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de Souza S, Laumet S, Hua H, Inyang KE, Sim J, Folger JK, Moeser AJ, Laumet G. Mast cell-derived chymases are essential for the resolution of inflammatory pain in mice. Pain 2025:00006396-990000000-00843. [PMID: 40035664 DOI: 10.1097/j.pain.0000000000003565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 12/02/2024] [Indexed: 03/06/2025]
Abstract
ABSTRACT Immune cells play a critical role in the transition from acute to chronic pain. However, the role of mast cells in pain remains underinvestigated. Here, we demonstrated that the resolution of inflammatory pain is markedly delayed in mast cell-deficient mice. In response to complete Freund adjuvant, mast cell-deficient mice showed greater levels of nitric oxide, leukocyte infiltration, and altered cytokine/chemokine profile in inflamed skin in both sexes. In wild-type mice, the number of mast cell and mast cell-derived chymases, chymase 1 (CMA1) and mast cell protease 4 (MCPT4), increased in the inflamed skin. Inhibiting chymase enzymatic activity delayed the resolution of inflammatory pain. Consistently, local pharmacological administration of recombinant CMA1 and MCPT4 promoted the resolution of pain hypersensitivity and attenuated the upregulation of cytokines and chemokines under inflammation. We identified CCL9 as a target of MCPT4. Inhibition of CCL9 promoted recruitment of CD206+ myeloid cells and alleviated inflammatory pain. Our work reveals a new role of mast cell-derived chymases in preventing the transition from acute to chronic pain and suggests new therapeutic avenues for the treatment of inflammatory pain.
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Affiliation(s)
- Sabrina de Souza
- Department of Physiology, Michigan State University, East Lansing, MI, United States
| | - Sophie Laumet
- Department of Physiology, Michigan State University, East Lansing, MI, United States
| | - Hannah Hua
- Department of Physiology, Michigan State University, East Lansing, MI, United States
| | - Kufreobong E Inyang
- Department of Physiology, Michigan State University, East Lansing, MI, United States
| | - Jaewon Sim
- Department of Physiology, Michigan State University, East Lansing, MI, United States
| | - Joseph K Folger
- Department of Physiology, Michigan State University, East Lansing, MI, United States
| | - Adam J Moeser
- Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, Mi, United States
| | - Geoffroy Laumet
- Department of Physiology, Michigan State University, East Lansing, MI, United States
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Wei Z, Tang X, Yi C, Ocansey DKW, Mao F, Mao Z. HucMSC-Ex alleviates DSS-induced colitis in mice by decreasing mast cell activation via the IL-33/ST2 axis. Am J Transl Res 2024; 16:2727-2744. [PMID: 39006299 PMCID: PMC11236658 DOI: 10.62347/exze5413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a chronic inflammatory disease that poses challenges in terms of treatment. The precise mechanism underlying the role of human umbilical cord mesenchymal stem cell-derived exosome (HucMSC-Ex) in the inflammatory repair process of IBD remains elusive. Mucosal mast cells accumulate within the intestinal tract and exert regulatory functions in IBD, thus presenting a novel target for addressing this intestinal disease. METHODS A mouse model of Dextran Sulfate Sodium (DSS)-induced colitis was established and hucMSC-Ex were administered to investigate their impact on the regulation of intestinal mast cells. An in vitro co-culture model using the human clonal colorectal adenocarcinoma cell line (Caco-2) and human mast cell line (LAD2) was also established for further exploration of the effect of hucMSC-Ex. RESULTS We observed the accumulation of mast cells in the intestines of patients with IBD as well as mice. In colitis mice, there was an upregulation of mast cell-related tryptase, interleukin-33 (IL-33), and suppression of tumorigenicity 2 receptor (ST2 or IL1RL1), and the function of the intestinal mucosal barrier related to intestinal tight junction protein was weakened. HucMSC-Ex treatment significantly reduced mast cell infiltration and intestinal damage. In the co-culture model, a substantial number of mast cells interact with the epithelial barrier, triggering activation of the IL-33/IL1RL1 (ST2) pathway and subsequent release of inflammatory factors and trypsin. This disruption leads to aberrant expression of tight junction proteins, which can be alleviated by supplementation with hucMSC-Ex. CONCLUSION Our results suggest that hucMSC-Ex may reduce the release of mast cell mediators via the IL-33/IL1RL1 (ST2) axis, thereby mitigating its detrimental effects on intestinal barrier function.
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Affiliation(s)
- Zhiping Wei
- Department of Laboratory Medicine, The Affiliated People’s Hospital, Jiangsu UniversityZhenjiang 212002, Jiangsu, P. R. China
- Department of Clinical Laboratory, The Third People’s Hospital of Xindu DistrictChengdu 610500, Sichuan, P. R. China
| | - Xiaohua Tang
- Department of Orthopaedics, The People’s Hospital of Danyang, Affiliated Danyang Hospital of Nantong UniversityZhenjiang 212300, Jiangsu, P. R. China
| | - Chengxue Yi
- School of Medical Technology, Zhenjiang CollegeZhenjiang 212028, Jiangsu, P. R. China
| | - Dickson Kofi Wiredu Ocansey
- Department of Laboratory Medicine, The Affiliated People’s Hospital, Jiangsu UniversityZhenjiang 212002, Jiangsu, P. R. China
- Department of Medical Laboratory Science, School of Allied Health Sciences, College of Health and Allied Sciences, University of Cape CoastCape Coast CC0959347, Ghana
| | - Fei Mao
- Department of Laboratory Medicine, The Affiliated People’s Hospital, Jiangsu UniversityZhenjiang 212002, Jiangsu, P. R. China
| | - Zhenwei Mao
- The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang City, Affiliated People’s Hospital of Jiangsu UniversityZhenjiang 212002, Jiangsu, P. R. China
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Céspedes N, Donnelly EL, Hansten G, Fellows AM, Dobson M, Kaylor HL, Coles TA, Schauer J, Van de Water J, Luckhart S. Mast cell-derived IL-10 protects intestinal barrier integrity during malaria in mice and regulates parasite transmission to Anopheles stephensi with a female-biased immune response. Infect Immun 2024; 92:e0036023. [PMID: 38299826 PMCID: PMC10929420 DOI: 10.1128/iai.00360-23] [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: 09/04/2023] [Accepted: 01/11/2024] [Indexed: 02/02/2024] Open
Abstract
Malaria is strongly predisposed to bacteremia, which is associated with increased gastrointestinal permeability and a poor clinical prognosis. We previously identified mast cells (MCs) as mediators of intestinal permeability in malaria and described multiple cytokines that rise with parasitemia, including interleukin (IL)-10, which could protect the host from an inflammatory response and alter parasite transmission to Anopheles mosquitoes. Here, we used the Cre-loxP system and non-lethal Plasmodium yoelii yoelii 17XNL to study the roles of MC-derived IL-10 in malaria immunity and transmission. Our data suggest a sex-biased and local inflammatory response mediated by MC-derived IL-10, supported by early increased number and activation of MCs in females relative to males. Increased parasitemia in female MC IL-10 (-) mice was associated with increased ileal levels of chemokines and plasma myeloperoxidase (MPO). We also observed increased intestinal permeability in female and male MC IL-10 (-) mice relative to MC IL-10 (+) mice but no differences in blood bacterial 16S DNA levels. Transmission success of P. yoelii to A. stephensi was higher in female relative to male mice and from female and male MC IL-10 (-) mice relative to MC IL-10 (+) mice. These patterns were associated with increased plasma levels of pro-inflammatory cytokines in female MC IL-10 (-) mice and increased plasma levels of chemokines and markers of neutrophil activation in male MC IL-10 (-) mice. Overall, these data suggest that MC-derived IL-10 protects intestinal barrier integrity, regulates parasite transmission, and controls local and systemic host immune responses during malaria, with a female bias.
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Affiliation(s)
- Nora Céspedes
- Department of Entomology, Plant Pathology and Nematology, University of Idaho, Moscow, Idaho, USA
| | - Erinn L. Donnelly
- Department of Biological Sciences, University of Idaho, Moscow, Idaho, USA
| | - Gretchen Hansten
- Department of Entomology, Plant Pathology and Nematology, University of Idaho, Moscow, Idaho, USA
| | - Abigail M. Fellows
- Department of Entomology, Plant Pathology and Nematology, University of Idaho, Moscow, Idaho, USA
| | - Megan Dobson
- Department of Entomology, Plant Pathology and Nematology, University of Idaho, Moscow, Idaho, USA
| | - Hannah L. Kaylor
- Department of Entomology, Plant Pathology and Nematology, University of Idaho, Moscow, Idaho, USA
| | - Taylor A. Coles
- Department of Entomology, Plant Pathology and Nematology, University of Idaho, Moscow, Idaho, USA
| | - Joseph Schauer
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, California, USA
| | - Judy Van de Water
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, California, USA
| | - Shirley Luckhart
- Department of Entomology, Plant Pathology and Nematology, University of Idaho, Moscow, Idaho, USA
- Department of Biological Sciences, University of Idaho, Moscow, Idaho, USA
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Wang RM, Mesfin JM, Karkanitsa M, Ungerleider JL, Zelus E, Zhang Y, Kawakami Y, Kawakami Y, Kawakami T, Christman KL. Immunomodulatory contribution of mast cells to the regenerative biomaterial microenvironment. NPJ Regen Med 2023; 8:53. [PMID: 37730736 PMCID: PMC10511634 DOI: 10.1038/s41536-023-00324-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 08/31/2023] [Indexed: 09/22/2023] Open
Abstract
Bioactive immunomodulatory biomaterials have shown promise for influencing the immune response to promote tissue repair and regeneration. Macrophages and T cells have been associated with this response; however, other immune cell types have been traditionally overlooked. In this study, we investigated the role of mast cells in the regulation of the immune response to decellularized biomaterial scaffolds using a subcutaneous implant model. In mast cell-deficient mice, there was dysregulation of the expected M1 to M2 macrophage transition typically induced by the biomaterial scaffold. Polarization progression deviated in a sex-specific manner with an early transition to an M2 profile in female mice, while the male response was unable to properly transition past a pro-inflammatory M1 state. Both were reversed with adoptive mast cell transfer. Further investigation of the later-stage immune response in male mice determined a greater sustained pro-inflammatory gene expression profile, including the IL-1 cytokine family, IL-6, alarmins, and chemokines. These results highlight mast cells as another important cell type that influences the immune response to pro-regenerative biomaterials.
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Affiliation(s)
- Raymond M Wang
- Shu Chien-Gene Lay Department of Bioengineering, Sanford Consortium of Regenerative Medicine, University of California San Diego, 2880 Torrey Pines Scenic Drive, La Jolla, CA, 92037, USA
| | - Joshua M Mesfin
- Shu Chien-Gene Lay Department of Bioengineering, Sanford Consortium of Regenerative Medicine, University of California San Diego, 2880 Torrey Pines Scenic Drive, La Jolla, CA, 92037, USA
| | - Maria Karkanitsa
- Shu Chien-Gene Lay Department of Bioengineering, Sanford Consortium of Regenerative Medicine, University of California San Diego, 2880 Torrey Pines Scenic Drive, La Jolla, CA, 92037, USA
| | - Jessica L Ungerleider
- Shu Chien-Gene Lay Department of Bioengineering, Sanford Consortium of Regenerative Medicine, University of California San Diego, 2880 Torrey Pines Scenic Drive, La Jolla, CA, 92037, USA
| | - Emma Zelus
- Shu Chien-Gene Lay Department of Bioengineering, Sanford Consortium of Regenerative Medicine, University of California San Diego, 2880 Torrey Pines Scenic Drive, La Jolla, CA, 92037, USA
| | - Yuxue Zhang
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Yu Kawakami
- Laboratory of Allergic Diseases, Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, California, 92037, USA
- Department of Dermatology, University of California San Diego, School of Medicine, La Jolla, CA, 92093, USA
| | - Yuko Kawakami
- Laboratory of Allergic Diseases, Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, California, 92037, USA
- Department of Dermatology, University of California San Diego, School of Medicine, La Jolla, CA, 92093, USA
| | - Toshiaki Kawakami
- Laboratory of Allergic Diseases, Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, California, 92037, USA
- Department of Dermatology, University of California San Diego, School of Medicine, La Jolla, CA, 92093, USA
| | - Karen L Christman
- Shu Chien-Gene Lay Department of Bioengineering, Sanford Consortium of Regenerative Medicine, University of California San Diego, 2880 Torrey Pines Scenic Drive, La Jolla, CA, 92037, USA.
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Wang Y, Huang B, Jin T, Ocansey DKW, Jiang J, Mao F. Intestinal Fibrosis in Inflammatory Bowel Disease and the Prospects of Mesenchymal Stem Cell Therapy. Front Immunol 2022; 13:835005. [PMID: 35370998 PMCID: PMC8971815 DOI: 10.3389/fimmu.2022.835005] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 01/26/2022] [Indexed: 12/12/2022] Open
Abstract
Intestinal fibrosis is an important complication of inflammatory bowel disease (IBD). In the course of the development of fibrosis, certain parts of the intestine become narrowed, significantly destroying the structure and function of the intestine and affecting the quality of life of patients. Chronic inflammation is an important initiating factor of fibrosis. Unfortunately, the existing anti-inflammatory drugs cannot effectively prevent and alleviate fibrosis, and there is no effective anti-fibrotic drug, which makes surgical treatment the mainstream treatment for intestinal fibrosis and stenosis. Mesenchymal stem cells (MSCs) are capable of tissue regeneration and repair through their self-differentiation, secretion of cytokines, and secretion of extracellular vesicles. MSCs have been shown to play an important therapeutic role in the fibrosis of many organs. However, the role of MSC in intestinal fibrosis largely remained unexplored. This review summarizes the mechanism of intestinal fibrosis, including the role of immune cells, TGF-β, and the gut microbiome and metabolites. Available treatment options for fibrosis, particularly, MSCs are also discussed.
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Affiliation(s)
- Yifei Wang
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, Suzhou, China
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Bin Huang
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, Suzhou, China
- General Surgery Department, Affiliated Aoyang Hospital of Jiangsu University, Suzhou, China
| | - Tao Jin
- Department of Gastrointestinal and Endoscopy, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Dickson Kofi Wiredu Ocansey
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China
- Directorate of University Health Services, University of Cape Coast, Cape Coast, Ghana
| | - Jiajia Jiang
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, Suzhou, China
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China
- *Correspondence: Jiajia Jiang, ; Fei Mao,
| | - Fei Mao
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, Suzhou, China
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China
- *Correspondence: Jiajia Jiang, ; Fei Mao,
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Bilotta S, Arbogast J, Schart N, Frei M, Lorentz A. Resveratrol Treatment Prevents Increase of Mast Cells in Both Murine OVA Enteritis and IL-10 -/- Colitis. Int J Mol Sci 2022; 23:ijms23031213. [PMID: 35163137 PMCID: PMC8836010 DOI: 10.3390/ijms23031213] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/11/2022] [Accepted: 01/19/2022] [Indexed: 02/07/2023] Open
Abstract
Mast cells are involved in allergic and other inflammatory diseases. The polyphenol resveratrol is known for its anti-inflammatory properties and may be used as nutraceutical in mast cell associated diseases. We analyzed the effect of resveratrol on mast cells in vivo in ovalbumin-induced allergic enteritis as well as experimental colitis in IL-10−/− mice which received resveratrol via drinking water. Treatment with resveratrol prevented the increase in mast cells in both allergic enteritis and chronic colitis in duodenum as well as in colon. Further, it delayed the onset of diseases symptoms and ameliorated diseases associated parameters such as tissue damage as well as inflammatory cell infiltration in affected colon sections. In addition to the findings in vivo, resveratrol inhibited IgE-dependent degranulation and expression of pro-inflammatory cytokines such as TNF-α in IgE/DNP-activated as well as in LPS-activated bone marrow-derived mast cells. These results indicate that resveratrol may be considered as an anti-allergic and anti-inflammatory plant-derived component for the prevention or treatment of mast cell-associated disorders of the gastrointestinal tract.
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Jin X, Gharibani P, Yin J, Chen JDZ. Neuro-Immune Modulation Effects of Sacral Nerve Stimulation for Visceral Hypersensitivity in Rats. Front Neurosci 2021; 15:645393. [PMID: 34276280 PMCID: PMC8282909 DOI: 10.3389/fnins.2021.645393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 06/01/2021] [Indexed: 11/21/2022] Open
Abstract
Background: Visceral hypersensitivity (VH) is one of the underlying pathophysiologies of irritable bowel syndrome. Mast cell overactivation has been found to be one of the main causes of VH. We investigated the effects and mechanisms of actions of sacral nerve stimulation (SNS) on visceral pain in a rodent model of VH. Methods: The VH was established by an intrarectal infusion of AA in 10-day-old pups. Rats were chronically implanted with electrodes for SNS and recording electromyogram (EMG) and electrocardiogram. The acute study was performed in 2-randomized sessions with SNS (14 Hz, 330 μs, 40% motor threshold or MT, 30 min) or sham-SNS. Later on, rats were randomized into SNS/sham-SNS groups and a chronic study was performed with 2 h-daily SNS or sham-SNS for 21 days. Visceromotor reflexes were assessed by abdominal EMG and withdrawal reflex (AWR). Colon tissues were collected to study colonic acetylcholine (ACh), the enteric neurons (ChAT, nNOS, and PGP9.5), mast cells activity [Tryptase, prostaglandins E2 (PGE2), and cyclooxygenases-2 (COX2)] and pain markers [nerve growth factor (NGF) and Sub-P]. Key Results: Sacral nerve stimulation significantly improved visceromotor reflexes assessed by the EMG and AWR, compared with sham-SNS. SNS normalized the protein expressions of ChAT and nNOS and regulated mast cells activity by downregulating Tryptase, COX2, and PGE2. Neonatal AA administration upregulated NGF and Sub-P; chronic SNS significantly decreased these pain biomarkers. Concurrently, chronic SNS increased ACh in colon tissues and vagal efferent activity. Conclusions: Sacral nerve stimulation reduces VH in rats and this ameliorating effect might be attributed to the suppression of mast cell overactivation in the colon tissue via the modulation of autonomic nervous system functions.
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Affiliation(s)
- Xue Jin
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Payam Gharibani
- Division of Neuroimmunology, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Jieyun Yin
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Jiande D Z Chen
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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Kyritsi K, Kennedy L, Meadows V, Hargrove L, Demieville J, Pham L, Sybenga A, Kundu D, Cerritos K, Meng F, Alpini G, Francis H. Mast Cells Induce Ductular Reaction Mimicking Liver Injury in Mice Through Mast Cell-Derived Transforming Growth Factor Beta 1 Signaling. Hepatology 2021; 73:2397-2410. [PMID: 32761972 PMCID: PMC7864988 DOI: 10.1002/hep.31497] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 06/15/2020] [Accepted: 06/28/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Following liver injury, mast cells (MCs) migrate into the liver and are activated in patients with cholestasis. Inhibition of MC mediators decreases ductular reaction (DR) and liver fibrosis. Transforming growth factor beta 1 (TGF-β1) contributes to fibrosis and promotes liver disease. Our aim was to demonstrate that reintroduction of MCs induces cholestatic injury through TGF-β1. APPROACH AND RESULTS Wild-type, KitW-sh (MC-deficient), and multidrug resistance transporter 2/ABC transporter B family member 2 knockout mice lacking l-histidine decarboxylase were injected with vehicle or PKH26-tagged murine MCs pretreated with 0.01% dimethyl sulfoxide (DMSO) or the TGF-β1 receptor inhibitor (TGF-βRi), LY2109761 (10 μM) 3 days before sacrifice. Hepatic damage was assessed by hematoxylin and eosin (H&E) and serum chemistry. Injected MCs were detected in liver, spleen, and lung by immunofluorescence (IF). DR was measured by cytokeratin 19 (CK-19) immunohistochemistry and F4/80 staining coupled with real-time quantitative PCR (qPCR) for interleukin (IL)-1β, IL-33, and F4/80; biliary senescence was evaluated by IF or qPCR for p16, p18, and p21. Fibrosis was evaluated by sirius red/fast green staining and IF for synaptophysin 9 (SYP-9), desmin, and alpha smooth muscle actin (α-SMA). TGF-β1 secretion/expression was measured by enzyme immunoassay and qPCR. Angiogenesis was detected by IF for von Willebrand factor and vascular endothelial growth factor C qPCR. In vitro, MC-TGF-β1 expression/secretion were measured after TGF-βRi treatment; conditioned medium was collected. Cholangiocytes and hepatic stellate cells (HSCs) were treated with MC-conditioned medium, and biliary proliferation/senescence was measured by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium and qPCR; HSC activation evaluated for α-SMA, SYP-9, and collagen type-1a expression. MC injection recapitulates cholestatic liver injury characterized by increased DR, fibrosis/TGF-β1 secretion, and angiogenesis. Injection of MC-TGF-βRi reversed these parameters. In vitro, MCs induce biliary proliferation/senescence and HSC activation that was reversed with MCs lacking TGF-β1. CONCLUSIONS Our study demonstrates that reintroduction of MCs mimics cholestatic liver injury and that MC-derived TGF-β1 may be a target in chronic cholestatic liver disease.
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Affiliation(s)
- Konstantina Kyritsi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine Research
| | - Lindsey Kennedy
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine Research
| | - Vik Meadows
- Richard L. Roudebush VA Medical Center, Indiana University School of Medicine Research
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine Research
| | - Laura Hargrove
- Texas A&M University Health Science Center, Texas A&M University-Central Texas
| | | | - Linh Pham
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine Research
| | | | - Debjyoti Kundu
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine Research
| | - Karla Cerritos
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine Research
| | - Fanyin Meng
- Richard L. Roudebush VA Medical Center, Indiana University School of Medicine Research
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine Research
| | - Gianfranco Alpini
- Richard L. Roudebush VA Medical Center, Indiana University School of Medicine Research
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine Research
| | - Heather Francis
- Richard L. Roudebush VA Medical Center, Indiana University School of Medicine Research
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine Research
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Kilinc E, Torun IE, Cetinkaya A, Tore F. Mast cell activation ameliorates pentylenetetrazole-induced seizures in rats: The potential role for serotonin. Eur J Neurosci 2021; 55:2912-2924. [PMID: 33565644 DOI: 10.1111/ejn.15145] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 02/03/2021] [Accepted: 02/05/2021] [Indexed: 12/13/2022]
Abstract
Neuroinflammation plays a key role in the pathogenesis of epilepsy, but the underlying mechanisms are not well understood. Mast cells are multifunctional immune cells that are also activated by stress. The effects of activated mast cells on epileptogenesis are not yet known. This study investigated the effects and mechanisms of compound 48/80-stimulated mast cell activation on pentylenetetrazole-induced epileptic seizures in rats. Male Wistar rats were separated into seven groups (n = 12). Group-1(NS+PTZ) received intraperitoneal saline solution, while groups 2(C-48/80+PTZ-1), 3(C-48/80+PTZ-2), and 4(C-48/80+PTZ-3) received compound-48/80 at doses of 0.5, 1, and 2 mg/kg, respectively, 30 min before 45 mg/kg pentylenetetrazole administration. Similarly, Group-5(Cr+C-48/80+PTZ) received 10 mg/kg cromolyn plus 2 mg/kg compound-48/80 before pentylenetetrazole, and Group-6(MC Dep+C-48/80+PTZ) was exposed to a mast cell-depletion process, and then received 2 mg/kg compound-48/80. Group-7(5-HT+PTZ) received 10 mg/kg serotonin. Seizure stages were evaluated using Racine's scale. Compound-48/80 at 2 mg/kg induced anticonvulsive effects against pentylenetetrazole-induced seizures by extending onset-times of both myoclonic-jerk and generalized tonic-clonic seizures (p = 0.0001), and by shortening the duration of generalized tonic-clonic seizure (p = 0.008). These effects were reversed by cromolyn (p = 0.0001). These effects were not observed in mast cell-depleted rats. Similarly to compound 48/80, serotonin also exhibited anticonvulsive effects against seizures (p < 0.05). Compound 48/80 acts as an anticonvulsant by activating mast cells in a dose-dependent manner. The anticonvulsive effects of mast cell activation may be mediated by serotonin. Mast cell activation may therefore provide protective activity against seizures under appropriate circumstances.
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Affiliation(s)
- Erkan Kilinc
- Department of Physiology, Bolu Abant Izzet Baysal University, Bolu, Turkey
| | | | - Ayhan Cetinkaya
- Department of Physiology, Bolu Abant Izzet Baysal University, Bolu, Turkey
| | - Fatma Tore
- Department of Physiology, Istanbul Health and Technology University, Istanbul, Turkey
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Antioxidant and Anti-Inflammatory Effects of Anacardium occidentale L. and Anacardium microcarpum D. Extracts on the Liver of IL-10 Knockout Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:3054521. [PMID: 33376496 PMCID: PMC7744185 DOI: 10.1155/2020/3054521] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 11/19/2020] [Accepted: 11/24/2020] [Indexed: 12/25/2022]
Abstract
Background The Anacardium occidentale L. (cashew) and Anacardium microcarpum D. (cajuí) are plants commonly found in Brazil. They present phytochemical compounds with antioxidant and anti-inflammatory action. Therefore, the objective of this study was to analyze the antioxidant and anti-inflammatory activities of ethanolic extracts from leaves of A. occidentale and A. microcarpum and its effect on the hepatic tissue in experimental knockout models after they received Paracetamol®. Methods Ethanol extracts from A. occidentale and A. microcarpum leaves were prepared. Total phenolics were determined by Folin–Ciocalteau reagent, and flavonoids are based on the complexation reaction with the aluminum metal, forming a colored complex. Fingerprint HPLC was performed to detect phenolic compounds. Knockout IL-10 mice randomly divided into six groups were used and received the following treatments: G1, only water; G2, A. occidentale extract; G3, A. microcarpum extract; G4, Paracetamol®; G5, Paracetamol® + A. occidentale extract (400 mg/kg); G6, Paracetamol® + A. microcarpum extract (400 mg/kg). Biochemical parameters of the blood and differential count of leukocytes were done. Oxidative markers and histopathological analyses were performed on their liver tissue. Results Phenolic compounds and total flavonoids were detected in both two extracts analyzed. The HPLC fingerprint detected phenolic acid, gallic acid, and catechin flavonoid in the two extracts. Histopathological analyses of the hepatic tissue permitted evaluation of nuclear increase, sinusoid congestion, and inflammatory infiltrate. A. microcarpum presented more antioxidant activity increasing antioxidant enzyme levels and reducing TBARS and carbonyl protein when compared to the other treatments after exposure to Paracetamol®. Histopathological analyses showed a decrease in the inflammatory infiltrate after treatment with extracts. Conclusion Our findings indicate that both extracts, especially A. microcarpum, can reduce hepatic damage in knockout mice exposed to paracetamol, indicating the curative power of these extracts reducing lipid peroxidation and in the morphofunctional damage to the liver parenchyma.
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Casao TDRL, Pinheiro CG, Sarandy MM, Zanatta AC, Vilegas W, Novaes RD, Gonçalves RV, Viana Leite JP. Croton urucurana Baillon stem bark ointment accelerates the closure of cutaneous wounds in knockout IL-10 mice. JOURNAL OF ETHNOPHARMACOLOGY 2020; 261:113042. [PMID: 32531412 DOI: 10.1016/j.jep.2020.113042] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 03/25/2020] [Accepted: 05/28/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Croton urucurana Baill. (Euphorbiaceae) is a plant used in Brazilian popular medicine for the treatment of wound healing, inflammatory diseases, gastritis, infections, and hemorrhoids. AIM The present study aimed to evaluate the in vivo wound healing activity of an ointment based on ethanolic extract of C. urucurana stem bark, at concentrations of 5% and 10%, and to relate it with compounds that could be associated with this activity. MATERIALS AND METHODS Analyses by FIA-ESI-IT-MSn were carried out to investigate the chemical composition of C. urucurana. Knockout IL-10 (n = 60) mice and wild type C57 (n = 12) mice were separated into 6 groups to evaluate the wound healing activity. Knockout IL-10 mice: SAL (0.9% saline); BAS (ointment base); SS (1% silver sulfadiazine); CR1 (ointment with extract of C. urucurana 5%); CR2 (ointment with extract of C. urucurana 10%); and wild mice C57: SALC57 (Saline 0.9%). A circular wound with 10 mm in diameter was generated on the dorsal of the animals. Tissue specimen of the wounds were removed on days 7 and 14 of the treatment for histopathological, oxidative status and analyses of pro-and anti-inflammatory cytokines in scar tissue. RESULTS In the phytochemical profile, twelve proanthocyanidins were identified (in the form of monomers, dimers, trimers, and tetramers), based on (epi)catechin and (epi)gallocatechin. Furthermore, two quercetin derivatives and two alkaloids were detected. The groups treated with CR1 and CR2 ointments presented higher rate of wound closure, increased total number of cells, mast cells, blood vessels and higher deposition of type III and I collagen. In addition, they showed increased amount of pro-inflammatory cytokines (IL- 2 and IFN-γ), and anti-inflmatory cytokines (IL-4), on the 7th day of treatment. CONCLUSION The results presented support the popular use of preparations based on the bark of C. urucurana as a healing compound.
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Affiliation(s)
- Thalia Del Rosario Loyo Casao
- Department of Biochemistry and Molecular Biology, Viçosa Federal University, 35570-900, Viçosa, Minas Gerais, Brazil.
| | - Camila Graça Pinheiro
- Department of Biochemistry and Molecular Biology, Viçosa Federal University, 35570-900, Viçosa, Minas Gerais, Brazil.
| | - Mariáurea Matias Sarandy
- Department of Animal Biology, Viçosa Federal University, 35570-900, Viçosa, Minas Gerais, Brazil.
| | - Ana Caroline Zanatta
- Institute of Chemistry, São Paulo State University, Araraquara, 14800-900, São Paulo, Brazil.
| | - Wagner Vilegas
- Institute of Biosciences, São Paulo State University, 05508-900, São Vicente, São Paulo, Brazil.
| | - Rômulo Dias Novaes
- Department of Structural Biology, Federal University of Alfenas, 37130-001, Alfenas, Minas Gerais, Brazil.
| | | | - João Paulo Viana Leite
- Department of Biochemistry and Molecular Biology, Viçosa Federal University, 35570-900, Viçosa, Minas Gerais, Brazil.
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Tu L, Gharibani P, Yin J, Chen JDZ. Sacral nerve stimulation ameliorates colonic barrier functions in a rodent model of colitis. Neurogastroenterol Motil 2020; 32:e13916. [PMID: 32537873 DOI: 10.1111/nmo.13916] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 03/30/2020] [Accepted: 05/19/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND The mucosal barrier damage is recognized as one of the key factors in the pathogenesis of colitis. While sacral nerve stimulation (SNS) was reported to have therapeutic potential for colitis, its mechanisms of actions on colonic permeability remained largely unknown. METHODS In this study, colitis was induced by intrarectal administration of TNBS in rats. Five days later, they were treated with SNS or sham-SNS for 10 days. The effects of SNS on colonic permeability were assessed by measuring the expression of tight-junction proteins involved in regulating permeability and the FITC-dextran test. The mechanism of actions of SNS was investigated by studying the function of the enteric nervous system (ENS) cells and analyzing the autonomic nervous system. KEY RESULTS SNS decreased the disease activity index, microscopic and macroscopic scores, myeloperoxidase activity, and pro-inflammatory cytokines (TNF-α, IL-6). SNS increased the expression of Zonula Occludens-1, Occludin, Claudin-1, and Junctional adhesion molecule-A in the colon tissue. The FITC-dextran test showed that the colonic permeability was lower with SCS than sham-SNS. SNS increased ChAT, pancreatic polypeptide, and GDNF and reduced norepinephrine NGF, sub-P, and mast cell overactivation in the colon tissue. Concurrently, SNS increased acetylcholine in colon tissues and elevated vagal efferent activity. CONCLUSIONS & INFERENCES SNS ameliorates colonic inflammation and enhances colonic barrier function with the proposed mechanisms involving the increase in parasympathetic activity and modulation of the activity of the ENS and immune system, including mast cells.
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Affiliation(s)
- Lei Tu
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Payam Gharibani
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jieyun Yin
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jiande D Z Chen
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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S-layer protein modulates the stimulatory effects of Lactobacillus acidophilus CICC 6074 by triggering PKC signaling cascade in RAW 264.7 cells. J Funct Foods 2020. [DOI: 10.1016/j.jff.2020.103841] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
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Li M, Zhao J, Cao M, Liu R, Chen G, Li S, Xie Y, Xie J, Cheng Y, Huang L, Su M, Xu Y, Zheng M, Zou K, Geng L, Xu W, Gong S. Mast cells-derived MiR-223 destroys intestinal barrier function by inhibition of CLDN8 expression in intestinal epithelial cells. Biol Res 2020; 53:12. [PMID: 32209121 PMCID: PMC7092522 DOI: 10.1186/s40659-020-00279-2] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 03/09/2020] [Indexed: 12/19/2022] Open
Abstract
Background Mast cells (MCs) have been found to play a critical role during development of inflammatory bowel disease (IBD) that characterized by dysregulation of inflammation and impaired intestinal barrier function. However, the function of MCs in IBD remains to be fully elucidated. Results In our study, we used exosomes isolated from human mast cells-1 (HMCs-1) to culture with NCM460, HT-29 or CaCO2 of intestinal epithelial cells (IECs) to investigate the communication between MCs and IECs. We found that MCs-derived exosomes significantly increased intestinal epithelial permeability and destroyed intestinal barrier function, which is attributed to exosome-mediated functional miRNAs were transferred from HMCs-1 into IECs, leading to inhibit tight junction-related proteins expression, including tight junction proteins 1 (TJP1, ZO-1), Occludin (OCLN), Claudin 8 (CLDN8). Microarray and bioinformatic analysis have further revealed that a panel of miRNAs target different tight junction-related proteins. Interestingly, miR-223 is enriched in mast cell-derived exosome, which inhibit CLDN8 expression in IECs, while treatment with miR-223 inhibitor in HT-29 cells significantly reversed the inhibitory effect of HMCs-1-derived exosomes on CLDN 8 expression. Most importantly, enrichment of MCs accumulation in intestinal mucosa of patients with IBD compared with those healthy control. Conclusions These results indicated that enrichment of exosomal miR-223 from HMCs-1 inhibited CLDN8 expression, leading to destroy intestinal barrier function. These finding provided a novel insight of MCs as a new target for therapeutic treatment of IBD.
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Affiliation(s)
- Musheng Li
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Junhong Zhao
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Meiwan Cao
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Ruitao Liu
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Guanhua Chen
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Songyu Li
- Department of Clinical Laboratory, Qionghai Hospital of Traditional Chinese Medicine, Qionghai, 571400, China
| | - Yuanwen Xie
- Department of Anorectal, Qionghai Hospital of Traditional Chinese Medicine, Qionghai, 571400, China
| | - Jing Xie
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Yang Cheng
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Ling Huang
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Mingmin Su
- Department of Cancer Biology and Therapeutics, School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Wales, CF103AT, UK
| | - Yuxin Xu
- Department of Preventive Medicine, School of School of Public Health, Fujian Medical University, Fuzhou, 350122, China
| | - Mingyue Zheng
- School of Marine Life Sciences, Ocean University of China, Qingdao, Shandong, 266003, China
| | - Kejian Zou
- Department of General Surgery, Hainan General Hospital, Haikou, China
| | - Lanlan Geng
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China. .,Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China.
| | - Wanfu Xu
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China. .,Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China.
| | - Sitang Gong
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China. .,Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China.
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Sen A, Stark H. Role of cytochrome P450 polymorphisms and functions in development of ulcerative colitis. World J Gastroenterol 2019; 25:2846-2862. [PMID: 31249444 PMCID: PMC6589734 DOI: 10.3748/wjg.v25.i23.2846] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 04/26/2019] [Accepted: 05/08/2019] [Indexed: 02/06/2023] Open
Abstract
Cytochromes P450s (CYPs) are terminal enzymes in CYP dependent monooxygenases, which constitute a superfamily of enzymes catalysing the metabolism of both endogenous and exogenous substances. One of their main tasks is to facilitate the excretion of these substances and eliminate their toxicities in most phase 1 reactions. Endogenous substrates of CYPs include steroids, bile acids, eicosanoids, cholesterol, vitamin D and neurotransmitters. About 80% of currently used drugs and environmental chemicals comprise exogenous substrates for CYPs. Genetic polymorphisms of CYPs may affect the enzyme functions and have been reported to be associated with various diseases and adverse drug reactions among different populations. In this review, we discuss the role of some critical CYP isoforms (CYP1A1, CYP2D6, CYP2J2, CYP2R1, CYP3A5, CYP3A7, CYP4F3, CYP24A1, CYP26B1 and CYP27B1) in the pathogenesis or aetiology of ulcerative colitis concerning gene polymorphisms. In addition, their significance in metabolism concerning ulcerative colitis in patients is also discussed showing a clear underestimation in genetic studies performed so far.
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Affiliation(s)
- Alaattin Sen
- Department of Molecular Biology and Genetics, Faculty of Life and Natural Sciences, Abdullah Gul University, Kayseri 38080, Turkey
- Biology Department, Faculty of Arts and Sciences, Pamukkale University, Denizli 20070, Turkey
| | - Holger Stark
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Duesseldorf 40225, Germany
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Zhou L, Hong J, Wan Z, Lu X, Shao Y. Effects of electroacupuncture combined with interleukin‑10 on chronic sinusitis in mice. Mol Med Rep 2019; 20:1952-1958. [PMID: 31257460 DOI: 10.3892/mmr.2019.10375] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 05/10/2019] [Indexed: 11/06/2022] Open
Abstract
Electroacupuncture (EA) has been documented as a form of therapy for chronic sinusitis (CRS). The present study aimed to assess the effects of EA combined with interleukin‑10 (IL‑10) overexpression on CRS in mice, and to investigate the associated mechanisms. A mouse model of CRS was established by the administration of ovalbumin (OVA), and overexpression of IL‑10 was induced using virus‑encoded IL‑10. The experimental groups were as follows: i) Control group; ii) OVA group; iii) OVA + EA group; iv) OVA + empty vector group; v) OVA + vector + EA group; vi) OVA + IL‑10 group; and vii) OVA + IL‑10 + EA group. Pathological changes and nasal mucus were analyzed using hematoxylin and eosin staining. Interferon‑γ (IFN‑γ) and IL‑10 were detected via reverse‑transcription quantitative PCR and western blot analyses. The pseudostratified epithelium of the mucosa of the nasal sinus was impaired following the induction of CRS. Treatment with EA and/or IL‑10 reversed the injury. Combination treatment with EA and IL‑10 induced synergistic effects. No infiltration of inflammatory cells was observed in the submucosa following EA and IL‑10 treatment. Compared with the control group, the expression of IFN‑γ and IL‑10 in the OVA group was reduced. By contrast, EA or the overexpression of IL‑10 inhibited this reduction. Furthermore, the combined application of EA and IL‑10 had a significantly more potent inhibitory effect on the reduction of IFN‑γ expression, but not IL‑10. Collectively, EA combined with IL‑10 induced specific effects on CRS in mice, likely through the upregulation of IFN‑γ and IL‑10. The current study presented mechanistic implications for the application of EA as an alternative treatment for CRS.
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Affiliation(s)
- Lanfei Zhou
- Department of Ear, Nose and Throat, The Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330006, P.R. China
| | - Jing Hong
- Department of Ear, Nose and Throat, The Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330006, P.R. China
| | - Zhichao Wan
- Department of Ear, Nose and Throat, The Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330006, P.R. China
| | - Xiaoxi Lu
- Department of Neurosurgery, The Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330006, P.R. China
| | - Yisen Shao
- Department of Dentistry, The Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330006, P.R. China
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Differential Helicobacter pylori Plasticity in the Gastric Niche of Subjects at Increased Gastric Cancer Risk. Pathogens 2019; 8:pathogens8020065. [PMID: 31109082 PMCID: PMC6630233 DOI: 10.3390/pathogens8020065] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 05/09/2019] [Accepted: 05/15/2019] [Indexed: 02/07/2023] Open
Abstract
Helicobacter pylori (H. pylori) represents an independent risk factor for Gastric Cancer (GC). First Degree Relatives (FDR) of GC subjects and Autoimmune Gastritis (AG) patients are both at increased risk for GC. H. pylori genetic heterogeneity within the gastric niche of FDR and AG individuals has been little explored. To understand whether they exploit an increased H. pylori stability and virulence, 14 AG, 25 FDR, 39 GC and 13 dyspeptic patients (D) were investigated by a cultural PCR-based approach characterizing single colonies-forming-units. We chose three loci within the Cytotoxin-associated gene-A Pathogenicity Island (CagPAI) (cagA,cagE,virB11), vacA, homA and homB as markers of virulence with reported association to GC. Inflammatory/precancerous lesions were staged according to Sydney System. When compared to D, FDR, similarly to GC patients, were associated to higher atrophy (OR = 6.29; 95% CI:1.23-31.96 in FDR; OR = 7.50; 95% CI:1.67-33.72 in GC) and a lower frequency of mixed infections (OR = 0.16; 95% CI:0.03-0.81 in FDR; OR = 0.10; 95% CI:0.02-0.48 in GC). FDR presented also an increased neutrophil infiltration (OR = 7.19; 95% CI:1.16-44.65). Both FDR and GC carried a higher proportion of CagPAI+vacAs1i1mx+homB+ profiles (OR = 2.71; 95% CI: 1.66-4.41 and OR = 3.43; 95% CI: 2.16-5.44, respectively). Conversely, AG patients presented a lower frequency of subtypes carrying a stable CagPAI and vacAs1i1mx. These results underline different H. pylori plasticity in FDR and AG individuals, and thus, a different host-bacterium interaction capacity that should be considered in the context of eradication therapies.
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