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Li L, Jiao Q, Yang Q, Lu H, Zhou X, Zhang Q, Zhang F, Li H, Tian Z, Zeng Z. A bladder-blood immune barrier constituted by suburothelial perivascular macrophages restrains uropathogen dissemination. Immunity 2025; 58:568-584.e6. [PMID: 40015270 DOI: 10.1016/j.immuni.2025.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 09/29/2024] [Accepted: 02/03/2025] [Indexed: 03/01/2025]
Abstract
Urinary tract infections (UTIs) predominantly occur in the bladder and can potentially progress into life-threatening sepsis if uropathogens spread unconstrainedly into the bloodstream. Here, we identified a subset of suburothelial perivascular macrophages (suPVMs) in the bladder that exerted a pivotal barrier function to prevent systemic bacterial dissemination during acute cystitis. During the initial phase of uropathogenic Escherichia coli (UPEC) infection, suPVMs actively captured UPEC invading the laminal propria and maintained the integrity of inflamed vessels. They subsequently underwent METosis to expel macrophage extracellular DNA traps (METs) into the urothelium to sequester bacteria within this avascular compartment. Matrix metallopeptidase-13 was released along with METs to promote neutrophil transuroepithelial migration. Replenished suPVMs from monocytes following a prior infection were functionally competent to confer protection against recurrent UTIs. Our study thus uncovers a bladder-blood immune barrier in restraining uropathogen dissemination, which could have implications for the prevention and treatment of urosepsis.
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Affiliation(s)
- Lu Li
- National Key Laboratory of Immune responses and Immunotherapy, Department of Oncology, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China
| | - Qiancheng Jiao
- National Key Laboratory of Immune responses and Immunotherapy, Department of Oncology, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China; Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Qianqian Yang
- Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Haisen Lu
- Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Xia Zhou
- National Key Laboratory of Immune responses and Immunotherapy, Department of Oncology, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China; Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Qing Zhang
- Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Futing Zhang
- Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Hai Li
- Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Zhigang Tian
- Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Zhutian Zeng
- National Key Laboratory of Immune responses and Immunotherapy, Department of Oncology, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China; Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
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Won JP, Lee HG, Yoon HJ, Seo HG. Biochanin A-mediated anti-ferroptosis is associated with reduction of septic kidney injury. Life Sci 2024; 358:123124. [PMID: 39396639 DOI: 10.1016/j.lfs.2024.123124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 09/30/2024] [Accepted: 10/08/2024] [Indexed: 10/15/2024]
Abstract
AIMS This study aimed to investigate the therapeutic potential of biochanin A in a sepsis associated- acute kidney injury (SA-AKI) mouse model induced by lipopolysaccharide (LPS). MAIN METHODS Male BALB/C mice (n = 7 per group) were injected with biochanin A (40 mg/kg, i.p.) or ferrostatin-1 (5 mg/kg, i.p.) in the presence or absence of LPS (10 mg/kg, i.p.). Survival rates were monitored twice a day for up to 2 weeks. Morphologic and functional changes in kidney tissue were assessed by H&E staining and by analyzing of levels of blood-urea nitrogen (BUN) and creatinine (CR) in serum, respectively. Kidney epithelial cell death was analyzed by TUNEL staining, Prussian blue staining, iron quantification, lipid peroxide quantification, and glutathione quantification. Anti-ferroptosis mechanism of biochanin A was analyzed by RNA sequencing in mouse embryonic fibroblast cells. KEY FINDINGS Biochanin A increased the survival rate of septic mice and inhibited the secretion of high mobility group box 1, an important inflammatory mediator in sepsis. Biochanin A inhibited LPS-induced kidney damage by suppressing dilatation and kidney tubular epithelial cell death. Furthermore, serum levels of BUN and CR were reduced in biochanin A-treated endotoxemic mice. Biochanin A inhibited the accumulation of iron and lipid peroxide and prevented glutathione depletion in the kidney tissue. Also, nine genes associated with the anti-ferroptosis effects of biochanin A were identified by RNA sequencing analysis. SIGNIFICANCE The present study suggests that biochanin A is an effective inhibitor of ferroptosis, representing a potential treatment or prophylactic for sepsis-related disorders such as SA-AKI.
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Affiliation(s)
- Jun Pil Won
- Department of Food Science and Biotechnology of Animal Resources, College of Sang-Huh Life Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Hyuk Gyoon Lee
- Department of Food Science and Biotechnology of Animal Resources, College of Sang-Huh Life Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Han Jun Yoon
- Department of Food Science and Biotechnology of Animal Resources, College of Sang-Huh Life Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Han Geuk Seo
- Department of Food Science and Biotechnology of Animal Resources, College of Sang-Huh Life Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
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Wang Y, Wang X, Niu X, Han K, Ru N, Xiang J, Linghu E. Identification of COL3A1 as a candidate protein involved in the crosstalk between obesity and diarrhea using quantitative proteomics and machine learning. Eur J Pharmacol 2024; 981:176881. [PMID: 39127300 DOI: 10.1016/j.ejphar.2024.176881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 06/05/2024] [Accepted: 08/08/2024] [Indexed: 08/12/2024]
Abstract
BACKGROUND Increasing epidemiologic studies have shown a positive correlation between obesity and chronic diarrhea. Nevertheless, the precise etiology remains uncertain. METHODS We performed a comprehensive proteomics analysis utilizing the data-independent acquisition (DIA) technique on jejunal tissues from patients with obesity and chronic diarrhea (OD, n = 33), obese patients (OB, n = 10), and healthy controls (n = 8). Differentially expressed proteins (DEPs) in OD vs. control and OD vs. OB comparisons were subjected to pathway enrichment and protein-protein interaction (PPI) network analysis. Machine learning algorithms were adopted on overlapping DEPs in both comparisons. The candidate protein was further validated using Western blot, immunohistochemistry (IHC), and in vitro experiments. RESULTS We identified 189 and 228 DEPs in OD vs. control and OD vs. OB comparisons, respectively. DEPs in both comparisons were co-enriched in extracellular matrix (ECM) organization. Downregulated DEPs were associated with tight junction and ECM-receptor interaction in OD vs. control and OD vs. OB comparisons, respectively. Machine learning algorithms selected 3 proteins from 14 overlapping DEPs in both comparisons, among which collagen alpha-1(III) chain (COL3A1) was identified as a core protein in PPI networks. Western blot and IHC verified the expression of COL3A1. Moreover, the tight junction-related proteins decreased after the knockdown of COL3A1 in Caco2 intestinal cells upon PA challenge, consistent with the proteomics results. CONCLUSIONS We generated in-depth profiling of a proteomic dataset from samples of OD patients and provided unique insights into disease pathogenesis. COL3A1 was involved in the crosstalk between obesity and intestinal homeostasis via the ECM-receptor interaction pathway.
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Affiliation(s)
- Yan Wang
- Nankai University School of Medicine, Nankai University, Tianjin, 300071, China; Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Xiangyao Wang
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Xiaotong Niu
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China; Medical School of Chinese PLA, Beijing, 100853, China
| | - Ke Han
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China; Medical School of Chinese PLA, Beijing, 100853, China
| | - Nan Ru
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Jingyuan Xiang
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China; Medical School of Chinese PLA, Beijing, 100853, China
| | - Enqiang Linghu
- Nankai University School of Medicine, Nankai University, Tianjin, 300071, China; Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China.
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Kayama H, Takeda K. Regulation of intestinal epithelial homeostasis by mesenchymal cells. Inflamm Regen 2024; 44:42. [PMID: 39327633 PMCID: PMC11426228 DOI: 10.1186/s41232-024-00355-0] [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: 03/18/2024] [Accepted: 09/17/2024] [Indexed: 09/28/2024] Open
Abstract
The gastrointestinal tract harbors diverse microorganisms in the lumen. Epithelial cells segregate the luminal microorganisms from immune cells in the lamina propria by constructing chemical and physical barriers through the production of various factors to prevent excessive immune responses against microbes. Therefore, perturbations of epithelial integrity are linked to the development of gastrointestinal disorders. Several mesenchymal stromal cell populations, including fibroblasts, myofibroblasts, pericytes, and myocytes, contribute to the establishment and maintenance of epithelial homeostasis in the gut through regulation of the self-renewal, proliferation, and differentiation of intestinal stem cells. Recent studies have revealed alterations in the composition of intestinal mesenchymal stromal cells in patients with inflammatory bowel disease and colorectal cancer. A better understanding of the interplay between mesenchymal stromal cells and epithelial cells associated with intestinal health and diseases will facilitate identification of novel biomarkers and therapeutic targets for gastrointestinal disorders. This review summarizes the key findings obtained to date on the mechanisms by which functionally distinct mesenchymal stromal cells regulate epithelial integrity in intestinal health and diseases at different developmental stages.
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Affiliation(s)
- Hisako Kayama
- Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
- WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
- Institute for Advanced Co-Creation Studies, Osaka University, Suita, Osaka, 565-0871, Japan.
| | - Kiyoshi Takeda
- Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka, Japan
- Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka, Japan
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Chatterjee S, Preval LV, Sin Z, Tran N, Ritter K, Su XB, Centlivre JP, Ragsac SJ, Van R, Park S, Han M, Liu Q, Hedlund BP, Saiardi A, Jessen H, Guha P. Inositol Hexaphosphate (InsP6) Activates the HDAC1/3 Epigenetic Axis to Maintain Intestinal Barrier Function. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.15.613154. [PMID: 39345537 PMCID: PMC11429887 DOI: 10.1101/2024.09.15.613154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
HDACs (histone deacetylase) play a crucial role in regulating gene expression, and the inhibition of these enzymes is gaining attention as a promising therapeutic approach for cancer treatment. Despite their significant physiological and clinical importance, the mechanisms of HDAC activation remain poorly understood. This study reveals that inositol polyphosphate multikinase (IPMK) is essential for activating HDAC1 and HDAC3 in cell lines and mice. IPMK deletion or inactivation of its kinase activity selectively impairs HDAC1/3's deacetylase activity, significantly influencing gene expression. Disruption of the IPMK-HDAC1/3 epigenetic axis results in transcriptional upregulation of matrix metalloproteinase (MMP) genes, exacerbating cell and intestinal permeability. Remarkably, treatment of IPMK KO cells with cell-permeable inositol hexaphosphate (InsP6) rescues these defects. This study elucidates the role of IPMK's kinase activity in HDAC1/3 activation and its implications for intestinal barrier function.
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Vilardi A, Przyborski S, Mobbs C, Rufini A, Tufarelli C. Current understanding of the interplay between extracellular matrix remodelling and gut permeability in health and disease. Cell Death Discov 2024; 10:258. [PMID: 38802341 PMCID: PMC11130177 DOI: 10.1038/s41420-024-02015-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 03/25/2024] [Accepted: 05/07/2024] [Indexed: 05/29/2024] Open
Abstract
The intestinal wall represents an interactive network regulated by the intestinal epithelium, extracellular matrix (ECM) and mesenchymal compartment. Under healthy physiological conditions, the epithelium undergoes constant renewal and forms an integral and selective barrier. Following damage, the healthy epithelium is restored via a series of signalling pathways that result in remodelling of the scaffolding tissue through finely-regulated proteolysis of the ECM by proteases such as matrix metalloproteinases (MMPs). However, chronic inflammation of the gastrointestinal tract, as occurs in Inflammatory Bowel Disease (IBD), is associated with prolonged disruption of the epithelial barrier and persistent damage to the intestinal mucosa. Increased barrier permeability exhibits distinctive signatures of inflammatory, immunological and ECM components, accompanied by increased ECM proteolytic activity. This narrative review aims to bring together the current knowledge of the interplay between gut barrier, immune and ECM features in health and disease, discussing the role of barrier permeability as a discriminant between homoeostasis and IBD.
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Affiliation(s)
- Aurora Vilardi
- Cancer Research Centre, University of Leicester, Leicester, LE2 7LX, United Kingdom
| | - Stefan Przyborski
- Department of Biosciences, Durham University, Durham, DH1 3LE, United Kingdom
| | - Claire Mobbs
- Department of Biosciences, Durham University, Durham, DH1 3LE, United Kingdom
| | - Alessandro Rufini
- Cancer Research Centre, University of Leicester, Leicester, LE2 7LX, United Kingdom.
- Department of Biosciences, University of Milan, Milan, 20133, Italy.
| | - Cristina Tufarelli
- Cancer Research Centre, University of Leicester, Leicester, LE2 7LX, United Kingdom.
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Ando F, Kashiwada T, Kuroda S, Fujii T, Takano R, Miyabe Y, Kunugi S, Sakatani T, Miyanaga A, Asatsuma-Okumura T, Hashiguchi M, Kanazawa Y, Ohashi R, Yoshida H, Seike M, Gemma A, Iwai Y. Combination of plasma MMPs and PD-1-binding soluble PD-L1 predicts recurrence in gastric cancer and the efficacy of immune checkpoint inhibitors in non-small cell lung cancer. Front Pharmacol 2024; 15:1384731. [PMID: 38774209 PMCID: PMC11106465 DOI: 10.3389/fphar.2024.1384731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Accepted: 04/22/2024] [Indexed: 05/24/2024] Open
Abstract
Background The tumor microenvironment (TME) impacts the therapeutic efficacy of immune checkpoint inhibitors (ICIs). No liquid biomarkers are available to evaluate TME heterogeneity. Here, we investigated the clinical significance of PD-1-binding soluble PD-L1 (bsPD-L1) in gastric cancer (GC) patients and non-small cell lung cancer (NSCLC) patients treated with PD-1/PD-L1 blockade. Methods We examined bsPD-L1, matrix metalloproteinases (MMPs), and IFN-γ levels in plasma samples from GC patients (n = 117) prior to surgery and NSCLC patients (n = 72) prior to and 2 months after ICI treatment. We also examined extracellular matrix (ECM) integrity, PD-L1 expression, and T cell infiltration in tumor tissues from 25 GC patients by Elastica Masson-Goldner staining and immunohistochemical staining for PD-L1 and CD3, respectively. Results bsPD-L1 was detected in 17/117 GC patients and 16/72 NSCLC patients. bsPD-L1 showed strong or moderate correlations with plasma MMP13 or MMP3 levels, respectively, in both GC and NSCLC patients. bsPD-L1 expression in GC was associated with IFN-γ levels and intra-tumoral T cell infiltration, whereas MMP13 levels were associated with loss of ECM integrity, allowing tumor cells to access blood vessels. Plasma MMP3 and MMP13 levels were altered during ICI treatment. Combined bsPD-L1 and MMP status had higher predictive accuracy to identify two patient groups with favorable and poor prognosis than tumor PD-L1 expression: bsPD-L1+MMP13high in GC and bsPD-L1+(MMP3 and MMP13)increased in NSCLC were associated with poor prognosis, whereas bsPD-L1+MMP13low in GC and bsPD-L1+(MMP3 or MMP13)decreased in NSCLC were associated with favorable prognosis. Conclusion Plasma bsPD-L1 and MMP13 levels indicate T cell response and loss of ECM integrity, respectively, in the TME. The combination of bsPD-L1 and MMPs may represent a non-invasive tool to predict recurrence in GC and the efficacy of ICIs in NSCLC.
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Affiliation(s)
- Fumihiko Ando
- Department of Cell Biology, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo, Japan
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Takeru Kashiwada
- Department of Pulmonary Medicine and Oncology, Nippon Medical School, Tokyo, Japan
| | - Shoko Kuroda
- Department of Cell Biology, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo, Japan
| | - Takenori Fujii
- Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo, Japan
| | - Ryotaro Takano
- Department of Cell Biology, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo, Japan
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Yoshishige Miyabe
- Department of Cell Biology, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo, Japan
- Department of Immunology and Parasitology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
| | - Shinobu Kunugi
- Department of Analytic Human Pathology, Nippon Medical School, Tokyo, Japan
| | - Takashi Sakatani
- Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo, Japan
| | - Akihiko Miyanaga
- Department of Pulmonary Medicine and Oncology, Nippon Medical School, Tokyo, Japan
| | - Tomoko Asatsuma-Okumura
- Department of Cell Biology, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo, Japan
| | - Masaaki Hashiguchi
- Department of Cell Biology, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo, Japan
| | - Yoshikazu Kanazawa
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Ryuji Ohashi
- Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo, Japan
| | - Hiroshi Yoshida
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Masahiro Seike
- Department of Pulmonary Medicine and Oncology, Nippon Medical School, Tokyo, Japan
| | - Akihiko Gemma
- Department of Pulmonary Medicine and Oncology, Nippon Medical School, Tokyo, Japan
| | - Yoshiko Iwai
- Department of Cell Biology, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo, Japan
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Sampaio Moura N, Schledwitz A, Alizadeh M, Patil SA, Raufman JP. Matrix metalloproteinases as biomarkers and therapeutic targets in colitis-associated cancer. Front Oncol 2024; 13:1325095. [PMID: 38288108 PMCID: PMC10824561 DOI: 10.3389/fonc.2023.1325095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 12/26/2023] [Indexed: 01/31/2024] Open
Abstract
Colorectal cancer (CRC) remains a major cause of morbidity and mortality. Therapeutic approaches for advanced CRC are limited and rarely provide long-term benefit. Enzymes comprising the 24-member matrix metalloproteinase (MMP) family of zinc- and calcium-dependent endopeptidases are key players in extracellular matrix degradation, a requirement for colon tumor expansion, invasion, and metastasis; hence, MMPs are an important research focus. Compared to sporadic CRC, less is known regarding the molecular mechanisms and the role of MMPs in the development and progression of colitis-associated cancer (CAC) - CRC on a background of chronic inflammatory bowel disease (IBD) - primarily ulcerative colitis and Crohn's disease. Hence, the potential of MMPs as biomarkers and therapeutic targets for CAC is uncertain. Our goal was to review data regarding the role of MMPs in the development and progression of CAC. We sought to identify promising prognostic and therapeutic opportunities and novel lines of investigation. A key observation is that since MMPs may be more active in early phases of CAC, using MMPs as biomarkers of advancing neoplasia and as potential therapeutic targets for adjuvant therapy in those with advanced stage primary CAC rather than overt metastases may yield more favorable outcomes.
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Affiliation(s)
- Natalia Sampaio Moura
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Alyssa Schledwitz
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Madeline Alizadeh
- The Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Seema A. Patil
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Jean-Pierre Raufman
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, United States
- Medical Service, Veterans Affairs Maryland Healthcare System, Baltimore, MD, United States
- Marlene and Stewart Greenebaum Cancer Center, University of Maryland Medical Center, Baltimore, MD, United States
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, United States
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Chrzanowski G, Pasternak G, Aebisher D, Dynarowicz K, Myśliwiec A, Bartusik-Aebisher D, Sosna B, Cieślar G, Kawczyk-Krupka A, Filip R. An Analysis of the Content of Metalloproteinases in the Intestinal Wall of Patients with Crohn's Disease. Life (Basel) 2023; 13:2013. [PMID: 37895400 PMCID: PMC10608236 DOI: 10.3390/life13102013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 09/27/2023] [Accepted: 10/03/2023] [Indexed: 10/29/2023] Open
Abstract
One of the inflammatory bowel diseases is Crohn's disease. Although this term has been used in the medical community since 1932, a significant increase in the number of publications occurs at the end of the 20th century and the beginning of the 21st century. Crohn's disease is a disease that cannot be fully cured. In many cases, it is chronic, i.e., recurrent. All preventive and therapeutic measures taken by doctors are aimed at inhibiting the development of the disease and minimizing the occurrence of any potential "side effects" resulting from the developing disease. One of the diagnostic methods is the qualitative and quantitative determination of metalloproteinases in inflammatory tissues and in the blood. The aim of the study was the quantitative and qualitative determination of metalloproteinases in inflammatory bowel tissues in patients diagnosed with Crohn's disease. The in vitro study was performed on surgical tissues from patients diagnosed with Crohn's disease. The results show that in inflammatory tissues the concentration of metalloproteinases -3, -7, -8, -9 was higher compared to tissues taken from the resection margin without signs of inflammation, defined as healthy. The experiment confirmed that the biochemical test, which is the determination of metalloproteinases in tissues, is a useful diagnostic tool to differentiate inflammatory from non-inflammatory tissues.
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Affiliation(s)
- Grzegorz Chrzanowski
- Department of Biology, College of Natural Sciences, University of Rzeszów, 35-310 Rzeszów, Poland;
| | - Grzegorz Pasternak
- Department of General Surgery, Provincial Clinical Hospital No. 2 in Rzeszów, 35-301 Rzeszów, Poland;
| | - David Aebisher
- Department of Photomedicine and Physical Chemistry, Medical College of University of Rzeszów, University of Rzeszów, 35-310 Rzeszów, Poland
| | - Klaudia Dynarowicz
- Center for Innovative Research in Medical and Natural Sciences, Medical College of the University of Rzeszów, 35-310 Rzeszów, Poland; (K.D.); (A.M.)
| | - Angelika Myśliwiec
- Center for Innovative Research in Medical and Natural Sciences, Medical College of the University of Rzeszów, 35-310 Rzeszów, Poland; (K.D.); (A.M.)
| | - Dorota Bartusik-Aebisher
- Department of Biochemistry and General Chemistry, Medical College of University of Rzeszów, University of Rzeszów, 35-310 Rzeszów, Poland;
| | - Barbara Sosna
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (G.C.); (A.K.-K.)
| | - Grzegorz Cieślar
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (G.C.); (A.K.-K.)
| | - Aleksandra Kawczyk-Krupka
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (G.C.); (A.K.-K.)
| | - Rafał Filip
- Department of Internal Medicine, Medical College of University of Rzeszów, University of Rzeszów, 35-310 Rzeszów, Poland;
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Wang Y, Wang Y, Ma J, Li Y, Cao L, Zhu T, Hu H, Liu H. YuPingFengSan ameliorates LPS-induced acute lung injury and gut barrier dysfunction in mice. JOURNAL OF ETHNOPHARMACOLOGY 2023; 312:116452. [PMID: 37019161 DOI: 10.1016/j.jep.2023.116452] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 03/24/2023] [Accepted: 03/31/2023] [Indexed: 05/08/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Yupingfengsan (YPFS) is a traditional Chinese medicine decoction. YPFS comprises Astragalus mongholicus Bunge (Huangqi), Atractylodes rubra Dekker (Baizhu), and Saposhnikovia divaricata (Turcz.ex Ledeb.) Schischk (Fangfeng). YPFS is commonly used to treat chronic obstructive pulmonary disease, asthma, respiratory infections, and pneumonia, but the mechanism of action remains unclear. AIM OF THE STUDY Acute lung injury (ALI) and its severe form of acute respiratory distress syndrome (ARDS) cause morbidity and mortality in critical patients. YPFS is a commonly used herbal soup to treat respiratory and immune system diseases. Nevertheless, the effect of YPFS on ALI remains unclear. This study aimed to investigate the effect of YPFS on lipopolysaccharide (LPS)-induced ALI in mice and elucidate its potential molecular mechanisms. MATERIALS AND METHODS The major components of YPFS were detected by High-performance liquid chromatography (HPLC). C57BL/6J mice were given YPFS for seven days and then treated with LPS. IL-1β, IL-6, TNF-α, IL-8, iNOS, NLRP3, PPARγ, HO-1, ZO-1, Occludin, Claudin-1, AQP3, AQP4, AQP5, ENaCα, ENaCβ, EnaCγ mRNA in lung and ZO-1, Occludin, Claudin-1, AQP3, AQP4, AQP5, ENaCα, ENaCβ, and EnaCγ mRNA in colon tissues were measured by Real-Time Quantitative PCR (RT-qPCR). The expressions of TLR4, MyD88, NOD-like receptor thermal protein domain associated protein 3 (NLRP3), ASC, MAPK signaling pathway, Nrf2, and HO-1 in the lung were detected by Western blot. Plasma inflammatory factors Interleukin (IL)-1β, IL-6, and Tumor Necrosis Factor-α (TNF-α) were determined by Enzyme-linked Immunosorbent Assay (ELISA). Lung tissues were processed for H & E staining, and colon tissues for HE, WGA-FITC, and Alcian Blue staining. RESULTS The results showed that YPFS administration alleviated lung injury and suppressed the production of inflammatory factors, including IL-1β, IL-6, and TNF-α. Additionally, YPFS reduced pulmonary edema by promoting the expressions of aquaporin and sodium channel-related genes (AQP3, AQP4, AQP5, ENaCα, ENaCβ, and EnaCγ). Further, YPFS intervention exhibited a therapeutic effect on ALI by inhibiting the activation of the NLRP3 inflammasome and MAPK signaling pathways. Finally, YPFS improved gut barrier integrity and suppressed intestinal inflammation in LPS-challenged mice. CONCLUSIONS YPFS protected mice against LPS-induced ALI by attenuating lung and intestinal tissue damage. This study sheds light on the potential application of YPFS to treat ALI/ARDS.
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Affiliation(s)
- Yao Wang
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan, 430065, PR China; College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan, 430065, PR China
| | - Yanchun Wang
- Clinical College of Traditional Chinese Medicine, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan, 430065, PR China
| | - Jun Ma
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan, 430065, PR China
| | - Yanan Li
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan, 430065, PR China
| | - Lu Cao
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan, 430065, PR China
| | - Tianxiang Zhu
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan, 430065, PR China
| | - Haiming Hu
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan, 430065, PR China.
| | - Hongtao Liu
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan, 430065, PR China.
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11
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Mackay S, Frazer LC, Bailey GK, Miller CM, Gong Q, Dewitt ON, Singh DK, Good M. Identification of serum biomarkers for necrotizing enterocolitis using aptamer-based proteomics. Front Pediatr 2023; 11:1184940. [PMID: 37325361 PMCID: PMC10264655 DOI: 10.3389/fped.2023.1184940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Accepted: 05/10/2023] [Indexed: 06/17/2023] Open
Abstract
Introduction Necrotizing enterocolitis (NEC) is a potentially fatal intestinal disease primarily affecting preterm infants. Early diagnosis of neonates with NEC is crucial to improving outcomes; however, traditional diagnostic tools remain inadequate. Biomarkers represent an opportunity to improve the speed and accuracy of diagnosis, but they are not routinely used in clinical practice. Methods In this study, we utilized an aptamer-based proteomic discovery assay to identify new serum biomarkers of NEC. We compared levels of serum proteins in neonates with and without NEC and identified ten differentially expressed serum proteins between these groups. Results We detected two proteins, C-C motif chemokine ligand 16 (CCL16) and immunoglobulin heavy constant alpha 1 and 2 heterodimer (IGHA1 IGHA2), that were significantly increased during NEC and eight that were significantly decreased. Generation of receiver operating characteristic (ROC) curves revealed that alpha-fetoprotein (AUC = 0.926), glucagon (AUC = 0.860), and IGHA1 IGHA2 (AUC = 0.826) were the proteins that best differentiated patients with and without NEC. Discussion These findings indicate that further investigation into these serum proteins as a biomarker for NEC is warranted. In the future, laboratory tests incorporating these differentially expressed proteins may improve the ability of clinicians to diagnose infants with NEC rapidly and accurately.
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Affiliation(s)
- Stephen Mackay
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, The University of North Carolina at Chapel Hill, NC, United States
| | - Lauren C. Frazer
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, The University of North Carolina at Chapel Hill, NC, United States
| | - Grace K. Bailey
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, The University of North Carolina at Chapel Hill, NC, United States
| | - Claire M. Miller
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, The University of North Carolina at Chapel Hill, NC, United States
| | - Qingqing Gong
- Division of Newborn Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
| | - Olivia N. Dewitt
- Division of Newborn Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
| | - Dhirendra K. Singh
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, The University of North Carolina at Chapel Hill, NC, United States
| | - Misty Good
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, The University of North Carolina at Chapel Hill, NC, United States
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12
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Rehman S, Gora AH, Abdelhafiz Y, Dias J, Pierre R, Meynen K, Fernandes JMO, Sørensen M, Brugman S, Kiron V. Potential of algae-derived alginate oligosaccharides and β-glucan to counter inflammation in adult zebrafish intestine. Front Immunol 2023; 14:1183701. [PMID: 37275890 PMCID: PMC10235609 DOI: 10.3389/fimmu.2023.1183701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 04/18/2023] [Indexed: 06/07/2023] Open
Abstract
Alginate oligosaccharides (AOS) are natural bioactive compounds with anti-inflammatory properties. We performed a feeding trial employing a zebrafish (Danio rerio) model of soybean-induced intestinal inflammation. Five groups of fish were fed different diets: a control (CT) diet, a soybean meal (SBM) diet, a soybean meal+β-glucan (BG) diet and 2 soybean meal+AOS diets (alginate products differing in the content of low molecular weight fractions - AL, with 31% < 3kDa and AH, with 3% < 3kDa). We analyzed the intestinal transcriptomic and plasma metabolomic profiles of the study groups. In addition, we assessed the expression of inflammatory marker genes and histological alterations in the intestine. Dietary algal β-(1, 3)-glucan and AOS were able to bring the expression of certain inflammatory genes altered by dietary SBM to a level similar to that in the control group. Intestinal transcriptomic analysis indicated that dietary SBM changed the expression of genes linked to inflammation, endoplasmic reticulum, reproduction and cell motility. The AL diet suppressed the expression of genes related to complement activation, inflammatory and humoral response, which can likely have an inflammation alleviation effect. On the other hand, the AH diet reduced the expression of genes, causing an enrichment of negative regulation of immune system process. The BG diet suppressed several immune genes linked to the endopeptidase activity and proteolysis. The plasma metabolomic profile further revealed that dietary SBM can alter inflammation-linked metabolites such as itaconic acid, taurochenodeoxycholic acid and enriched the arginine biosynthesis pathway. The diet AL helped in elevating one of the short chain fatty acids, namely 2-hydroxybutyric acid while the BG diet increased the abundance of a vitamin, pantothenic acid. Histological evaluation revealed the advantage of the AL diet: it increased the goblet cell number and length of villi of the intestinal mucosa. Overall, our results indicate that dietary AOS with an appropriate amount of < 3kDa can stall the inflammatory responses in zebrafish.
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Affiliation(s)
- Saima Rehman
- Faculty of Biosciences and Aquaculture, Nord University, Bodø, Norway
| | - Adnan H. Gora
- Faculty of Biosciences and Aquaculture, Nord University, Bodø, Norway
| | - Yousri Abdelhafiz
- Faculty of Biosciences and Aquaculture, Nord University, Bodø, Norway
| | | | - Ronan Pierre
- CEVA (Centre d’Etude et de Valorisation des Algues), Pleubian, France
| | - Koen Meynen
- Kemin Aquascience, Division of Kemin Europa N.V., Herentals, Belgium
| | | | - Mette Sørensen
- Faculty of Biosciences and Aquaculture, Nord University, Bodø, Norway
| | - Sylvia Brugman
- Animal Sciences Group, Host Microbe Interactomics, Wageningen University and Research, Wageningen, Netherlands
| | - Viswanath Kiron
- Faculty of Biosciences and Aquaculture, Nord University, Bodø, Norway
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13
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Jayawardena DP, Masciantonio MG, Wang L, Mehta S, DeGurse N, Pape C, Gill SE. Imbalance of Pulmonary Microvascular Endothelial Cell-Expression of Metalloproteinases and Their Endogenous Inhibitors Promotes Septic Barrier Dysfunction. Int J Mol Sci 2023; 24:ijms24097875. [PMID: 37175585 PMCID: PMC10178398 DOI: 10.3390/ijms24097875] [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: 02/23/2023] [Revised: 04/12/2023] [Accepted: 04/14/2023] [Indexed: 05/15/2023] Open
Abstract
Sepsis is a life-threatening disease characterized by excessive inflammation leading to organ dysfunction. During sepsis, pulmonary microvascular endothelial cells (PMVEC) lose barrier function associated with inter-PMVEC junction disruption. Matrix metalloproteinases (MMP) and a disintegrin and metalloproteinases (ADAM), which are regulated by tissue inhibitors of metalloproteinases (TIMPs), can cleave cell-cell junctional proteins, suggesting a role in PMVEC barrier dysfunction. We hypothesize that septic PMVEC barrier dysfunction is due to a disruption in the balance between PMVEC-specific metalloproteinases and TIMPs leading to increased metalloproteinase activity. The effects of sepsis on TIMPs and metalloproteinases were assessed ex vivo in PMVEC from healthy (sham) and septic (cecal ligation and perforation) mice, as well as in vitro in isolated PMVEC stimulated with cytomix, lipopolysaccharide (LPS), and cytomix + LPS vs. PBS. PMVEC had high basal Timp expression and lower metalloproteinase expression, and septic stimulation shifted expression in favour of metalloproteinases. Septic stimulation increased MMP13 and ADAM17 activity associated with a loss of inter-PMVEC junctional proteins and barrier dysfunction, which was rescued by treatment with metalloproteinase inhibitors. Collectively, our studies support a role for metalloproteinase-TIMP imbalance in septic PMVEC barrier dysfunction, and suggest that inhibition of specific metalloproteinases may be a therapeutic avenue for septic patients.
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Affiliation(s)
- Devika P Jayawardena
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON N6A 5W9, Canada
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
| | - Marcello G Masciantonio
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON N6A 5W9, Canada
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
| | - Lefeng Wang
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON N6A 5W9, Canada
- Division of Respirology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
- Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
| | - Sanjay Mehta
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON N6A 5W9, Canada
- Division of Respirology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
- Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
| | - Natalie DeGurse
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
| | - Cynthia Pape
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON N6A 5W9, Canada
- Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
| | - Sean E Gill
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON N6A 5W9, Canada
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
- Division of Respirology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
- Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
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14
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Wang YT, Sansone A, Smirnov A, Stallings CL, Orvedahl A. Myeloid autophagy genes protect mice against fatal TNF- and LPS-induced cytokine storm syndromes. Autophagy 2023; 19:1114-1127. [PMID: 36056542 PMCID: PMC10012903 DOI: 10.1080/15548627.2022.2116675] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 08/19/2022] [Accepted: 08/19/2022] [Indexed: 02/09/2023] Open
Abstract
ABBREVIATIONS ATG5: autophagy related 5; ATG7: autophagy related 7; ATG14: autophagy related 14; ATG16L1: autophagy related 16-like 1 (S. cerevisiae); BECN1: beclin 1, autophagy related; CASP1: caspase 1; CASP4/CASP11: caspase 4, apoptosis-related cysteine peptidase; CIM: conditionally immortalized macrophage; CLP: cecal ligation and puncture; CSS: cytokine storm syndrome; DC: dendritic cell; IFNG/IFNγ: interferon gamma; IFNGR1: interferon gamma receptor 1; ip: intraperitoneal; iv: intravenous; IL12/p70: interleukin 12, p70 heterodimer; IL18: Interleukin 18; ITGAX/CD11c: integrin alpha X; LAP: LC3-associated phagocytosis; LPS: lipopolysaccharide; LYZ2/LYSM: lysozyme 2; MAP1LC3A/LC3: microtubule-associated protein 1 light chain 3 alpha; RB1CC1/FIP200: RB1-inducible coiled-coil 1; S100A8/MRP8: S100 calcium binding protein A8 (calgranulin A); TICAM1/TRIF: TIR domain containing adaptor molecule 1; TLR4: toll-like receptor 4; TNF: tumor necrosis factor.
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Affiliation(s)
- Ya-Ting Wang
- Center for Infectious Disease Research, Department of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing, Haidian, China
| | - Amy Sansone
- Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
| | - Asya Smirnov
- Department of Molecular Microbiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
| | - Christina L. Stallings
- Department of Molecular Microbiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
| | - Anthony Orvedahl
- Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
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15
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Xu J, Tang C, Din AU, Lu Y, Ma X, Zhang T, Wu J, Zuoqin D, Luo P, Wu J. Oligosaccharides of Polygonatum Cyrtonema Hua ameliorates dextran sulfate sodium-induced colitis and regulates the gut microbiota. Biomed Pharmacother 2023; 161:114562. [PMID: 36934554 DOI: 10.1016/j.biopha.2023.114562] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 03/14/2023] [Accepted: 03/15/2023] [Indexed: 03/21/2023] Open
Abstract
Ulcerative colitis (UC) is one common chronic inflammatory bowel disease that causes severe side effects, and expensive treatment limits effective and sustained treatment of UC. Fructooligosaccharide was isolated from Polygonatum Cyrtonema Hua (PFOS) and exhibits anti-inflammatory effects. Therefore, we are curious whether PFOS could be used for the treatment of UC. PFOS was introduced via intragastric gavage to C57BL/6 J mice exposed to acute colitis induced by DSS. The results showed that doses of PFOS at 2 and 5 mg/kg/day alleviated the DSS-induced histopathological damage and improved intestinal barrier function. qPCR analysis revealed that PFOS exerted a significant downregulation of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and upregulation of antioxidant genes, including superoxide dismutase1 (SOD1), glutathion peroxidase2 (GPX2), and nuclear factor erythroid 2 related factor2 (Nrf2). Furthermore, PFOS suppressed the DSS-induced disruption of the mucosal barrier by downregulating MMP13. Moreover, using 16 S rRNA gene-based microbiota analysis, PFOS could selectively enhance the growth of probiotics, including Bifidobacterium, Alloprevofella, and Alistipes. Our findings indicated that PFOS attenuated DSS-induced colitis in mice, suggesting that PFOS might be used as an efficacious supplement for reducing inflammatory bowel disease.
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Affiliation(s)
- Jin Xu
- State Key Laboratory of Quality Research in Chinese Medicine (Macau University of Science and Technology), Avenida Wai Long, Taipa, Macau, China; Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China; Drug Discovery Research Center, Southwest Medical University, Luzhou 646000, China; Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China; Department of Gastroenterology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Chuankang Tang
- Department of Gastroenterology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Ahmad Ud Din
- Drug Discovery Research Center, Southwest Medical University, Luzhou 646000, China; Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
| | - Yu Lu
- Drug Discovery Research Center, Southwest Medical University, Luzhou 646000, China; Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
| | - Xiaoyu Ma
- Drug Discovery Research Center, Southwest Medical University, Luzhou 646000, China; Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
| | - Tao Zhang
- Drug Discovery Research Center, Southwest Medical University, Luzhou 646000, China; Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
| | - Jiaqi Wu
- Drug Discovery Research Center, Southwest Medical University, Luzhou 646000, China; Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
| | - Du Zuoqin
- Drug Discovery Research Center, Southwest Medical University, Luzhou 646000, China; Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
| | - Pei Luo
- State Key Laboratory of Quality Research in Chinese Medicine (Macau University of Science and Technology), Avenida Wai Long, Taipa, Macau, China; Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China
| | - Jianbo Wu
- State Key Laboratory of Quality Research in Chinese Medicine (Macau University of Science and Technology), Avenida Wai Long, Taipa, Macau, China; Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China; Drug Discovery Research Center, Southwest Medical University, Luzhou 646000, China; Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China.
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16
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Shakya R, Jiménez-Meléndez A, Robertson LJ, Myrmel M. Bovine Enteroids as an In Vitro Model for Infection with Bovine Coronavirus. Viruses 2023; 15:635. [PMID: 36992344 PMCID: PMC10054012 DOI: 10.3390/v15030635] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/24/2023] [Accepted: 02/24/2023] [Indexed: 03/02/2023] Open
Abstract
Bovine coronavirus (BCoV) is one of the major viral pathogens of cattle, responsible for economic losses and causing a substantial impact on animal welfare. Several in vitro 2D models have been used to investigate BCoV infection and its pathogenesis. However, 3D enteroids are likely to be a better model with which to investigate host-pathogen interactions. This study established bovine enteroids as an in vitro replication system for BCoV, and we compared the expression of selected genes during the BCoV infection of the enteroids with the expression previously described in HCT-8 cells. The enteroids were successfully established from bovine ileum and permissive to BCoV, as shown by a seven-fold increase in viral RNA after 72 h. Immunostaining of differentiation markers showed a mixed population of differentiated cells. Gene expression ratios at 72 h showed that pro-inflammatory responses such as IL-8 and IL-1A remained unchanged in response to BCoV infection. Expression of other immune genes, including CXCL-3, MMP13, and TNF-α, was significantly downregulated. This study shows that the bovine enteroids had a differentiated cell population and were permissive to BCoV. Further studies are necessary for a comparative analysis to determine whether enteroids are suitable in vitro models to study host responses during BCoV infection.
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Affiliation(s)
| | | | | | - Mette Myrmel
- Department of Paraclinical Sciences, Faculty of Veterinary Medicine, Norwegian University of Life Sciences (NMBU), 1430 Ås, Norway
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17
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Chi H, Dong Z, Gan Q, Tang X, Xing J, Sheng X, Zhan W. Matrix metalloproteinase 9 modulates immune response along with the formation of extracellular traps in flounder (Paralichthys olivaceus). FISH & SHELLFISH IMMUNOLOGY 2023; 133:108570. [PMID: 36717064 DOI: 10.1016/j.fsi.2023.108570] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 12/28/2022] [Accepted: 01/26/2023] [Indexed: 06/18/2023]
Abstract
MMP-9 belongs to the Matrix Metalloprotease family, which is mainly involved in the protein hydrolysis process of extracellular matrix and plays important roles in many biological processes, such as embryogenesis, tissue remodeling, angiogenesis, inflammatory processes and wound healing. In this study, we described the sequence characteristics of the MMP-9 gene in flounder (PoMMP-9). PoMMP-9 was highly homologous to MMP-9 from turbot, medaka, and Fugu rubripes. The mRNA of PoMMP-9 was constitutively expressed in all tested tissues of healthy flounder with the highest expression levels in the head kidney and spleen. A time-dependent expression pattern of PoMMP-9 in the head kidney and spleen was found after the bacterial and virus challenge. This indicates that PoMMP-9 is inducible and involved in immune responses. Indirect immunofluorescence assay showed that the PoMMP-9 was co-localization in the extracellular traps (ETs) released by the leukocytes. After overexpression, PoMMP-9 can recruit more inflammatory cells and play a broad immune process from pathogen elimination to wound healing at the inflammatory site through ETs. In summary, this study provided new insights into the biological function of MMP-9 in teleost.
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Affiliation(s)
- Heng Chi
- Laboratory of Pathology and Immunology of Aquatic Animals, KLMME, Ocean University of China, Qingdao, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Zhixiao Dong
- Laboratory of Pathology and Immunology of Aquatic Animals, KLMME, Ocean University of China, Qingdao, China
| | - Qiujie Gan
- Laboratory of Pathology and Immunology of Aquatic Animals, KLMME, Ocean University of China, Qingdao, China
| | - Xiaoqian Tang
- Laboratory of Pathology and Immunology of Aquatic Animals, KLMME, Ocean University of China, Qingdao, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Jing Xing
- Laboratory of Pathology and Immunology of Aquatic Animals, KLMME, Ocean University of China, Qingdao, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Xiuzhen Sheng
- Laboratory of Pathology and Immunology of Aquatic Animals, KLMME, Ocean University of China, Qingdao, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Wenbin Zhan
- Laboratory of Pathology and Immunology of Aquatic Animals, KLMME, Ocean University of China, Qingdao, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
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18
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Johnson TO, Akinsanmi AO, Ejembi SA, Adeyemi OE, Oche JR, Johnson GI, Adegboyega AE. Modern drug discovery for inflammatory bowel disease: The role of computational methods. World J Gastroenterol 2023; 29:310-331. [PMID: 36687123 PMCID: PMC9846937 DOI: 10.3748/wjg.v29.i2.310] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 11/02/2022] [Accepted: 12/21/2022] [Indexed: 01/06/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) comprising ulcerative colitis, Crohn’s disease and microscopic colitis are characterized by chronic inflammation of the gastrointestinal tract. IBD has spread around the world and is becoming more prevalent at an alarming rate in developing countries whose societies have become more westernized. Cell therapy, intestinal microecology, apheresis therapy, exosome therapy and small molecules are emerging therapeutic options for IBD. Currently, it is thought that low-molecular-mass substances with good oral bio-availability and the ability to permeate the cell membrane to regulate the action of elements of the inflammatory signaling pathway are effective therapeutic options for the treatment of IBD. Several small molecule inhibitors are being developed as a promising alternative for IBD therapy. The use of highly efficient and time-saving techniques, such as computational methods, is still a viable option for the development of these small molecule drugs. The computer-aided (in silico) discovery approach is one drug development technique that has mostly proven efficacy. Computational approaches when combined with traditional drug development methodology dramatically boost the likelihood of drug discovery in a sustainable and cost-effective manner. This review focuses on the modern drug discovery approaches for the design of novel IBD drugs with an emphasis on the role of computational methods. Some computational approaches to IBD genomic studies, target identification, and virtual screening for the discovery of new drugs and in the repurposing of existing drugs are discussed.
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Affiliation(s)
| | | | | | | | - Jane-Rose Oche
- Department of Biochemistry, University of Jos, Jos 930222, Plateau, Nigeria
| | - Grace Inioluwa Johnson
- Faculty of Clinical Sciences, College of Health Sciences, University of Jos, Jos 930222, Plateau, Nigeria
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19
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Koop K, Enderle K, Hillmann M, Ruspeckhofer L, Vieth M, Sturm G, Trajanoski Z, Kühl AA, Atreya R, Leppkes M, Baum P, Roy J, Martin A, Neurath MF, Neufert C. Interleukin 36 receptor-inducible matrix metalloproteinase 13 mediates intestinal fibrosis. Front Immunol 2023; 14:1163198. [PMID: 37207229 PMCID: PMC10189878 DOI: 10.3389/fimmu.2023.1163198] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 04/17/2023] [Indexed: 05/21/2023] Open
Abstract
Background Fibrostenotic disease is a common complication in Crohn's disease (CD) patients hallmarked by transmural extracellular matrix (ECM) accumulation in the intestinal wall. The prevention and medical therapy of fibrostenotic CD is an unmet high clinical need. Although targeting IL36R signaling is a promising therapy option, downstream mediators of IL36 during inflammation and fibrosis have been incompletely understood. Candidate molecules include matrix metalloproteinases which mediate ECM turnover and are thereby potential targets for anti-fibrotic treatment. Here, we have focused on understanding the role of MMP13 during intestinal fibrosis. Methods We performed bulk RNA sequencing of paired colon biopsies taken from non-stenotic and stenotic areas of patients with CD. Corresponding tissue samples from healthy controls and CD patients with stenosis were used for immunofluorescent (IF) staining. MMP13 gene expression was analyzed in cDNA of intestinal biopsies from healthy controls and in subpopulations of patients with CD in the IBDome cohort. In addition, gene regulation on RNA and protein level was studied in colon tissue and primary intestinal fibroblasts from mice upon IL36R activation or blockade. Finally, in vivo studies were performed with MMP13 deficient mice and littermate controls in an experimental model of intestinal fibrosis. Ex vivo tissue analysis included Masson's Trichrome and Sirius Red staining as well as evaluation of immune cells, fibroblasts and collagen VI by IF analysis. Results Bulk RNA sequencing revealed high upregulation of MMP13 in colon biopsies from stenotic areas, as compared to non-stenotic regions of patients with CD. IF analysis confirmed higher levels of MMP13 in stenotic tissue sections of CD patients and demonstrated αSMA+ and Pdpn+ fibroblasts as a major source. Mechanistic experiments demonstrated that MMP13 expression was regulated by IL36R signaling. Finally, MMP13 deficient mice, as compared to littermate controls, developed less fibrosis in the chronic DSS model and showed reduced numbers of αSMA+ fibroblasts. These findings are consistent with a model suggesting a molecular axis involving IL36R activation in gut resident fibroblasts and MMP13 expression during the pathogenesis of intestinal fibrosis. Conclusion Targeting IL36R-inducible MMP13 could evolve as a promising approach to interfere with the development and progression of intestinal fibrosis.
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Affiliation(s)
- Kristina Koop
- First Department of Medicine, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- *Correspondence: Kristina Koop,
| | - Karin Enderle
- First Department of Medicine, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Miriam Hillmann
- First Department of Medicine, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Laura Ruspeckhofer
- First Department of Medicine, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Michael Vieth
- Institute of Pathology, Klinikum Bayreuth, Friedrich-Alexander-Universität Erlangen-Nürnberg, Bayreuth, Germany
| | - Gregor Sturm
- Biocenter, Institute of Bioinformatics, Medical University Innsbruck, Innsbruck, Austria
| | - Zlatko Trajanoski
- Biocenter, Institute of Bioinformatics, Medical University Innsbruck, Innsbruck, Austria
- The Transregio 241 IBDome Consortium, Erlangen, Germany
| | - Anja A. Kühl
- The Transregio 241 IBDome Consortium, Erlangen, Germany
- iPATH.Berlin, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Raja Atreya
- First Department of Medicine, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- The Transregio 241 IBDome Consortium, Erlangen, Germany
| | - Moritz Leppkes
- First Department of Medicine, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Patrick Baum
- Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany
| | | | - Andrea Martin
- Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT, United States
| | - Markus F. Neurath
- First Department of Medicine, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Clemens Neufert
- First Department of Medicine, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
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20
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Porras AM, Zhou H, Shi Q, Xiao X, Longman R, Brito IL. Inflammatory Bowel Disease-Associated Gut Commensals Degrade Components of the Extracellular Matrix. mBio 2022; 13:e0220122. [PMID: 36445085 PMCID: PMC9765649 DOI: 10.1128/mbio.02201-22] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 11/02/2022] [Indexed: 12/03/2022] Open
Abstract
Extracellular matrix (ECM) remodeling has emerged as a key feature of inflammatory bowel disease (IBD), and ECM fragments have been proposed as markers of clinical disease severity. Recent studies report increased protease activity in the gut microbiota of IBD patients. Nonetheless, the relationship between gut microbiota and ECM remodeling has remained unexplored. We hypothesized that members of the human gut microbiome could degrade the host ECM and that bacteria-driven remodeling, in turn, could enhance colonic inflammation. Through a variety of in vitro assays, we first confirmed that multiple bacterial species found in the human gut are capable of degrading specific ECM components. Clinical stool samples obtained from ulcerative colitis patients also exhibited higher levels of proteolytic activity in vitro, compared to those of their healthy counterparts. Furthermore, culture supernatants from bacteria species that are capable of degrading human ECM accelerated inflammation in dextran sodium sulfate (DSS)-induced colitis. Finally, we identified several of the bacterial proteases and carbohydrate degrading enzymes (CAZymes) that are potentially responsible for ECM degradation in vitro. Some of these protease families and CAZymes were also found in increased abundance in a metagenomic cohort of IBD. These results demonstrate that some commensal bacteria in the gut are indeed capable of degrading components of human ECM in vitro and suggest that this proteolytic activity may be involved in the progression of IBD. A better understanding of the relationship between nonpathogenic gut microbes, host ECM, and inflammation could be crucial to elucidating some of the mechanisms underlying host-bacteria interactions in IBD and beyond. IMPORTANCE Healthy gut epithelial cells form a barrier that keeps bacteria and other substances from entering the blood or tissues of the body. Those cells sit on scaffolding that maintains the structure of the gut and informs our immune system about the integrity of this barrier. In patients with inflammatory bowel disease (IBD), breaks are formed in this cellular barrier, and bacteria gain access to the underlying tissue and scaffolding. In our study, we discovered that bacteria that normally reside in the gut can modify and disassemble the underlying scaffolding. Additionally, we discovered that changes to this scaffolding affect the onset of IBD in mouse models of colitis as well as the abilities of these mice to recover. We propose that this new information will reveal how breaks in the gut wall lead to IBD and will open up new avenues by which to treat patients with IBD.
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Affiliation(s)
- Ana Maria Porras
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
| | - Hao Zhou
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, USA
| | - Qiaojuan Shi
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, USA
| | - Xieyue Xiao
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, USA
| | - JRI Live Cell Bank
- Jill Roberts Institute for IBD Research, Weill Cornell Medicine, New York, New York, USA
| | - Randy Longman
- Jill Roberts Institute for IBD Research, Weill Cornell Medicine, New York, New York, USA
| | - Ilana Lauren Brito
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, USA
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21
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Acute Endotoxemia-Induced Respiratory and Intestinal Dysbiosis. Int J Mol Sci 2022; 23:ijms231911602. [PMID: 36232913 PMCID: PMC9569575 DOI: 10.3390/ijms231911602] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 09/23/2022] [Accepted: 09/26/2022] [Indexed: 11/09/2022] Open
Abstract
Systemic inflammatory response syndrome (SIRS) is a severe condition characterized by systemic inflammation, which may lead to multiple organ failure, shock and death. SIRS is common in burn patients, pancreatitis and sepsis. SIRS is often accompanied by intestinal dysbiosis. However, the mechanism, role and details of microbiome alterations during the early phase of acute SIRS are not completely understood. The current study aimed to characterize the dynamic alterations of both the intestinal and respiratory microbiome at two timepoints during the early phase of acute SIRS (4 and 8 h after LPS) and link these to the host response in a mouse model of a LPS-induced lethal SIRS. Acute SIRS had no effect on the microbiome in the large intestine but induced a rapid dysbiosis in the small intestine, which resembled the microbiome alterations commonly observed in SIRS patients. Later in the disease progression, a dysbiosis of the respiratory microbiome was observed, which was associated with the MMP9 expression in the lungs. Although similar bacteria were increased in both the lung and the small intestine, no evidence for a gut-lung translocation was observed. Gut dysbiosis is commonly observed in diseases involving inflammation in the gut. However, whether the inflammatory response associated with SIRS and sepsis can directly cause gut dysbiosis was still unclear. In the current study we provide evidence that a LPS-induced SIRS can directly cause dysbiosis of the small intestinal and respiratory microbiome.
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22
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Boros É, Hegedűs Z, Kellermayer Z, Balogh P, Nagy I. Global alteration of colonic microRNAome landscape associated with inflammatory bowel disease. Front Immunol 2022; 13:991346. [PMID: 36177008 PMCID: PMC9513375 DOI: 10.3389/fimmu.2022.991346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 08/22/2022] [Indexed: 11/13/2022] Open
Abstract
Inflammatory Bowel Disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract that associates with, among others, increased risk of colorectal cancer. There is a growing evidence that miRNAs have important roles in pathological processes, such as inflammation or carcinogenesis. Understanding the molecular mechanisms such as alterations in microRNAome upon chronic intestinal inflammation is critical for understanding the exact pathomechanism of IBD. Hence, we conducted a genome wide microRNAome analysis by applying miRNA-Seq in a rat model of experimental colitis, validated the data by QPCR, examined the expression of a selection of precursor and mature miRNAs, performed in depth biological interpretation using Ingenuity Pathway Analysis and tested the obtained results on samples derived from human patients. We identified specific, interdependent expression pattern of activator/repressor transcription factors, miRNAs and their direct targets in the inflamed colon samples. Particularly, decreased expression of the miR-200 family members (miR-200a/b/c,-141, and -429) and miR-27b correlates with the reduced level of their enhancers (HNF1B, E2F1), elevated expression of their repressors (ZEB2, NFKB1) and increased expression of their target genes (ZEB2, RUNX1). Moreover, the marked upregulation of six miR-27b target genes (IFI16, GCA, CYP1B1, RUNX1, MEF2C and MMP13) in the inflamed colon tissues is a possible direct consequence of the lack of repression due to the downregulated miRNA-27b expression. Our data indicate that changes in microRNAome are associated with the pathophysiology of IBD, consequently, microRNAs offer potential targets for the diagnosis, prognosis and treatment of IBD.
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Affiliation(s)
- Éva Boros
- Seqomics Biotechnology Ltd., Mórahalom, Hungary
- Institute of Biochemistry, Biological Research Centre, Eötvös Loránd Research Network, Szeged, Hungary
| | - Zoltán Hegedűs
- Institute of Biophysics, Biological Research Centre, Eötvös Loránd Research Network, Szeged, Hungary
- Department of Biochemistry and Medical Chemistry, Medical School, University of Pécs, Pécs, Hungary
| | - Zoltán Kellermayer
- Department of Immunology and Biotechnology, University of Pécs, Pécs, Hungary
- Lymphoid Organogenesis Research Group, Szentágothai János Research Center, University of Pécs, Pécs, Hungary
| | - Péter Balogh
- Department of Immunology and Biotechnology, University of Pécs, Pécs, Hungary
- Lymphoid Organogenesis Research Group, Szentágothai János Research Center, University of Pécs, Pécs, Hungary
| | - István Nagy
- Seqomics Biotechnology Ltd., Mórahalom, Hungary
- Institute of Biochemistry, Biological Research Centre, Eötvös Loránd Research Network, Szeged, Hungary
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23
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The Role of Matrix Metalloproteinase in Inflammation with a Focus on Infectious Diseases. Int J Mol Sci 2022; 23:ijms231810546. [PMID: 36142454 PMCID: PMC9500641 DOI: 10.3390/ijms231810546] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/06/2022] [Accepted: 09/08/2022] [Indexed: 11/25/2022] Open
Abstract
Matrix metalloproteinases (MMPs) are involved in extracellular matrix remodeling through the degradation of extracellular matrix components and are also involved in the inflammatory response by regulating the pro-inflammatory cytokines TNF-α and IL-1β. Dysregulation in the inflammatory response and changes in the extracellular matrix by MMPs are related to the development of various diseases including lung and cardiovascular diseases. Therefore, numerous studies have been conducted to understand the role of MMPs in disease pathogenesis. MMPs are involved in the pathogenesis of infectious diseases through a dysregulation of the activity and expression of MMPs. In this review, we discuss the role of MMPs in infectious diseases and inflammatory responses. Furthermore, we present the potential of MMPs as therapeutic targets in infectious diseases.
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24
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TAK-242 Ameliorates Hepatic Fibrosis by Regulating the Liver-Gut Axis. BIOMED RESEARCH INTERNATIONAL 2022; 2022:4949148. [PMID: 36017390 PMCID: PMC9398794 DOI: 10.1155/2022/4949148] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/15/2022] [Accepted: 07/25/2022] [Indexed: 11/17/2022]
Abstract
Objective. The aims of this study were to investigate the impact of TAK-242 on the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear transcription factor-κB (NF-κB) signal transduction pathway in rats with hepatic fibrosis (HF) using the liver gut axis and to investigate the molecular mechanism of its intervention on HF. Methods. SPF grade SD male rats were randomly allocated to the control, model, and TAK-242 groups. For 8 weeks, the model and TAK-242 groups received 3 mL·kg-1 (the initial dose 5 mL·kg-1) intraperitoneal injections of 40% CCL4 olive oil solution. TAK-242 (5 mg·kg-1) was administered once a day for 5 days after modeling. The pathological alterations of liver and small intestine tissues in each group were observed using H&E and Masson staining. ELISA was used to measure serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), direct bilirubin (DBIL), total bilirubin (TBIL), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). RT-qPCR was utilized to identify the mRNA expression level of IL-1β, IL-6, TNF-α, TLR4, MyD88, and NF-κB in rat liver and small intestine tissues. The protein level of IL-1β, IL-6, TNF-α, TLR4, MyD88, and NF-κB protein in rat liver and small intestine tissues was determined utilizing Western blot and IHC. Results. TAK-242 significantly reduced AST, ALT, TBIL, and DBIL expression in HF rats’ serum (
) and alleviated liver tissue injury. Hematoxylin-eosin (H&E) and Masson staining revealed inflammatory cell infiltration and fibrous proliferation in the liver and small intestine tissue in the model group and partial cell swelling in the TAK-242 group, which indicated a considerable improvement compared to the model group. RT-qPCR, Western blot, and IHC data indicated that TAK-242 reduced the IL-1β, IL-6, TNF-α, TLR4, MyD88, and NF-κB expression in the liver and small intestine tissues of HF rats. Conclusion. TAK-242 might downregulate the TLR4/MyD88/NF-κB signal pathway through the liver-gut axis, suppress the inflammatory response, and eventually alleviate HF in rats.
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25
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de Almeida LGN, Thode H, Eslambolchi Y, Chopra S, Young D, Gill S, Devel L, Dufour A. Matrix Metalloproteinases: From Molecular Mechanisms to Physiology, Pathophysiology, and Pharmacology. Pharmacol Rev 2022; 74:712-768. [PMID: 35738680 DOI: 10.1124/pharmrev.121.000349] [Citation(s) in RCA: 167] [Impact Index Per Article: 55.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The first matrix metalloproteinase (MMP) was discovered in 1962 from the tail of a tadpole by its ability to degrade collagen. As their name suggests, matrix metalloproteinases are proteases capable of remodeling the extracellular matrix. More recently, MMPs have been demonstrated to play numerous additional biologic roles in cell signaling, immune regulation, and transcriptional control, all of which are unrelated to the degradation of the extracellular matrix. In this review, we will present milestones and major discoveries of MMP research, including various clinical trials for the use of MMP inhibitors. We will discuss the reasons behind the failures of most MMP inhibitors for the treatment of cancer and inflammatory diseases. There are still misconceptions about the pathophysiological roles of MMPs and the best strategies to inhibit their detrimental functions. This review aims to discuss MMPs in preclinical models and human pathologies. We will discuss new biochemical tools to track their proteolytic activity in vivo and ex vivo, in addition to future pharmacological alternatives to inhibit their detrimental functions in diseases. SIGNIFICANCE STATEMENT: Matrix metalloproteinases (MMPs) have been implicated in most inflammatory, autoimmune, cancers, and pathogen-mediated diseases. Initially overlooked, MMP contributions can be both beneficial and detrimental in disease progression and resolution. Thousands of MMP substrates have been suggested, and a few hundred have been validated. After more than 60 years of MMP research, there remain intriguing enigmas to solve regarding their biological functions in diseases.
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Affiliation(s)
- Luiz G N de Almeida
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Hayley Thode
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Yekta Eslambolchi
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Sameeksha Chopra
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Daniel Young
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Sean Gill
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Laurent Devel
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Antoine Dufour
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
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Ma L, Zhang X, Zhang C, Hou B, Zhao H. FOSL1 knockdown ameliorates DSS‑induced inflammation and barrier damage in ulcerative colitis via MMP13 downregulation. Exp Ther Med 2022; 24:551. [PMID: 35978937 PMCID: PMC9366272 DOI: 10.3892/etm.2022.11488] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 05/19/2022] [Indexed: 11/06/2022] Open
Affiliation(s)
- Lizhuan Ma
- Department of Gastroenterology, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei 063000, P.R. China
| | - Xiujing Zhang
- Department of Gastroenterology, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei 063000, P.R. China
| | - Chao Zhang
- Department of Gastroenterology, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei 063000, P.R. China
| | - Bingxu Hou
- Department of Gastroenterology, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei 063000, P.R. China
| | - Hongtao Zhao
- Department of Gastroenterology, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei 063000, P.R. China
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27
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van Olst L, Coenen L, Nieuwland JM, Rodriguez-Mogeda C, de Wit NM, Kamermans A, Middeldorp J, de Vries HE. Crossing borders in Alzheimer's disease: A T cell's perspective. Adv Drug Deliv Rev 2022; 188:114398. [PMID: 35780907 DOI: 10.1016/j.addr.2022.114398] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 05/31/2022] [Accepted: 06/03/2022] [Indexed: 12/14/2022]
Abstract
Alzheimer's disease (AD) is the most common form of dementia affecting millions of people worldwide. While different immunotherapies are imminent, currently only disease-modifying medications are available and a cure is lacking. Over the past decade, immunological interfaces of the central nervous system (CNS) and their role in neurodegenerative diseases received increasing attention. Specifically, emerging evidence shows that subsets of circulating CD8+ T cells cross the brain barriers and associate with AD pathology. To gain more insight into how the adaptive immune system is involved in disease pathogenesis, we here provide a comprehensive overview of the contribution of T cells to AD pathology, incorporating changes at the brain barriers. In addition, we review studies that provide translation of these findings by targeting T cells to combat AD pathology and cognitive decline. Importantly, these data show that immunological changes in AD are not confined to the CNS and that AD-associated systemic immune changes appear to affect brain homeostasis.
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Affiliation(s)
- L van Olst
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands
| | - L Coenen
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands; Department of Neurobiology and Aging, Biomedical Primate Research Centre, Rijswijk, The Netherlands
| | - J M Nieuwland
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands; Department of Neurobiology and Aging, Biomedical Primate Research Centre, Rijswijk, The Netherlands
| | - C Rodriguez-Mogeda
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands
| | - N M de Wit
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands
| | - A Kamermans
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands
| | - J Middeldorp
- Department of Neurobiology and Aging, Biomedical Primate Research Centre, Rijswijk, The Netherlands
| | - H E de Vries
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands.
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28
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Barrila J, Yang J, Franco Meléndez KP, Yang S, Buss K, Davis TJ, Aronow BJ, Bean HD, Davis RR, Forsyth RJ, Ott CM, Gangaraju S, Kang BY, Hanratty B, Nydam SD, Nauman EA, Kong W, Steel J, Nickerson CA. Spaceflight Analogue Culture Enhances the Host-Pathogen Interaction Between Salmonella and a 3-D Biomimetic Intestinal Co-Culture Model. Front Cell Infect Microbiol 2022; 12:705647. [PMID: 35711662 PMCID: PMC9195300 DOI: 10.3389/fcimb.2022.705647] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 04/29/2022] [Indexed: 11/13/2022] Open
Abstract
Physical forces associated with spaceflight and spaceflight analogue culture regulate a wide range of physiological responses by both bacterial and mammalian cells that can impact infection. However, our mechanistic understanding of how these environments regulate host-pathogen interactions in humans is poorly understood. Using a spaceflight analogue low fluid shear culture system, we investigated the effect of Low Shear Modeled Microgravity (LSMMG) culture on the colonization of Salmonella Typhimurium in a 3-D biomimetic model of human colonic epithelium containing macrophages. RNA-seq profiling of stationary phase wild type and Δhfq mutant bacteria alone indicated that LSMMG culture induced global changes in gene expression in both strains and that the RNA binding protein Hfq played a significant role in regulating the transcriptional response of the pathogen to LSMMG culture. However, a core set of genes important for adhesion, invasion, and motility were commonly induced in both strains. LSMMG culture enhanced the colonization (adherence, invasion and intracellular survival) of Salmonella in this advanced model of intestinal epithelium using a mechanism that was independent of Hfq. Although S. Typhimurium Δhfq mutants are normally defective for invasion when grown as conventional shaking cultures, LSMMG conditions unexpectedly enabled high levels of colonization by an isogenic Δhfq mutant. In response to infection with either the wild type or mutant, host cells upregulated transcripts involved in inflammation, tissue remodeling, and wound healing during intracellular survival. Interestingly, infection by the Δhfq mutant led to fewer transcriptional differences between LSMMG- and control-infected host cells relative to infection with the wild type strain. This is the first study to investigate the effect of LSMMG culture on the interaction between S. Typhimurium and a 3-D model of human intestinal tissue. These findings advance our understanding of how physical forces can impact the early stages of human enteric salmonellosis.
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Affiliation(s)
- Jennifer Barrila
- Biodesign Center for Fundamental and Applied Microbiomics, Arizona State University, Tempe, AZ, United States
- *Correspondence: Jennifer Barrila, ; Cheryl A. Nickerson,
| | - Jiseon Yang
- Biodesign Center for Fundamental and Applied Microbiomics, Arizona State University, Tempe, AZ, United States
| | - Karla P. Franco Meléndez
- Biodesign Center for Fundamental and Applied Microbiomics, Arizona State University, Tempe, AZ, United States
- School of Life Sciences, Arizona State University, Tempe, AZ, United States
- Genomics and Bioinformatics Research Unit, Agricultural Research Service, U.S. Department of Agriculture, Gainesville, FL, United States
| | - Shanshan Yang
- Bioinformatics Core Facility, Bioscience, Knowledge Enterprise, Arizona State University, Tempe, AZ, United States
| | - Kristina Buss
- Bioinformatics Core Facility, Bioscience, Knowledge Enterprise, Arizona State University, Tempe, AZ, United States
| | - Trenton J. Davis
- Biodesign Center for Fundamental and Applied Microbiomics, Arizona State University, Tempe, AZ, United States
- School of Life Sciences, Arizona State University, Tempe, AZ, United States
| | - Bruce J. Aronow
- Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Heather D. Bean
- Biodesign Center for Fundamental and Applied Microbiomics, Arizona State University, Tempe, AZ, United States
- School of Life Sciences, Arizona State University, Tempe, AZ, United States
| | - Richard R. Davis
- Biodesign Center for Fundamental and Applied Microbiomics, Arizona State University, Tempe, AZ, United States
| | - Rebecca J. Forsyth
- Biodesign Center for Fundamental and Applied Microbiomics, Arizona State University, Tempe, AZ, United States
| | - C. Mark Ott
- Biomedical Research and Environmental Sciences Division, NASA Johnson Space Center, Houston, TX, United States
| | - Sandhya Gangaraju
- Biodesign Center for Fundamental and Applied Microbiomics, Arizona State University, Tempe, AZ, United States
| | - Bianca Y. Kang
- Biodesign Center for Fundamental and Applied Microbiomics, Arizona State University, Tempe, AZ, United States
| | - Brian Hanratty
- Bioinformatics Core Facility, Bioscience, Knowledge Enterprise, Arizona State University, Tempe, AZ, United States
| | - Seth D. Nydam
- Department of Animal Care & Technologies, Arizona State University, Tempe, AZ, United States
| | - Eric A. Nauman
- School of Mechanical Engineering, Weldon School of Biomedical Engineering and Department of Basic Medical Sciences, Purdue University, West Lafayette, IN, United States
| | - Wei Kong
- Biodesign Center for Immunotherapy, Vaccines and Virotherapy, Arizona State University, Tempe, AZ, United States
| | - Jason Steel
- Bioinformatics Core Facility, Bioscience, Knowledge Enterprise, Arizona State University, Tempe, AZ, United States
| | - Cheryl A. Nickerson
- Biodesign Center for Fundamental and Applied Microbiomics, Arizona State University, Tempe, AZ, United States
- School of Life Sciences, Arizona State University, Tempe, AZ, United States
- *Correspondence: Jennifer Barrila, ; Cheryl A. Nickerson,
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Cirrincione AM, Reimonn CA, Harrison BJ, Rieger S. Longitudinal RNA Sequencing of Skin and DRG Neurons in Mice with Paclitaxel-Induced Peripheral Neuropathy. DATA 2022; 7. [PMID: 36248261 PMCID: PMC9564132 DOI: 10.3390/data7060072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Paclitaxel-induced peripheral neuropathy is a condition of nerve degeneration induced by chemotherapy, which afflicts up to 70% of treated patients. Therapeutic interventions are unavailable due to an incomplete understanding of the underlying mechanisms. We previously discovered that major physiological changes in the skin underlie paclitaxel-induced peripheral neuropathy in zebrafish and rodents. The precise molecular mechanisms are only incompletely understood. For instance, paclitaxel induces the upregulation of MMP-13, which, when inhibited, prevents axon degeneration. To better understand other gene regulatory changes induced by paclitaxel, we induced peripheral neuropathy in mice following intraperitoneal injection either with vehicle or paclitaxel every other day four times total. Skin and dorsal root ganglion neurons were collected based on distinct behavioural responses categorised as “pain onset” (d4), “maximal pain” (d7), “beginning of pain resolution” (d11), and “recovery phase” (d23) for comparative longitudinal RNA sequencing. The generated datasets validate previous discoveries and reveal additional gene expression changes that warrant further validation with the goal to aid in the development of drugs that prevent or reverse paclitaxel-induced peripheral neuropathy.
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Affiliation(s)
| | - Cassandra A. Reimonn
- Department of Biomedical Sciences, University of New England, Biddeford, ME 04005, USA
| | - Benjamin J. Harrison
- Department of Biomedical Sciences, University of New England, Biddeford, ME 04005, USA
- Correspondence: (B.J.H.); (S.R.)
| | - Sandra Rieger
- Department of Biology, University of Miami, Coral Gables, FL 33146, USA
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- Correspondence: (B.J.H.); (S.R.)
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Figueiredo CA, Steffen J, Morton L, Arumugam S, Liesenfeld O, Deli MA, Kröger A, Schüler T, Dunay IR. Immune response and pathogen invasion at the choroid plexus in the onset of cerebral toxoplasmosis. J Neuroinflammation 2022; 19:17. [PMID: 35027063 PMCID: PMC8759173 DOI: 10.1186/s12974-021-02370-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 12/22/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Toxoplasma gondii (T. gondii) is a highly successful parasite being able to cross all biological barriers of the body, finally reaching the central nervous system (CNS). Previous studies have highlighted the critical involvement of the blood-brain barrier (BBB) during T. gondii invasion and development of subsequent neuroinflammation. Still, the potential contribution of the choroid plexus (CP), the main structure forming the blood-cerebrospinal fluid (CSF) barrier (BCSFB) have not been addressed. METHODS To investigate T. gondii invasion at the onset of neuroinflammation, the CP and brain microvessels (BMV) were isolated and analyzed for parasite burden. Additionally, immuno-stained brain sections and three-dimensional whole mount preparations were evaluated for parasite localization and morphological alterations. Activation of choroidal and brain endothelial cells were characterized by flow cytometry. To evaluate the impact of early immune responses on CP and BMV, expression levels of inflammatory mediators, tight junctions (TJ) and matrix metalloproteinases (MMPs) were quantified. Additionally, FITC-dextran was applied to determine infection-related changes in BCSFB permeability. Finally, the response of primary CP epithelial cells to T. gondii parasites was tested in vitro. RESULTS Here we revealed that endothelial cells in the CP are initially infected by T. gondii, and become activated prior to BBB endothelial cells indicated by MHCII upregulation. Additionally, CP elicited early local immune response with upregulation of IFN-γ, TNF, IL-6, host-defence factors as well as swift expression of CXCL9 chemokine, when compared to the BMV. Consequently, we uncovered distinct TJ disturbances of claudins, associated with upregulation of MMP-8 and MMP-13 expression in infected CP in vivo, which was confirmed by in vitro infection of primary CP epithelial cells. Notably, we detected early barrier damage and functional loss by increased BCSFB permeability to FITC-dextran in vivo, which was extended over the infection course. CONCLUSIONS Altogether, our data reveal a close interaction between T. gondii infection at the CP and the impairment of the BCSFB function indicating that infection-related neuroinflammation is initiated in the CP.
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Affiliation(s)
- Caio Andreeta Figueiredo
- Institute of Inflammation and Neurodegeneration, Medical Faculty, Otto-Von-Guericke University Magdeburg, Magdeburg, Germany
| | - Johannes Steffen
- Institute of Inflammation and Neurodegeneration, Medical Faculty, Otto-Von-Guericke University Magdeburg, Magdeburg, Germany
| | - Lorena Morton
- Institute of Inflammation and Neurodegeneration, Medical Faculty, Otto-Von-Guericke University Magdeburg, Magdeburg, Germany
| | - Sushmitha Arumugam
- Institute of Inflammation and Neurodegeneration, Medical Faculty, Otto-Von-Guericke University Magdeburg, Magdeburg, Germany
| | - Oliver Liesenfeld
- Institute for Microbiology and Hygiene, Charité Medical School, Berlin, Germany
| | - Mária A Deli
- Institute of Biophysics, Biological Research Centre, 6726, Szeged, Hungary
| | - Andrea Kröger
- Institute for Medical Microbiology and Hospital Hygiene, Medical Faculty, Otto-Von-Guericke University Magdeburg, Magdeburg, Germany
| | - Thomas Schüler
- Institute of Molecular and Clinical Immunology, Medical Faculty, Otto-Von-Guericke University Magdeburg, Magdeburg, Germany
| | - Ildiko Rita Dunay
- Institute of Inflammation and Neurodegeneration, Medical Faculty, Otto-Von-Guericke University Magdeburg, Magdeburg, Germany. .,Center for Behavioral Brain Sciences, CBBS, Magdeburg, Germany.
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Tang K, Wu Z, Sun M, Huang X, Sun J, Shi J, Wang X, Miao Z, Gao P, Song Y, Wang Z. Elevated MMP10/13 mediated barrier disruption and NF-κB activation aggravate colitis and colon tumorigenesis in both individual or full miR-148/152 family knockout mice. Cancer Lett 2022; 529:53-69. [PMID: 34979166 DOI: 10.1016/j.canlet.2021.12.033] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 12/07/2021] [Accepted: 12/28/2021] [Indexed: 12/13/2022]
Abstract
Dynamic miRNA alteration is known to occur in colitis-associated colon cancer (CAC), while the molecular mechanisms underpinning how miRNAs modulate the development from chronic inflammation to CAC is lacking. For the first time, we constructed knockout (KO) mice for individual miR-148/152 family members and entire miR-148/152 family. Based on these KO mice, we conduct the first comprehensive analysis of miR-148/152 family, demonstrating that deficiency of any member of miR-148/152 family aggravate colitis and CAC. Loss of individual miR-148/152 family members or full-family enhance MMP10 and MMP13 expression, causing disruption of intestinal barrier and cleaving pro-TNF-α into bioactive TNF-α fragments to activate NF-κB signaling, thereby aggravating colitis. Individual and full-family deletion also increase accumulation of IKKα and IKKβ, resulting in further hyperactivation of NF-κB signaling, exacerbating colitis and CAC. Moreover, blocking NF-κB signaling exerts a restorative effect on colitis and CAC models only in KO mice. Taken together, these findings demonstrate deleting the full miR-148/152 family or individual members exhibit similar effects in colitis and CAC. Mechanically, miR-148/152 family members deficiency in mice elevates MMP10 and MMP13 to accelerate colitis and CAC via disrupting intestinal barrier function and activating NF-κB signaling, suggesting a potential therapeutic strategy for colitis and CAC.
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Affiliation(s)
- Kaiwen Tang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, 155 North Nanjing Street, Heping District, Shenyang, 110001, China
| | - Zhonghua Wu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, 155 North Nanjing Street, Heping District, Shenyang, 110001, China
| | - Mingwei Sun
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, 155 North Nanjing Street, Heping District, Shenyang, 110001, China
| | - Xuanzhang Huang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, 155 North Nanjing Street, Heping District, Shenyang, 110001, China
| | - Jingxu Sun
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, 155 North Nanjing Street, Heping District, Shenyang, 110001, China
| | - Jinxin Shi
- Department of Gastrointestinal Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, PR China
| | - Xin Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, 155 North Nanjing Street, Heping District, Shenyang, 110001, China
| | - Zhifeng Miao
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, 155 North Nanjing Street, Heping District, Shenyang, 110001, China
| | - Peng Gao
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, 155 North Nanjing Street, Heping District, Shenyang, 110001, China.
| | - Yongxi Song
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, 155 North Nanjing Street, Heping District, Shenyang, 110001, China.
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, 155 North Nanjing Street, Heping District, Shenyang, 110001, China
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Zhang X, Ma L, Shen Y, Zhang C, Hou B, Zhou Y. Transcription factor paired related homeobox 1 (PRRX1) activates matrix metalloproteinases (MMP)13, which promotes the dextran sulfate sodium-induced inflammation and barrier dysfunction of NCM460 cells. Bioengineered 2021; 13:645-654. [PMID: 34967278 PMCID: PMC8805821 DOI: 10.1080/21655979.2021.2012549] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Paired related homeobox 1 (PRRX1) is a newly identified transcription factor that regulates the expression of various genes. We aimed to investigate the roles of PRRX1 and Matrix metalloproteinases (MMP)13 in dextran sulfate sodium (DSS)-induced inflammation and barrier dysfunction of NCM460 cells. PRRX1 expression in the mucosal tissues of patients with ulcerative colitis was analyzed using the GSE87466 microarray. PRRX1 and MMP13 expression was examined using Western blotting and RT-qPCR following the exposure of the NCM460 cells to DSS. The JASPAR database was used to predict the binding sites of PRRX1 to the MMP13 promoter, which was verified by luciferase reporter and chromatin immunoprecipitation assays. MMP13 expression was then detected following PRRX1 silencing or overexpression. The levels of inflammatory factors were determined using ELISA. Finally, the expression of intestinal barrier function-related proteins was evaluated using Western blotting and cellular permeability was detected by Transepithelial electrical resistance. PRRX1 was upregulated in the mucosal tissue samples of patients with UC. DSS induction upregulated PRRX1 and MMP13 expression. PRRX1 bound to the promoter of MMP13, which was further supported by the decreased expression of MMP13 observed following PRRX1 knockdown and its increased expression following PRRX1 overexpression. Furthermore, PRRX1 deletion decreased TNF-α, IL-1β and IL-6 levels in the DSS-challenged NCM460 cells, which were subjected to MMP13 overexpression. Moreover, PRRX1 silencing upregulated ZO-1, occludin and claudin-1 expression and elevated the TEER value, whereas MMP13 overexpression attenuated these effects. Collectively, PRRX1 activates MMP13, which in turn promotes the DSS-induced inflammation and barrier dysfunction of NCM460 cells.
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Affiliation(s)
- Xiujing Zhang
- Division of Gastroenterology, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei, China
| | - Lizhuan Ma
- Division of Gastroenterology, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei, China
| | - Ying Shen
- Department of Endoscopic Therapy, Tangshan People's Hospital, Tangshan, Hebei, China
| | - Chao Zhang
- Division of Gastroenterology, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei, China
| | - Bingxu Hou
- Division of Gastroenterology, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei, China
| | - Yanli Zhou
- Division of Gastroenterology, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei, China
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Cheng Y, Hall TR, Xu X, Yung I, Souza D, Zheng J, Schiele F, Hoffmann M, Mbow ML, Garnett JP, Li J. Targeting uPA-uPAR interaction to improve intestinal epithelial barrier integrity in inflammatory bowel disease. EBioMedicine 2021; 75:103758. [PMID: 34933179 PMCID: PMC8688562 DOI: 10.1016/j.ebiom.2021.103758] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 11/23/2021] [Accepted: 12/01/2021] [Indexed: 12/26/2022] Open
Abstract
Background Loss of intestinal epithelial barrier integrity is a critical component of Inflammatory Bowel Disease (IBD) pathogenesis. Co-expression regulation of ligand-receptor pairs in IBD mucosa has not been systematically studied. Targeting ligand-receptor pairs which are induced in IBD mucosa and function in intestinal epithelial barrier integrity may provide novel therapeutics for IBD. Methods We performed transcriptomic meta-analysis on public IBD datasets combined with cell surface protein-protein-interaction (PPI) databases. We explored primary human/mouse intestinal organoids and Caco-2 cells for expression and function studies of uPA-uPAR (prime hits from the meta-analysis). Epithelial barrier integrity was measured by Trans-Epithelial Electrical Resistance (TEER), FITC-Dextran permeability and tight junction assessment. Genetic (CRISPR, siRNA and KO mice) and pharmacological (small molecules, neutralizing antibody and peptide inhibitors) approaches were applied. Mice deficient of uPAR were studied using the Dextran Sulfate Sodium (DSS)-induced colitis model. Findings The IBD ligand-receptor meta-analysis led to the discovery of a coordinated upregulation of uPA and uPAR in IBD mucosa. Both genes were significantly upregulated during epithelial barrier breakdown in primary intestinal organoids and decreased during barrier formation. Genetic inhibition of uPAR or uPA, or pharmacologically blocking uPA-uPAR interaction protects against cytokine-induced barrier breakdown. Deficiency of uPAR in epithelial cells leads to enhanced EGF/EGFR signalling, a known regulator of epithelial homeostasis and repair. Mice deficient of uPAR display improved intestinal barrier function in vitro and during DSS-induced colitis in vivo. Interpretation Our findings suggest that blocking uPA-uPAR interaction via pharmacological agents protects the epithelial barrier from inflammation-induced damage, indicating a potential therapeutic target for IBD. Funding The study was funded by Boehringer Ingelheim.
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Affiliation(s)
- Yang Cheng
- Immunology and Respiratory Diseases Research, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA
| | - Tyler R Hall
- Immunology and Respiratory Diseases Research, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA
| | - Xiao Xu
- Computational Biology Group, Discovery Research, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA
| | - Ivy Yung
- Immunology and Respiratory Diseases Research, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA
| | - Donald Souza
- Immunology and Respiratory Diseases Research, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA
| | - Jie Zheng
- Immunology and Respiratory Diseases Research, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA
| | - Felix Schiele
- Biotherapeutics Discovery, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany
| | - Matthias Hoffmann
- Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany
| | - M Lamine Mbow
- Immunology and Respiratory Diseases Research, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA
| | - James P Garnett
- Immunology and Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany
| | - Jun Li
- Immunology and Respiratory Diseases Research, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA.
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Khawaja H, Fazal N, Yaqub F, Ahmad MR, Hanif M, Yousaf MA, Latief N. Protective and proliferative effect of Aesculus indica extract on stressed human adipose stem cells via downregulation of NF-κB pathway. PLoS One 2021; 16:e0258762. [PMID: 34679084 PMCID: PMC8535185 DOI: 10.1371/journal.pone.0258762] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 10/06/2021] [Indexed: 01/22/2023] Open
Abstract
Inflammatory microenvironment after transplantation affects the proliferation and causes senescence of adipose-derived mesenchymal stem cells (hADMSCs) thus compromising their clinical efficacy. Priming stem cells with herbal extracts is considered very promising to improve their viability in the inflammatory milieu. Aesculus indica (A. indica) is used to treat many inflammatory diseases in Asia for decades. Herein, we explored the protective role of A. indica extract on human adipose-derived Mesenchymal Stem Cells (hADMSCs) against Monosodium Iodoacetate (MIA) induced stress in vitro. A. indica ameliorated the injury as depicted by significantly enhanced proliferation, viability, improved cell migration and superoxide dismutase activity. Furthermore, reduced lactate dehydrogenase activity, reactive oxygen species release, senescent and apoptotic cells were detected in A. indica primed hADMSCs. Downregulation of NF-κB pathway and associated inflammatory genes, NF-κB p65/RelA and p50/NF-κB 1, Interleukin 6 (IL-6), Interleukin 1 (IL-1β), Tumor necrosis factor alpha (TNF-α) and matrix metalloproteinase 13 (MMP-13) were observed in A. indica primed hADMSCs as compared to stressed hADMSCs. Complementary to gene expression, A. indica priming reduced the release of transcription factor p65, inhibitory-κB kinase (IKK) α and β, IL-1β and TNF-α proteins expression. Our data elucidates that A. indica extract preconditioning rescued hADMSCs against oxidative stress and improved their therapeutic potential by relieving inflammation through regulation of NF-κB pathway.
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Affiliation(s)
- Hamzah Khawaja
- National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
- Institute of Laboratory Medicine, Clinical Chemistry, and Molecular Diagnostics, Leipzig University, Leipzig, Germany
| | - Numan Fazal
- National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Faiza Yaqub
- National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Muhammad Rauf Ahmad
- Department of Molecular Biology, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan
| | - Muzaffar Hanif
- National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Muhammad Amin Yousaf
- Department of Dermatology, Jinnah Burn & Reconstructive Surgery Centre, Lahore, Pakistan
| | - Noreen Latief
- National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
- * E-mail: ,
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Berlamont H, Bruggeman A, Bauwens E, Vandendriessche C, Clarebout E, Xie J, De Bruyckere S, Van Imschoot G, Van Wonterghem E, Ducatelle R, Santens P, Smet A, Haesebrouck F, Vandenbroucke RE. Gastric Helicobacter suis Infection Partially Protects against Neurotoxicity in A 6-OHDA Parkinson's Disease Mouse Model. Int J Mol Sci 2021; 22:ijms222111328. [PMID: 34768765 PMCID: PMC8582972 DOI: 10.3390/ijms222111328] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/12/2021] [Accepted: 10/14/2021] [Indexed: 12/21/2022] Open
Abstract
The exact etiology of Parkinson’s disease (PD) remains largely unknown, but more and more research suggests the involvement of the gut microbiota. Interestingly, idiopathic PD patients were shown to have at least a 10 times higher prevalence of Helicobacter suis (H. suis) DNA in gastric biopsies compared to control patients. H. suis is a zoonotic Helicobacter species that naturally colonizes the stomach of pigs and non-human primates but can be transmitted to humans. Here, we investigated the influence of a gastric H. suis infection on PD disease progression through a 6-hydroxydopamine (6-OHDA) mouse model. Therefore, mice with either a short- or long-term H. suis infection were stereotactically injected with 6-OHDA in the left striatum and sampled one week later. Remarkably, a reduced loss of dopaminergic neurons was seen in the H. suis/6-OHDA groups compared to the control/6-OHDA groups. Correspondingly, motor function of the H. suis-infected 6-OHDA mice was superior to that in the non-infected 6-OHDA mice. Interestingly, we also observed higher expression levels of antioxidant genes in brain tissue from H. suis-infected 6-OHDA mice, as a potential explanation for the reduced 6-OHDA-induced cell loss. Our data support an unexpected neuroprotective effect of gastric H. suis on PD pathology, mediated through changes in oxidative stress.
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Affiliation(s)
- Helena Berlamont
- Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium; (H.B.); (E.B.); (S.D.B.); (R.D.); (F.H.)
| | - Arnout Bruggeman
- VIB Center for Inflammation Research, 9052 Ghent, Belgium; (A.B.); (C.V.); (E.C.); (J.X.); (G.V.I.); (E.V.W.)
- Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
- Department of Neurology, Ghent University Hospital, 9000 Ghent, Belgium;
| | - Eva Bauwens
- Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium; (H.B.); (E.B.); (S.D.B.); (R.D.); (F.H.)
| | - Charysse Vandendriessche
- VIB Center for Inflammation Research, 9052 Ghent, Belgium; (A.B.); (C.V.); (E.C.); (J.X.); (G.V.I.); (E.V.W.)
- Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
| | - Elien Clarebout
- VIB Center for Inflammation Research, 9052 Ghent, Belgium; (A.B.); (C.V.); (E.C.); (J.X.); (G.V.I.); (E.V.W.)
- Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
| | - Junhua Xie
- VIB Center for Inflammation Research, 9052 Ghent, Belgium; (A.B.); (C.V.); (E.C.); (J.X.); (G.V.I.); (E.V.W.)
- Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
| | - Sofie De Bruyckere
- Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium; (H.B.); (E.B.); (S.D.B.); (R.D.); (F.H.)
| | - Griet Van Imschoot
- VIB Center for Inflammation Research, 9052 Ghent, Belgium; (A.B.); (C.V.); (E.C.); (J.X.); (G.V.I.); (E.V.W.)
- Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
| | - Elien Van Wonterghem
- VIB Center for Inflammation Research, 9052 Ghent, Belgium; (A.B.); (C.V.); (E.C.); (J.X.); (G.V.I.); (E.V.W.)
- Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
| | - Richard Ducatelle
- Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium; (H.B.); (E.B.); (S.D.B.); (R.D.); (F.H.)
| | - Patrick Santens
- Department of Neurology, Ghent University Hospital, 9000 Ghent, Belgium;
| | - Annemieke Smet
- Laboratory of Experimental Medicine and Pediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, 2610 Antwerp, Belgium;
| | - Freddy Haesebrouck
- Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium; (H.B.); (E.B.); (S.D.B.); (R.D.); (F.H.)
| | - Roosmarijn E. Vandenbroucke
- VIB Center for Inflammation Research, 9052 Ghent, Belgium; (A.B.); (C.V.); (E.C.); (J.X.); (G.V.I.); (E.V.W.)
- Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
- Correspondence: ; Tel.: +32-9-3313730
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Liu YF, Niu GC, Li CY, Guo JB, Song J, Li H, Zhang XL. Mechanism of Ulcerative Colitis-Aggravated Liver Fibrosis: The Activation of Hepatic Stellate Cells and TLR4 Signaling Through Gut-Liver Axis. Front Physiol 2021; 12:695019. [PMID: 34603071 PMCID: PMC8484790 DOI: 10.3389/fphys.2021.695019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 08/25/2021] [Indexed: 12/12/2022] Open
Abstract
Background: The progression of liver disorders is frequently associated with inflammatory bowel disease through the gut-liver axis. However, no direct evidence showed the mechanisms of ulcerative colitis (UC) in the development of liver fibrosis per se. Thus, this study aimed to evaluate the effects of UC on liver fibrosis and its potential mechanism in the experimental model. Methods: Male C57BL/6 mice were allocated into five groups (n = 10 per group) to receive either drinking water (control), 2% dextran sulfate sodium (DSS), olive oil, carbon tetrachloride (CCl4) or DSS + CCl4 for 4 cycles. Blood was collected for biochemical analysis. Colons were excised for the evaluation of colon length and morphological score. Liver, colon, and mesenteric lymph nodes (MLNs) were collected for histopathological staining, expression analysis, and bacterial translocation assay to evaluate the inflammation, fibrosis, the activation of hepatic stellate cells (HSCs), and gut barrier function. Results: DSS caused severe colitis in mice treated or treated with CCl4, as evident from the elevation of disease activity index (DAI), histological abnormalities, and increased pro-inflammatory cytokines (TNF-α, IFN-γ, and IL-17A). Histopathological staining revealed that DSS treatment aggravated the CCl4-induced extracellular matrix deposition, liver fibrosis, and inflammation in mice. Additionally, biochemical and expression analysis indicated the DSS treatment caused the increase of hydroxyproline and pro-inflammatory cytokines, as well as the abnormal liver function indexes in CCl4-induced mice. Gut barrier function was impaired in DSS- and DSS + CCl4-treated mice, manifesting as the increase in bacterial translocation and lipopolysaccharide level, and the reduction in tight junction proteins (occluding, claudin-1 and ZO-1) expression. Further, the activations of HSCs and TLR4 signaling pathway were observed after DSS + CCl4 treatment, presenting with the increase in expression of α-SMA, vimentin, TGF-β, collagen type I, collagen type II, TIMP-2, TLR4, TRAF6, and NF-κB p65, and a decrease in GFAP and MMP-2 expression. Conclusion: The present study verified that UC aggravated CCl4-induced liver injury, inflammation, and fibrosis in mice through the gut-liver axis. Gut barrier dysfunction in UC leads to bacterial translocation and elevated lipopolysaccharide, which may promote the activation of TLR4 signaling and HSCs in the liver.
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Affiliation(s)
- Yu-Feng Liu
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.,Department of Gastroenterology, Dingzhou People's Hospital of Hebei Province, Dingzhou, China
| | - Guo-Chao Niu
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Chen-Yang Li
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jin-Bo Guo
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jia Song
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Hui Li
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiao-Lan Zhang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
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Kaya SG, Inanc-Surer S, Cakan-Akdogan G, Oktay G, Utine CA, Kalyoncu S. Roles of matrix metalloproteinases in the cornea: A special focus on macular corneal dystrophy. MEDICINE IN DRUG DISCOVERY 2021. [DOI: 10.1016/j.medidd.2021.100095] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
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Liu Y, Huang W, Wang J, Ma J, Zhang M, Lu X, Liu J, Kou Y. Multifaceted Impacts of Periodontal Pathogens in Disorders of the Intestinal Barrier. Front Immunol 2021; 12:693479. [PMID: 34386004 PMCID: PMC8353228 DOI: 10.3389/fimmu.2021.693479] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 07/12/2021] [Indexed: 12/12/2022] Open
Abstract
Periodontal disease, a common inflammatory disease, is considered a hazardous factor that contributes to the development of diseases of the digestive system as well as other systems. The bridge between periodontitis and systemic diseases is believed to be periodontal pathogens. The intestine, as part of the lower gastrointestinal tract, has a close connection with the oral cavity. Within the intestine, the intestinal barrier acts as a multifunctional system including microbial, mucous, physical and immune barrier. The intestinal barrier forms the body's first line of defense against external pathogens; its breakdown can lead to pathological changes in the gut and other organs or systems. Reports in the literature have described how oral periodontal pathogens and pathobiont-reactive immune cells can transmigrate to the intestinal mucosa, causing the destruction of intestinal barrier homeostasis. Such findings might lead to novel ideas for investigating the relationship between periodontal disease and other systemic diseases. This review summarizes studies on the effects of periodontal pathogens on the intestinal barrier, which might contribute to understanding the link between periodontitis and gastrointestinal diseases.
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Affiliation(s)
- Yingman Liu
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Wenxuan Huang
- School of Stomatology, Shenyang Medical College, Shenyang, China
| | - Jiaqi Wang
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Jiaojiao Ma
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Manman Zhang
- Department of Oral Biology, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Xiaoying Lu
- Department of Oral Biology, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Jie Liu
- Science Experiment Center, China Medical University, Shenyang, China
| | - Yurong Kou
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
- Department of Oral Biology, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
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Zhou HC, Guo CA, Yu WW, Yan XY, Long JP, Liu ZC, Liang XQ, Liu HB. Zizyphus jujuba cv. Muzao polysaccharides enhance intestinal barrier function and improve the survival of septic mice. J Food Biochem 2021; 45:e13722. [PMID: 33855723 DOI: 10.1111/jfbc.13722] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 03/15/2021] [Accepted: 03/22/2021] [Indexed: 11/28/2022]
Abstract
This study aimed to examine the role of Zizyphus jujuba cv. Muzao polysaccharides (ZJPs) in protecting intestinal barrier function and the survival of septic mice. The sepsis mouse model was generated through cecal ligation and puncture (CLP) to observe the effect of ZJPs on the function of the intestinal barrier in the context of sepsis. We observed the clinical symptoms and survival time of the mice and evaluated serum inflammatory cytokines, intestinal pathological changes and intestinal permeability. Moreover, tight junction (TJ) proteins and apoptosis-associated proteins in intestinal tissue were examined. Finally, TLR4/NF-κB pathway-related proteins were measured in all groups. The results showed that pretreatment with ZJPs improved clinical and histological scores and reduced intestinal barrier permeability, and the levels of proinflammatory factors were decreased. Pretreatment with ZJPs also upregulated the levels of TJ proteins and downregulated the expression of proapoptotic proteins. Moreover, the activation of TLR4/NF-κB signaling was partly inhibited in septic mice by ZJPs pretreatment. The current study provides evidence that ZJPs have the potential to protect intestinal barrier function and improve the survival of septic mice via the attenuation of TLR4/NF-κB inflammatory signaling. PRACTICAL APPLICATIONS: This study reports the potential protective effect of ZJPs against cecal ligation and puncture (CLP)-induced sepsis. Our data reveal that CLP induced damage to the gut mucosal barrier, inflammation, and apoptosis in intestinal tissues. However, pretreatment with ZJPs improved clinical and histological scores, reduced intestinal barrier permeability, and decreased the levels of proinflammatory factors in mice. Pretreatment with ZJPs also upregulated the levels of TJ proteins and downregulated the expression of proapoptotic proteins. Moreover, the activation of TLR4/NF-κB signaling was partly inhibited in septic mice after ZJPs pretreatment. These findings provide evidence that pretreatment with ZJPs has the potential to attenuate CLP-induced gut damage in mice by restraining inflammation and apoptosis via the attenuation of NF-κB signaling. It provides a basis for further study of ZJPs in sepsis.
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Affiliation(s)
- Hai-Cun Zhou
- Second Clinical Medical College, Lanzhou University, Lanzhou, P.R. China.,Department of General Surgery, Gansu Maternal and Child Health Care Hospital, Lanzhou, P.R. China.,Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou, P.R. China
| | - Chang-An Guo
- Second Clinical Medical College, Lanzhou University, Lanzhou, P.R. China.,Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou, P.R. China
| | - Wen-Wen Yu
- Second Clinical Medical College, Lanzhou University, Lanzhou, P.R. China.,Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou, P.R. China
| | - Xin-Yan Yan
- Department of General Surgery, Gansu Maternal and Child Health Care Hospital, Lanzhou, P.R. China
| | - Jian-Ping Long
- Department of General Surgery, Gansu Maternal and Child Health Care Hospital, Lanzhou, P.R. China
| | - Zhi-Chang Liu
- Second Clinical Medical College, Lanzhou University, Lanzhou, P.R. China.,Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou, P.R. China
| | - Xiao-Qin Liang
- Second Clinical Medical College, Lanzhou University, Lanzhou, P.R. China.,Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou, P.R. China.,Pathology Department, Gansu Province People Hospital, Lanzhou, P.R. China
| | - Hong-Bin Liu
- Second Clinical Medical College, Lanzhou University, Lanzhou, P.R. China.,Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou, P.R. China.,Clinical Medical College, Northwest Minzu University, Lanzhou, P.R. China
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Mariaule V, Kriaa A, Soussou S, Rhimi S, Boudaya H, Hernandez J, Maguin E, Lesner A, Rhimi M. Digestive Inflammation: Role of Proteolytic Dysregulation. Int J Mol Sci 2021; 22:ijms22062817. [PMID: 33802197 PMCID: PMC7999743 DOI: 10.3390/ijms22062817] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/04/2021] [Accepted: 03/05/2021] [Indexed: 12/11/2022] Open
Abstract
Dysregulation of the proteolytic balance is often associated with diseases. Serine proteases and matrix metalloproteases are involved in a multitude of biological processes and notably in the inflammatory response. Within the framework of digestive inflammation, several studies have stressed the role of serine proteases and matrix metalloproteases (MMPs) as key actors in its pathogenesis and pointed to the unbalance between these proteases and their respective inhibitors. Substantial efforts have been made in developing new inhibitors, some of which have reached clinical trial phases, notwithstanding that unwanted side effects remain a major issue. However, studies on the proteolytic imbalance and inhibitors conception are directed toward host serine/MMPs proteases revealing a hitherto overlooked factor, the potential contribution of their bacterial counterpart. In this review, we highlight the role of proteolytic imbalance in human digestive inflammation focusing on serine proteases and MMPs and their respective inhibitors considering both host and bacterial origin.
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Affiliation(s)
- Vincent Mariaule
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, F-78350 Jouy-en-Josas, France; (V.M.); (A.K.); (S.S.); (S.R.); (H.B.); (E.M.)
| | - Aicha Kriaa
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, F-78350 Jouy-en-Josas, France; (V.M.); (A.K.); (S.S.); (S.R.); (H.B.); (E.M.)
| | - Souha Soussou
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, F-78350 Jouy-en-Josas, France; (V.M.); (A.K.); (S.S.); (S.R.); (H.B.); (E.M.)
| | - Soufien Rhimi
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, F-78350 Jouy-en-Josas, France; (V.M.); (A.K.); (S.S.); (S.R.); (H.B.); (E.M.)
| | - Houda Boudaya
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, F-78350 Jouy-en-Josas, France; (V.M.); (A.K.); (S.S.); (S.R.); (H.B.); (E.M.)
| | - Juan Hernandez
- Department of Clinical Sciences, Nantes-Atlantic College of Veterinary Medicine and Food Sciences (Oniris), University of Nantes, 101 Route de Gachet, 44300 Nantes, France;
| | - Emmanuelle Maguin
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, F-78350 Jouy-en-Josas, France; (V.M.); (A.K.); (S.S.); (S.R.); (H.B.); (E.M.)
| | - Adam Lesner
- Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, PL80-308 Gdansk, Poland;
| | - Moez Rhimi
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, F-78350 Jouy-en-Josas, France; (V.M.); (A.K.); (S.S.); (S.R.); (H.B.); (E.M.)
- Correspondence:
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Camba-Gómez M, Gualillo O, Conde-Aranda J. New Perspectives in the Study of Intestinal Inflammation: Focus on the Resolution of Inflammation. Int J Mol Sci 2021; 22:ijms22052605. [PMID: 33807591 PMCID: PMC7962019 DOI: 10.3390/ijms22052605] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/25/2021] [Accepted: 03/02/2021] [Indexed: 12/14/2022] Open
Abstract
Inflammation is an essential physiological process that is directed to the protection of the organism against invading pathogens or tissue trauma. Most of the existing knowledge related to inflammation is focused on the factors and mechanisms that drive the induction phase of this process. However, since the recognition that the resolution of the inflammation is an active and tightly regulated process, increasing evidence has shown the relevance of this process for the development of chronic inflammatory diseases, such as inflammatory bowel disease. For that reason, with this review, we aimed to summarize the most recent and interesting information related to the resolution process in the context of intestinal inflammation. We discussed the advances in the understanding of the pro-resolution at intestine level, as well as the new mediators with pro-resolutive actions that could be interesting from a therapeutic point of view.
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Affiliation(s)
- Miguel Camba-Gómez
- Molecular and Cellular Gastroenterology, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain;
| | - Oreste Gualillo
- SERGAS (Servizo Galego de Saúde) and IDIS (Instituto de Investigación Sanitaria de Santiago), The NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain;
| | - Javier Conde-Aranda
- Molecular and Cellular Gastroenterology, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain;
- Correspondence: ; Tel.: +34-981-955-091
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Anti-Metastatic and Anti-Inflammatory Effects of Matrix Metalloproteinase Inhibition by Ginsenosides. Biomedicines 2021; 9:biomedicines9020198. [PMID: 33671187 PMCID: PMC7921986 DOI: 10.3390/biomedicines9020198] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/12/2021] [Accepted: 02/14/2021] [Indexed: 12/12/2022] Open
Abstract
Matrix metalloproteinases (MMPs) are proteolytic enzymes which cleave extracellular matrix (ECM) and other substrates. They are deeply involved in both cancer metastasis and human chronic inflammatory diseases such as osteoarthritis and Crohn’s disease. Regulation of MMPs is closely associated with signaling molecules, especially mitogen-activated protein kinases (MAPKs), including three representative kinases, extracellular signal regulated kinases (ERK), p38 and c-Jun N-terminal kinases (JNK). Ginseng (Panax sp.) is a plant which has been traditionally used for medicinal applications. Ginsenosides are major metabolites which have potentials to treat various human diseases. In this review, the pharmacological effects of ginsenosides have been rigorously investigated; these include anti-metastatic and anti-inflammatory activities of ginsenosides associated with suppression of MMPs via regulation of various signaling pathways. This will highlight the importance of MMPs as therapeutic targets for anti-metastatic and anti-inflammatory drug development based on ginsenosides.
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ElTanbouly MA, Zhao Y, Schaafsma E, Burns CM, Mabaera R, Cheng C, Noelle RJ. VISTA: A Target to Manage the Innate Cytokine Storm. Front Immunol 2021; 11:595950. [PMID: 33643285 PMCID: PMC7905033 DOI: 10.3389/fimmu.2020.595950] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 12/11/2020] [Indexed: 12/12/2022] Open
Abstract
In recent years, the success of immunotherapy targeting immunoregulatory receptors (immune checkpoints) in cancer have generated enthusiastic support to target these receptors in a wide range of other immune related diseases. While the overwhelming focus has been on blockade of these inhibitory pathways to augment immunity, agonistic triggering via these receptors offers the promise of dampening pathogenic inflammatory responses. V-domain Ig suppressor of T cell activation (VISTA) has emerged as an immunoregulatory receptor with constitutive expression on both the T cell and myeloid compartments, and whose agonistic targeting has proven a unique avenue relative to other checkpoint pathways to suppress pathologies mediated by the innate arm of the immune system. VISTA agonistic targeting profoundly changes the phenotype of human monocytes towards an anti-inflammatory cell state, as highlighted by striking suppression of the canonical markers CD14 and Fcγr3a (CD16), and the almost complete suppression of both the interferon I (IFN-I) and antigen presentation pathways. The insights from these very recent studies highlight the impact of VISTA agonistic targeting of myeloid cells, and its potential therapeutic implications in the settings of hyperinflammatory responses such as cytokine storms, driven by dysregulated immune responses to viral infections (with a focus on COVID-19) and autoimmune diseases. Collectively, these findings suggest that the VISTA pathway plays a conserved, non-redundant role in myeloid cell function.
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Affiliation(s)
- Mohamed A. ElTanbouly
- Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, United States
| | - Yanding Zhao
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Evelien Schaafsma
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, United States
| | | | - Rodwell Mabaera
- Department of Medicine, Norris Cotton Cancer Center, Lebanon, NH, United States
| | - Chao Cheng
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, United States
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, United States
| | - Randolph J. Noelle
- Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, United States
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Gerber A, Goldklang M, Stearns K, Ma X, Xiao R, Zelonina T, D'Armiento J. Attenuation of pulmonary injury by an inhaled MMP inhibitor in the endotoxin lung injury model. Am J Physiol Lung Cell Mol Physiol 2020; 319:L1036-L1047. [PMID: 33026238 DOI: 10.1152/ajplung.00420.2019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Acute respiratory distress syndrome (ARDS) is characterized by pulmonary edema and poor gas exchange resulting from severe inflammatory lung injury. Neutrophilic infiltration and increased pulmonary vascular permeability are hallmarks of early ARDS and precipitate a self-perpetuating cascade of inflammatory signaling. The biochemical processes initiating these events remain unclear. Typically associated with extracellular matrix degradation, recent data suggest matrix metalloproteinases (MMPs) are regulators of pulmonary inflammation. To demonstrate that inhalation of a broad MMP inhibitor attenuates LPS induced pulmonary inflammation. Nebulized CGS27023AM (CGS) was administered to LPS-injured mice. Pulmonary CGS levels were examined by mass spectroscopy. Inflammatory scoring of hematoxylin-eosin sections, examination of vascular integrity via lung wet/dry and bronchoalveolar lvage/serum FITC-albumin ratios were performed. Cleaved caspase-3 levels were also assessed. Differential cell counts and pulse-chase labeling were utilized to determine the effects of CGS on neutrophil migration. The effects of CGS on human neutrophil migration and viability were examined using Boyden chambers and MTT assays. Nebulization successfully delivered CGS to the lungs. Treatment decreased pulmonary inflammatory scores, edema, and apoptosis in LPS treated animals. Neutrophil chemotaxis was reduced by CGS treatment, with inhalation causing significant reductions in both the total number and newly produced bromodeoxyuridine-positive cells infiltrating the lung. Mechanistic studies on cells isolated from humans demonstrate that CGS-treated neutrophils exhibit decreased chemotaxis. The protective effect observed following treatment with a nonspecific MMP inhibitor indicates that one or more MMPs mediate the development of pulmonary edema and neutrophil infiltration in response to LPS injury. In accordance with this, inhaled MMP inhibitors warrant further study as a potential new therapeutic avenue for treatment of acute lung injury.
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Affiliation(s)
- Adam Gerber
- Department of Anesthesiology, Columbia University Irving Medical Center, New York, New York
| | - Monica Goldklang
- Department of Anesthesiology, Columbia University Irving Medical Center, New York, New York
| | - Kyle Stearns
- Department of Anesthesiology, Columbia University Irving Medical Center, New York, New York
| | - Xinran Ma
- Department of Anesthesiology, Columbia University Irving Medical Center, New York, New York
| | - Rui Xiao
- Department of Anesthesiology, Columbia University Irving Medical Center, New York, New York
| | - Tina Zelonina
- Department of Anesthesiology, Columbia University Irving Medical Center, New York, New York
| | - Jeanine D'Armiento
- Department of Anesthesiology, Columbia University Irving Medical Center, New York, New York
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Fazal N, Khawaja H, Naseer N, Khan AJ, Latief N. Daphne mucronata enhances cell proliferation and protects human adipose stem cells against monosodium iodoacetate induced oxidative stress in vitro. Adipocyte 2020; 9:495-508. [PMID: 32867575 PMCID: PMC7714443 DOI: 10.1080/21623945.2020.1812242] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 08/11/2020] [Accepted: 08/15/2020] [Indexed: 01/01/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are being used to treat many diseases as they exhibit great regenerative potential. However, MSC's transplantation sometimes does not yield the maximum regenerative outcome as they are unable to survive in inflammatory conditions. Several approaches including preconditioning are used to improve the survival rate of mesenchymal stem cells. One such recently reported approach is preconditioning MSCs with plant extracts. The present study was designed to evaluate the effect of Daphne mucronata extract on stressed human adipose-derived mesenchymal stem cells (hADMSCs). Isolated hADMSCs were preconditioned with different concentrations of Daphne muconata extract and the protective, proliferative, antioxidant and anti-inflammatory effect was assessed through various assays and expression analysis of inflammatory markers regulated through NF-κB pathway. Results suggest that preconditioning hADMSCs with Daphne mucronata increased the cell viability, proliferative and protective potential of hADMSCs with a concomitant reduction in LDH, ROS and elevation in SOD activity. Moreover, both the ELISA and gene expression analysis demonstrated down regulations of inflammatory markers (IL1-β, TNF-α, p65, p50, MMP13) in Daphne mucronata preconditioned hADMSCs as compared to stress. This is the first study to report the use of MIA induced oxidative stress against hADMSC's and effect of Daphne mucronata on stressed hADMSCs. Results of these studies provided evidence that Daphne mucronata protects the hADMSCs during stress conditions by down regulating the inflammatory markers and hence increase the viability and proliferative potential of hADMSCs that is crucial for transplantation purposes.
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Affiliation(s)
- Numan Fazal
- National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Hamzah Khawaja
- National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Nadia Naseer
- National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Azim Jahangir Khan
- Allama Iqbal Medical College, University of Health Sciences, Lahore, Pakistan
| | - Noreen Latief
- National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
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Chen PY, Tsai YW, Chang AYW, Chang HH, Hsiao YH, Huang CW, Sung PS, Chen BH, Fu TF. Increased leptin-b expression and metalloprotease expression contributed to the pyridoxine-associated toxicity in zebrafish larvae displaying seizure-like behavior. Biochem Pharmacol 2020; 182:114294. [DOI: 10.1016/j.bcp.2020.114294] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 10/14/2020] [Accepted: 10/15/2020] [Indexed: 12/26/2022]
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Gowler PRW, Mapp PI, Burston JJ, Shahtaheri M, Walsh DA, Chapman V. Refining surgical models of osteoarthritis in mice and rats alters pain phenotype but not joint pathology. PLoS One 2020; 15:e0239663. [PMID: 32991618 PMCID: PMC7523978 DOI: 10.1371/journal.pone.0239663] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 09/10/2020] [Indexed: 11/18/2022] Open
Abstract
The relationship between osteoarthritis (OA) structural change and pain is complex. Surgical models of OA in rodents are often rapid in onset, limiting mechanistic utility and translational validity. We aimed to investigate the effect of refining surgical small rodent models of OA on both joint pathology and pain behaviour. Adult male C57BL/6 mice (n = 76, 10-11 weeks of age at time of surgery) underwent either traditional (transection of the medial meniscotibial ligament [MMTL]) or modified (MMTL left intact, transection of the coronary ligaments) DMM surgery, or sham surgery. Adult male Sprague Dawley rats (n = 76, weight 175-199g) underwent either modified meniscal transection (MMNX) surgery (transection of the medial meniscus whilst the medial collateral ligament is left intact) or sham surgery. Pain behaviours (weight bearing asymmetry [in mice and rats] and paw withdrawal thresholds [in rats]) were measured pre-surgery and weekly up to 16 weeks post-surgery. Post-mortem knee joints were scored for cartilage damage, synovitis, and osteophyte size. There was a significant increase in weight bearing asymmetry from 13 weeks following traditional, but not modified, DMM surgery when compared to sham operated mice. Both traditional and modified DMM surgery led to similar joint pathology. There was significant pain behaviour from 6 weeks following MMNX model compared to sham operated control rats. Synovitis was significant 4 weeks after MMNX surgery, whereas significant chondropathy was first evident 8 weeks post-surgery, compared to sham controls. Pain behaviour is not always present despite significant changes in medial tibial plateau cartilage damage and synovitis, reflecting the heterogeneity seen in human OA. The development of a slowly progressing surgical model of OA pain in the rat suggests that synovitis precedes pain behaviour and that chondropathy is evident later, providing the foundations for future mechanistic studies into the disease.
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Affiliation(s)
- Peter R. W. Gowler
- Pain Centre Versus Arthritis, School of Life Sciences, Queen’s Medical Centre, University of Nottingham, Nottingham, United Kingdom
| | - Paul I. Mapp
- Pain Centre Versus Arthritis, Academic Rheumatology, City Hospital, University of Nottingham, Nottingham, United Kingdom
| | - James J. Burston
- Pain Centre Versus Arthritis, School of Life Sciences, Queen’s Medical Centre, University of Nottingham, Nottingham, United Kingdom
| | - Mohsen Shahtaheri
- Pain Centre Versus Arthritis, Academic Rheumatology, City Hospital, University of Nottingham, Nottingham, United Kingdom
| | - David A. Walsh
- Pain Centre Versus Arthritis, Academic Rheumatology, City Hospital, University of Nottingham, Nottingham, United Kingdom
| | - Victoria Chapman
- Pain Centre Versus Arthritis, School of Life Sciences, Queen’s Medical Centre, University of Nottingham, Nottingham, United Kingdom
- * E-mail:
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48
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Green TRF, Ortiz JB, Wonnacott S, Williams RJ, Rowe RK. The Bidirectional Relationship Between Sleep and Inflammation Links Traumatic Brain Injury and Alzheimer's Disease. Front Neurosci 2020; 14:894. [PMID: 32982677 PMCID: PMC7479838 DOI: 10.3389/fnins.2020.00894] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 07/31/2020] [Indexed: 12/18/2022] Open
Abstract
Traumatic brain injury (TBI) and Alzheimer's disease (AD) are diseases during which the fine-tuned autoregulation of the brain is lost. Despite the stark contrast in their causal mechanisms, both TBI and AD are conditions which elicit a neuroinflammatory response that is coupled with physical, cognitive, and affective symptoms. One commonly reported symptom in both TBI and AD patients is disturbed sleep. Sleep is regulated by circadian and homeostatic processes such that pathological inflammation may disrupt the chemical signaling required to maintain a healthy sleep profile. In this way, immune system activation can influence sleep physiology. Conversely, sleep disturbances can exacerbate symptoms or increase the risk of inflammatory/neurodegenerative diseases. Both TBI and AD are worsened by a chronic pro-inflammatory microenvironment which exacerbates symptoms and worsens clinical outcome. Herein, a positive feedback loop of chronic inflammation and sleep disturbances is initiated. In this review, the bidirectional relationship between sleep disturbances and inflammation is discussed, where chronic inflammation associated with TBI and AD can lead to sleep disturbances and exacerbated neuropathology. The role of microglia and cytokines in sleep disturbances associated with these diseases is highlighted. The proposed sleep and inflammation-mediated link between TBI and AD presents an opportunity for a multifaceted approach to clinical intervention.
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Affiliation(s)
- Tabitha R. F. Green
- BARROW Neurological Institute at Phoenix Children’s Hospital, Phoenix, AZ, United States
- Department of Child Health, University of Arizona College of Medicine – Phoenix, Phoenix, AZ, United States
| | - J. Bryce Ortiz
- BARROW Neurological Institute at Phoenix Children’s Hospital, Phoenix, AZ, United States
- Department of Child Health, University of Arizona College of Medicine – Phoenix, Phoenix, AZ, United States
| | - Sue Wonnacott
- Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom
| | - Robert J. Williams
- Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom
| | - Rachel K. Rowe
- BARROW Neurological Institute at Phoenix Children’s Hospital, Phoenix, AZ, United States
- Department of Child Health, University of Arizona College of Medicine – Phoenix, Phoenix, AZ, United States
- Phoenix Veteran Affairs Health Care System, Phoenix, AZ, United States
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Liu Z, Jiang J, Dai W, Wei H, Zhang X, Yang Z, Xiong Y. MicroRNA-674-5p induced by HIF-1α targets XBP-1 in intestinal epithelial cell injury during endotoxemia. Cell Death Discov 2020; 6:44. [PMID: 32550011 PMCID: PMC7272402 DOI: 10.1038/s41420-020-0280-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 04/30/2020] [Accepted: 05/19/2020] [Indexed: 01/15/2023] Open
Abstract
Intestinal mucosal integrity dysfunction during endotoxemia can contribute to translocation of intestinal bacteria and a persistent systemic inflammatory response, which both fuel the pathophysiological development of sepsis or endotoxemia. The pathogenesis of intestinal damage induced by endotoxemia remains poorly understood. Here, we identified the microRNA (miR)-674-5p/X-box binding protein 1 (XBP-1) axis as a critical regulator and therapeutic target in preventing intestinal crypt cell proliferation during endotoxemia. MiR-674-5p was markedly increased in intestinal epithelial cells (IECs) during endotoxemia and its induction depended on hypoxia-inducible factor-1α (HIF-1α). Intriguingly, gene expression microanalysis revealed that expression of XBP-1 was down-regulated in IECs with over-expression of miR-674-5p. miR-674-5p was found to directly target XBP-1 protein expression. Upon in vitro, anti-miR-674-5p enhanced sXBP-1 expression and facilitated intestinal crypt cell proliferation. Blockade of miR-674-5p promoted XBP-1 activity, attenuated intestinal inflammation, and expedited intestinal regeneration, resulting in protection against endotoxemia-induced intestinal injury in mice. More importantly, the survival in endotoxemia mice was significantly improved by inhibiting intestinal miR-674-5p. Collectively, these data indicate that control of a novel miR-674-5p/XBP-1 signaling axis may mitigate endotoxemia -induced intestinal injury.
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Affiliation(s)
- Zhihao Liu
- Division of Emergency Medicine, Department of General Internal Medicine, Department of Emergency Intensive Care Unit, The First Affiliated Hospital of Sun Yat-sen University, No.58, Zhongshan 2nd Road, 510080 Guangzhou, China
| | - Jie Jiang
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, No.600, Tianhe Road, 510360 Guangzhou, China
| | - Weigang Dai
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, No.58, Zhongshan 2nd Road, 510080 Guangzhou, China
| | - Hongyan Wei
- Division of Emergency Medicine, Department of General Internal Medicine, Department of Emergency Intensive Care Unit, The First Affiliated Hospital of Sun Yat-sen University, No.58, Zhongshan 2nd Road, 510080 Guangzhou, China
| | - Xiaofei Zhang
- Department of Critical Care Medicine, The Sixth Affiliated Hospital of Sun Yat-sen University, No.26, YuanCunErHeng Road, 510655 Guangzhou, China
| | - Zhen Yang
- Division of Emergency Medicine, Department of General Internal Medicine, Department of Emergency Intensive Care Unit, The First Affiliated Hospital of Sun Yat-sen University, No.58, Zhongshan 2nd Road, 510080 Guangzhou, China
| | - Yan Xiong
- Division of Emergency Medicine, Department of General Internal Medicine, Department of Emergency Intensive Care Unit, The First Affiliated Hospital of Sun Yat-sen University, No.58, Zhongshan 2nd Road, 510080 Guangzhou, China
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Astragaloside IV attenuates sepsis-induced intestinal barrier dysfunction via suppressing RhoA/NLRP3 inflammasome signaling. Int Immunopharmacol 2020; 78:106066. [DOI: 10.1016/j.intimp.2019.106066] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 11/10/2019] [Accepted: 11/18/2019] [Indexed: 12/20/2022]
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