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Li YR, Wang G, He WT, Liu T. Application of aggregation-induced emission materials in gastrointestinal diseases. World J Gastroenterol 2025; 31:105378. [PMID: 40308804 PMCID: PMC12038521 DOI: 10.3748/wjg.v31.i16.105378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 03/12/2025] [Accepted: 04/11/2025] [Indexed: 04/27/2025] Open
Abstract
Aggregation-induced emission (AIE) is a phenomenon characterized by certain fluorescent molecules that exhibit weak or no luminescence in solution but demonstrate significantly enhanced luminescence upon aggregation. Accordingly, AIE materials have successfully addressed the limitations associated with aggregation-caused quenching effects and have made significant progress in the application of various fields of medicine in recent years. At present, the application of AIE materials in gastrointestinal (GI) diseases is mainly in GI imaging, diagnosis and treatment. In this review, we summarize the applications of AIE materials in GI pathogens and GI diseases, including inflammatory bowel disease and GI tumors, and outline combined treatment methods of AIE materials in GI tumor therapy.
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Affiliation(s)
- Yi-Rong Li
- School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Digestive System Tumor Prevention and Treatment and Translational Medicine Engineering Innovation Center of Lanzhou University, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Digestive System Tumor Translational Medicine Engineering Research Center of Gansu Province, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Gansu Provincial Key Laboratory of Environmental Oncology, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Gang Wang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Digestive System Tumor Prevention and Treatment and Translational Medicine Engineering Innovation Center of Lanzhou University, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Digestive System Tumor Translational Medicine Engineering Research Center of Gansu Province, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Gansu Provincial Key Laboratory of Environmental Oncology, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Wen-Ting He
- School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Digestive System Tumor Prevention and Treatment and Translational Medicine Engineering Innovation Center of Lanzhou University, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Digestive System Tumor Translational Medicine Engineering Research Center of Gansu Province, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Gansu Provincial Key Laboratory of Environmental Oncology, Lanzhou University, Lanzhou 730000, Gansu Province, China
- The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, Gansu Province, China
| | - Tao Liu
- School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Digestive System Tumor Prevention and Treatment and Translational Medicine Engineering Innovation Center of Lanzhou University, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Digestive System Tumor Translational Medicine Engineering Research Center of Gansu Province, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Gansu Provincial Key Laboratory of Environmental Oncology, Lanzhou University, Lanzhou 730000, Gansu Province, China
- The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, Gansu Province, China
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Silva-Lagos L, Ijaz A, Buwalda P, Kassai S, Klostermann CE, Leemhuis H, Veldhuizen EJA, Schols HA, López-Velázquez G, de Vos P. Immunostimulatory effects of isomalto/malto-polysaccharides via TLR2 and TLR4 in preventing doxycycline-induced cytokine loss. Carbohydr Polym 2025; 350:122980. [PMID: 39647934 DOI: 10.1016/j.carbpol.2024.122980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 10/11/2024] [Accepted: 11/11/2024] [Indexed: 12/10/2024]
Abstract
Isomalto/malto-polysaccharides (IMMPs) are α-glucans with prebiotic potential used as food ingredients. However, their ability to exert direct cellular effects remains unknown. IMMPs may enhance immunity by activating toll-like receptors (TLRs), key for defense against pathogens. Doxycycline is an antibiotic that requires an effective immune function but paradoxically has immune-attenuating effects by reducing TLR2 activity, potentially increasing antibiotic needs. We hypothesize that IMMPs are recognized by various cell surface TLRs, leading to the activation of the NF-κB signaling pathway. Furthermore, IMMPs' immune-stimulating effect could prevent the doxycycline-induced reduction of TLR2 activity in immune cells. IMMPs activated TLR2, increasing NF-κB signaling by 3.42- and 6.37-fold at 1 and 2 mg/mL, respectively. TLR4 activation increased 5.47-, 7.39-, and 8.34-fold at 0.5, 1, and 2 mg/mL. IMMPs enhanced IL-8, TNFα, and IL1-RA production in THP-1 monocytes. Additionally, preincubation of macrophages with IMMPs enhanced cytokine production and partially prevented doxycycline-induced cytokine reduction in response to TLR2 activation. Molecular docking analyses support IMMPs and doxycycline binding to these TLRs. These findings suggest that IMMPs stimulate immunity via TLR2 and TLR4, partially mitigating doxycycline's adverse effects. This provides a dietary strategy to enhance pathogen clearance, reduce antibiotic needs, and support immune health.
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Affiliation(s)
- Luis Silva-Lagos
- Immunoendocrinology, Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, the Netherlands.
| | - Adil Ijaz
- Division Infectious Diseases and Immunology, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands; Immunology Center of Georgia, Augusta University, Augusta, GA, United States
| | - P Buwalda
- Biobased Chemistry and Technology, Wageningen University & Research, Wageningen, the Netherlands; Innovation Center, Royal Avebe, Groningen, the Netherlands
| | - Sonia Kassai
- Immunoendocrinology, Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, the Netherlands
| | - Cynthia E Klostermann
- Biobased Chemistry and Technology, Wageningen University & Research, Wageningen, the Netherlands; Laboratory of Food Chemistry, Wageningen University & Research, Wageningen, the Netherlands
| | - Hans Leemhuis
- Innovation Center, Royal Avebe, Groningen, the Netherlands
| | - Edwin J A Veldhuizen
- Division Infectious Diseases and Immunology, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands
| | - Henk A Schols
- Laboratory of Food Chemistry, Wageningen University & Research, Wageningen, the Netherlands
| | - Gabriel López-Velázquez
- Laboratorio de Biomoléculas y Salud Infantil, Instituto Nacional de Pediatría, Cuidad de México, Mexico
| | - Paul de Vos
- Immunoendocrinology, Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, the Netherlands
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Bosáková V, Papatheodorou I, Kafka F, Tomášiková Z, Kolovos P, Hortová Kohoutková M, Frič J. Serotonin attenuates tumor necrosis factor-induced intestinal inflammation by interacting with human mucosal tissue. Exp Mol Med 2025; 57:364-378. [PMID: 39894823 PMCID: PMC11873120 DOI: 10.1038/s12276-025-01397-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 10/13/2024] [Accepted: 11/19/2024] [Indexed: 02/04/2025] Open
Abstract
The intestine hosts the largest immune system and peripheral nervous system in the human body. The gut‒brain axis orchestrates communication between the central and enteric nervous systems, playing a pivotal role in regulating overall body function and intestinal homeostasis. Here, using a human three-dimensional in vitro culture model, we investigated the effects of serotonin, a neuromodulator produced in the gut, on immune cell and intestinal tissue interactions. Serotonin attenuated the tumor necrosis factor-induced proinflammatory response, mostly by affecting the expression of chemokines. Serotonin affected the phenotype and distribution of tissue-migrating monocytes, without direct contact with the cells, by remodeling the intestinal tissue. Collectively, our results show that serotonin plays a crucial role in communication among gut-brain axis components and regulates monocyte migration and plasticity, thereby contributing to gut homeostasis and the progression of inflammation. In vivo studies focused on the role of neuromodulators in gut inflammation have shown controversial results, highlighting the importance of human experimental models. Moreover, our results emphasize the importance of human health research in human cell-based models and suggest that the serotonin signaling pathway is a new therapeutic target for inflammatory bowel disease.
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Affiliation(s)
- Veronika Bosáková
- International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Ioanna Papatheodorou
- International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Filip Kafka
- International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Zuzana Tomášiková
- International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Petros Kolovos
- Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece
| | - Marcela Hortová Kohoutková
- International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
- International Clinical Research Center, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
| | - Jan Frič
- International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
- International Clinical Research Center, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
- Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
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Zeng C, Zhu Q, Peng W, Huang C, Chen H, Huang H, Zhou Y, Zhao C. The protective effect of amitriptyline on experimental colitis through inhibiting TLR-4/MD-2 signaling pathway. J Pharmacol Exp Ther 2025; 392:100024. [PMID: 39892990 DOI: 10.1124/jpet.124.002207] [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: 03/08/2024] [Revised: 08/23/2024] [Accepted: 08/26/2024] [Indexed: 10/10/2024] Open
Abstract
Amitriptyline, a pleiotropic tricyclic antidepressant, possesses antioxidant and anti-inflammatory properties. Despite its diverse benefits, the specific effects of amitriptyline on inflammatory bowel disease (IBD) are not yet well defined. To explore this, we used a dextran sulfate sodium (DSS)-induced colitis model to examine the anti-inflammatory effects of amitriptyline and the underlying mechanisms by which it operates. Our research revealed that amitriptyline is effective in alleviating several pathological manifestations associated with colitis. This includes improving body weight retention, reducing disease activity index, lessening of colon length shortening, and repairing of colonic mucosal damage. Treatment with amitriptyline significantly protected mucosal injury by preserving the population of goblet cells and increasing the expression of tight junction proteins. Furthermore, we observed that amitriptyline effectively countered immune cell infiltration, specifically neutrophils and macrophages, while simultaneously lowering the levels of inflammatory cytokines such as tumor necrosis factor α, interleukin (IL)-1β, and IL-6. Additionally, RNA sequencing analysis pointed to the potential involvement of the Toll-like receptor (TLR) pathway in the anticolitic effects induced by amitriptyline. Subsequent Western blot analysis indicated that amitriptyline significantly inhibited the TLR-4-mediated nuclear factor (NF)-κB signaling pathway. To bolster our findings, in vitro studies demonstrated that amitriptyline downregulated the TLR-4/NF-κB/mitogen-activated protein kinase signaling cascades in mouse macrophages stimulated with lipopolysaccharide. Further molecular investigations revealed that amitriptyline was able to suppress the elevated expression of myeloid differentiation factor 2 that lipopolysaccharide stimulation typically induces. In summary, our findings suggest that amitriptyline effectively mitigates DSS-induced colitis in mice through the inhibition of TLR-4/myeloid differentiation 2 pathway signaling, indicating its potential repurposing for IBD treatment. SIGNIFICANCE STATEMENT: The potential of using amitriptyline in treating inflammatory bowel disease appears promising, leveraging its established safety and dosing profile as an antidepressant. The study results show that amitriptyline can alleviate pathological symptoms, inflammation, and intestinal mucosal damage in mice with colitis induced by DSS. The protective effect observed appears to be linked to the inhibition of TLR-4/myeloid differentiation 2 signaling pathway. By exploring novel applications for existing medications, we can optimize amitriptyline's efficacy and broaden its impact in both medical and commercial contexts.
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Affiliation(s)
- Chengcheng Zeng
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medical, South China University of Technology, Guangzhou, Guangdong, China; Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, China
| | - Qingqing Zhu
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medical, South China University of Technology, Guangzhou, Guangdong, China; Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, China
| | - Wu Peng
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medical, South China University of Technology, Guangzhou, Guangdong, China; Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, China
| | - Chen Huang
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medical, South China University of Technology, Guangzhou, Guangdong, China; Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, China
| | - Huiting Chen
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medical, South China University of Technology, Guangzhou, Guangdong, China; Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, China
| | - Hongli Huang
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medical, South China University of Technology, Guangzhou, Guangdong, China; Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, China
| | - Yongjian Zhou
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medical, South China University of Technology, Guangzhou, Guangdong, China; Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, China
| | - Chong Zhao
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medical, South China University of Technology, Guangzhou, Guangdong, China; Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, China.
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Yao X, Wang S, Li X, Wen J, Huang Y, Lan W, Huang X, Li H, Sun Y, Zhao X, Zhang T. Genetically predict the association between 91 human blood cell perturbation phenotypes and IBD: A Mendelian randomization study. Medicine (Baltimore) 2024; 103:e40647. [PMID: 39809186 PMCID: PMC11596769 DOI: 10.1097/md.0000000000040647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 11/05/2024] [Indexed: 01/16/2025] Open
Abstract
Inflammatory bowel disease (IBD), encompassing Crohn disease and ulcerative colitis, is a group of persistent and recurrent gastrointestinal disorders. Despite the prevalence of these conditions, no studies have been conducted to examine the connection between altered human blood cell phenotypes and the underlying mechanisms of IBD pathogenesis. By utilizing summary statistics from genome-wide association studies, we executed a systematic two-sample Mendelian randomization (MR) investigation on 91 genetically determined blood cell perturbation traits in relation to 3 separate IBD phenotypes. Our analysis sought to delineate the putative causal links between these blood cell perturbation phenotypes and IBD, thereby contributing to a more nuanced comprehension of the pathophysiological underpinnings and offering a foundation for the development of novel therapeutic approaches. The forward MR analysis identified 7 human blood cell perturbation phenotypes associated with various IBD outcomes, while the reverse MR analysis revealed that 9 human blood cell perturbation phenotypes were influenced by various IBD phenotypes. The study has uncovered human blood cell perturbation phenotypes associated with various IBD diseases, contributing to a deeper understanding of the pathogenesis of IBD. It also provides new insights for early clinical diagnosis, disease activity monitoring, immune surveillance, prognosis assessment, and personalized treatment.
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Affiliation(s)
- Xin Yao
- Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Song Wang
- Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Xiao Li
- Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Jieying Wen
- Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Yunsi Huang
- Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Weixuan Lan
- Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Xuyu Huang
- Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Hao Li
- Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Yunlong Sun
- Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Xiaoqian Zhao
- Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Tao Zhang
- Department of Gastroenterology, Ruikang Hospital of Guangxi Traditional Chinese Medical University, Nanning, Guangxi, China
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Tardalkar K, Patil S, Chaudhari L, Kshersagar J, Damle M, Kawale A, Bhamare N, Desai V, Pathak N, Gaikwad V, Joshi MG. Decellularized small intestine scaffolds: a potential xenograft for restoration of intestinal perforation. Tissue Barriers 2024; 12:2290940. [PMID: 38053224 PMCID: PMC11583676 DOI: 10.1080/21688370.2023.2290940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 11/25/2023] [Accepted: 11/29/2023] [Indexed: 12/07/2023] Open
Abstract
Small intestine perforation is a serious medical condition that requires immediate medical attention. The traditional course of treatment entails resection followed by anastomosis; however, it has complications such as small bowel syndrome (SBS), anastomotic leakage, and fistula formation. Here, a novel strategy is demonstrated, that utilizes the xenogeneic, decellularized goat small intestine as a patch for small intestine regeneration in cases of intestinal perforation. The goat small intestine scaffold underwent sodium dodecyl sulfate decellularization, which revealed consistent, quick, and effective decellularization. Decellularization contributed the least amount of extracellular matrix degradation while maintaining the intestinal architecture. By implanting the decellularized goat small intestine scaffolds (DGSIS) on the chorioallantoic membrane (CAM), no discernible loss of angiogenesis was seen in the CAM region, and this enabled the DGSIS to be evaluated for biocompatibility in ovo. The DGSIS was then xeno-transplanted as a patch on a small intestine perforation rat model. After 30 days post transplant, barium salt used as contrast gastrointestinal X-ray imaging revealed no leakage or obstruction in the small intestine. Histology, scanning electron microscopy, and immunohistochemistry assisted in analyzing the engraftment of host cells into the xeno patch. The xeno-patch expressed high levels of E-cadherin, α-smooth muscle actin (α-SMA), Occludin, Zonnula occluden (ZO-1), Ki 67, and Na+/K+-ATPase. The xeno-patch was consequently recellularized and incorporated into the host without causing an inflammatory reaction. As an outcome, decellularized goat small intestine was employed as a xenograft and could be suitable for regeneration of the perforated small intestine.
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Affiliation(s)
- Kishor Tardalkar
- Department of Stem Cells & Regenerative Medicine, D. Y. Patil Education Society (Deemed to be University), Kolhapur, MS, India
| | | | - Leena Chaudhari
- Department of Stem Cells & Regenerative Medicine, D. Y. Patil Education Society (Deemed to be University), Kolhapur, MS, India
- Department of Surgery, Dr. D Y Patil Medical College, Hospital and Research Institute, Kolhapur, India
- Stem Plus Biotech, Sangli, MS, India
| | - Jeevitaa Kshersagar
- Department of Stem Cells & Regenerative Medicine, D. Y. Patil Education Society (Deemed to be University), Kolhapur, MS, India
| | - Mrunal Damle
- Department of Stem Cells & Regenerative Medicine, D. Y. Patil Education Society (Deemed to be University), Kolhapur, MS, India
- Department of Surgery, Dr. D Y Patil Medical College, Hospital and Research Institute, Kolhapur, India
- Stem Plus Biotech, Sangli, MS, India
| | - Akshay Kawale
- Department of Stem Cells & Regenerative Medicine, D. Y. Patil Education Society (Deemed to be University), Kolhapur, MS, India
- Department of Surgery, Dr. D Y Patil Medical College, Hospital and Research Institute, Kolhapur, India
- Stem Plus Biotech, Sangli, MS, India
| | - Nilesh Bhamare
- Department of Stem Cells & Regenerative Medicine, D. Y. Patil Education Society (Deemed to be University), Kolhapur, MS, India
| | - Vaishnavi Desai
- Department of Stem Cells & Regenerative Medicine, D. Y. Patil Education Society (Deemed to be University), Kolhapur, MS, India
| | - Narayani Pathak
- Department of Stem Cells & Regenerative Medicine, D. Y. Patil Education Society (Deemed to be University), Kolhapur, MS, India
| | - Vaishali Gaikwad
- Department of Surgery, Dr. D Y Patil Medical College, Hospital and Research Institute, Kolhapur, India
| | - Meghnad G Joshi
- Department of Stem Cells & Regenerative Medicine, D. Y. Patil Education Society (Deemed to be University), Kolhapur, MS, India
- Stem Plus Biotech, Sangli, MS, India
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Singh D, Mehghini P, Rodriguez-Palacios A, Di Martino L, Cominelli F, Basson AR. Anti-Inflammatory Effect of Dietary Pentadecanoic Fatty Acid Supplementation on Inflammatory Bowel Disease in SAMP1/YitFc Mice. Nutrients 2024; 16:3031. [PMID: 39275347 PMCID: PMC11397537 DOI: 10.3390/nu16173031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 09/03/2024] [Accepted: 09/05/2024] [Indexed: 09/16/2024] Open
Abstract
BACKGROUND/OBJECTIVES Dietary fats have been linked to the increasing incidence of chronic diseases, including inflammatory bowel diseases (IBD), namely, Crohn's disease (CD). METHODS This study investigated the impact of pentadecanoic acid (C15:0), a type of an odd-numbered chain saturated fatty acid, for its potential anti-inflammatory properties in different mouse models of experimental IBD using the SAMP1/YitFc (SAMP) mouse line (14- or 24-week-old), including chronic ileitis and DSS-induced colitis. To quantitively assess the effect of C:15, we tested two dosages of C:15 in selected experiments in comparison to control mice. Intestinal inflammation and intestinal permeability were used as primary outcomes. RESULTS In ileitis, C:15 supplementation showed an anti-inflammatory effect in SAMP mice (e.g., a reduction in ileitis severity vs. control p < 0.0043), which was reproducible when mice were tested in the DSS model of colitis (e.g., reduced permeability vs. control p < 0.0006). Of relevance, even the short-term C:15 therapy prevented colitis in mice by maintaining body weight, decreasing inflammation, preserving gut integrity, and alleviating colitis signs. CONCLUSIONS Collectively, the findings from both ileitis and colitis in SAMP mice indicate that C:15 may have therapeutic effects in the treatment of IBD (colitis in the short term). This promising effect has major translational potential for the alleviation of IBD in humans.
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Affiliation(s)
- Drishtant Singh
- Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA;
- Division of Gastroenterology & Liver Diseases, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; (P.M.); (A.R.-P.); (F.C.)
| | - Paola Mehghini
- Division of Gastroenterology & Liver Diseases, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; (P.M.); (A.R.-P.); (F.C.)
- Digestive Health Research Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
| | - Alexander Rodriguez-Palacios
- Division of Gastroenterology & Liver Diseases, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; (P.M.); (A.R.-P.); (F.C.)
- Digestive Health Research Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
- Mouse Models Core, Silvio O’Conte Cleveland Digestive Diseases Research Core Center, Cleveland, OH 44106, USA
- Germ-Free and Gut Microbiome Core, Digestive Health Research Institute, Case Western Reserve University, Cleveland, OH 44106, USA
- Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Luca Di Martino
- Case Digestive Health Research Institute, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA;
- Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Fabio Cominelli
- Division of Gastroenterology & Liver Diseases, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; (P.M.); (A.R.-P.); (F.C.)
- Digestive Health Research Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
- Mouse Models Core, Silvio O’Conte Cleveland Digestive Diseases Research Core Center, Cleveland, OH 44106, USA
- Germ-Free and Gut Microbiome Core, Digestive Health Research Institute, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Abigail Raffner Basson
- Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA;
- Division of Gastroenterology & Liver Diseases, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; (P.M.); (A.R.-P.); (F.C.)
- Digestive Health Research Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
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Singh SB, Braun CA, Carroll-Portillo A, Coffman CN, Lin HC. Sulfate-Reducing Bacteria Induce Pro-Inflammatory TNF-α and iNOS via PI3K/Akt Pathway in a TLR 2-Dependent Manner. Microorganisms 2024; 12:1833. [PMID: 39338507 PMCID: PMC11434237 DOI: 10.3390/microorganisms12091833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 08/31/2024] [Accepted: 09/02/2024] [Indexed: 09/30/2024] Open
Abstract
Desulfovibrio, resident gut sulfate-reducing bacteria (SRB), are found to overgrow in diseases such as inflammatory bowel disease and Parkinson's disease. They activate a pro-inflammatory response, suggesting that Desulfovibrio may play a causal role in inflammation. Class I phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway regulates key events in the inflammatory response to infection. Dysfunctional PI3K/Akt signaling is linked to numerous diseases. Bacterial-induced PI3K/Akt pathway may be activated downstream of toll-like receptor (TLR) signaling. Here, we tested the hypothesis that Desulfovibrio vulgaris (DSV) may induce tumor necrosis factor alpha (TNF-α) and inducible nitric oxide synthase (iNOS) expression via PI3K/Akt in a TLR 2-dependent manner. RAW 264.7 macrophages were infected with DSV, and protein expression of p-Akt, p-p70S6K, p-NF-κB, p-IkB, TNF-α, and iNOS was measured. We found that DSV induced these proteins in a time-dependent manner. Heat-killed and live DSV, but not bacterial culture supernatant or a probiotic Lactobacillus plantarum, significantly caused PI3K/AKT/TNF/iNOS activation. LY294002, a PI3K/Akt signaling inhibitor, and TL2-C29, a TLR 2 antagonist, inhibited DSV-induced PI3K/AKT pathway. Thus, DSV induces pro-inflammatory TNF-α and iNOS via PI3K/Akt pathway in a TLR 2-dependent manner. Taken together, our study identifies a novel mechanism by which SRB such as Desulfovibrio may trigger inflammation in diseases associated with SRB overgrowth.
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Affiliation(s)
- Sudha B Singh
- Biomedical Research Institute of New Mexico, New Mexico Veterans Affairs (VA) Health Care System, 1501 San Pedro Dr. SE, Albuquerque, NM 87108, USA
| | - Cody A Braun
- Biomedical Research Institute of New Mexico, New Mexico Veterans Affairs (VA) Health Care System, 1501 San Pedro Dr. SE, Albuquerque, NM 87108, USA
| | - Amanda Carroll-Portillo
- Division of Gastroenterology and Hepatology, Department of Medicine, University of New Mexico, Albuquerque, NM 87131, USA
| | - Cristina N Coffman
- Biomedical Research Institute of New Mexico, New Mexico Veterans Affairs (VA) Health Care System, 1501 San Pedro Dr. SE, Albuquerque, NM 87108, USA
| | - Henry C Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, University of New Mexico, Albuquerque, NM 87131, USA
- Medicine Service, New Mexico Veterans Affairs (VA) Health Care System, 1501 San Pedro Dr. SE, Albuquerque, NM 87108, USA
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9
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Kuri PR, Goswami P. Reverse vaccinology-based multi-epitope vaccine design against Indian group A rotavirus targeting VP7, VP4, and VP6 proteins. Microb Pathog 2024; 193:106775. [PMID: 38960216 DOI: 10.1016/j.micpath.2024.106775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 06/25/2024] [Accepted: 06/30/2024] [Indexed: 07/05/2024]
Abstract
Rotavirus, a primary contributor to severe cases of infantile gastroenteritis on a global scale, results in significant morbidity and mortality in the under-five population, particularly in middle to low-income countries, including India. WHO-approved live-attenuated vaccines are linked to a heightened susceptibility to intussusception and exhibit low efficacy, primarily attributed to the high genetic diversity of rotavirus, varying over time and across different geographic regions. Herein, molecular data on Indian rotavirus A (RVA) has been reviewed through phylogenetic analysis, revealing G1P[8] to be the prevalent strain of RVA in India. The conserved capsid protein sequences of VP7, VP4 and VP6 were used to examine helper T lymphocyte, cytotoxic T lymphocyte and linear B-cell epitopes. Twenty epitopes were identified after evaluation of factors such as antigenicity, non-allergenicity, non-toxicity, and stability. These epitopes were then interconnected using suitable linkers and an N-terminal beta defensin adjuvant. The in silico designed vaccine exhibited structural stability and interactions with integrins (αvβ3 and αIIbβ3) and toll-like receptors (TLR2 and TLR4) indicated by docking and normal mode analyses. The immune simulation profile of the designed RVA multiepitope vaccine exhibited its potential to trigger humoral as well as cell-mediated immunity, indicating that it is a promising immunogen. These computational findings indicate potential efficacy of the designed vaccine against rotavirus infection.
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Affiliation(s)
- Pooja Rani Kuri
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam, 781039, India.
| | - Pranab Goswami
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam, 781039, India.
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10
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Luo Y, Zhang G, Hu C, Huang L, Wang D, Chen Z, Wang Y. The Role of Natural Products from Herbal Medicine in TLR4 Signaling for Colorectal Cancer Treatment. Molecules 2024; 29:2727. [PMID: 38930793 PMCID: PMC11206024 DOI: 10.3390/molecules29122727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 05/24/2024] [Accepted: 06/05/2024] [Indexed: 06/28/2024] Open
Abstract
The toll-like receptor 4 (TLR4) signaling pathway constitutes an intricate network of protein interactions primarily involved in inflammation and cancer. This pathway triggers intracellular signaling cascades, modulating transcription factors that regulate gene expression related to immunity and malignancy. Previous studies showed that colon cancer patients with low TLR4 expression exhibit extended survival times and the TLR4 signaling pathway holds a significant role in CRC pathogenesis. In recent years, traditional Chinese medicines (TCMs) have garnered substantial attention as an alternative therapeutic modality for CRC, primarily due to their multifaceted composition and ability to target multiple pathways. Emerging evidence indicates that specific TCM products, such as andrographolide, rosmarinic acid, baicalin, etc., have the potential to impede CRC development through the TLR4 signaling pathway. Here, we review the role and biochemical processes of the TLR4 signaling pathway in CRC, and natural products from TCMs affecting the TLR4 pathway. This review sheds light on potential treatment strategies utilizing natural TLR4 inhibitors for CRC, which contributes to the advancement of research and accelerates their clinical integration into CRC treatment.
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Affiliation(s)
- Yan Luo
- School of Basic Medical Sciences, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (Y.L.); (G.Z.); (L.H.); (D.W.)
| | - Guochen Zhang
- School of Basic Medical Sciences, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (Y.L.); (G.Z.); (L.H.); (D.W.)
| | - Chao Hu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China;
| | - Lijun Huang
- School of Basic Medical Sciences, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (Y.L.); (G.Z.); (L.H.); (D.W.)
| | - Dong Wang
- School of Basic Medical Sciences, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (Y.L.); (G.Z.); (L.H.); (D.W.)
| | - Zhejie Chen
- Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Institute of Molecular Medicine (IMM), Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Yumei Wang
- School of Basic Medical Sciences, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (Y.L.); (G.Z.); (L.H.); (D.W.)
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11
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Speciale A, Molonia MS, Muscarà C, Cristani M, Salamone FL, Saija A, Cimino F. An overview on the cellular mechanisms of anthocyanins in maintaining intestinal integrity and function. Fitoterapia 2024; 175:105953. [PMID: 38588905 DOI: 10.1016/j.fitote.2024.105953] [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: 02/02/2024] [Revised: 04/02/2024] [Accepted: 04/04/2024] [Indexed: 04/10/2024]
Abstract
Structural and functional changes of the intestinal barrier, as a consequence of a number of (epi)genetic and environmental causes, have a main role in penetrations of pathogens and toxic agents, and lead to the development of inflammation-related pathological conditions, not only at the level of the GI tract but also in other extra-digestive tissues and organs. Anthocyanins (ACNs), a subclass of polyphenols belonging to the flavonoid group, are well known for their health-promoting properties and are widely distributed in the human diet. There is large evidence about the correlation between the human intake of ACN-rich products and a reduction of intestinal inflammation and dysfunction. Our review describes the more recent advances in the knowledge of cellular and molecular mechanisms through which ACNs can modulate the main mechanisms involved in intestinal dysfunction and inflammation, in particular the inhibition of the NF-κB, JNK, MAPK, STAT3, and TLR4 proinflammatory pathways, the upregulation of the Nrf2 transcription factor and the expression of tight junction proteins and mucins.
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Affiliation(s)
- Antonio Speciale
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno D'Alcontres 31, Messina 98166, Italy.
| | - Maria Sofia Molonia
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno D'Alcontres 31, Messina 98166, Italy; "Prof. Antonio Imbesi" Foundation, University of Messina, Messina 98100, Italy.
| | - Claudia Muscarà
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno D'Alcontres 31, Messina 98166, Italy.
| | - Mariateresa Cristani
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno D'Alcontres 31, Messina 98166, Italy.
| | - Federica Lina Salamone
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno D'Alcontres 31, Messina 98166, Italy.
| | - Antonella Saija
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno D'Alcontres 31, Messina 98166, Italy.
| | - Francesco Cimino
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno D'Alcontres 31, Messina 98166, Italy.
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12
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Olivo-Martínez Y, Martínez-Ruiz S, Cordero-Alday C, Bosch M, Badia J, Baldoma L. Modulation of Serotonin-Related Genes by Extracellular Vesicles of the Probiotic Escherichia coli Nissle 1917 in the Interleukin-1β-Induced Inflammation Model of Intestinal Epithelial Cells. Int J Mol Sci 2024; 25:5338. [PMID: 38791376 PMCID: PMC11121267 DOI: 10.3390/ijms25105338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 05/07/2024] [Accepted: 05/09/2024] [Indexed: 05/26/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory condition involving dysregulated immune responses and imbalances in the gut microbiota in genetically susceptible individuals. Current therapies for IBD often have significant side-effects and limited success, prompting the search for novel therapeutic strategies. Microbiome-based approaches aim to restore the gut microbiota balance towards anti-inflammatory and mucosa-healing profiles. Extracellular vesicles (EVs) from beneficial gut microbes are emerging as potential postbiotics. Serotonin plays a crucial role in intestinal homeostasis, and its dysregulation is associated with IBD severity. Our study investigated the impact of EVs from the probiotic Nissle 1917 (EcN) and commensal E. coli on intestinal serotonin metabolism under inflammatory conditions using an IL-1β-induced inflammation model in Caco-2 cells. We found strain-specific effects. Specifically, EcN EVs reduced free serotonin levels by upregulating SERT expression through the downregulation of miR-24, miR-200a, TLR4, and NOD1. Additionally, EcN EVs mitigated IL-1β-induced changes in tight junction proteins and oxidative stress markers. These findings underscore the potential of postbiotic interventions as a therapeutic approach for IBD and related pathologies, with EcN EVs exhibiting promise in modulating serotonin metabolism and preserving intestinal barrier integrity. This study is the first to demonstrate the regulation of miR-24 and miR-200a by probiotic-derived EVs.
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Affiliation(s)
- Yenifer Olivo-Martínez
- Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, 08028 Barcelona, Spain; (Y.O.-M.); (S.M.-R.); (C.C.-A.)
- Biochemistry and Diseases Research Group, Facultad de Medicina, Universidad de Cartagena, Cartagena 130015, Colombia
| | - Sergio Martínez-Ruiz
- Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, 08028 Barcelona, Spain; (Y.O.-M.); (S.M.-R.); (C.C.-A.)
- Institut de Biomedicina de la Universitat de Barcelona (IBUB), 08028 Barcelona, Spain
- Institut de Recerca Sant Joan de Déu (IRSJD), 08950 Barcelona, Spain
| | - Cecilia Cordero-Alday
- Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, 08028 Barcelona, Spain; (Y.O.-M.); (S.M.-R.); (C.C.-A.)
- Institut de Biomedicina de la Universitat de Barcelona (IBUB), 08028 Barcelona, Spain
- Institut de Recerca Sant Joan de Déu (IRSJD), 08950 Barcelona, Spain
| | - Manel Bosch
- Unitat de Microscòpia Òptica Avançada, Centres Científics i Tecnològics, Universitat de Barcelona, 08028 Barcelona, Spain;
| | - Josefa Badia
- Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, 08028 Barcelona, Spain; (Y.O.-M.); (S.M.-R.); (C.C.-A.)
- Institut de Biomedicina de la Universitat de Barcelona (IBUB), 08028 Barcelona, Spain
- Institut de Recerca Sant Joan de Déu (IRSJD), 08950 Barcelona, Spain
| | - Laura Baldoma
- Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, 08028 Barcelona, Spain; (Y.O.-M.); (S.M.-R.); (C.C.-A.)
- Institut de Biomedicina de la Universitat de Barcelona (IBUB), 08028 Barcelona, Spain
- Institut de Recerca Sant Joan de Déu (IRSJD), 08950 Barcelona, Spain
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13
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Chen Y, Jin T, Zhang M, Hong B, Jin B, Hu C, Wang J, Chen Y, Zhang L, Wang Y, Huang L. Flavokawain B inhibits NF-κB inflammatory signaling pathway activation in inflammatory bowel disease by targeting TLR2. Toxicol Appl Pharmacol 2024; 486:116922. [PMID: 38583725 DOI: 10.1016/j.taap.2024.116922] [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: 12/03/2023] [Revised: 03/11/2024] [Accepted: 04/04/2024] [Indexed: 04/09/2024]
Abstract
Inflammatory bowel disease (IBD) is characterized by recurrent inflammatory reactions in the intestinal mucosa, including ulcerative colitis (UC) and Crohn's disease (CD). The expression of Toll-like receptor 2 (TLR2) has been observed to increase during the progression of IBD. Flavokawain B (FKB), a natural chalcone with potent anti-inflammatory activity, exerts its effects through inhibition of the NF-κB pathway. In this study, we aimed to investigate the effects and mechanisms of FKB targeting TLR2 in IBD. C57BL/6 J mice were treated with 2.5% dextran sulfate sodium (DSS) for 7 days, with administration of FKB or TLR2 inhibitor C29 starting on day 2 to establish the model of IBD. In vitro, bone marrow-derived macrophages (BMDMs) were stimulated with the TLR2 agonist Pam3CSK4 to explore the therapeutic effect of FKB and its pharmacological mechanism. Compared with the model group, the FKB-treated group showed significant reductions in colitis-related injuries in the IBD mouse model, including weight gain, increased colon length and reduced inflammation. FKB decreased the formation of TLR2-MyD88 complex by targeting TLR2, leading to suppression of downstream NF-κB signaling pathway. Similar therapeutic effects were observed in the C29-treated group. Additionally, in vitro data suggested that FKB exerted its anti-inflammatory effect by targeting TLR2 and inhibiting Pam3CSK4-induced activation of the NF-κB pathway. The anti-inflammatory effects of FKB were demonstrated through drug affinity responsive target stability assay and cellular thermal shift assay, revealing its binding affinity to TLR2. By inhibiting the activation of the TLR2/NF-κB signaling pathway, FKB effectively prevented DSS-induced IBD and exhibited promising potential as a therapeutic candidate for IBD treatment.
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Affiliation(s)
- Yi Chen
- Joint Research Center on Medicine, the Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, Zhejiang, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Tianyang Jin
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Mengpei Zhang
- Joint Research Center on Medicine, the Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, Zhejiang, China
| | - Bo Hong
- Joint Research Center on Medicine, the Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, Zhejiang, China
| | - Bo Jin
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Chenghong Hu
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Jiong Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yue Chen
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Lingxi Zhang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yi Wang
- Joint Research Center on Medicine, the Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, Zhejiang, China; School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China.
| | - Lijiang Huang
- Joint Research Center on Medicine, the Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, Zhejiang, China.
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14
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Kim HJ, Jeon HJ, Kim JY, Shim JJ, Lee JH. Lactiplantibacillus plantarum HY7718 Improves Intestinal Integrity in a DSS-Induced Ulcerative Colitis Mouse Model by Suppressing Inflammation through Modulation of the Gut Microbiota. Int J Mol Sci 2024; 25:575. [PMID: 38203747 PMCID: PMC10779067 DOI: 10.3390/ijms25010575] [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: 12/13/2023] [Revised: 12/27/2023] [Accepted: 12/29/2023] [Indexed: 01/12/2024] Open
Abstract
Inflammatory bowel disease (IBD), a chronic condition that causes persistent inflammation in the digestive system, is closely associated with the intestinal microbiome. Here, we evaluated the effects of Lactiplantibacillus plantarum HY7718 (HY7718) on IBD symptoms in mice with dextran sulfate sodium (DSS)-induced colitis. Oral administration of HY7718 led to significant improvement in the disease activity index score and the histological index, as well as preventing weight loss, in model mice. HY7718 upregulated the expression of intestinal tight junction (TJ)-related genes and downregulated the expression of genes encoding pro-inflammatory cytokines and genes involved in the TLR/MyD88/NF-κB signaling pathway. Additionally, HY7718 reduced the blood levels of pro-inflammatory cytokines, as well as reversing DSS-induced changes to the composition of the intestinal microbiome. HY7718 also increased the percentage of beneficial bacteria (Lactiplantibacillus and Bifidobacterium), which correlated positively with the expression of intestinal TJ-related genes. Finally, HY7718 decreased the population of pathogens such as Escherichia, which correlated with IBD symptoms. The data suggest that HY7718 improves intestinal integrity in colitis model mice by regulating the expression of TJ proteins and inflammatory cytokines, as well as the composition of the intestinal microflora. Thus, L. plantarum HY7718 may be suitable as a functional supplement that improves IBD symptoms and gut health.
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Affiliation(s)
| | | | - Joo-Yun Kim
- R&BD Center, hy Co., Ltd., 22, Giheungdanji-ro 24beon-gil, Giheung-gu, Yongin-si 17086, Republic of Korea; (H.-J.K.); (H.-J.J.); (J.-J.S.); (J.-H.L.)
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15
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Padoan A, Musso G, Contran N, Basso D. Inflammation, Autoinflammation and Autoimmunity in Inflammatory Bowel Diseases. Curr Issues Mol Biol 2023; 45:5534-5557. [PMID: 37504266 PMCID: PMC10378236 DOI: 10.3390/cimb45070350] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 06/28/2023] [Accepted: 06/28/2023] [Indexed: 07/29/2023] Open
Abstract
In this review, the role of innate and adaptive immunity in the pathogenesis of inflammatory bowel diseases (IBD) is reported. In IBD, an altered innate immunity is often found, with increased Th17 and decreased Treg cells infiltrating the intestinal mucosa. An associated increase in inflammatory cytokines, such as IL-1 and TNF-α, and a decrease in anti-inflammatory cytokines, such as IL-10, concur in favoring the persistent inflammation of the gut mucosa. Autoinflammation is highlighted with insights in the role of inflammasomes, which activation by exogenous or endogenous triggers might be favored by mutations of NOD and NLRP proteins. Autoimmunity mechanisms also take place in IBD pathogenesis and in this context of a persistent immune stimulation by bacterial antigens and antigens derived from intestinal cells degradation, the adaptive immune response takes place and results in antibodies and autoantibodies production, a frequent finding in these diseases. Inflammation, autoinflammation and autoimmunity concur in altering the mucus layer and enhancing intestinal permeability, which sustains the vicious cycle of further mucosal inflammation.
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Affiliation(s)
- Andrea Padoan
- Department of Medicine-DIMED, University of Padova, Via Giustiniani 2, 35128 Padova, Italy
| | - Giulia Musso
- Department of Medicine-DIMED, University of Padova, Via Giustiniani 2, 35128 Padova, Italy
| | - Nicole Contran
- Department of Medicine-DIMED, University of Padova, Via Giustiniani 2, 35128 Padova, Italy
| | - Daniela Basso
- Department of Medicine-DIMED, University of Padova, Via Giustiniani 2, 35128 Padova, Italy
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16
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Markelova M, Senina A, Khusnutdinova D, Siniagina M, Kupriyanova E, Shakirova G, Odintsova A, Abdulkhakov R, Kolesnikova I, Shagaleeva O, Lyamina S, Abdulkhakov S, Zakharzhevskaya N, Grigoryeva T. Association between Taxonomic Composition of Gut Microbiota and Host Single Nucleotide Polymorphisms in Crohn's Disease Patients from Russia. Int J Mol Sci 2023; 24:ijms24097998. [PMID: 37175705 PMCID: PMC10178390 DOI: 10.3390/ijms24097998] [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: 04/07/2023] [Revised: 04/25/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
Crohn's disease (CD) is a chronic relapsing inflammatory bowel disease of unknown etiology. Genetic predisposition and dysbiotic gut microbiota are important factors in the pathogenesis of CD. In this study, we analyzed the taxonomic composition of the gut microbiota and genotypes of 24 single nucleotide polymorphisms (SNP) associated with the risk of CD. The studied cohorts included 96 CD patients and 24 healthy volunteers from Russia. Statistically significant differences were found in the allele frequencies for 8 SNPs and taxonomic composition of the gut microbiota in CD patients compared with controls. In addition, two types of gut microbiota communities were identified in CD patients. The main distinguishing driver of bacterial families for the first community type are Bacteroidaceae and unclassified members of the Clostridiales order, and the second type is characterized by increased abundance of Streptococcaceae and Enterobacteriaceae. Differences in the allele frequencies of the rs9858542 (BSN), rs3816769 (STAT3), and rs1793004 (NELL1) were also found between groups of CD patients with different types of microbiota communities. These findings confirm the complex multifactorial nature of CD.
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Affiliation(s)
- Maria Markelova
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Anastasia Senina
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Dilyara Khusnutdinova
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Maria Siniagina
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Elena Kupriyanova
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | | | | | - Rustam Abdulkhakov
- Hospital Therapy Department, Kazan State Medical University, 420012 Kazan, Russia
| | - Irina Kolesnikova
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia
| | - Olga Shagaleeva
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia
| | - Svetlana Lyamina
- Molecular Pathology of Digestion Laboratory, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, 127473 Moscow, Russia
| | - Sayar Abdulkhakov
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Natalia Zakharzhevskaya
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia
| | - Tatiana Grigoryeva
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
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17
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Wang W, Wu Y, Wang Y, Wang R, Deng C, Yi L, Wang L, He M, Zhou W, Xie Y, Jin Q, Chen Y, Gao T, Zhang L, Xie M. Orally Administrable Aggregation-Induced Emission-Based Bionic Probe for Imaging and Ameliorating Dextran Sulfate Sodium-Induced Inflammatory Bowel Diseases. Adv Healthc Mater 2023; 12:e2202420. [PMID: 36575111 DOI: 10.1002/adhm.202202420] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 12/12/2022] [Indexed: 12/29/2022]
Abstract
As macrophage infiltration is significantly related to the progression of inflammatory bowel disease (IBD), monitoring the macrophages is a valuable strategy for IBD diagnosis. However, owing to the harsh physiological environment of the gastrointestinal tract and enzymatic degradation, the development of orally administrable imaging probes for tracking macrophages remains a considerable challenge. Accordingly, herein, an orally administrable aggregation-induced emission biomimetic probe (HBTTPIP/β-glucan particles [GPs]) is developed for tracing macrophages; HBTTPIP/GPs can diagnose and alleviate dextran sulfate sodium (DSS)-induced colonic inflammation and self-report the treatment efficiency. The fluorophore HBTTPIP can effectively aggregate in GPs, restricting intramolecular rotation and activating the fluorescence of HBTTPIP. After being orally administrated, HBTTPIP/GPs are phagocytosed by intestinal macrophages, which then migrate to colonic lesions, enabling non-invasive monitoring of the severity of IBD via in vivo fluorescence imaging. Notably, oral HBTTPIP/GPs ameliorate DSS-induced IBD by inhibiting the expressions of pro-inflammatory factors and improving colonic mucosal barrier function. Furthermore, these HBTTPIP/GPs realize self-feedback of the therapeutic effects of GPs on DSS-induced colitis. The oral biomimetic probe HBTTPIP/GPs reported herein provide a novel theranostic platform for IBD, integrating non-invasive diagnosis of IBD in situ and the corresponding treatment.
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Affiliation(s)
- Wenyuan Wang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Ya Wu
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
- Department of Vascular Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Yihui Wang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Rui Wang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Cheng Deng
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Luyang Yi
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Lufang Wang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Mengrong He
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Wuqi Zhou
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yuji Xie
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Qiaofeng Jin
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yihan Chen
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Tang Gao
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Li Zhang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Mingxing Xie
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
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18
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Buisson C, Leuzy V, Loizon E, Meugnier E, Monnoye M, Philippe C, Gérard P, Michalski MC, Laugerette F. Soy Lecithin in High-Fat Diets Exerts Dual Effects on Adipose Tissue Versus Ileum. Mol Nutr Food Res 2023; 67:e2200461. [PMID: 36708587 DOI: 10.1002/mnfr.202200461] [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: 07/12/2022] [Revised: 01/10/2023] [Indexed: 01/30/2023]
Abstract
SCOPE Lipopolysaccharides and their transporters, LBP and sCD14, are involved in systemic inflammation following a high-fat diet. Natural emulsifiers such as soy lecithin, rich in soybean polar lipids (SPL), are often used by the food industry but little is known about effects of associating SPL with different oils. METHODS AND RESULTS Thus, this study investigates the effects of 4 weeks feeding of palm (P) or rapeseed (R) oil-enriched diets with or without SPL in mice, on white adipose tissue (WAT) inflammation, on ileum permeability, and on microbiota composition. When SPL are associated with rapeseed oil, a greater gene expression of leptin and inflammation in WAT is observed compared to P-SPL. In ileum, R-SPL group results in a lower expression of TLR4, IAP that detoxify bacterial LPS and tight junction proteins than R group. In turn, the gene expression of Reg3β and Reg3γ, which have antimicrobial activity, is higher in ileum of R-SPL group than in R group. SPL in rapeseed oil increases specific bacterial species belonging to Lachnospiraceae, Alistipes, and Bacteroidales. CONCLUSION The incorporation of SPL in a diet with rapeseed oil exerts differential effect on WAT and ileum, with respectively an inflammation of WAT and an antimicrobial activity in ileum, associated with specific microbiota changes.
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Affiliation(s)
- Charline Buisson
- Univ Lyon, CarMeN laboratory INRAE, UMR1397, INSERM, U1060, Université Claude Bernard Lyon 1, Pierre Bénite, 69310, France
| | - Valentin Leuzy
- Univ Lyon, CarMeN laboratory INRAE, UMR1397, INSERM, U1060, Université Claude Bernard Lyon 1, Pierre Bénite, 69310, France
| | - Emmanuelle Loizon
- Univ Lyon, CarMeN laboratory INRAE, UMR1397, INSERM, U1060, Université Claude Bernard Lyon 1, Pierre Bénite, 69310, France
| | - Emmanuelle Meugnier
- Univ Lyon, CarMeN laboratory INRAE, UMR1397, INSERM, U1060, Université Claude Bernard Lyon 1, Pierre Bénite, 69310, France
| | - Magali Monnoye
- Micalis Institute, Université Paris-Saclay, INRAE, AgroParisTech, Jouy-en-Josas, 78350, France
| | - Catherine Philippe
- Micalis Institute, Université Paris-Saclay, INRAE, AgroParisTech, Jouy-en-Josas, 78350, France
| | - Philippe Gérard
- Micalis Institute, Université Paris-Saclay, INRAE, AgroParisTech, Jouy-en-Josas, 78350, France
| | - Marie-Caroline Michalski
- Univ Lyon, CarMeN laboratory INRAE, UMR1397, INSERM, U1060, Université Claude Bernard Lyon 1, Pierre Bénite, 69310, France.,CRNH Rhône-Alpes, Oullins, 69310, France
| | - Fabienne Laugerette
- Univ Lyon, CarMeN laboratory INRAE, UMR1397, INSERM, U1060, Université Claude Bernard Lyon 1, Pierre Bénite, 69310, France
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19
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Wang J, Cao W, Ji T, Zhao M, Liu T, Wu J, Feng F, Zhou A, Peng X. Gut microbiota and transcriptome profiling revealed the protective effect of aqueous extract of Tetrastigma hemsleyanum leaves on ulcerative colitis in mice. Curr Res Food Sci 2022; 6:100426. [PMID: 36618099 PMCID: PMC9816909 DOI: 10.1016/j.crfs.2022.100426] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 11/17/2022] [Accepted: 12/21/2022] [Indexed: 12/29/2022] Open
Abstract
Tetrastigma hemsleyanum, a traditional Chinese medicinal plant, possesses various biological activities, including anti-inflammatory and immunomodulatory functions. The purpose of this study was to determine the alleviating effect of the water extract of Tetrastigma hemsleyanum leaves (THLW) on ulcerative colitis (UC) and its relationship with gut microbiota. The administration of THLW significantly decreased the severity of dextran sulfate sodium (DSS)-induced intestinal damage, as demonstrated by the stabilization of body weight and colon length, and decreased disease activity index (DAI) and histological scores. THLW also decreased NF-κB protein expression in colon tissues and reduced the serum levels of IL-6, IL-1β, and TNF-α. Further co-housing experiment confirmed that the anti-UC effect of THLW was possibly by regulating the structure and composition of gut microbiota, including increasing the abundance of Oscillospiraceae, Prevotellaceae and Corynebacterium. Additionally, the expression of genes related to inflammation and immunity was also regulated by THLW treatment as evidenced by transcriptome analysis. These results suggested that the protective effect of THLW on DSS-induced colitis was mediated by alleviating inflammation and modulating the microbiota composition. This work proved the potent protective effects of THLW treatment on colitis and may have potential for UC relief.
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Affiliation(s)
- Jing Wang
- Ningbo Innovation Center, Zhejiang University, Ningbo, 315100, China,College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, 310058, China,School of Biological and Chemical Engineering, NingboTech University, Ningbo, 315100, China
| | - Wen Cao
- Zhejiang Pharmaceutical College, Ningbo, 315100, China
| | - Tao Ji
- Zhejiang Pharmaceutical College, Ningbo, 315100, China
| | - Minjie Zhao
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, 310058, China
| | - Tao Liu
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, 310058, China
| | - Junhao Wu
- Ningbo Innovation Center, Zhejiang University, Ningbo, 315100, China,College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, 310058, China
| | - Fengqin Feng
- Ningbo Innovation Center, Zhejiang University, Ningbo, 315100, China,College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, 310058, China
| | - Aicun Zhou
- Zhejiang Provincial Key Laboratory of Resources Protection and Innovation of Traditional Chinese Medicine, Zhejiang A&F University, Hangzhou, 311300, China
| | - Xin Peng
- Ningbo Innovation Center, Zhejiang University, Ningbo, 315100, China,Zhejiang Pharmaceutical College, Ningbo, 315100, China,Ningbo Municipal Hospital of TCM, Affiliated Hospital of Zhejiang Chinese Medical University, Ningbo, 315010, China,Corresponding author. Ningbo Innovation Center, Zhejiang University, Ningbo, 315100, China
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20
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Yuan S, Wang Q, Li J, Xue JC, Li Y, Meng H, Hou XT, Nan JX, Zhang QG. Inflammatory bowel disease: an overview of Chinese herbal medicine formula-based treatment. Chin Med 2022; 17:74. [PMID: 35717380 PMCID: PMC9206260 DOI: 10.1186/s13020-022-00633-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 06/02/2022] [Indexed: 12/14/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic recurrent inflammatory disease of the intestine, including Crohn's disease (CD) and ulcerative colitis (UC), whose etiology and pathogenesis have not been fully understood. Due to its prolonged course and chronic recurrence, IBD imposes a heavy economic burden and psychological stress on patients. Traditional Chinese Herbal Medicine has unique advantages in IBD treatment because of its symptomatic treatment. However, the advantages of the Chinese Herbal Medicine Formula (CHMF) have rarely been discussed. In recent years, many scholars have conducted fundamental studies on CHMF to delay IBD from different perspectives and found that CHMF may help maintain intestinal integrity, reduce inflammation, and decrease oxidative stress, thus playing a positive role in the treatment of IBD. Therefore, this review focuses on the mechanisms associated with CHMF in IBD treatment. CHMF has apparent advantages. In addition to the exact composition and controlled quality of modern drugs, it also has multi-component and multi-target synergistic effects. CHMF has good prospects in the treatment of IBD, but its multi-agent composition and wide range of targets exacerbate the difficulty of studying its treatment of IBD. Future research on CHMF-related mechanisms is needed to achieve better efficacy.
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Affiliation(s)
- Shuo Yuan
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, 133002 Jilin China
- Present Address: Chronic Disease Research Center, Medical College, Dalian University, Dalian, 116622 Liaoning China
| | - Qi Wang
- Present Address: Chronic Disease Research Center, Medical College, Dalian University, Dalian, 116622 Liaoning China
| | - Jiao Li
- Present Address: Chronic Disease Research Center, Medical College, Dalian University, Dalian, 116622 Liaoning China
- Department of Immunology and Pathogenic Biology, Yanbian University College of Basic Medicine, Yanji, 133002 Jilin China
| | - Jia-Chen Xue
- Present Address: Chronic Disease Research Center, Medical College, Dalian University, Dalian, 116622 Liaoning China
- Department of Immunology and Pathogenic Biology, Yanbian University College of Basic Medicine, Yanji, 133002 Jilin China
| | - You Li
- Present Address: Chronic Disease Research Center, Medical College, Dalian University, Dalian, 116622 Liaoning China
| | - Huan Meng
- Present Address: Chronic Disease Research Center, Medical College, Dalian University, Dalian, 116622 Liaoning China
| | - Xiao-Ting Hou
- Present Address: Chronic Disease Research Center, Medical College, Dalian University, Dalian, 116622 Liaoning China
| | - Ji-Xing Nan
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, 133002 Jilin China
| | - Qing-Gao Zhang
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, 133002 Jilin China
- Present Address: Chronic Disease Research Center, Medical College, Dalian University, Dalian, 116622 Liaoning China
- Department of Immunology and Pathogenic Biology, Yanbian University College of Basic Medicine, Yanji, 133002 Jilin China
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21
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Dai Z, Shang L, Wang F, Zeng X, Yu H, Liu L, Zhou J, Qiao S. Effects of Antimicrobial Peptide Microcin C7 on Growth Performance, Immune and Intestinal Barrier Functions, and Cecal Microbiota of Broilers. Front Vet Sci 2022; 8:813629. [PMID: 35071396 PMCID: PMC8780134 DOI: 10.3389/fvets.2021.813629] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 11/26/2021] [Indexed: 12/15/2022] Open
Abstract
Microcin C7 is an antimicrobial peptide produced by Escherichia coli, composed of a heptapeptide with a modified adenosine monophosphate. This study was performed to evaluate the effects of Microcin C7 as a potential substrate to traditional antibiotics on growth performance, immune functions, intestinal barrier, and cecal microbiota of broilers. In the current study, 300 healthy Arbor Acres broiler chicks were randomly assigned to one of five treatments including a corn-soybean basal diet and basal diet supplemented with antibiotic or 2, 4, and 6 mg/kg Microcin C7. Results showed that Microcin C7 significantly decreased the F/G ratio of broilers; significantly increased the levels of serum cytokine IL-10, immunoglobulins IgG and IgM, and ileal sIgA secretion; significantly decreased the level of serum cytokine TNF-α. Microcin C7 significantly increased villus height and V/C ratio and significantly decreased crypt depth in small intestine of broilers. Microcin C7 significantly increased gene expression of tight junction protein Occludin and ZO-1 and significantly decreased gene expression of pro-inflammatory and chemokine TNF-α, IL-8, IFN-γ, Toll-like receptors TLR2 and TLR4, and downstream molecular MyD88 in the jejunum of broilers. Microcin C7 significantly increased the number of Lactobacillus and decreased the number of total bacteria and Escherichia coli in the cecum of broilers. Microcin C7 also significantly increased short-chain fatty acid (SCFA) and lactic acid levels in the ileum and cecum of broilers. In conclusion, diet supplemented with Microcin C7 significantly improved growth performance, strengthened immune functions, enhanced intestinal barrier, and regulated cecal microbiota of broilers. Therefore, the antimicrobial peptide Microcin C7 may have the potential to be an ideal alternative to antibiotic.
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Affiliation(s)
- Ziqi Dai
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Centre, China Agricultural University, Beijing, China.,Beijing Bio-Feed Additives Key Laboratory, Beijing, China
| | - Lijun Shang
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Centre, China Agricultural University, Beijing, China.,Beijing Bio-Feed Additives Key Laboratory, Beijing, China
| | - Fengming Wang
- Fengguangde Laboratory of Sichuan Tieqilishi Group, Mianyang, China
| | - Xiangfang Zeng
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Centre, China Agricultural University, Beijing, China.,Beijing Bio-Feed Additives Key Laboratory, Beijing, China
| | - Haitao Yu
- Department of Immunology, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Institute of Systems Biomedicine, Peking University Health Science Center, Beijing, China
| | - Lu Liu
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Centre, China Agricultural University, Beijing, China.,Beijing Bio-Feed Additives Key Laboratory, Beijing, China
| | - Jianchuan Zhou
- Fengguangde Laboratory of Sichuan Tieqilishi Group, Mianyang, China
| | - Shiyan Qiao
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Centre, China Agricultural University, Beijing, China.,Beijing Bio-Feed Additives Key Laboratory, Beijing, China
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22
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The Multifaceted Effects of Gut Microbiota on the Immune System of the Intestinal Mucosa. IMMUNO 2021. [DOI: 10.3390/immuno1040041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The gut microbiota has diverse microbial components, including bacteria, viruses, and fungi. The interaction between gut microbiome components and immune responses has been studied extensively over the last decade. Several studies have reported the potential role of the gut microbiome in maintaining gut homeostasis and the development of disease. The commensal microbiome can preserve the integrity of the mucosal barrier by acting on the host immune system. Contrastingly, dysbiosis-induced inflammation can lead to the initiation and progression of several diseases through inflammatory processes and oxidative stress. In this review, we describe the multifaceted effects of the gut microbiota on several diseases from the perspective of mucosal immunological responses.
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23
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Spindler LM, Feuerhake A, Ladel S, Günday C, Flamm J, Günday-Türeli N, Türeli E, Tovar GEM, Schindowski K, Gruber-Traub C. Nano-in-Micro-Particles Consisting of PLGA Nanoparticles Embedded in Chitosan Microparticles via Spray-Drying Enhances Their Uptake in the Olfactory Mucosa. Front Pharmacol 2021; 12:732954. [PMID: 34539414 PMCID: PMC8440808 DOI: 10.3389/fphar.2021.732954] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 08/16/2021] [Indexed: 12/12/2022] Open
Abstract
Intranasal delivery has gained prominence since 1990, when the olfactory mucosa was recognized as the window to the brain and the central nervous system (CNS); this has enabled the direct site specific targeting of neurological diseases for the first time. Intranasal delivery is a promising route because general limitations, such as the blood-brain barrier (BBB) are circumvented. In the treatment of multiple sclerosis (MS) or Alzheimer’s disease, for example, future treatment prospects include specialized particles as delivery vehicles. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles are well known as promising delivery systems, especially in the area of nose-to-brain (N2B) delivery. Chitosan is also broadly known as a functional additive due to its ability to open tight junctions. In this study, we produced PLGA nanoparticles of different sizes and revealed for the first time their size-time-dependent uptake mechanism into the lamina propria of porcine olfactory mucosa. The intracellular uptake was observed for 80 and 175 nm within only 5 min after application to the epithelium. After 15 min, even 520 nm particles were detected, associated with nuclei. Especially the presence of only 520 nm particles in neuronal fibers is remarkable, implying transcellular and intracellular transport via the olfactory or the trigeminal nerve to the brain and the CNS. Additionally, we developed successfully specialized Nano-in-Micro particles (NiMPs) for the first time via spray drying, consisting of PLGA nanoparticles embedded into chitosan microparticles, characterized by high encapsulation efficiencies up to 51%, reproducible and uniform size distribution, as well as smooth surface. Application of NiMPs accelerated the uptake compared to purely applied PLGA nanoparticles. NiMPs were spread over the whole transverse section of the olfactory mucosa within 15 min. Faster uptake is attributed to additional paracellular transport, which was examined via tight-junction-opening. Furthermore, a separate chitosan penetration gradient of ∼150 µm caused by dissociation from PLGA nanoparticles was observed within 15 min in the lamina propria, which was demonstrated to be proportional to an immunoreactivity gradient of CD14. Due to the beneficial properties of the utilized chitosan-derivative, regarding molecular weight (150–300 kDa), degree of deacetylation (80%), and particle size (0.1–10 µm) we concluded that M2-macrophages herein initiated an anti-inflammatory reaction, which seems to already take place within 15 min following chitosan particle application. In conclusion, we demonstrated the possibility for PLGA nanoparticles, as well as for chitosan NiMPs, to take all three prominent intranasal delivery pathways to the brain and the CNS; namely transcellular, intracellular via neuronal cells, and paracellular transport.
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Affiliation(s)
- Lena Marie Spindler
- Fraunhofer Institute for Interfacial Engineering and Biotechnology, Innovation Field Functional Surfaces and Materials, Fraunhofer-Gesellschaft, Stuttgart, Germany.,Institute of Interfacial Process Engineering and Plasma Technology, University of Stuttgart, Stuttgart, Germany
| | - Andreas Feuerhake
- Fraunhofer Institute for Interfacial Engineering and Biotechnology, Innovation Field Functional Surfaces and Materials, Fraunhofer-Gesellschaft, Stuttgart, Germany
| | - Simone Ladel
- Institute for Applied Biotechnology, Biberach University of Applied Science, Biberach, Germany.,Faculty of Natural Science, University of Ulm, Ulm, Germany
| | | | - Johannes Flamm
- Institute for Applied Biotechnology, Biberach University of Applied Science, Biberach, Germany.,Faculty of Natural Science, University of Ulm, Ulm, Germany
| | | | | | - Günter E M Tovar
- Fraunhofer Institute for Interfacial Engineering and Biotechnology, Innovation Field Functional Surfaces and Materials, Fraunhofer-Gesellschaft, Stuttgart, Germany.,Institute of Interfacial Process Engineering and Plasma Technology, University of Stuttgart, Stuttgart, Germany
| | - Katharina Schindowski
- Institute for Applied Biotechnology, Biberach University of Applied Science, Biberach, Germany
| | - Carmen Gruber-Traub
- Fraunhofer Institute for Interfacial Engineering and Biotechnology, Innovation Field Functional Surfaces and Materials, Fraunhofer-Gesellschaft, Stuttgart, Germany
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24
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Li XX, Chen SG, Yue GGL, Kwok HF, Lee JKM, Zheng T, Shaw PC, Simmonds MSJ, Lau CBS. Natural flavone tricin exerted anti-inflammatory activity in macrophage via NF-κB pathway and ameliorated acute colitis in mice. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 90:153625. [PMID: 34256329 DOI: 10.1016/j.phymed.2021.153625] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 05/30/2021] [Accepted: 06/11/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Ulcerative colitis is a subtype of inflammatory bowel disease, characterized by relapsing inflammation in the gastrointestinal tract with limited treatment options. Previous studies suggested that the natural compound tricin, a flavone isolated from rice bran, could suppress chemically-induced colitis in mice, while our recent study also demonstrated the anti-metastatic effect of tricin in colon tumor-bearing mice. HYPOTHESIS/PURPOSE Here we further investigated the underlying mechanism of the inhibitory effects of tricin on lipopolysaccharides-activated macrophage RAW264.7 cells and explored the efficacy of tricin in acute colitis mouse model induced by 4.5% dextran sulfate sodium (DSS) for 7 days. METHODS Tricin (75, 100, and 150 mg/kg) or the positive control drug sulfasalazine (200 mg/kg) were orally administered to mice for 7 days. Stool consistency scores, stool blood scores, and body weight were recorded daily. Disease activity index (DAI) was examined on day 7, and colon tissues were collected for biochemical analyses. The fecal microbiome of colitis mice after tricin treatment was characterized for the first time in this study using 16S rDNA amplicon sequencing. RESULTS Results showed that tricin (50 µM) remarkably reduced nitric oxide production in lipopolysaccharides-activated RAW264.7 cells and the anti-inflammatory activity of tricin was shown to act through the NF-κB pathway. Besides, tricin treatment at 150 mg/kg significantly reversed colon length reduction, reduced myeloperoxidase activities and DAI scores, as well as restored the elevated myeloid-derived suppressive cells population in acute colitis mice. The influence from DSS on gut microbiota, such as the increased population of Proteobacteria phylum and Ruminococcaceae family, was shown to be relieved after tricin treatment. CONCLUSION Our present study firstly demonstrated that tricin ameliorated acute colitis by improving colonic inflammation and modulating gut microbiota profile, which supports the potential therapeutic use of tricin for colitis treatment.
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Affiliation(s)
- Xiao-Xiao Li
- Li Dak Sum Yip Yio Chin R&D Centre for Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Sin-Guang Chen
- Li Dak Sum Yip Yio Chin R&D Centre for Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Grace Gar-Lee Yue
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants (CUHK), The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Hin-Fai Kwok
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants (CUHK), The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Julia Kin-Ming Lee
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants (CUHK), The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Tao Zheng
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants (CUHK), The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Pang-Chui Shaw
- Li Dak Sum Yip Yio Chin R&D Centre for Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants (CUHK), The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; School of Life Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | | | - Clara Bik-San Lau
- Li Dak Sum Yip Yio Chin R&D Centre for Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants (CUHK), The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
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25
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Maasfeh L, Härtlova A, Isaksson S, Sundin J, Mavroudis G, Savolainen O, Strid H, Öhman L, Magnusson MK. Impaired Luminal Control of Intestinal Macrophage Maturation in Patients With Ulcerative Colitis During Remission. Cell Mol Gastroenterol Hepatol 2021; 12:1415-1432. [PMID: 34126236 PMCID: PMC8479254 DOI: 10.1016/j.jcmgh.2021.06.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 06/08/2021] [Accepted: 06/08/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Intestinal macrophages adopt a hyporesponsive phenotype through education by local signals. Lack of proper macrophage maturation in patients with ulcerative colitis (UC) in remission may initiate gut inflammation. The aim, therefore, was to determine the effects of fecal luminal factors derived from healthy donors and UC patients in remission on macrophage phenotype and function. METHODS Fecal supernatants (FS) were extracted from fecal samples of healthy subjects and UC patients in remission. Monocytes were matured into macrophages in the presence of granulocyte-macrophage colony-stimulating factor without/with FS, stimulated with lipopolysaccharide, and macrophage phenotype and function were assessed. Fecal metabolomic profiles were analyzed by gas-chromatography/mass-spectrometry. RESULTS Fecal luminal factors derived from healthy donors were effective in down-regulating Toll-like receptor signaling, cytokine signaling, and antigen presentation in macrophages. Fecal luminal factors derived from UC patients in remission were less potent in inducing lipopolysaccharide hyporesponsiveness and modulating expression of genes involved in macrophage cytokine and Toll-like receptor signaling pathways. Although phagocytic and bactericidal abilities of macrophages were not affected by FS treatment, healthy FS-treated macrophages showed a greater ability to suppress cluster of differentiation 4+ T-cell activation and interferon γ secretion compared with UC remission FS-treated counterparts. Furthermore, metabolomic analysis showed differential fecal metabolite composition for healthy donors and UC patients in remission. CONCLUSIONS Our data indicate that UC patients in remission lack luminal signals able to condition macrophages toward a hyporesponsive and tolerogenic phenotype, which may contribute to their persistent vulnerability to relapse.
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Affiliation(s)
- Lujain Maasfeh
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Anetta Härtlova
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden,Wallenberg Centre for Molecular and Translational Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Stefan Isaksson
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Johanna Sundin
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden,Department of Internal Medicine and Clinical Nutrition, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | | | - Otto Savolainen
- Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
| | - Hans Strid
- Department of Internal Medicine, Södra Älvsborg Hospital, Borås, Sweden
| | - Lena Öhman
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Maria K. Magnusson
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden,Correspondence Address correspondence to: Maria K. Magnusson, PhD, Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Box 435, 405 30 Gothenburg, Sweden. fax: (46) 31-786 6210
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Tatiya-Aphiradee N, Chatuphonprasert W, Jarukamjorn K. Ethanolic Garcinia mangostana extract and α-mangostin improve dextran sulfate sodium-induced ulcerative colitis via the suppression of inflammatory and oxidative responses in ICR mice. JOURNAL OF ETHNOPHARMACOLOGY 2021; 265:113384. [PMID: 32927006 DOI: 10.1016/j.jep.2020.113384] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 09/01/2020] [Accepted: 09/04/2020] [Indexed: 05/14/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Ulcerative colitis (UC) is an inflammatory disorder of the colon. Garcinia mangostana Linn. (GM) has been traditionally used for its anti-inflammatory and antioxidant activities. AIM OF THE STUDY The effects of GM and its bioactive constituent α-mangostin on dextran sulfate sodium (DSS)-induced UC in mice were investigated. MATERIALS AND METHODS Adult ICR mice (n = 63) were pretreated with ethanolic GM extract at 40, 200, and 1000 mg/kg/day (GM40, GM200, and GM1000), α-mangostin at 30 mg/kg/day, or sulfasalazine at 100 mg/kg/day (SA) for 7 consecutive days. On days 4-7, UC was induced in the mice by the oral administration of DSS (40 kDa, 6 g/kg/day), while control mice received distilled water. The UC disease activity index (DAI) and histological changes were recorded. The activities of myeloperoxidase, catalase, and superoxide dismutase, and the levels of reactive oxygen species (ROS), nitric oxide (NO), and malondialdehyde (MDA) were determined. The mRNA expression of inflammatory related genes including proinflammatory cytokine Tnf-α, Toll-like receptor (Tlr-2), adhesion molecules (Icam-1 and Vcam-1), and monocyte chemoattractant protein (Mcp-1) were evaluated. RESULTS Treatment with GM or α-mangostin decreased the UC DAI and protected against colon shortening and spleen and kidney enlargement. GM and α-mangostin prevented histological damage, reduced mast cell infiltration in the colon, and decreased myeloperoxidase activity. GM and α-mangostin increased catalase and superoxide dismutase activity and decreased ROS, NO, and MDA production. GM downregulated mRNA expression of Tnf-α, Tlr-2, Icam-1, Vcam-1, and Mcp-1. CONCLUSIONS GM and α-mangostin attenuated the severity of DSS-induced UC via anti-inflammatory and antioxidant effects. Therefore, GM is a promising candidate for development into a novel therapeutic agent for UC.
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Affiliation(s)
- Nitima Tatiya-Aphiradee
- Research Group for Pharmaceutical Activities of Natural Products Using Pharmaceutical Biotechnology (PANPB), Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand
| | | | - Kanokwan Jarukamjorn
- Research Group for Pharmaceutical Activities of Natural Products Using Pharmaceutical Biotechnology (PANPB), Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand.
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Bao WL, Wu Q, Hu B, Sun D, Zhao S, Shen X, Cheng H, Shen W. Oral Nanoparticles of SNX10-shRNA Plasmids Ameliorate Mouse Colitis. Int J Nanomedicine 2021; 16:345-357. [PMID: 33488076 PMCID: PMC7814243 DOI: 10.2147/ijn.s286392] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 12/28/2020] [Indexed: 12/18/2022] Open
Abstract
Background Our previous study found that deletion of Sorting nexin 10 (SNX10) can protect against colonic inflammation and pathological damage induced by dextran sulfate sodium (DSS). This inspired us that modulation of SNX10 expression in colonic epithelial cells might represent a promising therapeutic strategy for inflammatory bowel disease (IBD). Methods Effective delivery of siRNA/shRNA to silence genes is a highly sought-after means in the treatment of multiple diseases. Here, we encapsulated SNX10-shRNA plasmids (SRP) with polylactide-polyglycolide (PLGA) to make oral nanoparticles (NPs), and then applied them to acute and chronic IBD mice model, respectively. The characteristics of the nanoparticles were assayed and the effects of SRP-NPs on mouse IBD were evaluated. Results High-efficiency SNX10-shRNA plasmids were successfully constructed and coated with PLGA to obtain nanoparticles, with a particle size of 275.2 ± 11.4mm, uniform PDI distribution, entrapment efficiency of 87.6 ± 2.5%, and drug loading of 13.11 ± 1.38%, displayed dominant efficiency of SNX10 RNA interference in the colon. In both acute and chronic IBD models, SRP-NPs could effectively reduce the loss of mice body weight, relieve the intestinal mucosal damage and inflammatory infiltration, inhibit the expression of inflammatory cytokines IL-1β, IL-23, TNF-α, and down-regulate the expression of toll-like receptors (TLRs) 2 and 4. Conclusion Oral nanoparticles of SNX10-shRNA plasmid displayed dominant efficiency of SNX10 RNA interference in the colon and ameliorate mouse colitis via TLR signaling pathway. SNX10 is a new target for IBD treatment and nanoparticles of SNX10-shRNA plasmid might be a promising treatment option for IBD.
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Affiliation(s)
- Wei-Lian Bao
- The First Clinical Medical College of Nanjing University of Chinese Medicine, Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Jiangsu, Nanjing 210023, People's Republic of China.,Department of Pharmacology & the Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, People's Republic of China
| | - Qibiao Wu
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, People's Republic of China
| | - Bin Hu
- Department of Pharmacology & the Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, People's Republic of China
| | - Dongdong Sun
- The First Clinical Medical College of Nanjing University of Chinese Medicine, Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Jiangsu, Nanjing 210023, People's Republic of China
| | - Shengnan Zhao
- The First Clinical Medical College of Nanjing University of Chinese Medicine, Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Jiangsu, Nanjing 210023, People's Republic of China
| | - Xiaoyan Shen
- Department of Pharmacology & the Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, People's Republic of China
| | - Haibo Cheng
- The First Clinical Medical College of Nanjing University of Chinese Medicine, Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Jiangsu, Nanjing 210023, People's Republic of China
| | - Weixing Shen
- The First Clinical Medical College of Nanjing University of Chinese Medicine, Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Jiangsu, Nanjing 210023, People's Republic of China
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Ciobanu L, Tefas C, Oancea DM, Berce C, Vodnar D, Mester A, Onica S, Toma C, Taulescu M. Effect of Lactobacillus plantarum ACTT 8014 on 5-fluorouracil induced intestinal mucositis in Wistar rats. Exp Ther Med 2020; 20:209. [PMID: 33149773 PMCID: PMC7604756 DOI: 10.3892/etm.2020.9339] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 09/29/2020] [Indexed: 12/21/2022] Open
Abstract
Some previous studies reported that probiotics might decrease the severity of chemotherapy-induced mucositis. This study assessed the potential protective effect of Lactobacillus plantarum ATCC 8014 on 5-fluorouracil (5-FU) induced intestinal mucositis in the Wistar rats. The Crl:WI rats were divided into two groups of six animals (F, L) and one group of 5 animals (M). Group L received for 9 days 3.32x109 CFU/ml of Lactobacillus plantarum orally. In the 7th day of the experiment 400 mg of 5-FU was administered intraperitoneally in groups L and F. Group M received only the vehicles. All animals were sacrificed in the 9th day. Eleven histological characteristics of mucositis were quantified from 0 (normal) to 3 (severe) for duodenum, jejunum and colon. Semiquantitative grades measured Toll-like receptor 4 (TLR4) immunopositive cells. The independent groups were analyzed using the Kruskal-Wallis test, Mann-Whitney U test, with a Bonferroni correction for alpha (P≤0.016). In the group F, treated with 5-FU, the most affected areas were the jejunum and the duodenum. The medium score of histological lesions was 27 for jejunum (minimum 25, maximum 32) and 21 for duodenum (minimum 18, maximum 29). Graded microscopic mucosal changes of the jejunum were significantly lower in group L compared with group F (U=0, P=0.009, Mann-Whitney test). The histological changes depicted on the duodenal and colonic mucosa were less severe in group L than in group F, but without reaching the statistical significance (duodenum: U=6, P=0.172, Mann-Whitney test; colon: U=12, P=0.916, Mann-Whitney test). Although the TLR4 immunoexpression was more intense in group L, no significant statistical difference was revealed at duodenum, jejunum or colonic mucosa. Significantly fewer microscopic changes were depicted in L group on the jejunum, suggesting a potential beneficial effect of Lactobacillus plantarum at this level in 5-FU induced mucositis.
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Affiliation(s)
- Lidia Ciobanu
- Department of Internal Medicine, 'Iuliu Hatieganu' University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania.,Department of Gastroenterology, 'Professor Doctor Octavian Fodor' Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Cristian Tefas
- Department of Internal Medicine, 'Iuliu Hatieganu' University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania.,Department of Gastroenterology, 'Professor Doctor Octavian Fodor' Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Diana Maria Oancea
- Department of Internal Medicine, 'Iuliu Hatieganu' University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Cristian Berce
- Department of Internal Medicine, 'Iuliu Hatieganu' University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Dan Vodnar
- Institute of Life Sciences, Faculty of Food Science and Technology, University ofAgricultural Sciences and Veterinary Medicine, 400372 Cluj-Napoca, Romania
| | - Alexandru Mester
- Department of Internal Medicine, 'Iuliu Hatieganu' University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Sorina Onica
- Department of Internal Medicine, 'Iuliu Hatieganu' University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Corina Toma
- Department of Veterinary Pathology, Faculty of Veterinary Medicine, University ofAgricultural Sciences and Veterinary Medicine, 400372 Cluj-Napoca, Romania
| | - Marian Taulescu
- Department of Veterinary Pathology, Faculty of Veterinary Medicine, University ofAgricultural Sciences and Veterinary Medicine, 400372 Cluj-Napoca, Romania
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29
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Ghavami SB, Yadegar A, Aghdaei HA, Sorrentino D, Farmani M, Mir AS, Azimirad M, Balaii H, Shahrokh S, Zali MR. Immunomodulation and Generation of Tolerogenic Dendritic Cells by Probiotic Bacteria in Patients with Inflammatory Bowel Disease. Int J Mol Sci 2020; 21:6266. [PMID: 32872480 PMCID: PMC7503552 DOI: 10.3390/ijms21176266] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 08/27/2020] [Accepted: 08/27/2020] [Indexed: 12/15/2022] Open
Abstract
In inflammatory bowel diseases (IBD), the therapeutic benefit and mucosal healing from specific probiotics may relate to the modulation of dendritic cells (DCs). Herein, we assessed the immunomodulatory effects of four probiotic strains including Lactobacillus salivarius, Bifidobacterium bifidum, Bacillus coagulans and Bacillus subtilis natto on the expression of co-stimulatory molecules, cytokine production and gene expression of signal-transducing receptors in DCs from IBD patients. Human monocyte-derived DCs from IBD patients and healthy controls were exposed to four probiotic strains. The expression of co-stimulatory molecules was assessed and supernatants were analyzed for anti-inflammatory cytokines. The gene expression of toll-like receptors (TLRs), IL-12p40 and integrin αvβ8 were also analyzed. CD80 and CD86 were induced by most probiotic strains in ulcerative colitis (UC) patients whereas only B. bifidum induced CD80 and CD86 expression in Crohn's disease (CD) patients. IL-10 and TGF-β production was increased in a dose-independent manner while TLR expression was decreased by all probiotic bacteria except B. bifidum in DCs from UC patients. TLR-4 and TLR-9 expression was significantly downregulated while integrin ß8 was significantly increased in the DCs from CD patients. IL-12p40 expression was only significantly downregulated in DCs from CD patients. Our findings point to the general beneficial effects of probiotics in DC immunomodulation and indicate that probiotic bacteria favorably modulate the expression of co-stimulatory molecules, proinflammatory cytokines and TLRs in DCs from IBD patients.
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Affiliation(s)
- Shaghayegh Baradaran Ghavami
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran; (S.B.G.); (H.A.A.); (M.F.)
| | - Abbas Yadegar
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran; (A.Y.); (M.A.)
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran; (S.B.G.); (H.A.A.); (M.F.)
| | - Dario Sorrentino
- IBD Center, Division of Gastroenterology, Virginia Tech Carilion School of Medicine, Roanoke, VA 24016, USA
- Department of Clinical and Experimental Medical Sciences, University of Udine School of Medicine, 33100 Udine, Italy
| | - Maryam Farmani
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran; (S.B.G.); (H.A.A.); (M.F.)
| | - Adil Shamim Mir
- Department of Internal Medicine, Roanoke Memorial Hospital, Carilion Clinic, VA 24014, USA;
| | - Masoumeh Azimirad
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran; (A.Y.); (M.A.)
| | - Hedieh Balaii
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran; (H.B.); (S.S.); (M.R.Z.)
| | - Shabnam Shahrokh
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran; (H.B.); (S.S.); (M.R.Z.)
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran; (H.B.); (S.S.); (M.R.Z.)
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30
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Sharma U, Olson RK, Erhart FN, Zhang L, Meng J, Segura B, Banerjee S, Sharma M, Saluja AK, Ramakrishnan S, Abreu MT, Roy S. Prescription Opioids induce Gut Dysbiosis and Exacerbate Colitis in a Murine Model of Inflammatory Bowel Disease. J Crohns Colitis 2020; 14:801-817. [PMID: 31773170 PMCID: PMC7346895 DOI: 10.1093/ecco-jcc/jjz188] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Opioids are the most prescribed analgesics for pain in inflammatory bowel diseases [IBD]; however, the consequences of opioid use on IBD severity are not well defined. This is the first study investigating consequences of hydromorphone in both dextran sodium sulphate [DSS]-induced colitis and spontaneous colitis (IL-10 knockout [IL-10-/-]) mouse models of IBD. METHODS To determine the consequences of opioids on IBD pathogenesis, wild-type [WT] mice were treated with clinically relevant doses of hydromorphone and colitis was induced via 3% DSS in drinking water for 5 days. In parallel we also determined the consequences of opioids in a spontaneous colitis model. RESULTS Hydromorphone and DSS independently induced barrier dysfunction, bacterial translocation, disruption of tight junction organisation and increased intestinal and systemic inflammation, which were exacerbated in mice receiving hydromorphone in combination with DSS. Hydromorphone + DSS-treated mice exhibited significant microbial dysbiosis. Predictive metagenomic analysis of the gut microbiota revealed high abundance in the bacterial communities associated with virulence, antibiotic resistance, toxin production, and inflammatory properties. Hydromorphone modulates tight junction organisation in a myosin light chain kinase [MLCK]-dependent manner. Treatment with MLCK inhibitor ML-7 ameliorates the detrimental effects of hydromorphone on DSS-induced colitis and thus decreases severity of IBD. Similarly, we demonstrated that hydromorphone treatment in IL-10-/- mice resulted in accelerated clinical manifestations of colitis compared with control mice. CONCLUSIONS Opioids used for pain management in IBD accelerate IBD progression by dysregulation of the gut microbiota, leading to expansion of pathogenic bacteria, translocation of bacteria, immune deregulation and sustained inflammation.
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Affiliation(s)
- Umakant Sharma
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | | | | | - Li Zhang
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Jingjing Meng
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Bradley Segura
- Department of Surgery, University of Minnesota, Minneapolis, MN, USA
| | - Santanu Banerjee
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Madhulika Sharma
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Ashok Kumar Saluja
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Sundaram Ramakrishnan
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Maria T Abreu
- Division of Gastroenterology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Sabita Roy
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
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31
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Homsak E, Gruson D. Soluble ST2: A complex and diverse role in several diseases. Clin Chim Acta 2020; 507:75-87. [PMID: 32305537 DOI: 10.1016/j.cca.2020.04.011] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 04/08/2020] [Accepted: 04/09/2020] [Indexed: 12/13/2022]
Abstract
The Suppression of Tumorigenicity 2 protein (ST2) is a member of the interleukin (IL) 1 receptor family with transmembrane (ST2L) and soluble (sST2) isoforms that are (over)expressed in several cells in different conditions and following various triggers (e.g. inflammation, stress). The ligand of ST2 is IL-33, which on binding to ST2L results in nuclear signalling and immunomodulatory action in various cells (tumour, immune, heart). sST2, that is released in the circulation, functions as a »decoy« receptor of IL-33 and inhibits IL-33/ST2L signalling and beneficial effects. The importance and role of the ST2/IL-33 axis and sST2 have been evaluated and confirmed in several inflammatory, cancer and cardiac diseases. sST2 is involved in homeostasis/pathogenesis of these diseases, as the counterbalance/response on IL-33/ST2L axis activation, which is triggered and expressed during developing fibrosis, tissue damage/inflammation and remodelling. In clinical studies, sST2 has been recognised as an important prognostic marker in patients with cardiac disease, including patients with chronic kidney disease where specific characteristics of sST2 enable better assessment of the risk of End-Stage Renal Disease patients on dialysis. sST2 is also recognised as an important marker for monitoring treatment in heart failure patients. However, accurate measurement and interpretation of ST2 concentration in serum/plasma samples for routine and research applications require the use of appropriate methods and recognition of essential characteristics of both the methods and the analyte that may influence the result. sST2, as one of the most promising disease biomarkers, is deserving of further study and wider application in clinical practice.
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Affiliation(s)
- Evgenija Homsak
- Department of Laboratory Diagnostics, University Medical Centre Maribor, Maribor, Slovenia.
| | - Damien Gruson
- Department of Laboratory Medicine, Cliniques Universitaires St-Luc and Universite Catholique de Lovain, Brussels, Belgium
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32
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Gross-Vered M, Shmuel-Galia L, Zarmi B, Humphries F, Thaiss C, Salame TM, David E, Chappell-Maor L, Fitzgerald KA, Shai Y, Jung S. TLR2 Dimerization Blockade Allows Generation of Homeostatic Intestinal Macrophages under Acute Colitis Challenge. THE JOURNAL OF IMMUNOLOGY 2020; 204:707-717. [PMID: 31882517 DOI: 10.4049/jimmunol.1900470] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 11/16/2019] [Indexed: 11/19/2022]
Abstract
Recruited blood monocytes contribute to the establishment, perpetuation, and resolution of tissue inflammation. Specifically, in the inflamed intestine, monocyte ablation was shown to ameliorate colitis scores in preclinical animal models. However, the majority of intestinal macrophages that seed the healthy gut are also monocyte derived. Monocyte ablation aimed to curb inflammation would therefore likely interfere with intestinal homeostasis. In this study, we used a TLR2 trans-membrane peptide that blocks TLR2 dimerization that is critical for TLR2/1 and TLR2/6 heterodimer signaling to blunt inflammation in a murine colitis model. We show that although the TLR2 peptide treatment ameliorated colitis, it allowed recruited monocytes to give rise to macrophages that lack the detrimental proinflammatory gene signature and reduced potentially damaging neutrophil infiltrates. Finally, we demonstrate TLR blocking activity of the peptide on in vitro cultured human monocyte-derived macrophages. Collectively, we provide a significantly improved anti-inflammatory TLR2 peptide and critical insights in its mechanism of action toward future potential use in the clinic.
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Affiliation(s)
- Mor Gross-Vered
- Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Liraz Shmuel-Galia
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Batya Zarmi
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Fiachra Humphries
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; and
| | - Christoph Thaiss
- Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Tomer-Meir Salame
- Department of Life Science Core Facilities, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Eyal David
- Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
| | | | - Katherine A Fitzgerald
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; and
| | - Yechiel Shai
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel;
| | - Steffen Jung
- Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel;
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Sireswar S, Biswas S, Dey G. Adhesion and anti-inflammatory potential of Lactobacillus rhamnosus GG in a sea buckthorn based beverage matrix. Food Funct 2020; 11:2555-2572. [DOI: 10.1039/c9fo02249j] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
A seabuckthorn based beverage matrix retains the functionality of L. rhamnosus GG and exhibits enhanced anti-inflammatory effects against LPS-induced inflammation in zebrafish.
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Affiliation(s)
- Srijita Sireswar
- School of Biotechnology
- Kalinga Institute of Industrial Technology
- Deemed to be University
- Bhubaneswar
- India
| | | | - Gargi Dey
- School of Biotechnology
- Kalinga Institute of Industrial Technology
- Deemed to be University
- Bhubaneswar
- India
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34
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Zheng JD, He Y, Yu HY, Liu YL, Ge YX, Li XT, Li X, Wang Y, Guo MR, Qu YL, Qin XF, Jiang MS, Wang XH. Unconjugated bilirubin alleviates experimental ulcerative colitis by regulating intestinal barrier function and immune inflammation. World J Gastroenterol 2019; 25:1865-1878. [PMID: 31057300 PMCID: PMC6478610 DOI: 10.3748/wjg.v25.i15.1865] [Citation(s) in RCA: 30] [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: 01/04/2019] [Revised: 03/05/2019] [Accepted: 03/15/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Unconjugated bilirubin (UCB) is generally considered toxic but has gained recent prominence for its anti-inflammatory properties. However, the effects of it on the interaction between intestinal flora and organisms and how it influences immune responses remain unresolved. AIM To investigate the role of UCB in intestinal barrier function and immune inflammation in mice with dextran-sulfate-sodium-induced colitis. METHODS Acute colitis was induced by 3% (w/v) dextran sulfate sodium salt in drinking water for 6 d followed by untreated water for 2 d. Concurrently, mice with colitis were administered 0.2 mL UCB (400 μmol/L) by intra-gastric gavage for 7 d. Disease activity index (DAI) was monitored daily. Mice were sacrificed at the end of the experiment. The length of the colon and weight of the spleen were recorded. Serum level of D-lactate, intestinal digestive proteases activity, and changes to the gut flora were analyzed. In addition, colonic specimens were analyzed by histology and for expression of inflammatory markers and proteins. RESULTS Mice treated with UCB had significantly relieved severity of colitis, including lower DAI, longer colon length, and lower spleen weight (colon length: 4.92 ± 0.09 cm vs 3.9 ± 0.15 cm; spleen weight: 0.33 ± 0.04 vs 0.74 ± 0.04, P < 0.001). UCB administration inactivated digestive proteases (chymotrypsin: 18.70 ± 0.69 U/g vs 44.81 ± 8.60 U/g; trypsin: 1.52 ± 0.23 U/g vs 9.05 ± 1.77 U/g, P < 0.01), increased expression of tight junction (0.99 ± 0.05 vs 0.57 ± 0.03, P < 0.001), decreased serum level of D-lactate (31.76 ± 3.37 μmol/L vs 54.25 ± 1.45 μmol/L, P < 0.001), and lowered histopathological score (4 ± 0.57 vs 7 ± 0.57, P < 0.001) and activity of myeloperoxidase (46.79 ± 2.57 U/g vs 110.32 ± 19.19 U/g, P < 0.001). UCB also regulated the intestinal microbiota, inhibited expression of tumor necrosis factor (TNF) α and interleukin 1β (TNF-α: 52.61 ± 7.81 pg/mg vs 105.04 ± 11.92 pg/mg, interleukin 1β: 13.43 ± 1.68 vs 32.41 ± 4.62 pg/mg, P < 0.001), decreased expression of Toll-like receptor 4 (0.61 ± 0.09 vs 1.07 ± 0.03, P < 0.001) and myeloid differentiation primary response gene 88 (0.73 ± 0.08 vs 1.01 ± 0.07, P < 0.05), and increased expression of TNF-receptor-associated factor 6 (0.79 ± 0.02 vs 0.43 ± 0.09 P < 0.05) and inhibitor of kappa B α (0.93 ± 0.07 vs 0.72 ± 0.07, P < 0.05) in the colon. CONCLUSION UCB can protect intestinal barrier function, regulate normal intestinal homeostasis, and suppress inflammation via the Toll-like receptor 4/ nuclear factor-κB signaling pathway.
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Affiliation(s)
- Jia-Dong Zheng
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Yan He
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Heng-Yuan Yu
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Yuan-Li Liu
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Yi-Xuan Ge
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Xue-Ting Li
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Xue Li
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Yan Wang
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Meng-Ru Guo
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Yi-Lin Qu
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Xiao-Fa Qin
- Founder, GI Biopharma Inc., Westfield, NJ 07090, United States
| | - Ming-Shan Jiang
- Department of General Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Xiu-Hong Wang
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin 150086, Heilongjiang Province, China
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Curcumin and Resveratrol Regulate Intestinal Bacteria and Alleviate Intestinal Inflammation in Weaned Piglets. Molecules 2019; 24:molecules24071220. [PMID: 30925757 PMCID: PMC6479679 DOI: 10.3390/molecules24071220] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Revised: 03/23/2019] [Accepted: 03/27/2019] [Indexed: 01/13/2023] Open
Abstract
Human infants or piglets are vulnerable to intestinal microbe-caused disorders and inflammation due to their rapidly changing gut microbiota and immaturity of their immune systems at weaning. Resveratrol and curcumin have significant anti-inflammatory, bacteria-regulating and immune-promoting effects. The purpose of this study was to investigate whether dietary supplementation with resveratrol and curcumin can change the intestinal microbiota and alleviate intestinal inflammation induced by weaning in piglets. One hundred eighty piglets weaned at 21 ± 2 d were fed a control diet (CON group) or supplemented diet (300 mg/kg of antibiotics, ANT group; 300 mg/kg of resveratrol and curcumin, respectively, HRC group; 100 mg/kg of resveratrol and curcumin, respectively, LRC group; 300 mg/kg of resveratrol, RES group; 300 mg/kg of curcumin, CUR group) for 28 days. The results showed that compared with the CON group, curcumin alone and antibiotics decreased the copy numbers of Escherichia coli. Both curcumin and resveratrol down-regulated the level of Toll-like-receptor 4 mRNA and protein expression in the intestine to inhibit the release of critical inflammation molecules (interleukin-1β, tumor necrosis factor-α), and increase the secretion of immunoglobulin. Our results suggested that curcumin and resveratrol can regulate weaned piglet gut microbiota, down-regulate the TLR4 signaling pathway, alleviate intestinal inflammation, and ultimately increase intestinal immune function.
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Interactions between Host PPARs and Gut Microbiota in Health and Disease. Int J Mol Sci 2019; 20:ijms20020387. [PMID: 30658440 PMCID: PMC6359605 DOI: 10.3390/ijms20020387] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 12/28/2018] [Accepted: 01/05/2019] [Indexed: 12/12/2022] Open
Abstract
The human gastrointestinal tract is inhabited by many types of microbiota, including bacteria, viruses, and fungi. Dysregulations of their microenvironment are associated with various health problems, not only limited to gastrointestinal disorders, such as inflammatory bowel disease, but to impacts beyond the intestine. For example, intestinal microbiota can affect the liver in non-alcoholic fatty liver disease, visceral adipose tissue during adipogenesis, and the heart in atherosclerosis. The factors contributing to these pathogeneses involve the gut microbiota and the effector organs of the host, and everything in between. The nuclear receptor peroxisome proliferator-activated receptors (PPARs) are pivotal for the modulation of many of the pathogeneses mentioned above. It is, therefore, conceivable that, in the process of host-microbiota interactions, PPARs play important roles. In this review, we focus on the interactions between host PPARs in different organs and gut microbiota and their impacts on maintaining health and various diseases.
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Canine primary jejunal and colonic epithelial cells predominantly express TLR5 and TLR9 but do not change TLR expression pattern after stimulation with certain Toll-like receptor ligands. Vet Immunol Immunopathol 2018; 206:16-24. [PMID: 30502908 DOI: 10.1016/j.vetimm.2018.11.003] [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: 07/24/2018] [Revised: 10/29/2018] [Accepted: 11/01/2018] [Indexed: 11/23/2022]
Abstract
The intestinal mucosa is in contact with abundant luminal antigens and coordinates immune responses to differentiate commensals from pathogens. Intestinal epithelial cells (IECs) not only represent a physical barrier but also an immunologically important cell type that recognizes microbe-associated molecular patterns via Toll-like receptors (TLR). The importance of TLR expression has been elucidated for intestinal disorders in humans, mice and dogs. However, as knowledge about canine intestinal TLRs is mainly limited to the transcriptional level, the present study analyzed the protein expression of TLR2, TLR3, TLR4, TLR5 and TLR9 by primary canine IECs in the steady state and after stimulation with TLR ligands. This exhibited TLR5 and TLR9 to be predominantly expressed in canine IECs. TLR stimulation did not result in changes of the TLR expression pattern. Further studies are needed to elucidate whether this implicates hyporesponsiveness of canine IECs towards TLR stimulation under steady state conditions.
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Bo L, Fu H, Yang J. Comprehensive analysis of gene expression profiles provides insight into the pathogenesis of Crohn's disease. Mol Med Rep 2018; 18:2643-2650. [PMID: 30015893 PMCID: PMC6102736 DOI: 10.3892/mmr.2018.9267] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2017] [Accepted: 05/18/2018] [Indexed: 12/21/2022] Open
Abstract
Crohn's disease (CD) is a type of inflammatory bowel disease that cannot be fully cured by medication or surgery. In the present study, the aim was to understand the underlying mechanisms of CD. Two CD microarray datasets were downloaded from The Gene Expression Omnibus database: GSE36807 (13 CD and 7 normal samples) and GSE59071 (8 CD and 11 normal samples). A series of bioinformatics analyses were conducted, including weighted gene co‑expression network analysis to identify stable modules, and analysis of differentially expressed genes (DEGs) between CD and normal samples. The common DEGs in the GSE36807 and GSE59071 datasets were screened. Subsequently, overlapping genes in the stable modules and the DEGs were selected to construct a protein‑protein interaction (PPI) network using Cytoscape software. Enrichment analysis of genes in the network was performed to explore their biological functions. A total of 10 stable modules and 927 DEGs were identified, of which 234 genes were shared in the stable modules and the DEGs. After removal of 32 uncharacterized genes, 202 genes were selected to build the PPI network. Low density lipoprotein receptor (LDLR), toll‑like receptor 2 (TLR2), lipoprotein lipase (LPL), forkhead box protein M1 (FOXM1) and neuropeptide Y (NPY) were revealed as key nodes with high degree. Pathway enrichment analysis demonstrated that LPL was enriched in the peroxisome proliferator‑activated receptor (PPAR) signaling pathway. In conclusion, LDLR, TLR2, FOXM1 and NPY, as well as LPL in the PPAR signaling pathway may serve critical roles in the pathogenesis of CD.
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Affiliation(s)
- Lumin Bo
- Department of Gastroenterology, Changhai Hospital, Shanghai 200433, P.R. China
| | - Hongyu Fu
- Department of Gastroenterology, Changhai Hospital, Shanghai 200433, P.R. China
| | - Junchi Yang
- Department of Gastrointestinal Surgery, Changhai Hospital, Shanghai 200433, P.R. China
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Kordjazy N, Haj-Mirzaian A, Haj-Mirzaian A, Rohani MM, Gelfand EW, Rezaei N, Abdolghaffari AH. Role of toll-like receptors in inflammatory bowel disease. Pharmacol Res 2018; 129:204-215. [PMID: 29155256 DOI: 10.1016/j.phrs.2017.11.017] [Citation(s) in RCA: 89] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Revised: 10/05/2017] [Accepted: 11/14/2017] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel disease (IBD) is the chronic inflammation of the gastrointestinal tract. Recently, studies of the interplay between the adaptive and innate immune responses have provided a better understanding of the immunopathogenesis of inflammatory disorders such as IBD, as well as identification of novel targets for more potent interventions. Toll-like receptors (TLRs) are a class of proteins that play a significant role in the innate immune system and are involved in inflammatory processes. Activation of TLR signal transduction pathways lead to the induction of numerous genes that function in host defense, including those for inflammatory cytokines, chemokines, and antigen presenting molecules. It was proposed that TLR mutations and dysregulation are major contributing factors to the predisposition and susceptibility to IBD. Thus, modulating TLRs represent an innovative immunotherapeutic approach in IBD therapy. This article outlines the role of TLRs in IBD, focusing on both animal and human studies; the role of TLR-targeted agonists or antagonists as potential therapeutic agents in the different stages of the disease is discussed.
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Affiliation(s)
- Nastaran Kordjazy
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Arvin Haj-Mirzaian
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Shahid Beheshti Universtity of Medical Sciences, Tehran, Iran
| | - Arya Haj-Mirzaian
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Mojtaba Rohani
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Erwin W Gelfand
- Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO, USA
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Boston, MA, USA.
| | - Amir Hossein Abdolghaffari
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Tehran, Iran; Department of Pharmacology, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran; Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran; Gastrointestinal Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
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Chen Y, Wu Z, Yuan B, Dong Y, Zhang L, Zeng Z. MicroRNA-146a-5p attenuates irradiation-induced and LPS-induced hepatic stellate cell activation and hepatocyte apoptosis through inhibition of TLR4 pathway. Cell Death Dis 2018; 9:22. [PMID: 29348414 PMCID: PMC5833436 DOI: 10.1038/s41419-017-0038-z] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 10/05/2017] [Accepted: 10/06/2017] [Indexed: 12/14/2022]
Abstract
Elevated toll-like receptor 4 (TLR4) expression is associated with a high risk of radiation-induced liver disease (RILD). MicroRNA (miR)-146a-5p is a key regulator of lipopolysaccharide (LPS)/TLR4 signaling, but its role in modulation of RILD remains unclear. Here, we found that irradiation and LPS stimulation induced TLR4 and miR-146a-5p expression in the human hepatic stellate cell (HSC) line LX2. Ectopic expression of miR-146a-5p in LX2 inhibited irradiation-induced and LPS-induced pro-inflammatory cytokine secretion and cell proliferation, and promoted cell apoptosis by down-regulating the expression levels of TLR4, interleukin-1 receptor associated kinase 1 (IRAK1), tumor necrosis factor receptor associated factor 6 (TRAF6) and phosphorylation of nuclear factor-kappa B. In addition, the culture medium from the irradiated and LPS-stimulated HSCs transfected with miR-146a-5p significantly attenuated apoptosis in irradiated hepatocytes. Overexpression of miR-146a-5p reduced α-smooth muscle actin production in irradiated and LPS-stimulated LX2 cells, which was associated with inhibition of TRAF6-mediated JNK and Smad2 phosphorylation. Knockdown of TRAF6 or IRAK1 mimicked the effects of miR-146a-5p on HSC function. Furthermore, miR-146a-5p treatment alleviated irradiation-induced and endotoxin-induced hepatic inflammatory response and fibrogenesis in mice through inhibition of the TLR4 signaling pathway. Collectively, this study reveals the anti-pro-inflammatory and anti-fibrotic effects of miR-146a-5p on liver injury, and suggests a potential application of miR-146a-5p in the therapeutic prevention of RILD.
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Affiliation(s)
- Yuhan Chen
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180# Fenglin Road, 200032, Shanghai, China
| | - Zhifeng Wu
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180# Fenglin Road, 200032, Shanghai, China
| | - Baoying Yuan
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180# Fenglin Road, 200032, Shanghai, China
| | - Yinying Dong
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180# Fenglin Road, 200032, Shanghai, China
| | - Li Zhang
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180# Fenglin Road, 200032, Shanghai, China
| | - Zhaochong Zeng
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180# Fenglin Road, 200032, Shanghai, China.
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Li X, Zhang X, Gong P, Xia F, Li L, Yang Z, Li J. TLR2 -/- Mice Display Decreased Severity of Giardiasis via Enhanced Proinflammatory Cytokines Production Dependent on AKT Signal Pathway. Front Immunol 2017; 8:1186. [PMID: 28979269 PMCID: PMC5611375 DOI: 10.3389/fimmu.2017.01186] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 09/07/2017] [Indexed: 02/05/2023] Open
Abstract
Giardia infection is one of the most common causes of waterborne diarrheal disease in a wide array of mammalian hosts, including humans globally. Although numerous studies have indicated that adaptive immune responses are important for Giardia defense, however, whether the host innate immune system such as TLRs recognizes Giardia remains poorly understood. TLR2 plays a crucial role in pathogen recognition, innate immunity activation, and the eventual pathogen elimination. In this study, we investigated the role of TLR2 as a non-protective inflammatory response on controlling the severity of giardiasis. RT-PCR analysis suggested that TLR2 expression was increased in vitro. We demonstrated that Giardia lamblia-induced cytokines expression by the activation of p38 and ERK pathways via TLR2. Interestingly, the expression of IL-12 p40, TNF-α, and IL-6, but not IFN-γ, was enhanced in TLR2-blocked and TLR2−/− mouse macrophages exposed to G. lamblia trophozoites compared with wild-type (WT) mouse macrophages. Further analysis demonstrated that G. lamblia trophozoites reduced cytokines secretion by activating AKT pathway in WT mouse macrophages. Immunohistochemical staining in G. lamblia cysts infected TLR2−/− and WT mice showed that TLR2 was highly expressed in duodenum in infected WT mice. Also, infected TLR2−/− and AKT-blocked mice showed an increased production of IL-12 p40 and IFN-γ compared with infected WT mice at the early stage during infection. Interestingly, infected TLR2−/− and AKT-blocked mice displayed a decreased parasite burden, an increased weight gain rate, and short parasite persistence. Histological morphometry showed shortened villus length, hyperplastic crypt and decreased ratio of villus height/crypt depth in infected WT mice compared with in infected TLR2−/− and AKT-blocked mice. Together, our results suggested that TLR2 deficiency leads to alleviation of giardiasis and reduction of parasite burden through the promotion of proinflammatory cytokines production. For the first time, our results demonstrated that TLR2 played a negative role in host defense against Giardia.
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Affiliation(s)
- Xin Li
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Xichen Zhang
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Pengtao Gong
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Feifei Xia
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Ling Li
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Zhengtao Yang
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Jianhua Li
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
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Latorre E, Layunta E, Grasa L, Pardo J, García S, Alcalde AI, Mesonero JE. Toll-like receptors 2 and 4 modulate intestinal IL-10 differently in ileum and colon. United European Gastroenterol J 2017; 6:446-453. [PMID: 29774159 DOI: 10.1177/2050640617727180] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Accepted: 07/26/2017] [Indexed: 12/22/2022] Open
Abstract
Background Inflammatory bowel diseases are consequence of an intestinal homeostasis breakdown in which innate immune dysregulation is implicated. Toll-like receptor (TLR)2 and TLR4 are immune recognition receptors expressed in the intestinal epithelium, the first physical-physiological barrier for microorganisms, to inform the host of the presence of Gram-positive and Gram-negative organisms. Interleukin (IL)-10 is an essential anti-inflammatory cytokine that contributes to maintenance of intestinal homeostasis. Aim Our main aim was to investigate intestinal IL-10 synthesis and release, and whether TLR2 and TLR4 are determinants of IL-10 expression in the intestinal tract. Methods We used Caco-2 cell line as an enterocyte-like cell model, and also ileum and colon from mice deficient in TLR2, TLR4 or TLR2/4 to test the involvement of TLR signaling. Results Intestinal epithelial cells are able to synthesize and release IL-10 and their expression is increased after TLR2 or TLR4 activation. IL-10 regulation seems to be tissue specific, with IL-10 expression in the ileum regulated by a compensation between TLR2 and TLR4 expression, whereas in the colon, TLR2 and TLR4 affect IL-10 expression independently. Conclusions Intestinal epithelial cells could release IL-10 in response to TLR activation, playing an intestinal tissue-dependent and critical intestinal immune role.
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Affiliation(s)
- Eva Latorre
- 1Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter, United Kingdom.,Departamento Farmacología y Fisiología, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón (IIS), Universidad de Zaragoza, Zaragoza, Spain
| | - Elena Layunta
- Departamento Farmacología y Fisiología, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón (IIS), Universidad de Zaragoza, Zaragoza, Spain.,Instituto Agroalimentario de Aragón - IA2 - (Universidad de Zaragoza - CITA), Zaragoza, Spain
| | - Laura Grasa
- Departamento Farmacología y Fisiología, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón (IIS), Universidad de Zaragoza, Zaragoza, Spain.,Instituto Agroalimentario de Aragón - IA2 - (Universidad de Zaragoza - CITA), Zaragoza, Spain
| | - Julián Pardo
- Departamento Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Instituto de Investigación Sanitaria de Aragón (IIS), Universidad de Zaragoza, Zaragoza, Spain
| | - Santiago García
- Servicio de Sistema Digestivo, Hospital Clínico Universitario "Miguel Servet", Instituto de Investigación Sanitaria de Aragón (IIS) Zaragoza, Spain
| | - Ana I Alcalde
- Departamento Farmacología y Fisiología, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón (IIS), Universidad de Zaragoza, Zaragoza, Spain
| | - José E Mesonero
- Departamento Farmacología y Fisiología, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón (IIS), Universidad de Zaragoza, Zaragoza, Spain.,Instituto Agroalimentario de Aragón - IA2 - (Universidad de Zaragoza - CITA), Zaragoza, Spain
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Chang YC, Ching YH, Chiu CC, Liu JY, Hung SW, Huang WC, Huang YT, Chuang HL. TLR2 and interleukin-10 are involved in Bacteroides fragilis-mediated prevention of DSS-induced colitis in gnotobiotic mice. PLoS One 2017; 12:e0180025. [PMID: 28683149 PMCID: PMC5500315 DOI: 10.1371/journal.pone.0180025] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Accepted: 06/08/2017] [Indexed: 02/07/2023] Open
Abstract
Background and aims Bacteroides fragilis (BF) are Gram-negative anaerobe symbionts present in the colon. Recent studies have reported the beneficial role of BF in maintaining intestinal homeostasis, stimulating host immunologic development, and preventing infectious colitis caused by pathogenic bacteria. Our previous studies showed that monocolonization of germ-free mice with BF significantly reduced colon inflammations and damage. Methods In order to investigate the Toll-like receptor-2 (TLR2), TLR4, and interleukin 10 (IL-10) molecular signaling pathways involved in BF-mediated prevention of dextran sulfate sodium (DSS)-induced colitis. The wild-type (WT), TLR4, TLR2, and IL-10 knockout (-/-) germ-free mice grown were with or without BF colonization for 28 days, and then administered 1% DSS in drinking water for 7 day to induce acute ulcerative colitis. Results We compared phenotypes such as weight loss, disease activity, intestinal histological scores, and immunohistochemistry for inflammatory cells. Unlike WT and TLR4-/- mice, the severity of DSS-colitis did not improve in TLR2-/- animals after BF colonization. The BF enhanced anti-inflammatory cytokines IL-10 expression and inhibited pro-inflammatory-related tumor necrosis factor (TNF-α) and IL-6 mRNA expression in both WT and TLR4-/- mice. In contrast, the failed to up-regulated IL-10 and down-regulated the TNF-α and IL-6 in BF colonization TLR2-/- mice. In addition, we further perform IL-10-/- mice to clarify whether the BF through TLR2 /IL-10 pathway to alleviate DSS-colitis. There were no significant differences in colitis severity and pro-inflammatory related genes expression in the IL-10-/- mice with or without BF colonization. Conclusions These results indicate the disease-preventing effects of BF in acute DSS-induced colitis may occur through the TLR2/IL-10 signal pathway.
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Affiliation(s)
- Yi-Chih Chang
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan
| | - Yung-Hao Ching
- Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan
| | - Chien-Chao Chiu
- Division of Animal Resources, Animal Technology Laboratories, Agricultural Technology Research Institute, Hsinchu, Taiwan
| | - Ju-Yun Liu
- National Laboratory Animal Center, National Applied Research Laboratories, Taipei, Taiwan
| | - Shao-Wen Hung
- Division of Animal Resources, Animal Technology Laboratories, Agricultural Technology Research Institute, Hsinchu, Taiwan
| | - Wen-Ching Huang
- Department of Exercise and Health Science, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan
| | - Yen-Te Huang
- National Laboratory Animal Center, National Applied Research Laboratories, Taipei, Taiwan
| | - Hsiao-Li Chuang
- National Laboratory Animal Center, National Applied Research Laboratories, Taipei, Taiwan
- * E-mail:
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Yokoyama N, Ohta H, Kagawa Y, Nagata N, Nisa K, Morita T, Osuga T, Sasaki N, Morishita K, Nakamura K, Takiguchi M. Stimulation of colorectal biopsies from miniature dachshunds with inflammatory colorectal polyps with toll-like receptor ligands: A pilot study. Vet Immunol Immunopathol 2017; 188:78-83. [PMID: 28615131 DOI: 10.1016/j.vetimm.2017.05.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Revised: 05/01/2017] [Accepted: 05/16/2017] [Indexed: 12/19/2022]
Abstract
Inflammatory colorectal polyps (ICRPs) in miniature dachshunds (MDs) are a possible novel form of breed-specific canine inflammatory bowel disease (IBD). In this pilot study, we investigated the effects of different Toll like receptor (TLR2, TLR4, TLR5 and TLR9) ligands on pro-inflammatory cytokines (IL-1β, IL-6, IL-8 and TNF-α) gene expression in ex vivo-cultured colorectal samples from four MDs with ICRPs and four healthy MDs. At baseline, no significant difference in the mRNA expression levels of TLRs and pro-inflammatory cytokines was observed between cases and control MDs. After 4-h incubation, the relative ratios of TNF-α mRNA expression in the TLR2- or TLR4-stimulated colorectal samples, and IL-1β mRNA expression in the TLR9-stimulated colorectal samples form cases showed higher tendency compared with healthy MDs (P<0.05), although statistically not significant. The results of this pilot study using small number of cases indicated that reactivity against TLR2, TLR4 or TLR9 ligand in the production of pro-inflammatory cytokines might be enhanced in the colorectal mucosa of ICRPs. Further research is needed to perform the functional analysis of TLRs in the sole cell population using intestinal epithelial primary culture and the mononuclear cells isolated from colonic mucosa.
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Affiliation(s)
- Nozomu Yokoyama
- Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
| | - Hiroshi Ohta
- Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
| | - Yumiko Kagawa
- Department of Diagnostic Pathology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
| | - Noriyuki Nagata
- Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
| | - Khoirun Nisa
- Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
| | - Tomoya Morita
- Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
| | - Tatsuyuki Osuga
- Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
| | - Noboru Sasaki
- Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
| | - Keitaro Morishita
- Veterinary Teaching Hospital, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
| | - Kensuke Nakamura
- Veterinary Teaching Hospital, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
| | - Mitsuyoshi Takiguchi
- Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
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Banskota S, Regmi SC, Gautam J, Gurung P, Lee YJ, Ku SK, Lee JH, Lee J, Chang HW, Park SJ, Kim JA. Serotonin disturbs colon epithelial tolerance of commensal E. coli by increasing NOX2-derived superoxide. Free Radic Biol Med 2017; 106:196-207. [PMID: 28216386 DOI: 10.1016/j.freeradbiomed.2017.02.034] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 02/04/2017] [Accepted: 02/15/2017] [Indexed: 02/06/2023]
Abstract
Adherent-invasive E. coli colonization and Toll-like receptor (TLR) expression are increased in the gut of inflammatory bowel disease (IBD) patients. However, the underlying mechanism of such changes has not been determined. In the current study, it was examined whether gut serotonin (5-hydroxytryptamine, 5-HT) can induce adherent-invasive E. coli colonization and increase TLR expression. In a co-culture system, commensal E. coli strain (BW25113, BW) adhered minimally to colon epithelial cells, but this was significantly enhanced by 5-HT to the level of a pathogenic strain (EDL933). Without inducing bacterial virulence, such as, biofilm formation, 5-HT enhanced BW-induced signaling in colon epithelial cells, that is, NADPH oxidase (NOX)-dependent superoxide production, the up-regulations of IL-8, TLR2, TLR4, and ICAM-1, and the down-regulations of E-cadherin and claudin-2. In a manner commensurate with these gene modulations, BW induced an increase in NF-κB and a decrease in GATA reporter signals in colon epithelial cells. However, 5-HT-enhanced BW adhesion and colon epithelial responses were blocked by knock-down of NOX2, TLR2, or TLR4. In normal mice, 5-HT induced the invasion of BW into gut submucosa, and the observed molecular changes were similar to those observed in vitro, except for significant increases in TNFα and IL-1β, and resulted in death. In dextran sulfate sodium-induced colitis mice (an IBD disease model), in which colonic 5-HT levels were markedly elevated, BW administration induced death in along with large amount of BW invasion into colon submucosa, and time to death was negatively related to the amount of BW injected. Taken together, our results demonstrate that 5-HT induces the invasion of commensal E. coli into gut submucosa by amplifying commensal bacteria-induced epithelial signaling (superoxide production and the inductions of NOX2 and TLR2/TLR4). The authors suggest that these changes may constitute the molecular basis for the pathogenesis of IBD.
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Affiliation(s)
- Suhrid Banskota
- College of Pharmacy Yeungnam University, 280 Daehak-ro, Gyeongsan 38541, Republic of Korea
| | - Sushil Chandra Regmi
- College of Pharmacy Yeungnam University, 280 Daehak-ro, Gyeongsan 38541, Republic of Korea
| | - Jaya Gautam
- College of Pharmacy Yeungnam University, 280 Daehak-ro, Gyeongsan 38541, Republic of Korea
| | - Pallavi Gurung
- College of Pharmacy Yeungnam University, 280 Daehak-ro, Gyeongsan 38541, Republic of Korea
| | - Yu-Jeong Lee
- College of Pharmacy Yeungnam University, 280 Daehak-ro, Gyeongsan 38541, Republic of Korea
| | - Sae Kwang Ku
- Department of Anatomy and Histology, College of Korean Medicine, Daegu Hany University, Gyeongsan 38610, Republic of Korea
| | - Jin-Hyung Lee
- School of Chemical Engineering, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Jintae Lee
- School of Chemical Engineering, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Hyeun Wook Chang
- College of Pharmacy Yeungnam University, 280 Daehak-ro, Gyeongsan 38541, Republic of Korea
| | - Sang Joon Park
- Department of Histology, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Jung-Ae Kim
- College of Pharmacy Yeungnam University, 280 Daehak-ro, Gyeongsan 38541, Republic of Korea.
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46
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Relative Abundance of Streptococcus spp. and its Association with Disease Activity in Inflammatory Bowel Disease Patients Compared with Controls. ARCHIVES OF CLINICAL INFECTIOUS DISEASES 2017. [DOI: 10.5812/archcid.57291] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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All-Trans Retinoic Acid Modulates TLR4/NF- κB Signaling Pathway Targeting TNF- α and Nitric Oxide Synthase 2 Expression in Colonic Mucosa during Ulcerative Colitis and Colitis Associated Cancer. Mediators Inflamm 2017; 2017:7353252. [PMID: 28408791 PMCID: PMC5376956 DOI: 10.1155/2017/7353252] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2016] [Revised: 01/05/2017] [Accepted: 02/19/2017] [Indexed: 12/24/2022] Open
Abstract
Colitis associated cancer (CAC) is the colorectal cancer (CRC) subtype that is associated with bowel disease such as ulcerative colitis (UC). The data on role of NF-κB signaling in development and progression of CAC were derived from preclinical studies, whereas data from human are rare. The aim of this work was to study the contribution of NF-κB pathway during UC and CAC, as well as the immunomodulatory effect of all-trans retinoic acid (AtRA). We analyzed the expression of NOS2, TNF-α, TLR4, and NF-κB, in colonic mucosa. We also studied NO/TNF-α modulation by LPS in colonic mucosa pretreated with AtRA. A marked increase in TLR4, NF-κB, TNF-α, and NOS2 expression was reported in colonic mucosa. The relationship between LPS/TLR4 and TNF-α/NO production, as well as the role of NF-κB signaling, was confirmed by ex vivo experiments and the role of LPS/TLR4 in NOS2/TNF-α induction through NF-κB pathway was suggested. AtRA downregulates NOS2 and TNF-α expression. Collectively, our study indicates that AtRA modulates in situ LPS/TLR4/NF-κB signaling pathway targeting NOS2 and TNF-α expression. Therefore, we suggest that AtRA has a potential value in new strategies to improve the current therapy, as well as in the clinical prevention of CAC development and progression.
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Yao P, Tan F, Gao H, Wang L, Yang T, Cheng Y. Effects of probiotics on Toll‑like receptor expression in ulcerative colitis rats induced by 2,4,6‑trinitro‑benzene sulfonic acid. Mol Med Rep 2017; 15:1973-1980. [PMID: 28260106 PMCID: PMC5364977 DOI: 10.3892/mmr.2017.6226] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Accepted: 10/24/2016] [Indexed: 12/19/2022] Open
Abstract
The present study aimed to investigate the regulatory effect of probiotics on the expression of Toll‑like receptors (TLRs) in an ulcerative colitis (UC) rat model, and to determine the role of probiotics in the underlying mechanisms through which UC develops and progresses in rat models. Rats were randomly allocated to one of the four following groups: i) The healthy control, ii) the model, iii) the Golden bifid treatment group, and iv) the TLR4 monoclonal antibody (TLR4mAb) intervention group. The UC rat model was established using 2,4,6‑trinitro‑benzene sulfonic acid. The general status and histological changes of rats were scored using the disease activity index and the histopathological scoring method, respectively. In these rats, the expression of TLR4 and TLR2 was measured using reverse transcription‑quantitative polymerase chain reaction. The expression of TLR4 and TLR2 in the model group was significantly higher than that in the healthy control group. However, when compared with the model rats, those that received either Golden bifid treatment or TLR4mAb intervention exhibited significantly decreased mRNA expression levels of TLR4 and TLR2 (P<0.05). The development of UC is characterized by an abnormal immune response in the intestines. Probiotics alleviated inflammatory reactions in rats with UC. The underlying mechanism of UC may be associated with the expression of TLRs and the subsequent release of inflammatory cytokines.
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Affiliation(s)
- Ping Yao
- Department of Gastroenterology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Fang Tan
- Department of Gastroenterology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Hongliang Gao
- Department of Gastroenterology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Lei Wang
- Department of Gastroenterology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Tao Yang
- Department of Gastroenterology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Yongbo Cheng
- Department of Gastroenterology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
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Inoue R, Yajima T, Tsukahara T. Expression of TLR2 and TLR4 in murine small intestine during postnatal development. Biosci Biotechnol Biochem 2017; 81:350-358. [DOI: 10.1080/09168451.2016.1254534] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Abstract
The important role played by the gut microbiota in host immunity is mediated, in part, through toll-like receptors (TLRs). We evaluated the postnatal changes in expression of TLR2 and TLR4 in the murine small intestine and assessed how expression is influenced by gut microbiota. The expression of TLR2 and TLR4 in the murine small intestine was highly dynamic during development. The changes were especially profound during the suckling period, with the maximal mRNA levels detected in the mid-suckling period. Immunohistochemical and flow-cytometric analyses indicated that the changes in TLR2 and TLR4 expression involve primarily epithelial cells. The germ-free mice showed minor changes in TLR2/TLR4 mRNA and TLR2 protein during the suckling period. This study demonstrated that the postnatal expression of TLR2 and TLR4 in small intestinal epithelial cells is dynamic and depends on the presence of commensal intestinal microbiota.
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Affiliation(s)
- Ryo Inoue
- Laboratory of Animal Science, Department of Agricultural and Life Sciences, Kyoto Prefectural University, Kyoto, Japan
- Creative Research Initiative “Sousei” (CRIS), Hokkaido University, Sapporo, Japan
| | - Takaji Yajima
- Creative Research Initiative “Sousei” (CRIS), Hokkaido University, Sapporo, Japan
| | - Takamitsu Tsukahara
- Laboratory of Animal Science, Department of Agricultural and Life Sciences, Kyoto Prefectural University, Kyoto, Japan
- Kyoto Institute of Nutrition and Pathology, Kyoto, Japan
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Cui B, Lu S, Lai L, Xie Y, He J, Xue Y, Xiao P, Pan T, Chen L, Liu Y, Cao X, Wang Q. Protective function of interleukin 27 in colitis-associated cancer via suppression of inflammatory cytokines in intestinal epithelial cells. Oncoimmunology 2017; 6:e1268309. [PMID: 28344880 DOI: 10.1080/2162402x.2016.1268309] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Revised: 11/22/2016] [Accepted: 11/30/2016] [Indexed: 12/13/2022] Open
Abstract
Numerous studies have demonstrated that inflammation contributes to a variety of cancer formation, among them, colitis-associated cancer (CAC) represents a typical inflammation-related cancer. Interleukin 27 (IL-27) has been demonstrated to play an important role in inflammation-related disease. The effect of IL-27 in intestinal inflammation is controversial and its role in CAC is not elucidated yet. In our present study, we found that IL-27 has protective function in murine model of CAC through suppression of inflammatory cytokines in intestinal epithelial cells (IECs). IL-27Rα (WSX-1) deficiency promotes the CAC development in mice, which is driven by enhanced tumor cell proliferation, more intensive myeloid-derived suppressor cells (MDSC) accumulation in colon lamina propria and higher level of inflammatory cytokines and chemokines in IECs. The levels of IL-6, TNF-α, GM-CSF and CXCL1 triggered in vitro by toll-like receptor ligands are significantly upregulated in IECs from WSX-1 KO mice. Removal of commensal microorganism through antibiotic treatment in mice to eliminate TLR ligands deprives the protective function of IL-27 on CAC tumor growth. Thus, IL-27 suppresses CAC formation through an anti-inflammation mechanism targeting IECs and in turn resists the tumorigenesis. Hence, our study explained how IL-27 exerts its anti-inflammatory function on epithelial cells to fight against chronic-inflammation-associated cancer, which might provide new insights on the potential therapeutic strategies for cancer.
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Affiliation(s)
- Bijun Cui
- Institute of Immunology, Zhejiang University School of Medicine , Hangzhou, China
| | - Shen Lu
- Institute of Immunology, Zhejiang University School of Medicine , Hangzhou, China
| | - Lihua Lai
- Institute of Immunology, Zhejiang University School of Medicine , Hangzhou, China
| | - Yiwei Xie
- Institute of Immunology, Zhejiang University School of Medicine , Hangzhou, China
| | - Jia He
- Institute of Immunology, Zhejiang University School of Medicine , Hangzhou, China
| | - Yue Xue
- Institute of Immunology, Zhejiang University School of Medicine , Hangzhou, China
| | - Peng Xiao
- Institute of Immunology, Zhejiang University School of Medicine , Hangzhou, China
| | - Ting Pan
- Institute of Immunology, Zhejiang University School of Medicine , Hangzhou, China
| | - Luoquan Chen
- Institute of Immunology, Zhejiang University School of Medicine , Hangzhou, China
| | - Yang Liu
- Institute of Immunology, Zhejiang University School of Medicine , Hangzhou, China
| | - Xuetao Cao
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China; National Key Laboratory of Medical Molecular Biology and Department of Immunology, Chinese Academy of Medical Sciences, Beijing, China
| | - Qingqing Wang
- Institute of Immunology, Zhejiang University School of Medicine , Hangzhou, China
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