimmune conditions only to be followed by post-partal exacerbations in disease.
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Affiliation(s)
- Jonathon J Graham
- Institute of Liver Studies, King's College Hospital, London, SE5 9RS, United Kingdom
| | - Maria Serena Longhi
- Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA
| | - Michael A Heneghan
- Institute of Liver Studies, King's College Hospital, London, SE5 9RS, United Kingdom.
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Selective estrogen receptor modulator lasofoxifene suppresses spondyloarthritis manifestation and affects characteristics of gut microbiota in zymosan-induced SKG mice. Sci Rep 2021; 11:11923. [PMID: 34099783 PMCID: PMC8184804 DOI: 10.1038/s41598-021-91320-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 05/07/2021] [Indexed: 12/22/2022] Open
Abstract
Ankylosing spondylitis is a male-predominant disease and previous study revealed that estrogens have an anti-inflammatory effect on the spondyloarthritis (SpA) manifestations in zymosan-induced SKG mice. This study aimed to evaluate the effect of selective estrogen receptor modulator (SERM) lasofoxifene (Laso) on disease activity of SpA. Mice were randomized into zymosan-treated, zymosan + 17β-estradiol (E2)-treated, and zymosan + Laso-treated groups. Arthritis was assessed by 18F-fluorodeoxyglucose (18F-FDG) small-animal positron emission tomography/computed tomography and bone mineral density (BMD) was measured. Fecal samples were collected and 16S ribosomal RNA gene sequencing was used to determine gut microbiota differences. Both zymosan + E2-treated mice and zymosan + Laso-treated mice showed lower arthritis clinical scores and lower 18F-FDG uptake than zymosan-treated mice. BMD was significantly higher in zymosan + E2-treated mice and zymosan + Laso-treated mice than zymosan-treated mice, respectively. Fecal calprotectin levels were significantly elevated at 8 weeks after zymosan injection in zymosan-treated mice, but it was not significantly changed in zymosan + E2-treated mice and zymosan + Laso-treated mice. Gut microbiota diversity of zymosan-treated mice was significantly different from zymosan + E2-treated mice and zymosan + Laso-treated mice, respectively. There was no significant difference in gut microbiota diversity between zymosan + E2-treated mice and zymosan + Laso -treated mice. Laso inhibited joint inflammation and enhanced BMD in SKG mice, a model of SpA. Laso also affected the composition and biodiversity of gut microbiota. This study provides new knowledge regarding that selected SpA patients could benefit from SERM treatment.
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Ghosh MK, Chen KHE, Dill-Garlow R, Ma LJ, Yonezawa T, Itoh Y, Rivera L, Radecki KC, Wu QP, Arnold AP, Muller HK, Walker AM. Sex Differences in the Immune System Become Evident in the Perinatal Period in the Four Core Genotypes Mouse. Front Endocrinol (Lausanne) 2021; 12:582614. [PMID: 34122327 PMCID: PMC8191418 DOI: 10.3389/fendo.2021.582614] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 05/07/2021] [Indexed: 01/02/2023] Open
Abstract
We have used the four core genotypes (FCG) mouse model, which allows a distinction between effects of gonadal secretions and chromosomal complement, to determine when sex differences in the immune system first appear and what influences their development. Using splenic T cell number as a measure that could be applied to neonates with as yet immature immune responses, we found no differences among the four genotypes at postnatal day 1, but by day 7, clear sex differences were observed. These sex differences were unexpectedly independent of chromosomal complement and similar in degree to gonadectomized FCG adults: both neonatal and gonadectomized adult females (XX and XY) showed 2-fold the number of CD4+ and 7-fold the number of CD8+ T cells versus their male (XX and XY) counterparts. Appearance of this long-lived sex difference between days 1 and 7 suggested a role for the male-specific perinatal surge of testicular testosterone. Interference with the testosterone surge significantly de-masculinized the male CD4+, but not CD8+ splenic profile. Treatment of neonates demonstrated elevated testosterone limited mature cell egress from the thymus, whereas estradiol reduced splenic T cell seeding in females. Neonatal male splenic epithelium/stroma expressed aromatase mRNA, suggesting capacity for splenic conversion of perinatal testosterone into estradiol in males, which, similar to administration of estradiol in females, would result in reduced splenic T cell seeding. These sex steroid effects affected both CD4+ and CD8+ cells and yet interference with the testosterone surge only significantly de-masculinized the splenic content of CD4+ cells. For CD8+ cells, male cells in the thymus were also found to express one third the density of sphingosine-1-phosphate thymic egress receptors per cell compared to female, a male characteristic most likely an indirect result of Sry expression. Interestingly, the data also support a previously unrecognized role for non-gonadal estradiol in the promotion of intra-thymic cell proliferation in neonates of both sexes. Microarray analysis suggested the thymic epithelium/stroma as the source of this hormone. We conclude that some immune sex differences appear long before puberty and more than one mechanism contributes to differential numbers and distribution of T cells.
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Affiliation(s)
- Mrinal K. Ghosh
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States
| | - Kuan-hui E. Chen
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States
| | - Riva Dill-Garlow
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States
| | - Lisa J. Ma
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States
| | - Tomohiro Yonezawa
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States
| | - Yuichiro Itoh
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA, United States
| | - Lorena Rivera
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States
| | - Kelly C. Radecki
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States
| | - Quiming P. Wu
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States
| | - Arthur P. Arnold
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA, United States
| | - H. Konrad Muller
- School of Medicine, University of Tasmania, Hobart, TAS, Australia
| | - Ameae M. Walker
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States
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Liu SD, Timur Y, Xu L, Meng WX, Sun B, Qiu DY. Inhibiting the ROCK Pathway Ameliorates Acute Lung Injury in Mice following Myocardial Ischemia/reperfusion. Immunol Invest 2021; 51:931-946. [PMID: 33655821 DOI: 10.1080/08820139.2021.1887887] [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: 10/22/2022]
Abstract
To clarify the role of Y-27632, a selective inhibitor of Rho-associated coiled-coil forming protein kinase (ROCK), in acute lung injury (ALI) induced by myocardial ischemia/reperfusion (I/R). Mice were randomized into Sham, I/R, and Y-27632 (10, 20 or 30 mg/kg) + I/R groups, and hemodynamics, infarcted area, the protein concentration, neutrophils in bronchoalveolar lavage fluid (BALF), malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels were assessed. Pathological changes were evaluated by hematoxylin-eosin (HE) staining; protein and gene expression were measured by Western blotting, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry and quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR); and apoptosis was assessed by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) staining. ROCK1 and ROCK2 expression was up-regulated in lung tissues of I/R mice compared to sham mice. Y-27632 decreased the protein concentration and the neutrophils in BALF in I/R mice, improved hemodynamics and reduced infarct size (IS)/area at risk (AAR) ratio. In addition, pathological changes in lung tissues of Y-27632-treated mice were mitigated, and these alterations were accompanied by decreases in MDA levels in lung tissues and increases in SOD and GSH-Px levels. Moreover, in I/R group, the number of apoptotic cells in lung tissue was higher than that in sham group, and p53, Caspase-3 and Bax expression was up-regulated; however, following treatment with Y-27632 (10, 20 and 30 mg/kg), these changes were reversed. Inhibition of ROCK pathway by Y-27632 ameliorated ALI in myocardial I/R mice by mitigating oxidative stress, inflammation and cell apoptosis.
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Affiliation(s)
- Shang-Dian Liu
- Department of Cardiovascular Surgery, The First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Yagudin Timur
- Department of Pharmacology, Harbin Medical University, Harbin, China.,Department of Pharmacology, Central Laboratory of Scientific Research, Bashkir State Medical University, Ufa, Russian Federation
| | - Lei Xu
- Department of Cardiovascular Surgery, The First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Wei-Xin Meng
- Department of Cardiovascular Surgery, The First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Bo Sun
- Department of Cardiovascular Surgery, The First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Dong-Yun Qiu
- Department of Cardiovascular Surgery, The First Affiliated Hospital, Harbin Medical University, Harbin, China
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12
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Wang Q, Li Z, Liu K, Liu J, Chai S, Chen G, Wen S, Ming T, Wang J, Ma Y, Zeng H, Liu C, Xue B. Activation of the G Protein-Coupled Estrogen Receptor Prevented the Development of Acute Colitis by Protecting the Crypt Cell. J Pharmacol Exp Ther 2021; 376:281-293. [PMID: 33318078 DOI: 10.1124/jpet.120.000216] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 10/05/2020] [Indexed: 12/13/2022] Open
Abstract
G protein-coupled estrogen receptor (GPER) might be involved in ulcerative colitis (UC), but the direct effect of GPER on UC is still unclear. We used male C57BL/6 mice to establish the acute colitis model with administration of dextran sulfate sodium and explored the effect of GPER on acute colitis and its possible mechanism. The selective GPER agonist G-1 inhibited weight loss and colon shortening and decreased the disease activity index for colitis and histologic damage in mice with colitis. All of these effects were prevented by a selective GPER blocker. G-1 administration prevented the dysfunction of tight junction protein expression and goblet cells in colitis model and thus inhibited the increase of mucosal permeability in colitis-suffering mice significantly. GPER activation reduced expression of glucose-regulating peptide-78 and anti-CCAAT/enhancer-binding protein homologous protein and attenuated the three arms of the unfolded protein response in colitis. G-1 therapy inhibited the increase of cleavage caspase-3- and TUNEL-positive cells in colonic crypts in the colitis model, increased the number of Ki67- and bromodeoxyuridine-positive cells in crypts, and reversed the decrease of cyclin D1 and cyclin B1 expression in colitis, indicating its protective effect on crypt cells. In cultured CCD841 cells, G-1 treatment fought against cell injury induced by endoplasmic reticulum stress. These findings demonstrate that GPER activation prevents colitis by protecting the colonic crypt cells, which are associated with inhibition of endoplasmic reticulum stress. SIGNIFICANCE STATEMENT: We demonstrate that G protein-coupled estrogen receptor (GPER) activation prevents dextran sulfate sodium-induced acute colitis by protecting the crypt cells, showing that it inhibited the crypt cell apoptosis and protected proliferation of crypt cells, which resulted in protection of the intestinal mucosal barrier. This protective effect was achieved (at least in part) by inhibiting endoplasmic reticulum stress. Mucosal healing is regarded as a key therapeutic target for colitis, and GPER is expected to become a new therapeutic target for colitis.
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Affiliation(s)
- Qian Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Zhao Li
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Kaixuan Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Jianbo Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Shiquan Chai
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Guanyu Chen
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Shuyu Wen
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Tian Ming
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Jiayi Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Yuntao Ma
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Honghui Zeng
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Chuanyong Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Bing Xue
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
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Abstract
The disease course of autoimmune diseases such as rheumatoid arthritis is altered during pregnancy, and a similar modulatory role of pregnancy on inflammatory bowel disease (IBD) has been proposed. Hormonal, immunological, and microbial changes occurring during normal pregnancy may interact with the pathophysiology of IBD. IBD consists of Crohn's disease and ulcerative colitis, and because of genetic, immunological, and microbial differences between these disease entities, they may react differently during pregnancy and should be described separately. This review will address the pregnancy-induced physiological changes and their potential effect on the disease course of ulcerative colitis and Crohn's disease, with emphasis on the modulation of epithelial barrier function and immune profiles by pregnancy hormones, microbial changes, and microchimerism.
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Juliano GR, Skaf MF, Ramalho LS, Juliano GR, Torquato BGS, Oliveira MS, Oliveira FA, Espíndula AP, Cavellani CL, Teixeira VDPA, Ferraz MLDF. Analysis of mast cells and myocardial fibrosis in autopsied patients with hypertensive heart disease. Rev Port Cardiol 2020; 39:89-96. [PMID: 32205013 DOI: 10.1016/j.repc.2019.11.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 10/07/2019] [Accepted: 11/02/2019] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE To analyze the percentage of collagen fibers and mast cell density in the left ventricular myocardium of autopsied patients with and without hypertensive heart disease. METHODS Thirty fragments of left ventricular myocardium were obtained from individuals autopsied at the Clinical Hospital of the Federal University of Triângulo Mineiro (UFTM) in the period from 1987 to 2017. Individuals were divided into two groups: those with hypertensive heart disease (HD) and those with no heart disease (ND). Subjects were also assessed according to age, gender and race (white and non-white). Collagen fibers were quantified by computed morphometry and mast cell density was assessed by immunohistochemical methods. RESULTS There were significantly more collagen fibers in the left ventricle in the HD group than in the ND group (p<0.001). Mast cell density was significantly higher in the left ventricle of individuals with HD immunolabeled with anti-chymase and anti-tryptase antibodies (p=0.02) and also of those immunolabeled only with anti-tryptase antibodies (p=0.03). Analyzing the HD group, there was a significant positive correlation between the percentage of collagen fibers in the left ventricle and mast cell density immunolabeled by anti-chymase and anti-tryptase antibodies (p=0.04) and also mast cell density immunolabeled only with anti-tryptase antibodies (p=0.02). CONCLUSIONS Mast cells are involved in the development of hypertensive heart disease, contributing to the remodeling of collagen fibers in this disease.
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Affiliation(s)
- Guilherme Ribeiro Juliano
- General Pathology Department, Biological and Natural Sciences Institute (ICBN), Federal University of Triângulo Mineiro (UFTM), Uberaba, MG, Brazil.
| | - Mariana Fleury Skaf
- General Pathology Department, Biological and Natural Sciences Institute (ICBN), Federal University of Triângulo Mineiro (UFTM), Uberaba, MG, Brazil
| | - Luciana Santos Ramalho
- General Pathology Department, Biological and Natural Sciences Institute (ICBN), Federal University of Triângulo Mineiro (UFTM), Uberaba, MG, Brazil
| | - Gabriela Ribeiro Juliano
- General Pathology Department, Biological and Natural Sciences Institute (ICBN), Federal University of Triângulo Mineiro (UFTM), Uberaba, MG, Brazil
| | - Bianca Gonçalves Silva Torquato
- General Pathology Department, Biological and Natural Sciences Institute (ICBN), Federal University of Triângulo Mineiro (UFTM), Uberaba, MG, Brazil
| | - Mariana Silva Oliveira
- General Pathology Department, Biological and Natural Sciences Institute (ICBN), Federal University of Triângulo Mineiro (UFTM), Uberaba, MG, Brazil
| | - Flávia Aparecida Oliveira
- Institute of Tropical Pathology and Public Health (IPTSP), Federal University of Goiás (UFG), Goiânia, GO, Brazil
| | - Ana Paula Espíndula
- General Pathology Department, Biological and Natural Sciences Institute (ICBN), Federal University of Triângulo Mineiro (UFTM), Uberaba, MG, Brazil
| | - Camila Lourencini Cavellani
- General Pathology Department, Biological and Natural Sciences Institute (ICBN), Federal University of Triângulo Mineiro (UFTM), Uberaba, MG, Brazil
| | - Vicente de Paula Antunes Teixeira
- General Pathology Department, Biological and Natural Sciences Institute (ICBN), Federal University of Triângulo Mineiro (UFTM), Uberaba, MG, Brazil
| | - Mara Lúcia da Fonseca Ferraz
- General Pathology Department, Biological and Natural Sciences Institute (ICBN), Federal University of Triângulo Mineiro (UFTM), Uberaba, MG, Brazil
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15
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Juliano GR, Skaf MF, Ramalho LS, Juliano GR, Torquato BGS, Oliveira MS, Oliveira FA, Espíndula AP, Cavellani CL, Teixeira VDPA, Ferraz MLDF. Analysis of mast cells and myocardial fibrosis in autopsied patients with hypertensive heart disease. REVISTA PORTUGUESA DE CARDIOLOGIA (ENGLISH EDITION) 2020. [DOI: 10.1016/j.repce.2020.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
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16
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Jacenik D, Krajewska WM. Significance of G Protein-Coupled Estrogen Receptor in the Pathophysiology of Irritable Bowel Syndrome, Inflammatory Bowel Diseases and Colorectal Cancer. Front Endocrinol (Lausanne) 2020; 11:390. [PMID: 32595606 PMCID: PMC7303275 DOI: 10.3389/fendo.2020.00390] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 05/15/2020] [Indexed: 12/12/2022] Open
Abstract
The regulatory role of estrogens and nuclear estrogen receptors, i. e., estrogen receptor α and β has been reported in gastrointestinal diseases. However, the contribution of G protein-coupled estrogen receptor, the membrane-bound estrogen receptor, is still poorly understood. Unlike nuclear estrogen receptors, which are responsible for the genomic activity of estrogens, the G protein-coupled estrogen receptor affects the "rapid" non-genomic activity of estrogens, leading to modulation of many signaling pathways and ultimately changing gene expression. Recently, the crucial role of G protein-coupled estrogen receptor in intestinal pathogenesis has been documented. It has been shown that the G protein-coupled estrogen receptor can modulate the progression of irritable bowel syndrome, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis as well as colorectal cancer. The G protein-coupled estrogen receptor appears to be a potent factor regulating abdominal sensitivity and pain, intestinal peristalsis, colitis development, proliferation and migration potential of colorectal cancer cells and seems to be a useful target in gastrointestinal diseases. In this review, we present the current state of knowledge about the contribution of the G protein-coupled estrogen receptor to irritable bowel syndrome, inflammatory bowel diseases and colorectal cancer.
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17
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Klepsch V, Moschen AR, Tilg H, Baier G, Hermann-Kleiter N. Nuclear Receptors Regulate Intestinal Inflammation in the Context of IBD. Front Immunol 2019; 10:1070. [PMID: 31139192 PMCID: PMC6527601 DOI: 10.3389/fimmu.2019.01070] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 04/26/2019] [Indexed: 12/26/2022] Open
Abstract
Gastrointestinal (GI) homeostasis is strongly dependent on nuclear receptor (NR) functions. They play a variety of roles ranging from nutrient uptake, sensing of microbial metabolites, regulation of epithelial intestinal cell integrity to shaping of the intestinal immune cell repertoire. Several NRs are associated with GI pathologies; therefore, systematic analysis of NR biology, the underlying molecular mechanisms, and regulation of target genes can be expected to help greatly in uncovering the course of GI diseases. Recently, an increasing number of NRs has been validated as potential drug targets for therapeutic intervention in patients with inflammatory bowel disease (IBD). Besides the classical glucocorticoids, especially PPARγ, VDR, or PXR-selective ligands are currently being tested with promising results in clinical IBD trials. Also, several pre-clinical animal studies are being performed with NRs. This review focuses on the complex biology of NRs and their context-dependent anti- or pro-inflammatory activities in the regulation of gastrointestinal barrier with special attention to NRs already pharmacologically targeted in clinic and pre-clinical IBD treatment regimens.
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Affiliation(s)
- Victoria Klepsch
- Translational Cell Genetics, Department of Pharmacology and Genetics, Medical University of Innsbruck, Innsbruck, Austria
| | - Alexander R. Moschen
- Department of Internal Medicine I, Gastroenterology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Gottfried Baier
- Translational Cell Genetics, Department of Pharmacology and Genetics, Medical University of Innsbruck, Innsbruck, Austria
| | - Natascha Hermann-Kleiter
- Translational Cell Genetics, Department of Pharmacology and Genetics, Medical University of Innsbruck, Innsbruck, Austria
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G protein-coupled estrogen receptor mediates anti-inflammatory action in Crohn's disease. Sci Rep 2019; 9:6749. [PMID: 31043642 PMCID: PMC6494840 DOI: 10.1038/s41598-019-43233-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Accepted: 01/31/2019] [Indexed: 01/05/2023] Open
Abstract
Estrogens exert immunomodulatory action in many autoimmune diseases. Accumulating evidence highlights the meaningful impact of estrogen receptors in physiology and pathophysiology of the colon. However, the significance of G protein-coupled estrogen receptor (GPER) on Crohn's disease (CD), one of the inflammatory bowel disease (IBD) types, is still elusive. Our study revealed GPER overexpression at the mRNA and protein levels in patients with CD. To evaluate the effects of GPER activation/inhibition on colitis development, a murine 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced model of CD was used. We showed that activation of GPER reduces mortality, improves macroscopic and microscopic scores and lowers C-reactive protein (CRP) level. The impact of estrogen signaling on the suppression of the intestinal inflammation was proved by immunohistochemistry. It was demonstrated that GPER activation is accompanied by modulation of extracellular-signal regulated kinase (ERK) signaling pathway and expression level of genes involved in signal transmission and immune response as well as the expression of some microRNAs (miR-145, miR-148-5p and miR-592). Our study revealed that the membrane-bound estrogen receptor GPER mediates anti-inflammatory action and seems to be a potent therapeutic target in maintaining remission in CD.
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19
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van der Giessen J, van der Woude CJ, Peppelenbosch MP, Fuhler GM. A Direct Effect of Sex Hormones on Epithelial Barrier Function in Inflammatory Bowel Disease Models. Cells 2019; 8:E261. [PMID: 30893871 PMCID: PMC6468635 DOI: 10.3390/cells8030261] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 03/10/2019] [Accepted: 03/14/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Pregnancy is often described as an immune-tolerant state, and a disease modulatory role for pregnancy on inflammatory bowel disease (IBD) has been suggested. The direct effect of estrogen and progesterone on the intestinal epithelial barrier is underexplored. We investigated the direct consequences of these pregnancy hormones on barrier cells and their function. METHODS We used IBD patient-derived inflammatory organoid models and 2D cell lines models. Epithelial barrier function was analyzed by measuring transepithelial electrical resistance; wound closure was determined by scratch assay; and cell viability was measured by MTT assays. Pro-inflammatory cytokine production was determined by enzyme-linked immunosorbent assays. Molecular modulation of endoplasmic reticulum (ER) stress induced by tunicamycin was studied by western blot analysis of the ER stress markers GRP78, CHOP and p-IRE1. RESULTS Progesterone and estrogen improved wound healing and epithelial barrier function in intestinal epithelial cells via upregulation of tight junction proteins. Furthermore, these sex hormones significantly reduced ER-stress and reduce pro-inflammatory cytokine production in intestinal epithelial models. CONCLUSION Our study shows that estrogen and progesterone alleviate ER stress, decrease pro-inflammatory cytokine production, stimulate wound healing, and increase barrier function of epithelial cells. Combined, these data suggest that pregnancy hormones can have beneficial effects on disease activity by positively modulating the intestinal epithelial lining.
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Affiliation(s)
- Janine van der Giessen
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, 3015CE Rotterdam, The Netherlands.
| | - C Janneke van der Woude
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, 3015CE Rotterdam, The Netherlands.
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, 3015CE Rotterdam, The Netherlands.
| | - Gwenny M Fuhler
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, 3015CE Rotterdam, The Netherlands.
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Song CH, Kim N, Sohn SH, Lee SM, Nam RH, Na HY, Lee DH, Surh YJ. Effects of 17β-Estradiol on Colonic Permeability and Inflammation in an Azoxymethane/Dextran Sulfate Sodium-Induced Colitis Mouse Model. Gut Liver 2019; 12:682-693. [PMID: 30400733 PMCID: PMC6254630 DOI: 10.5009/gnl18221] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 08/28/2018] [Accepted: 09/12/2018] [Indexed: 12/20/2022] Open
Abstract
Background/Aims Intestinal barrier dysfunction is a hallmark of inflammatory bowel diseases (IBDs) such as ulcerative colitis. This dysfunction is caused by increased permeability and the loss of tight junctions in intestinal epithelial cells. The aim of this study was to investigate whether estradiol treatment reduces colonic permeability, tight junction disruption, and inflammation in an azoxymethane (AOM)/dextran sodium sulfate (DSS) colon cancer mouse model. Methods The effects of 17β-estradiol (E2) were evaluated in ICR male mice 4 weeks after AOM/DSS treatment. Histological damage was scored by hematoxylin and eosin staining and the levels of the colonic mucosal cytokine myeloperoxidase (MPO) were assessed by enzyme-linked immunosorbent assay (ELISA). To evaluate the effects of E2 on intestinal permeability, tight junctions, and inflammation, we performed quantitative real-time polymerase chain reaction and Western blot analysis. Furthermore, the expression levels of mucin 2 (MUC2) and mucin 4 (MUC4) were measured as target genes for intestinal permeability, whereas zonula occludens 1 (ZO-1), occludin (OCLN), and claudin 4 (CLDN4) served as target genes for the tight junctions. Results The colitis-mediated induced damage score and MPO activity were reduced by E2 treatment (p<0.05). In addition, the mRNA expression levels of intestinal barrier-related molecules (i.e., MUC2, ZO-1, OCLN, and CLDN4) were decreased by AOM/DSS-treatment; furthermore, this inhibition was rescued by E2 supplementation. The mRNA and protein expression of inflammation-related genes (i.e., KLF4, NF-κB, iNOS, and COX-2) was increased by AOM/DSS-treatment and ameliorated by E2. Conclusions E2 acts through the estrogen receptor β signaling pathway to elicit anti-inflammatory effects on intestinal barrier by inducing the expression of MUC2 and tight junction molecules and inhibiting pro-inflammatory cytokines.
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Affiliation(s)
- Chin-Hee Song
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Korea
| | - Sung Hwa Sohn
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Sun Min Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Ryoung Hee Nam
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hee Young Na
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Korea
| | - Young-Joon Surh
- Tumor Microenvironment Global Core Research Center, Seoul National University College of Pharmacy, Seoul, Korea
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21
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Zhao M, Chen Y, Wang C, Xiao W, Chen S, Zhang S, Yang L, Li Y. Systems Pharmacology Dissection of Multi-Scale Mechanisms of Action of Huo-Xiang-Zheng-Qi Formula for the Treatment of Gastrointestinal Diseases. Front Pharmacol 2019; 9:1448. [PMID: 30687082 PMCID: PMC6336928 DOI: 10.3389/fphar.2018.01448] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 11/26/2018] [Indexed: 12/19/2022] Open
Abstract
Multi-components Traditional Chinese Medicine (TCM) treats various complex diseases (multi-etiologies and multi-symptoms) via herbs interactions to exert curative efficacy with less adverse effects. However, the ancient Chinese compatibility theory of herbs formula still remains ambiguous. Presently, this combination principle is dissected through a systems pharmacology study on the mechanism of action of a representative TCM formula, Huo-xiang-zheng-qi (HXZQ) prescription, on the treatment of functional dyspepsia (FD), a chronic or recurrent clinical disorder of digestive system, as typical gastrointestinal (GI) diseases which burden human physical and mental health heavily and widely. In approach, a systems pharmacology platform which incorporates the pharmacokinetic and pharmaco-dynamics evaluation, target fishing and network pharmacological analyses is employed. As a result, 132 chemicals and 48 proteins are identified as active compounds and FD-related targets, and the mechanism of HXZQ formula for the treatment of GI diseases is based on its three function modules of anti-inflammation, immune protection and gastrointestinal motility regulation mainly through four, i.e., PIK-AKT, JAK-STAT, Toll-like as well as Calcium signaling pathways. In addition, HXZQ formula conforms to the ancient compatibility rule of "Jun-Chen-Zuo-Shi" due to the different, while cooperative roles that herbs possess, specifically, the direct FD curative effects of GHX (serving as Jun drug), the anti-bacterial efficacy and major accompanying symptoms-reliving bioactivities of ZS and BZ (as Chen), the detoxication and ADME regulation capacities of GC (as Shi), as well as the minor symptoms-treating efficacy of the rest 7 herbs (as Zuo). This work not only provides an insight of the therapeutic mechanism of TCMs on treating GI diseases from a multi-scale perspective, but also may offer an efficient way for drug discovery and development from herbal medicine as complementary drugs.
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Affiliation(s)
- Miaoqing Zhao
- Key Laboratory of Industrial Ecology and Environmental Engineering, Faculty of Chemical, Environmental and Biological Science and Technology, Dalian University of Technology, Dalian, China.,Key Laboratory of Xinjiang Endemic Phytomedicine Resources, Pharmacy School, Shihezi University, Shihezi, China
| | - Yangyang Chen
- Lab of Systems Pharmacology, Center of Bioinformatics, College of Life Sciences, Northwest A&F University, Yangling, China
| | - Chao Wang
- Key Laboratory of Industrial Ecology and Environmental Engineering, Faculty of Chemical, Environmental and Biological Science and Technology, Dalian University of Technology, Dalian, China
| | - Wei Xiao
- State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process, Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, China
| | - Shusheng Chen
- Systems Biology Laboratory, Department of Computer & Information Science & Engineering, University of Florida, Gainesville, FL, United States
| | - Shuwei Zhang
- Key Laboratory of Industrial Ecology and Environmental Engineering, Faculty of Chemical, Environmental and Biological Science and Technology, Dalian University of Technology, Dalian, China
| | - Ling Yang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yan Li
- Key Laboratory of Industrial Ecology and Environmental Engineering, Faculty of Chemical, Environmental and Biological Science and Technology, Dalian University of Technology, Dalian, China.,Key Laboratory of Xinjiang Endemic Phytomedicine Resources, Pharmacy School, Shihezi University, Shihezi, China
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22
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Hou F, Dai Y, Fan CY, Suen JY, Richter GT. Estrogen is involved in hemangioma regression associated with mast cells. Orphanet J Rare Dis 2018; 13:181. [PMID: 30340617 PMCID: PMC6195721 DOI: 10.1186/s13023-018-0928-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 10/05/2018] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Estrogen plays a role in infantile hemangioma (IH) development, but the underlying mechanism remains unclear. This study aimed to assess estrogen and estrogen receptor (ER) localization and expression levels in IH. In addition, the unexpected relationship between mast cells (MCs) and estrogen in human IH was discussed. METHODS IH (n = 29), vascular malformation (VMs, n = 33) and normal skin (n = 15) specimens were assessed. IH was classified into proliferative (n = 9; age, 3.56 ± 1.01 months), early involuting (n = 10; age, 8.90 ± 2.69 months) and late involuting (n = 10; age, 20.10 ± 4.93 months) groups. Estradiol (E2), ER-a, ER-β, and tryptase (MC marker) levels were determined immunohistochemically and/or by double immunofluorescence staining. Quantification and localization of tryptase, ER-a, and E2 were assessed for each specimen. RESULTS ER-a, E2, and tryptase were expressed in the cytoplasm and nucleus of MCs in IH. The IH specimens showed significantly more tryptase, ER-a, and E2 positive MCs (30.6 ± 12.7, 9.7 ± 5.6, and 19.8 ± 8.7 cells/high-power field [HPF], respectively) compared with VM specimens (9.0 ± 9.8, 1.5 ± 2.4, and 2.5 ± 4.1 cells/HPF, respectively) and normal skin (6.1 ± 8.5, 0.5 ± 1.2, and 1.9 ± 3.4 cells/HPF, respectively). Proliferating IH displayed fewer E2 positive MCs (14.0 6.3 cells/HPF) compared with early (22.3 ± 10.2 cells/HPF, P = 0.023) and late (22.4 ± 6.8 cells/HPF, P = 0.006) involuting specimens. In addition, proliferating IH showed fewer tryptase positive MCs (24.7 ± 10.8 cells/HPF) compared with early involuting specimens (35.7 ± 15.3 cells/HPF, P = 0.043). All IH specimens were ER-a positive and ER-β negative. CONCLUSIONS E2 and ER-a are expressed on MCs and not on IH endothelial cells. Furthermore, activated MCs may be involved in IH regression.
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Affiliation(s)
- Fang Hou
- Department of Pediatric Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, 610072 China
- School of medicine, University of Electronic Science and Technology of China, Chengdu, 610072 China
- Center for the Investigation of Congenital Aberrancies of Vascular Development, Little Rock, AR USA
| | - Yuemeng Dai
- Center for the Investigation of Congenital Aberrancies of Vascular Development, Little Rock, AR USA
| | - Chun-Yang Fan
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - James Y. Suen
- Department of Otolaryngology, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Gresham T. Richter
- Center for the Investigation of Congenital Aberrancies of Vascular Development, Little Rock, AR USA
- Division of Pediatric Otolaryngology, Arkansas Children’s Hospital, 1 Children’s Way, Little Rock, AR 72202 USA
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23
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Sehl ME, Ganz PA. Potential Mechanisms of Age Acceleration Caused by Estrogen Deprivation: Do Endocrine Therapies Carry the Same Risks? JNCI Cancer Spectr 2018; 2:pky035. [PMID: 31360862 PMCID: PMC6649786 DOI: 10.1093/jncics/pky035] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 05/30/2018] [Accepted: 06/22/2018] [Indexed: 02/06/2023] Open
Abstract
Longer duration of endocrine therapy decreases breast cancer recurrence and mortality, but these benefits need to be weighed against potential risks to overall health. Notable side effects of endocrine therapy include cataracts, uterine cancer, thromboembolic events, osteoporosis and fracture risk, chronic musculoskeletal complaints, as well as vaginal dryness and discharge, and vasomotor symptoms. Estrogen deprivation in healthy women younger than 50 years undergoing bilateral oophorectomy has been shown to accelerate the development of diseases related to aging, including coronary artery disease, cardiac arrhythmias, stroke, dementia, and osteoporosis, raising concern that even less dramatic modulation of estrogen homeostasis may adversely affect health outcomes. Diminished available estrogen at the cellular and molecular level may facilitate mechanisms that underlie the aging process, often termed the hallmarks of aging. In this review, we describe estrogen's role in normal physiology across tissues, review the effects of estrogen deprivation on health outcomes in the setting of both surgical and natural menopause, and examine the hallmarks of aging with attention to the effects of estrogen and estrogen blockade on each molecular mechanism underlying the aging process.
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Affiliation(s)
- Mary E Sehl
- Medicine, Hematology-Oncology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.,Biomathematics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
| | - Patricia A Ganz
- Medicine, Hematology-Oncology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.,Health Policy and Management, School of Public Health, University of California Los Angeles, Los Angeles, CA
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24
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Jacenik D, Cygankiewicz AI, Fichna J, Mokrowiecka A, Małecka-Panas E, Krajewska WM. Estrogen signaling deregulation related with local immune response modulation in irritable bowel syndrome. Mol Cell Endocrinol 2018; 471:89-96. [PMID: 28774781 DOI: 10.1016/j.mce.2017.07.036] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 07/25/2017] [Accepted: 07/28/2017] [Indexed: 12/19/2022]
Abstract
The etiology and pathogenesis underlying irritable bowel syndrome (IBS), a common gastrointestinal disorder are still unclear. Cumulating data suggest dysregulation of inflammatory and immune response pathways and changes of epithelial barrier function. The role of estrogens albeit varied, in responses of immune system is well documented. The aim of this study was to investigate estrogen receptors engagment in IBS subtypes, i.e. constipation predominant (IBS-C) and diarrhea predominant (IBS-D). Furthermore, we analyzed whether estrogen signaling is accompanied by alteration in expression of pro- and anti-inflammatory cytokines and microRNAs that can regulate among others genes involved in immune responses. It was found that estrogen receptor α (ERα) and G protein-coupled estrogen receptor (GPER) expression is up-regulated in IBS while estrogen receptor β (ERβ) appears to be down-regulated at mRNA but up-regulated at the protein level. When gender and female age were included statistically significant overexpression of ERα in IBS-D women under the age of 50, while of GPER in IBS-D men was stated. In all studied IBS samples disturbances in expression of cytokines IL-6, IL-10 and TNF-α as well as miR-145, miR-148-5p and miR-592 were observed. This research reveals the association of estrogen receptors with IBS. Simultaneous alterations of studied immunomodulatory cytokines and microRNAs suggest that in IBS dysregulation of local immune response may involve estrogen-dependent way.
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Affiliation(s)
- Damian Jacenik
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska St. 141/143, 90-236 Lodz, Poland.
| | - Adam I Cygankiewicz
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska St. 141/143, 90-236 Lodz, Poland.
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka St. 6/8, 92-215 Lodz, Poland.
| | - Anna Mokrowiecka
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Stefana Kopcinskiego St. 22, 90-001 Lodz, Poland.
| | - Ewa Małecka-Panas
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Stefana Kopcinskiego St. 22, 90-001 Lodz, Poland.
| | - Wanda M Krajewska
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska St. 141/143, 90-236 Lodz, Poland.
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25
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Szymanska K, Gonkowski S. Bisphenol A—Induced changes in the enteric nervous system of the porcine duodenum. Neurotoxicology 2018; 66:78-86. [DOI: 10.1016/j.neuro.2018.03.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Revised: 03/06/2018] [Accepted: 03/19/2018] [Indexed: 12/11/2022]
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26
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Bradley F, Birse K, Hasselrot K, Noël-Romas L, Introini A, Wefer H, Seifert M, Engstrand L, Tjernlund A, Broliden K, Burgener AD. The vaginal microbiome amplifies sex hormone-associated cyclic changes in cervicovaginal inflammation and epithelial barrier disruption. Am J Reprod Immunol 2018; 80:e12863. [PMID: 29709092 DOI: 10.1111/aji.12863] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 03/28/2018] [Indexed: 12/27/2022] Open
Abstract
PROBLEM Susceptibility to HIV is associated with the menstrual cycle and vaginal microbiome, but their collective impact on vaginal inflammation remains unclear. Here, we characterized the cervicovaginal proteome, inflammation, and microbiome community structure and function during the menstrual cycle. METHOD OF STUDY Cervicovaginal secretions were collected from regularly cycling women (n = 16) at median day 10, 16, and 24 of each menstrual cycle and analyzed by mass spectrometry, 16S rRNA gene sequencing, and a multiplex bead array immunoassay. Follicular, ovulatory, and luteal phases were defined by serum sex hormone levels. RESULTS Ovulation showed the largest mucosal proteome changes, where 30% and 19% of the 406 human proteins identified differed compared to the luteal and follicular phases, respectively. Neutrophil/leukocyte migration pathways were lowest during ovulation and peaked in the luteal phase, while antimicrobial and epithelial barrier promoting proteins were highest during ovulation. Vaginal microbial community structure and function did not vary significantly during the menstrual cycle, with the majority consistently Lactobacillus-dominant (63%) or non-Lactobacillus-dominant (25%). Fluctuations in the epithelial barrier protein RPTN between the ovulatory and luteal phase were amplified in women with Gardnerella vaginalis and anaerobic bacteria and reduced when Lactobacillus was dominant. CONCLUSION This small study demonstrates that sex hormones modulate neutrophil/leukocyte inflammation, barrier function, and antimicrobial pathways in the female genital tract with the strongest changes occurring during ovulation. The data further suggest a microbiome context for hormone-driven changes in vaginal immunity which may have implications for HIV susceptibility.
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Affiliation(s)
- Frideborg Bradley
- Department of Medicine Solna, Unit of Infectious Diseases, Center for Molecular Medicine, Karolinska Institutet Karolinska University Hospital, Stockholm, Sweden
| | - Kenzie Birse
- Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada.,National HIV and Retrovirology Labs, JC Wilt Infectious Disease Centre, Public Health Agency of Canada, Winnipeg, MB, Canada
| | - Klara Hasselrot
- Department of Medicine Solna, Unit of Infectious Diseases, Center for Molecular Medicine, Karolinska Institutet Karolinska University Hospital, Stockholm, Sweden.,Department of Gynaecology, Danderyds Hospital, Stockholm, Sweden
| | - Laura Noël-Romas
- Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada.,National HIV and Retrovirology Labs, JC Wilt Infectious Disease Centre, Public Health Agency of Canada, Winnipeg, MB, Canada
| | - Andrea Introini
- Department of Medicine Solna, Unit of Infectious Diseases, Center for Molecular Medicine, Karolinska Institutet Karolinska University Hospital, Stockholm, Sweden
| | - Hugo Wefer
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.,Science for Life Laboratory, Clinical Genomics Facility, Solna, Sweden
| | - Maike Seifert
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.,Science for Life Laboratory, Clinical Genomics Facility, Solna, Sweden
| | - Lars Engstrand
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.,Science for Life Laboratory, Clinical Genomics Facility, Solna, Sweden
| | - Annelie Tjernlund
- Department of Medicine Solna, Unit of Infectious Diseases, Center for Molecular Medicine, Karolinska Institutet Karolinska University Hospital, Stockholm, Sweden
| | - Kristina Broliden
- Department of Medicine Solna, Unit of Infectious Diseases, Center for Molecular Medicine, Karolinska Institutet Karolinska University Hospital, Stockholm, Sweden
| | - Adam D Burgener
- Department of Medicine Solna, Unit of Infectious Diseases, Center for Molecular Medicine, Karolinska Institutet Karolinska University Hospital, Stockholm, Sweden.,Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada.,National HIV and Retrovirology Labs, JC Wilt Infectious Disease Centre, Public Health Agency of Canada, Winnipeg, MB, Canada
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27
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Szymanska K, Makowska K, Gonkowski S. The Influence of High and Low Doses of Bisphenol A (BPA) on the Enteric Nervous System of the Porcine Ileum. Int J Mol Sci 2018; 19:ijms19030917. [PMID: 29558425 PMCID: PMC5877778 DOI: 10.3390/ijms19030917] [Citation(s) in RCA: 37] [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: 02/13/2018] [Revised: 03/13/2018] [Accepted: 03/14/2018] [Indexed: 11/24/2022] Open
Abstract
Bisphenol A, used in the production of plastic, is able to leach from containers into food and cause multidirectional adverse effects in living organisms, including neurodegeneration and metabolic disorders. Knowledge of the impact of BPA on enteric neurons is practically non-existent. The destination of this study was to investigate the influence of BPA at a specific dose (0.05 mg/kg body weight/day) and at a dose ten times higher (0.5 mg/kg body weight/day), given for 28 days, on the porcine ileum. The influence of BPA on enteric neuron immunoreactive to selected neuronal active substances, including substance P (SP), vasoactive intestinal polypeptide (VIP), galanin (GAL), vesicular acetylcholine transporter (VAChT—used here as a marker of cholinergic neurons), and cocaine- and amphetamine-regulated transcript peptide (CART), was studied by the double immunofluorescence method. Both doses of BPA affected the neurochemical characterization of the enteric neurons. The observed changes depended on the type of enteric plexus but were generally characterized by an increase in the number of cells immunoreactive to the particular substances. More visible fluctuations were observed after treatment with higher doses of BPA. The results confirm that even low doses of BPA may influence the neurochemical characterization of the enteric neurons and are not neutral for living organisms.
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Affiliation(s)
- Kamila Szymanska
- Department of Clinical Physiology, Faculty of Veterinary Medicine, University of Warmia and Mazury, Oczapowskiego Str. 13, 10-719 Olsztyn, Poland.
| | - Krystyna Makowska
- Department of Clinical Physiology, Faculty of Veterinary Medicine, University of Warmia and Mazury, Oczapowskiego Str. 13, 10-719 Olsztyn, Poland.
| | - Slawomir Gonkowski
- Department of Clinical Physiology, Faculty of Veterinary Medicine, University of Warmia and Mazury, Oczapowskiego Str. 13, 10-719 Olsztyn, Poland.
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28
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Nie X, Xie R, Tuo B. Effects of Estrogen on the Gastrointestinal Tract. Dig Dis Sci 2018; 63:583-596. [PMID: 29387989 DOI: 10.1007/s10620-018-4939-1] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Accepted: 01/19/2018] [Indexed: 02/06/2023]
Abstract
Estrogen is a kind of steroid compound that has extensive biologic activities. The effect of estrogen is pleiotropic, affecting multiple systems in the body. There is accumulating evidence that estrogen has important effects on the gastrointestinal tract. Longer exposure to estrogen may decrease the risk of gastric cancer. Use of the anti-estrogen drug tamoxifen might increase the risk of gastric adenocarcinoma. Estrogen receptor β may serve as a target for colorectal cancer prevention. In addition, estrogen has been reported to be closely related to the mucosal barrier, gastrointestinal function and intestinal inflammation. However, the role of estrogen in the gastrointestinal tract has not been systematically summarized. In this review, we aim to provide an overview of the role of estrogen in the gastrointestinal tract and evaluate it from various aspects, including estrogen receptors, the mucosal barrier, intestinal inflammation and gastrointestinal tract tumors, which may provide the basis for the development of therapeutic strategies to manage gastrointestinal diseases.
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Affiliation(s)
- Xubiao Nie
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, 149 Dalian Road, Zunyi, 563003, China
| | - Rui Xie
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, 149 Dalian Road, Zunyi, 563003, China
| | - Biguang Tuo
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, 149 Dalian Road, Zunyi, 563003, China.
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29
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Miragem AA, Homem de Bittencourt PI. Nitric oxide-heat shock protein axis in menopausal hot flushes: neglected metabolic issues of chronic inflammatory diseases associated with deranged heat shock response. Hum Reprod Update 2018; 23:600-628. [PMID: 28903474 DOI: 10.1093/humupd/dmx020] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Accepted: 06/28/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Although some unequivocal underlying mechanisms of menopausal hot flushes have been demonstrated in animal models, the paucity of similar approaches in humans impedes further mechanistic outcomes. Human studies might show some as yet unexpected physiological mechanisms of metabolic adaptation that permeate the phase of decreased oestrogen levels in both symptomatic and asymptomatic women. This is particularly relevant because both the severity and time span of hot flushes are associated with increased risk of chronic inflammatory disease. On the other hand, oestrogen induces the expression of heat shock proteins of the 70 kDa family (HSP70), which are anti-inflammatory and cytoprotective protein chaperones, whose expression is modulated by different types of physiologically stressful situations, including heat stress and exercise. Therefore, lower HSP70 expression secondary to oestrogen deficiency increases cardiovascular risk and predisposes the patient to senescence-associated secretory phenotype (SASP) that culminates in chronic inflammatory diseases, such as obesities, type 2 diabetes, neuromuscular and neurodegenerative diseases. OBJECTIVE AND RATIONALE This review focuses on HSP70 and its accompanying heat shock response (HSR), which is an anti-inflammatory and antisenescent pathway whose intracellular triggering is also oestrogen-dependent via nitric oxide (NO) production. The main goal of the manuscript was to show that the vasomotor symptoms that accompany hot flushes may be a disguised clue for important neuroendocrine alterations linking oestrogen deficiency to the anti-inflammatory HSR. SEARCH METHODS Results from our own group and recent evidence on hypothalamic control of central temperature guided a search on PubMed and Google Scholar websites. OUTCOMES Oestrogen elicits rapid production of the vasodilatory gas NO, a powerful activator of HSP70 expression. Whence, part of the protective effects of oestrogen over cardiovascular and neuroendocrine systems is tied to its capacity of inducing the NO-elicited HSR. The hypothalamic areas involved in thermoregulation (infundibular nucleus in humans and arcuate nucleus in other mammals) and whose neurons are known to have their function altered after long-term oestrogen ablation, particularly kisspeptin-neurokinin B-dynorphin neurons, (KNDy) are the same that drive neuroprotective expression of HSP70 and, in many cases, this response is via NO even in the absence of oestrogen. From thence, it is not illogical that hot flushes might be related to an evolutionary adaptation to re-equip the NO-HSP70 axis during the downfall of circulating oestrogen. WIDER IMPLICATIONS Understanding of HSR could shed light on yet uncovered mechanisms of menopause-associated diseases as well as on possible manipulation of HSR in menopausal women through physiological, pharmacological, nutraceutical and prebiotic interventions. Moreover, decreased HSR indices (that can be clinically determined with ease) in perimenopause could be of prognostic value in predicting the moment and appropriateness of starting a HRT.
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Affiliation(s)
- Antônio Azambuja Miragem
- Laboratory of Cellular Physiology, Department of Physiology, Federal University of Rio Grande do Sul, Rua Sarmento Leite 500, ICBS, 2nd Floor, Suite 350, Porto Alegre, RS 90050-170, Brazil.,Federal Institute of Education, Science and Technology 'Farroupilha', Rua Uruguai 1675, Santa Rosa, RS 98900-000, Brazil
| | - Paulo Ivo Homem de Bittencourt
- Laboratory of Cellular Physiology, Department of Physiology, Federal University of Rio Grande do Sul, Rua Sarmento Leite 500, ICBS, 2nd Floor, Suite 350, Porto Alegre, RS 90050-170, Brazil
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30
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Linares PM, Algaba A, Urzainqui A, Guijarro-Rojas M, González-Tajuelo R, Garrido J, Chaparro M, Gisbert JP, Bermejo F, Guerra I, Castellano V, Fernández-Contreras ME. Ratio of Circulating Estrogen Receptors Beta and Alpha (ERβ/ERα) Indicates Endoscopic Activity in Patients with Crohn's Disease. Dig Dis Sci 2017; 62:2744-2754. [PMID: 28823012 DOI: 10.1007/s10620-017-4717-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 08/07/2017] [Indexed: 12/24/2022]
Abstract
BACKGROUND Data supporting a role of female hormones and/or their receptors in inflammatory bowel disease (IBD) are increasing, but most of them are derived from animal models. Estrogen receptors alpha (ERα) and beta (ERβ) participate in immune and inflammatory response, among a variety of biological processes. Their effects are antagonistic, and the net action of estrogens may depend on their relative proportions. AIM To determine the possible association between the balance of circulating ERβ and ERα (ERβ/ERα) and IBD risk and activity. METHODS Serum samples from 145 patients with IBD (79 Crohn's disease [CD] and 66 ulcerative colitis [UC]) and 39 controls were retrospectively studied. Circulating ERα and ERβ were measured by ELISA. Disease activities were assessed by clinical and endoscopic indices specific for CD and UC. RESULTS Low values of ERβ/ERα ratio were directly associated with clinical (p = 0.019) and endoscopic (p = 0.002) disease activity. Further analyses by type of IBD confirmed a strong association between low ERβ/ERα ratio and CD clinical (p = 0.011) and endoscopic activity (p = 0.002). The receiver operating curve (ROC) analysis showed that an ERβ/ERα ratio under 0.85 was a good marker of CD endoscopic activity (area under the curve [AUC]: 0.84; p = 0.002; sensitivity: 70%; specificity: 91%). ERβ/ERα ratio was not useful to predict UC activity. CONCLUSIONS An ERβ/ERα ratio under 0.85 indicated CD endoscopic activity. The determination of serum ERβ/ERα might be a useful noninvasive screening tool for CD endoscopic activity.
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Affiliation(s)
- Pablo M Linares
- Department of Gastroenterology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), C/ Diego de León 62, 28006, Madrid, Spain
| | - Alicia Algaba
- Department of Gastroenterology, Hospital Universitario de Fuenlabrada, C/ Camino del Molino 2, 28942, Fuenlabrada-Madrid, Spain
| | - Ana Urzainqui
- Department of Immunology, Hospital Universitario de la Princesa, IIS-IP, C/ Diego de León 62, 28006, Madrid, Spain
| | - Mercedes Guijarro-Rojas
- Department of Pathology, Hospital Universitario de la Princesa, IIS-IP, C/ Diego de León 62, 28006, Madrid, Spain
| | - Rafael González-Tajuelo
- Department of Immunology, Hospital Universitario de la Princesa, IIS-IP, C/ Diego de León 62, 28006, Madrid, Spain
| | - Jesús Garrido
- Department of Social Psychology and Methodology, School of Psychology, Universidad Autónoma de Madrid (UAM), C/ Ivan Pavlov 6. Ciudad Universitaria de Cantoblanco, 28049, Madrid, Spain
| | - María Chaparro
- Department of Gastroenterology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), C/ Diego de León 62, 28006, Madrid, Spain
| | - Javier P Gisbert
- Department of Gastroenterology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), C/ Diego de León 62, 28006, Madrid, Spain
| | - Fernando Bermejo
- Department of Gastroenterology, Hospital Universitario de Fuenlabrada, C/ Camino del Molino 2, 28942, Fuenlabrada-Madrid, Spain
| | - Iván Guerra
- Department of Gastroenterology, Hospital Universitario de Fuenlabrada, C/ Camino del Molino 2, 28942, Fuenlabrada-Madrid, Spain
| | - Víctor Castellano
- Department of Pathology, Hospital Universitario de Fuenlabrada, C/ Camino del Molino 2, 28942, Fuenlabrada-Madrid, Spain
| | - María-Encarnación Fernández-Contreras
- Department of Gastroenterology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), C/ Diego de León 62, 28006, Madrid, Spain.
- Departments of Anatomy I and Immunology, School of Medicine, Universidad Alfonso X El Sabio (UAX), Avda. de la Universidad 1, 28691, Villanueva de la Cañada, Madrid, Spain.
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31
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Salaritabar A, Darvishi B, Hadjiakhoondi F, Manayi A, Sureda A, Nabavi SF, Fitzpatrick LR, Nabavi SM, Bishayee A. Therapeutic potential of flavonoids in inflammatory bowel disease: A comprehensive review. World J Gastroenterol 2017; 23:5097-5114. [PMID: 28811706 PMCID: PMC5537178 DOI: 10.3748/wjg.v23.i28.5097] [Citation(s) in RCA: 128] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Revised: 05/12/2017] [Accepted: 07/04/2017] [Indexed: 02/06/2023] Open
Abstract
The inflammatory process plays a central role in the development and progression of numerous pathological situations, such as inflammatory bowel disease (IBD), autoimmune and neurodegenerative diseases, metabolic syndrome, and cardiovascular disorders. IBDs involve inflammation of the gastrointestinal area and mainly comprise Crohn’s disease (CD) and ulcerative colitis (UC). Both pathological situations usually involve recurring or bloody diarrhea, pain, fatigue and weight loss. There is at present no pharmacological cure for CD or UC. However, surgery may be curative for UC patients. The prescribed treatment aims to ameliorate the symptoms and prevent and/or delay new painful episodes. Flavonoid compounds are a large family of hydroxylated polyphenolic molecules abundant in plants, including vegetables and fruits which are the major dietary sources of these compounds for humans, together with wine and tea. Flavonoids are becoming very popular because they have many health-promoting and disease-preventive effects. Most interest has been directed towards the antioxidant activity of flavonoids, evidencing a remarkable free-radical scavenging capacity. However, accumulating evidence suggests that flavonoids have many other biological properties, including anti-inflammatory, antiviral, anticancer, and neuroprotective activities through different mechanisms of action. The present review analyzes the available data about the different types of flavonoids and their potential effectiveness as adjuvant therapy of IBDs.
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Abstract
The incidence and prevalence of inflammatory bowel disease (IBD) continues to rise with time, signifying its emergence as a global disease. Clinical onset of IBD, comprising Crohn's disease and ulcerative colitis, typically occurs before or at peak reproductive age. Although active disease in female patients is associated with reduced fertility and adverse obstetric outcomes in pregnancy, the molecular mechanisms underlying this altered reproductive course, and its impact on IBD transmission to offspring, remain poorly understood. Clinical and experimental studies have now begun to elucidate the hormonal, environmental, and microbial factors that modulate immune-reproductive cross talk in IBD and define their impact on maternal health, fetal development, and heritability of disease risk. Evolving insight into maternal-fetal imprinting in IBD has important implications for patient counseling and disease management during pregnancy and may help predict clinical outcomes for both mother and child.
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Pierdominici M, Maselli A, Varano B, Barbati C, Cesaro P, Spada C, Zullo A, Lorenzetti R, Rosati M, Rainaldi G, Limiti MR, Guidi L, Conti L, Gessani S. Linking estrogen receptor β expression with inflammatory bowel disease activity. Oncotarget 2016; 6:40443-51. [PMID: 26497217 PMCID: PMC4747344 DOI: 10.18632/oncotarget.6217] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2015] [Accepted: 10/02/2015] [Indexed: 12/13/2022] Open
Abstract
Crohn disease (CD) and ulcerative colitis (UC) are chronic forms of inflammatory bowel disease (IBD) whose pathogenesis is only poorly understood. Estrogens have a complex role in inflammation and growing evidence suggests that these hormones may impact IBD pathogenesis. Here, we demonstrated a significant reduction (p < 0.05) of estrogen receptor (ER)β expression in peripheral blood T lymphocytes from CD/UC patients with active disease (n = 27) as compared to those in remission (n = 21) and healthy controls (n = 29). Accordingly, in a subgroup of CD/UC patients undergoing to anti-TNF-α therapy and responsive to treatment, ERβ expression was higher (p < 0.01) than that observed in not responsive patients and comparable to that of control subjects. Notably, ERβ expression was markedly decreased in colonic mucosa of CD/UC patients with active disease, reflecting the alterations observed in peripheral blood T cells. ERβ expression inversely correlated with interleukin (IL)-6 serum levels and exogenous exposure of both T lymphocytes and intestinal epithelial cells to this cytokine resulted in ERβ downregulation. These results demonstrate that the ER profile is altered in active IBD patients at both mucosal and systemic levels, at least in part due to IL-6 dysregulation, and highlight the potential exploitation of T cell-associated ERβ as a biomarker of endoscopic disease activity.
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Affiliation(s)
- Marina Pierdominici
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
| | - Angela Maselli
- Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy
| | - Barbara Varano
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Cristiana Barbati
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
| | - Paola Cesaro
- Digestive Endoscopy Unit, Catholic University, Rome, Italy
| | | | - Angelo Zullo
- Gastroenterology and Digestive Endoscopy, Nuovo Regina Margherita Hospital, Rome, Italy
| | - Roberto Lorenzetti
- Gastroenterology and Digestive Endoscopy, Nuovo Regina Margherita Hospital, Rome, Italy
| | - Marco Rosati
- Histopathology Complex Unit, Santo Spirito Hospital, Rome, Italy
| | - Gabriella Rainaldi
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | | | - Luisa Guidi
- IBD Unit, Complesso Integrato Columbus, Catholic University, Rome, Italy
| | - Lucia Conti
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Sandra Gessani
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
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Bábíčková J, Tóthová Ľ, Lengyelová E, Bartoňová A, Hodosy J, Gardlík R, Celec P. Sex Differences in Experimentally Induced Colitis in Mice: a Role for Estrogens. Inflammation 2016; 38:1996-2006. [PMID: 25962374 DOI: 10.1007/s10753-015-0180-7] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Sex differences have been found in the incidence and progression of inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease. The reported differences in observational studies are controversial, and the effects of sex hormones on the pathogenesis of IBD are not clear. The aim of this study was to analyze sex differences in the progression of experimentally induced colitis. Experimental colitis was induced in adult mice by adding 2% dextran sodium sulfate (DSS) into drinking water. Male and female mice were used as intact, gonadectomized, and supplemented with either estradiol or testosterone. In comparison to males, female mice with induced colitis had significantly longer colon (p < 0.05), lower decrease in body weight (p < 0.001), and lower stool consistency score (p < 0.05). Histopathological analysis showed less inflammatory infiltrates (p < 0.001) and crypt damage (p < 0.001) in female mice. Female mice with colitis had also lower concentration of TNF-α in colon homogenates (p < 0.01). Supplementation with estradiol in ovariectomized mice ameliorated the severity of colitis. Female mice are partially protected against chemically induced colitis. This protection seems to be mediated by estradiol.
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Affiliation(s)
- Janka Bábíčková
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08, Bratislava, Slovakia,
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Pigrau M, Rodiño-Janeiro BK, Casado-Bedmar M, Lobo B, Vicario M, Santos J, Alonso-Cotoner C. The joint power of sex and stress to modulate brain-gut-microbiota axis and intestinal barrier homeostasis: implications for irritable bowel syndrome. Neurogastroenterol Motil 2016; 28:463-86. [PMID: 26556786 DOI: 10.1111/nmo.12717] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 10/05/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Intestinal homeostasis is a dynamic process that takes place at the interface between the lumen and the mucosa of the gastrointestinal tract, where a constant scrutiny for antigens and toxins derived from food and microorganisms is carried out by the vast gut-associated immune system. Intestinal homeostasis is preserved by the ability of the mucus layer and the mucosal barrier to keep the passage of small-sized and antigenic molecules across the epithelium highly selective. When combined and preserved, immune surveillance and barrier's selective permeability, the host capacity of preventing the development of intestinal inflammation is optimized, and viceversa. In addition, the brain-gut-microbiome axis, a multidirectional communication system that integrates distant and local regulatory networks through neural, immunological, metabolic, and hormonal signaling pathways, also regulates intestinal function. Dysfunction of the brain-gut-microbiome axis may induce the loss of gut mucosal homeostasis, leading to uncontrolled permeation of toxins and immunogenic particles, increasing the risk of appearance of intestinal inflammation, mucosal damage, and gut disorders. Irritable bowel syndrome is prevalent stress-sensitive gastrointestinal disorder that shows a female predominance. Interestingly, the role of stress, sex and gonadal hormones in the regulation of intestinal mucosal and the brain-gut-microbiome axis functioning is being increasingly recognized. PURPOSE We aim to critically review the evidence linking sex, and stress to intestinal barrier and brain-gut-microbiome axis dysfunction and the implications for irritable bowel syndrome.
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Affiliation(s)
- M Pigrau
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada.,Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - B K Rodiño-Janeiro
- Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - M Casado-Bedmar
- Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - B Lobo
- Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - M Vicario
- Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - J Santos
- Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - C Alonso-Cotoner
- Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
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Sex Differences in Gastrointestinal Physiology and Diseases. SEX DIFFERENCES IN PHYSIOLOGY 2016. [DOI: 10.1016/b978-0-12-802388-4.00008-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Janicki JS, Brower GL, Levick SP. The emerging prominence of the cardiac mast cell as a potent mediator of adverse myocardial remodeling. Methods Mol Biol 2015; 1220:121-39. [PMID: 25388248 DOI: 10.1007/978-1-4939-1568-2_8] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Cardiac mast cells store and release a variety of biologically active mediators, several of which have been implicated in the activation of matrix metalloproteinases in the volume-overloaded heart, while others are involved in the fibrotic process in pressure-overloaded hearts. Increased numbers of mast cells have been reported in explanted human hearts with dilated cardiomyopathy and in animal models of experimentally induced hypertension, myocardial infarction, and chronic cardiac volume overload. Also, there is evolving evidence implicating the cardiac mast cell as having a major role in the adverse remodeling underlying these cardiovascular disorders. Thus, the cardiac mast cell is the focus of this chapter that begins with a historical background, followed by sections on methods for their isolation and characterization, endogenous secretagogues, phenotype, and ability of estrogen to alter their phenotype so as to provide cardioprotection. Finally the role of mast cells in myocardial remodeling secondary to a sustained cardiac volume overload, hypertension, and ischemic injury and future research directions are discussed.
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Affiliation(s)
- Joseph S Janicki
- Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC, 29208, USA,
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38
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Estrogen alleviates acetic acid-induced gastric or colonic damage via both ERα- and ERβ-mediated and direct antioxidant mechanisms in rats. Inflammation 2015; 37:694-705. [PMID: 24323397 DOI: 10.1007/s10753-013-9786-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In order to demonstrate the possible protective effects of estrogen receptor (ER)-α and ERβ receptor subtypes in the pathogenesis of colonic and gastric oxidant damage, experimental ulcer and colitis were induced by acetic acid, and the animals were randomly divided as colitis, ulcer, and their corresponding non-ulcer and non-colitis control groups. Each group of rats was treated intramuscularly with the vehicle, selective ERα agonist propylpyrazole-triol (1 mg/kg), ERβ agonist diarylpropionitrile (1 mg/kg), non-selective ER agonist 17β estradiol (E2; 1 mg/kg), or E2 plus non-selective ER antagonist ICI-182780 (1 mg/kg). The results revealed that induction of ulcer or colitis resulted in systemic inflammation as assessed by increased levels of plasma TNF-α and IL-6 levels. In both tissues, the presence of oxidant damage was verified by histological analysis and elevated myleoperoxidase activity. In the colitis and ulcer groups, both ER agonists and the non-selective E2 reversed the oxidative damage in a similar manner. These findings indicate that estrogen acts via both ERα- and ERβ-mediated and direct antioxidant mechanisms, where both ER subtypes play equal and efficient roles in the anti-inflammatory action of estrogen, in limiting the migration of neutrophils to the inflamed tissue, reducing the release and activation of cytokines and thereby alleviating tissue damage.
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Zhang EY, Zhu BT. Estriol strongly inhibits DNCB-induced contact dermatitis: role of antigen-specific antibodies in pathogenesis. Endocr Connect 2014; 3:161-72. [PMID: 25150251 PMCID: PMC4165036 DOI: 10.1530/ec-14-0080] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The endogenous estrogens are important modulators of the immune system and its functions. However, their effects are rather complex and many aspects have not been studied. In this study, we used the 1-chloro-2,4-dinitrobenzene (DNCB)-induced contact dermatitis as a disease model and investigated the effect of estriol (E3), along with two other estrogens, 17β-estradiol and estrone, on the pathogenesis of contact hypersensitivity. A series of parameters, such as ear swelling, skin inflammation, antigen-specific immunoglobulins, and lymphocyte compositions in peripheral lymphoid organs, were evaluated in mice following development of contact dermatitis. We found that administration of all three estrogens elicited strong inhibition of DNCB-induced dermatitis, while E3 exerted the strongest suppressive effect. Administration of E3 alleviated dermatitis, and this effect was accompanied by decreases in serum DNCB-specific immunoglobulins, such as IgA, IgG1, IgG2a, and IgG2b. Besides, treatment with E3 reduced B cell population, especially IgG-producing cells in the peripheral lymphoid organs following the induction of dermatitis. These observations consistently suggest that the antibody (Ab)-mediated humoral immune reactions play a critical role in the pathogenesis of DNCB-induced contact dermatitis. The results from this study demonstrate, for the first time, that estrogen administration has a strong suppressive effect on the pathogenesis of contact dermatitis. These findings offer important insights concerning the pathogenic role of antigen-specific Abs in contact dermatitis and the treatment of chemical-induced, Ab-mediated skin hypersensitivity reactions in humans.
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Affiliation(s)
- Elizabeth Yan Zhang
- Department of PharmacologyToxicology and Therapeutics, School of Medicine, University of Kansas Medical Center, Room 4061 of KLSIC Building, 2146 West 39th Street, Kansas City, Kansas 66160, USADepartment of BiologySouth University of Science and Technology of China, Shenzhen, Guangdong 518055, China
| | - Bao-Ting Zhu
- Department of PharmacologyToxicology and Therapeutics, School of Medicine, University of Kansas Medical Center, Room 4061 of KLSIC Building, 2146 West 39th Street, Kansas City, Kansas 66160, USADepartment of BiologySouth University of Science and Technology of China, Shenzhen, Guangdong 518055, China Department of PharmacologyToxicology and Therapeutics, School of Medicine, University of Kansas Medical Center, Room 4061 of KLSIC Building, 2146 West 39th Street, Kansas City, Kansas 66160, USADepartment of BiologySouth University of Science and Technology of China, Shenzhen, Guangdong 518055, China
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Fávaro-Moreira NC, Okoti LW, Furini R, Tambeli CH. Gonadal hormones modulate the responsiveness to local β-blocker-induced antinociception in the temporomandibular joint of male and female rats. Eur J Pain 2014; 19:772-80. [PMID: 25363860 DOI: 10.1002/ejp.601] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/03/2014] [Indexed: 11/06/2022]
Abstract
BACKGROUND We have previously demonstrated that blockade of β-adrenoreceptors (β-AR) located in the temporomandibular joint (TMJ) of rats suppresses formalin-induced TMJ nociceptive behaviour in both male and female rats, but female rats are more responsive. In this study, we investigated whether gonadal hormones modulate the responsiveness to local β-blocker-induced antinociception in the TMJ of rats. METHODS Co-administration of each of the selective β1 (atenolol), β2 (ICI 118.551) and β3 (SR59230A)-AR antagonists with equi-nociceptive concentrations of formalin in the TMJ of intact, gonadectomized and hormone-treated gonadectomized male and female rats. RESULTS Atenolol, ICI 118.551 and SR59230A significantly reduced formalin-induced TMJ nociception in a dose response fashion in all groups tested. However, a lower dose of each β-AR antagonist was sufficient to significantly reduce nociceptive responses in gonadectomized but not in intact and testosterone-treated gonadectomized male rats. In the female groups, a lower dose of β1 -AR antagonist was sufficient to significantly reduce nociceptive responses in gonadectomized but not in intact or gonadectomized rats treated with progesterone or a high dose of oestradiol; a lower dose of β2 -AR antagonist was sufficient to significantly reduce nociceptive responses in gonadectomized but not in intact and gonadectomized rats treated with low or high dose of oestradiol. CONCLUSION Gonadal hormones may reduce the responsiveness to local β-blocker-induced antinociception in the TMJ of male and female rats. However, their effect depends upon their plasma level, the subtype of β-AR and the dose of β-blockers used.
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Affiliation(s)
- N C Fávaro-Moreira
- Department of Physiological Sciences, Laboratory of Orofacial Pain, Piracicaba Dental School, State University of Campinas - UNICAMP, Piracicaba, Brazil
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Principi M, Barone M, Pricci M, De Tullio N, Losurdo G, Ierardi E, Di Leo A. Ulcerative colitis: from inflammation to cancer. Do estrogen receptors have a role? World J Gastroenterol 2014; 20:11496-11504. [PMID: 25206257 PMCID: PMC4155343 DOI: 10.3748/wjg.v20.i33.11496] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Revised: 03/29/2014] [Accepted: 05/23/2014] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis (UC) is a condition at increased risk for colorectal carcinoma (CRC) development. Nowadays, screening and follow-up programs are routinely performed worldwide to promote the early detection of CRCs in subjects with well known risk factors (extent, duration and severity of the disorder). The diffusion of these procedures is presumably the main reason for the marked reduction of cancer incidence and mortality in the course of UC. In addition, chemoprevention has been widely investigated and developed in many medical fields, and aspirin has shown a preventive effect against CRC, while mesalazine has been strongly invoked as a potential chemopreventive agent in UC. However, available studies show some limitations due to the obvious ethical implications of drug withdrawal in UC in order to design a control group. The estrogen receptors (ER) alpha/beta balance seems to have a relevant influence on colorectal carcinogenesis and ER beta appears to parallel apoptosis, and hence an anti-carcinogenic effect. Phytoestrogens are compounds acting as ER beta agonists and have shown a promising chemopreventive effect on sporadic as well as genetically inherited CRC. There is evidence suggesting a role for ERs in UC-related carcinogenesis. In this perspective, since these substances can be considered as dietary supplements and are completely free from side effects, phytoestrogens could be an interesting option for CRC prevention, even when the disease is a consequence of long-term chronic inflammation, as in the course of UC. Further studies of their effects are warranted in both the basic research and clinical fields.
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Goodman WA, Garg RR, Reuter BK, Mattioli B, Rissman EF, Pizarro TT. Loss of estrogen-mediated immunoprotection underlies female gender bias in experimental Crohn's-like ileitis. Mucosal Immunol 2014; 7:1255-65. [PMID: 24621993 PMCID: PMC4139459 DOI: 10.1038/mi.2014.15] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Revised: 02/01/2014] [Accepted: 02/10/2014] [Indexed: 02/04/2023]
Abstract
The incidence and severity of Crohn's disease (CD) are increased in female patients. Using SAMP1/YitFc (SAMP) mice, a spontaneous model of chronic intestinal inflammation that displays histologic and pathogenic similarities to human CD, we investigated the potential mechanism(s) contributing to sex differences observed in CD. Similar to gender differences observed in CD patients, SAMP female (SAMP-F) mice displayed an earlier onset and more severe ileitis compared with SAMP male (SAMP-M) mice. Furthermore, T-regulatory cells (Tregs) from gut-associated lymphoid tissue (GALT) of SAMP-F mice were reduced in frequency and impaired in their in vitro and in vivo suppressive functions compared with that of SAMP-M mice. Given the interaction between sex hormones and Treg function, we investigated the possible role of estrogen (E2) in SAMP ileitis. SAMP-M mice responded to exogenous E2 administration by expanding Treg frequency and reducing ileal inflammation, whereas SAMP-F mice were resistant. Conventional T cells and Tregs responded differentially to estrogen signaling, leading to distinct immunoprotective effects mediated by distinct estrogen receptor (ER) isoforms. These mechanisms were impaired in T cells from SAMP-F mice. Thus, hormone signaling influences the expansion and function of GALT Tregs in an ER-dependent manner and contributes to gender-based differences in experimental CD.
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Affiliation(s)
- Wendy A. Goodman
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Rekha R. Garg
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Brian K. Reuter
- Centre of Excellence for Gastrointestinal Inflammation and Immunity Research, University of Alberta, Edmonton, Alberta, Canada T6G 2X8
| | - Benedetta Mattioli
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Emilie F. Rissman
- Department of Biochemistry & Molecular Genetics, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Theresa T. Pizarro
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
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Penney RB, Lundgreen A, Yao-Borengasser A, Edavana VK, Williams S, Dhakal I, Wolff RK, Kadlubar S, Slattery ML. CYP19A1 single nucleotide polymorphism associations with CYP19A1, NFκB1, and IL6 gene expression in human normal colon and normal liver samples. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2014; 7:163-71. [PMID: 25114581 PMCID: PMC4109316 DOI: 10.2147/pgpm.s62238] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Background Estrogen is known to decrease the risk of colon cancer in postmenopausal women, and may exert its actions by decreasing interleukin-6 (IL6) production via stabilization of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). Estrogens are biosynthesized by CYP19A1 (aromatase), so it is possible that genetic variations in CYP19A1 influences the risk of colon cancer by altering expression of CYP19A1. Further, studies on gene-gene interactions suggest that single nucleotide polymorphisms in one gene may affect expression of other genes. The current study aims to explore the role of CYP19A1 single nucleotide polymorphisms on CYP19A1, NFκB1 and IL6 gene expression. Methods Phenotype–genotype associations, cross-associations between genes, and haplotype analyses were performed in both normal human colon (n=82) and liver (n=238) samples. Results CYP19A1 rs10459592, rs1961177, and rs6493497 were associated with CYP19A1 expression in colon samples (P=0.042, P=0.041, and P=0.013, respectively). CYP19A1 single nucleotide polymorphisms (rs12908960, rs730154, rs8025191, and rs17523880) were correlated with NFκB1 expression (P=0.047, P=0.04, P=0.05, and P=0.03, respectively), and CYP19A1 rs11856927, rs2470152, and rs2470144 (P=0.049, P=0.025, P=0.047, respectively) were associated with IL6 expression in the colon. While rs730154 and rs17523880 could not be analyzed in the liver samples, none of the other associations with the colon were replicated in the liver samples. Haplotype analysis revealed three separate haplotypes of the CYP19A1 single nucleotide polymorphism that were significantly associated with CYP19A1, NFκB1, and IL6 gene expression. Conclusion CYP19A1 single nucleotide polymorphisms are associated not only with CYP19A1 expression but also with NFκB1 and IL6 expression. These data demonstrate the possible functional consequences of genetic variation within the CYP19A1 gene on other genes in a biologically plausible pathway.
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Affiliation(s)
- Rosalind B Penney
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Abbie Lundgreen
- Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, USA
| | - Aiwei Yao-Borengasser
- Division of Medical Genetics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Vineetha K Edavana
- Division of Medical Genetics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Suzanne Williams
- Division of Medical Genetics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Ishwori Dhakal
- Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Roger K Wolff
- Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, USA
| | - Susan Kadlubar
- Division of Medical Genetics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Martha L Slattery
- Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, USA
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Cook LC, Hillhouse AE, Myles MH, Lubahn DB, Bryda EC, Davis JW, Franklin CL. The role of estrogen signaling in a mouse model of inflammatory bowel disease: a Helicobacter hepaticus model. PLoS One 2014; 9:e94209. [PMID: 24709804 PMCID: PMC3978010 DOI: 10.1371/journal.pone.0094209] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Accepted: 03/13/2014] [Indexed: 12/23/2022] Open
Abstract
The pathogenesis of inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis, is due in part to interactions between the immune system, genetics, the environment, and endogenous microbiota. Gonadal sex hormones (GSH), such as estrogen, are thought to be involved in the development of IBD as variations in disease severity occur during pregnancy, menopause, or oral contraceptives use. In certain strains of mice, infection with Helicobacter hepaticus triggers IBD-like mucosal inflammation that is more severe in female mice than in males, suggesting a role for GSH in this model. To determine the role of estrogen signaling in microbiota-induced intestinal inflammation, estrogen receptor (ER) α and β knock-out (KO) mice, ER agonists, and adoptive transfers were utilized. We demonstrate that, when signaling is limited to ERβ on a non-CD4+ cell subset, disease is less severe and this correlates with decreased expression of pro-inflammatory mediators.
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Affiliation(s)
- Lydia C. Cook
- Department of Veterinary Pathobiology, University of Missouri, Columbia, Missouri, United States of America
| | - Andrew E. Hillhouse
- Department of Veterinary Pathobiology, University of Missouri, Columbia, Missouri, United States of America
- Department of Molecular Microbiology & Immunology, University of Missouri, Columbia, Missouri, United States of America
| | - Matthew H. Myles
- Department of Veterinary Pathobiology, University of Missouri, Columbia, Missouri, United States of America
- IDEXX Laboratories, Columbia, Missouri, United States of America
| | - Dennis B. Lubahn
- Department of Biochemistry, University of Missouri, Columbia, Missouri, United States of America
| | - Elizabeth C. Bryda
- Department of Veterinary Pathobiology, University of Missouri, Columbia, Missouri, United States of America
| | - J. Wade Davis
- Departments of Health Management and Informatics, and Statistics, University of Missouri, Columbia, Missouri, United States of America
| | - Craig L. Franklin
- Department of Veterinary Pathobiology, University of Missouri, Columbia, Missouri, United States of America
- * E-mail:
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Böttner M, Thelen P, Jarry H. Estrogen receptor beta: tissue distribution and the still largely enigmatic physiological function. J Steroid Biochem Mol Biol 2014; 139:245-51. [PMID: 23523517 DOI: 10.1016/j.jsbmb.2013.03.003] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2013] [Revised: 03/11/2013] [Accepted: 03/12/2013] [Indexed: 01/26/2023]
Abstract
UNLABELLED In 1996, the molecular biology of E2 had to be reevaluated: in an effort to identify novel nuclear receptors or unknown isoforms of existing receptors Kuiper and colleague described the expression of a novel subtype of the estrogen receptor (ER) in rat prostate and ovary. Upon this pioneering discovery the already known ER was renamed ERα while the newly described ER was termed ERβ. In this review an attempt is made to summarize the current knowledge regarding the expression and function of ERβ in selected reproductive and non-reproductive organs under physiological conditions. The data suggest that ERβ may be considered as a dominant-negative regulator of ERα modulating transcriptional responses to estrogens. The ratio of ER α vs. β. within a cell may determine the cell sensitivity to estrogens and its biological responses to the hormone. CONCLUSION It is not the ligand, it is the multiplicity of receptors which determines the plethora of estrogen actions. This article is part of a Special Issue entitled 'Phytoestrogens'.
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Affiliation(s)
- M Böttner
- Department of Anatomy, University of Kiel, Germany
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Pastorelli L, De Salvo C, Mercado JR, Vecchi M, Pizarro TT. Central role of the gut epithelial barrier in the pathogenesis of chronic intestinal inflammation: lessons learned from animal models and human genetics. Front Immunol 2013; 4:280. [PMID: 24062746 PMCID: PMC3775315 DOI: 10.3389/fimmu.2013.00280] [Citation(s) in RCA: 327] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2013] [Accepted: 08/29/2013] [Indexed: 12/12/2022] Open
Abstract
The gut mucosa is constantly challenged by a bombardment of foreign antigens and environmental microorganisms. As such, the precise regulation of the intestinal barrier allows the maintenance of mucosal immune homeostasis and prevents the onset of uncontrolled inflammation. In support of this concept, emerging evidence points to defects in components of the epithelial barrier as etiologic factors in the pathogenesis of inflammatory bowel diseases (IBDs). In fact, the integrity of the intestinal barrier relies on different elements, including robust innate immune responses, epithelial paracellular permeability, epithelial cell integrity, as well as the production of mucus. The purpose of this review is to systematically evaluate how alterations in the aforementioned epithelial components can lead to the disruption of intestinal immune homeostasis, and subsequent inflammation. In this regard, the wealth of data from mouse models of intestinal inflammation and human genetics are pivotal in understanding pathogenic pathways, for example, that are initiated from the specific loss of function of a single protein leading to the onset of intestinal disease. On the other hand, several recently proposed therapeutic approaches to treat human IBD are targeted at enhancing different elements of gut barrier function, further supporting a primary role of the epithelium in the pathogenesis of chronic intestinal inflammation and emphasizing the importance of maintaining a healthy and effective intestinal barrier.
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Affiliation(s)
- Luca Pastorelli
- Department of Pathology, Case Western Reserve University School of Medicine , Cleveland, OH , USA ; Department of Biomedical Sciences for Health, University of Milan , Milan , Italy ; Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato , San Donato Milanese , Italy
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McLarty JL, Li J, Levick SP, Janicki JS. Estrogen modulates the influence of cardiac inflammatory cells on function of cardiac fibroblasts. J Inflamm Res 2013; 6:99-108. [PMID: 24062614 PMCID: PMC3780290 DOI: 10.2147/jir.s48422] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Background Inflammatory cells play a major role in the pathology of heart failure by stimulating cardiac fibroblasts to regulate the extracellular matrix in an adverse way. In view of the fact that inflammatory cells have estrogen receptors, we hypothesized that estrogen provides cardioprotection by decreasing the ability of cardiac inflammatory cells to influence fibroblast function. Methods Male rats were assigned to either an untreated or estrogen-treated group. In the treated group, estrogen was delivered for 2 weeks via a subcutaneous implanted pellet containing 17β-estradiol. A mixed population of cardiac inflammatory cells, including T-lymphocytes (about 70%), macrophages (about 12%), and mast cells (about 12%), was isolated from each rat and cultured in a Boyden chamber with cardiac fibroblasts from untreated adult male rats for 24 hours. To examine if tumor necrosis factor-alpha (TNF-α) produced by inflammatory cells represents a mechanism contributing to the stimulatory effects of inflammatory cells on cardiac fibroblasts, inflammatory cells from the untreated group were incubated with cardiac fibroblasts in a Boyden chamber system for 24 hours in the presence of a TNF-α-neutralizing antibody. Cardiac fibroblasts were also incubated with 5 ng/mL of TNF-α for 24 hours. Fibro-blast proliferation, collagen synthesis, matrix metalloproteinase activity, β1 integrin protein levels, and the ability of fibroblasts to contract collagen gels were determined in all groups and statistically compared via one-way analysis of variance. Results Inflammatory cells from the untreated group resulted in: 1) an increased fibroblast proliferation, collagen production and matrix metalloproteinase activity; and 2) a loss of β1 integrin protein and a reduced ability to contract collagen gels. In contrast, inflammatory cells from the treated group resulted in: 1) an attenuated fibroblast proliferation; 2) a nonsignificant reduction in collagen production; 3) the prevention of matrix metalloproteinase activation and the loss of β1 integrin by fibroblasts and 4) a preservation of the fibroblasts’ ability to contract collagen gels. The TNF-α neutralizing antibody attenuated or prevented the untreated inflammatory cell-induced fibroblast proliferation, collagen production, matrix metalloproteinase activation and loss of β1 integrin protein as well as preserved fibroblast contractile ability. Incubation with TNF-α yielded changes in the cardiac fibroblast parameters that were directionally similar to the results obtained with untreated inflammatory cells. Conclusion These results and those of our previous in vivo studies suggest that a major mechanism by which estrogen provides cardioprotection is its ability to modulate synthesis of TNF-α by inflammatory cells, thereby preventing inflammatory cell induction of cardiac fibroblast events that contribute to adverse extracellular matrix remodeling.
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Affiliation(s)
- Jennifer L McLarty
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
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Son TG, Gong EJ, Bae MJ, Kim SD, Heo K, Moon C, Yang K, Kim JS. Protective effect of genistein on radiation-induced intestinal injury in tumor bearing mice. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 13:103. [PMID: 23672582 PMCID: PMC3671128 DOI: 10.1186/1472-6882-13-103] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/02/2013] [Accepted: 05/09/2013] [Indexed: 01/01/2023]
Abstract
BACKGROUND Radiation therapy is the most widely used treatment for cancer, but it causes the side effect of mucositis due to intestinal damage. We examined the protective effect of genistein in tumor-bearing mice after abdominal irradiation by evaluation of apoptosis and intestinal morphological changes. METHODS Mouse colon cancer CT26 cells were subcutaneously injected at the flank of BALB/c mice to generate tumors. The tumor-bearing mice were treated with abdominal radiation at 5 and 10 Gy, and with genistein at 200 mg/kg body weight per day for 1 d before radiation. The changes in intestinal histology were evaluated 12 h and 3.5 d after irradiation. To assess the effect of the combination treatment on the cancer growth, the tumor volume was determined at sacrifice before tumor overgrowth occurred. RESULTS Genistein significantly decreased the number of apoptotic nuclei compared with that in the irradiation group 12 h after 5 Gy irradiation. Evaluation of histological changes showed that genistein ameliorated intestinal morphological changes such as decreased crypt survival, villus shortening, and increased length of the basal lamina 3.5 d after 10 Gy irradiation. Moreover, the genistein-treated group exhibited more Ki-67-positive proliferating cells in the jejunum than the irradiated control group, and crypt depths were greater in the genistein-treated group than in the irradiated control group. The mean weight of the CT26 tumors was reduced in the group treated with genistein and radiation compared with the control group. CONCLUSION Genistein had a protective effect on intestinal damage induced by irradiation and delayed tumor growth. These results suggest that genistein is a useful candidate for preventing radiotherapy-induced intestinal damage in cancer patients.
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Affiliation(s)
- Tae Gen Son
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan, Republic of Korea
| | - Eun Ji Gong
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan, Republic of Korea
| | - Min Ji Bae
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan, Republic of Korea
| | - Sung Dae Kim
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan, Republic of Korea
| | - Kyu Heo
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan, Republic of Korea
| | - Changjong Moon
- Department of Veterinary Anatomy, College of Veterinary Medicine and Veterinary Medical Research Center, Chonnam National University, Gwangju, South Korea
| | - Kwangmo Yang
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan, Republic of Korea
| | - Joong Sun Kim
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan, Republic of Korea
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Huynh D, Akçora D, Malaterre J, Chan CK, Dai XM, Bertoncello I, Stanley ER, Ramsay RG. CSF-1 receptor-dependent colon development, homeostasis and inflammatory stress response. PLoS One 2013; 8:e56951. [PMID: 23451116 PMCID: PMC3579891 DOI: 10.1371/journal.pone.0056951] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2012] [Accepted: 01/16/2013] [Indexed: 01/09/2023] Open
Abstract
The colony stimulating factor-1 (CSF-1) receptor (CSF-1R) directly regulates the development of Paneth cells (PC) and influences proliferation and cell fate in the small intestine (SI). In the present study, we have examined the role of CSF-1 and the CSF-1R in the large intestine, which lacks PC, in the steady state and in response to acute inflammation induced by dextran sulfate sodium (DSS). As previously shown in mouse, immunohistochemical (IHC) analysis of CSF-1R expression showed that the receptor is baso-laterally expressed on epithelial cells of human colonic crypts, indicating that this expression pattern is shared between species. Colons from Csf1r null and Csf1(op/op) mice were isolated and sectioned for IHC identification of enterocytes, enteroendocrine cells, goblet cells and proliferating cells. Both Csf1r(-/-) and Csf1(op/op) mice were found to have colon defects in enterocytes and enteroendocrine cell fate, with excessive goblet cell staining and reduced cell proliferation. In addition, the gene expression profiles of the cell cycle genes, cyclinD1, c-myc, c-fos, and c-myb were suppressed in Csf1r(-/-) colonic crypt, compared with those of WT mice and the expression of the stem cell marker gene Lgr5 was markedly reduced. However, analysis of the proliferative responses of immortalized mouse colon epithelial cells (lines; Immorto-5 and YAMC) indicated that CSF-1R is not a major regulator of colonocyte proliferation and that its effects on proliferation are indirect. In an examination of the acute inflammatory response, Csf1r(+/-) male mice were protected from the adverse affects of DSS-induced colitis compared with WT mice, while Csf1r(+/-) female mice were significantly less protected. These data indicate that CSF-1R signaling plays an important role in colon homeostasis and stem cell gene expression but that the receptor exacerbates the response to inflammatory challenge in male mice.
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Affiliation(s)
- Duy Huynh
- Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
- Department of Genetics, Latrobe University, Victoria, Australia
| | - Dilara Akçora
- Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
- Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia
| | - Jordane Malaterre
- Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
| | - Chee Kai Chan
- Department of Genetics, Latrobe University, Victoria, Australia
| | - Xu-Ming Dai
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, New York, United States of America
| | - Ivan Bertoncello
- Department of Pharmacology the University of Melbourne, Parkville, Victoria, Australia
| | - E. Richard Stanley
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, New York, United States of America
| | - Robert G. Ramsay
- Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
- Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
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50
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Chen D, Xiong Y, Tang Z, Lv B, Lin Y. Inhibitory effects of daidzein on intestinal motility in normal and high contractile states. PHARMACEUTICAL BIOLOGY 2012; 50:1561-1566. [PMID: 22979946 DOI: 10.3109/13880209.2012.698285] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
CONTEXT Daidzein is a naturally occurring compound and has various health benefits. However, its effects on intestinal smooth muscle contractility remain unknown. AIMS The present study was to characterize the effects of daidzein on the contractility of isolated jejunal smooth muscle and its underlying mechanisms. METHODS Ex vivo assay was selected as the major method to determine the effects of daidzein on the contractility of isolated jejunal smooth muscle fragment (JSMF). RESULTS Daidzein (5-160 µmol/L) inhibited the contractility of JSMF in normal contractile state and in a dose-dependent manner. Daidzein also inhibited the contractility of JSMF induced by ACh, histamine, erythromycin and high Ca²⁺, respectively, and decreased charcoal propulsion in the small intestine in vivo. The inhibitory effects of daidzein were partially blocked by phentolamine or propranolol and were abolished in the presence of varapamil or at Ca²⁺-free assay condition. However, the inhibitory effects of daidzein on jejunal contraction were not significantly influenced by nitric oxide (NO) synthase inhibitor L-NG-nitro-arginine (L-NNA). Daidzein was also found to directly inhibit the phosphorylation and Mg²⁺-ATPase activity of smooth muscle myosin. DISCUSSION AND CONCLUSION The results implicated that α- and β-adrenergic receptors were involved in the inhibitory effects produced by daidzein rather than via NO pathway. As a phytoestrogen, daidzein has shown its potential value in relieving the hypercontractility of small intestine.
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MESH Headings
- Animals
- Ca(2+) Mg(2+)-ATPase/antagonists & inhibitors
- Ca(2+) Mg(2+)-ATPase/metabolism
- Dose-Response Relationship, Drug
- Enzyme Inhibitors/pharmacology
- Gastrointestinal Agents/pharmacology
- Gastrointestinal Motility/drug effects
- Gastrointestinal Transit/drug effects
- Isoflavones/pharmacology
- Jejunum/drug effects
- Jejunum/physiology
- Mice
- Muscle Contraction/drug effects
- Muscle, Smooth/drug effects
- Muscle, Smooth/physiology
- Myosins/antagonists & inhibitors
- Myosins/metabolism
- Nitric Oxide/metabolism
- Phosphorylation
- Phytoestrogens/pharmacology
- Rats
- Rats, Sprague-Dawley
- Receptors, Adrenergic, alpha/drug effects
- Receptors, Adrenergic, alpha/metabolism
- Receptors, Adrenergic, beta/drug effects
- Receptors, Adrenergic, beta/metabolism
- Signal Transduction/drug effects
- Time Factors
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Affiliation(s)
- Dapeng Chen
- Department of Pharmacology, Dalian Medical University, Dalian, China
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