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Snyder JD, Yoon TW, Lee S, Halder P, Fitzpatrick EA, Yi AK. Protein kinase D1 in myeloid lineage cells contributes to the accumulation of CXCR3 +CCR6 + nonconventional Th1 cells in the lungs and potentiates hypersensitivity pneumonitis caused by S. rectivirgula. Front Immunol 2024; 15:1403155. [PMID: 39464896 PMCID: PMC11502317 DOI: 10.3389/fimmu.2024.1403155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 09/18/2024] [Indexed: 10/29/2024] Open
Abstract
Introduction Hypersensitivity pneumonitis (HP) is an extrinsic allergic alveolitis characterized by inflammation of the interstitium, bronchioles, and alveoli of the lung that leads to granuloma formation. We previously found that activation of protein kinase D1 (PKD1) in the lungs following exposures to Saccharopolyspora rectivirgula contributes to the acute pulmonary inflammation, IL-17A expression in the lungs, and development of HP. In the present study, we investigated whether PKD1 in myeloid-lineage cells affects the pathogenic course of the S. rectivirgula-induced HP. Methods Mice were exposed intranasally to S. rectivirgula once or 3 times/week for 3 weeks. The protein and mRNA expression levels of cytokines/chemokines were detected by enzyme-linked immunosorbent assay and quantitative real-time PCR, respectively. Flow cytometry was used to detect the different types of immune cells and the levels of surface proteins. Lung tissue sections were stained with hematoxylin and eosin, digital images were captured, and immune cells influx into the interstitial lung tissue were detected. Results Compared to control PKD1-sufficient mice, mice with PKD1 deficiency in myeloid-lineage cells (PKD1mKO) showed significantly suppressed expression of TNFα, IFNγ, IL-6, CCL2, CCL3, CCL4, CXCL1, CXCL2, and CXCL10 and neutrophilic alveolitis after single intranasal exposure to S. rectivirgula. Substantially reduced levels of alveolitis and granuloma formation were observed in the PKD1mKO mice repeatedly exposed to S. rectivirgula for 3 weeks. In addition, expression levels of the Th1/Th17 polarizing cytokines and chemokines such as IFNγ, IL-17A, CXCL9, CXCL10, CXCL11, and CCL20 in lungs were significantly reduced in the PKD1mKO mice repeatedly exposed to S. rectivirgula. Moreover, accumulation of CXCR3+CCR6+ nonconventional Th1 in the lungs were significantly reduced in PKD1mKO mice repeatedly exposed to S. rectivirgula. Discussion Our results demonstrate that PKD1 in myeloid-lineage cells plays an essential role in the development and progress of HP caused by repeated exposure to S. rectivirgula by contributing Th1/Th17 polarizing proinflammatory responses, alveolitis, and accumulation of pathogenic nonconventional Th1 cells in the lungs.
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Affiliation(s)
- John D. Snyder
- Integrated Biomedical Science Graduate Program, The University of Tennessee Health Science Center, Memphis, TN, United States
- Department of Microbiology, Immunology and Biochemistry, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Tae Won Yoon
- Integrated Biomedical Science Graduate Program, The University of Tennessee Health Science Center, Memphis, TN, United States
- Department of Microbiology, Immunology and Biochemistry, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Sangmin Lee
- Department of Microbiology, Immunology and Biochemistry, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Priyanka Halder
- Department of Microbiology, Immunology and Biochemistry, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Elizabeth Ann Fitzpatrick
- Integrated Biomedical Science Graduate Program, The University of Tennessee Health Science Center, Memphis, TN, United States
- Department of Microbiology, Immunology and Biochemistry, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Ae-Kyung Yi
- Integrated Biomedical Science Graduate Program, The University of Tennessee Health Science Center, Memphis, TN, United States
- Department of Microbiology, Immunology and Biochemistry, The University of Tennessee Health Science Center, Memphis, TN, United States
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Panaro MA, Budriesi R, Calvello R, Cianciulli A, Mattioli LB, Corazza I, Rotondo NP, Porro C, Lamonaca A, Ferraro V, Muraglia M, Corbo F, Clodoveo ML, Monaci L, Cavalluzzi MM, Lentini G. Lentil Waste Extracts for Inflammatory Bowel Disease (IBD) Symptoms Control: Anti-Inflammatory and Spasmolytic Effects. Nutrients 2024; 16:3327. [PMID: 39408293 PMCID: PMC11478658 DOI: 10.3390/nu16193327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 09/25/2024] [Accepted: 09/26/2024] [Indexed: 10/20/2024] Open
Abstract
BACKGROUND/OBJECTIVES In the contest of agro-industrial waste valorization, we focused our attention on lentil seed coats as a source of health-promoting phytochemicals possibly useful in managing inflammatory bowel diseases (IBDs), usually characterized by inflammation and altered intestinal motility. METHODS Both traditional (maceration) and innovative microwave-assisted extractions were performed using green solvents, and the anti-inflammatory and spasmolytic activities of the so-obtained extracts were determined through in vitro and ex vivo assays, respectively. RESULTS The extract obtained through the microwave-assisted procedure using ethyl acetate as the extraction solvent (BEVa) proved to be the most useful in inflammation and intestinal motility management. In LPS-activated Caco-2 cells, BEVa down-regulated TLR4 expression, reduced iNOS expression and the pro-inflammatory cytokine IL-1 production, and upregulated the anti-inflammatory cytokine IL-10 production, thus positively affecting cell inflammatory responses. Moreover, a significant decrease in the longitudinal and circular tones of the guinea pig ileum, with a reduction of transit speed and pain at the ileum level, together with reduced transit speed, pain, and muscular tone at the colon level, was observed with BEVa. HPLC separation combined with an Orbitrap-based high-resolution mass spectrometry (HRMS) technique indicated that 7% of all the identified metabolites were endowed with proven anti-inflammatory and antispasmodic activities, among which niacinamide, apocynin, and p-coumaric acid were the most abundant. CONCLUSIONS Our results suggest that lentil hull extract consumption could contribute to overall intestinal health maintenance, with BEVa possibly representing a dietary supplementation and a promising approach to treating intestinal barrier dysfunction.
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Affiliation(s)
- Maria Antonietta Panaro
- Department of Biosciences, Biotechnologies and Environment, University of Bari, 70125 Bari, Italy; (M.A.P.); (R.C.)
| | - Roberta Budriesi
- Department of Pharmacy and Biotechnology, Food Chemistry and Nutraceutical Lab, Alma Mater Studiorum—University of Bologna, 40126 Bologna, Italy; (R.B.); (L.B.M.)
| | - Rosa Calvello
- Department of Biosciences, Biotechnologies and Environment, University of Bari, 70125 Bari, Italy; (M.A.P.); (R.C.)
| | - Antonia Cianciulli
- Department of Biosciences, Biotechnologies and Environment, University of Bari, 70125 Bari, Italy; (M.A.P.); (R.C.)
| | - Laura Beatrice Mattioli
- Department of Pharmacy and Biotechnology, Food Chemistry and Nutraceutical Lab, Alma Mater Studiorum—University of Bologna, 40126 Bologna, Italy; (R.B.); (L.B.M.)
| | - Ivan Corazza
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum—University of Bologna, 40138 Bologna, Italy;
| | - Natalie Paola Rotondo
- Department of Pharmacy—Drug Sciences, University Aldo Moro-Bari, 70126 Bari, Italy; (N.P.R.); (V.F.); (M.M.); (F.C.); (G.L.)
| | - Chiara Porro
- Department of Clinical and Experimental Medicine, University of Foggia, 71100 Foggia, Italy;
| | - Antonella Lamonaca
- Institute of Sciences of Food Production, National Research Council of Italy (CNR-ISPA), 70126 Bari, Italy; (A.L.); (L.M.)
- Department of Soil, Plant and Food Sciences, University Aldo Moro-Bari, 70126 Bari, Italy
| | - Valeria Ferraro
- Department of Pharmacy—Drug Sciences, University Aldo Moro-Bari, 70126 Bari, Italy; (N.P.R.); (V.F.); (M.M.); (F.C.); (G.L.)
| | - Marilena Muraglia
- Department of Pharmacy—Drug Sciences, University Aldo Moro-Bari, 70126 Bari, Italy; (N.P.R.); (V.F.); (M.M.); (F.C.); (G.L.)
| | - Filomena Corbo
- Department of Pharmacy—Drug Sciences, University Aldo Moro-Bari, 70126 Bari, Italy; (N.P.R.); (V.F.); (M.M.); (F.C.); (G.L.)
| | - Maria Lisa Clodoveo
- Interdisciplinary Department of Medicine, University of Bari, 70124 Bari, Italy;
| | - Linda Monaci
- Institute of Sciences of Food Production, National Research Council of Italy (CNR-ISPA), 70126 Bari, Italy; (A.L.); (L.M.)
| | - Maria Maddalena Cavalluzzi
- Department of Pharmacy—Drug Sciences, University Aldo Moro-Bari, 70126 Bari, Italy; (N.P.R.); (V.F.); (M.M.); (F.C.); (G.L.)
| | - Giovanni Lentini
- Department of Pharmacy—Drug Sciences, University Aldo Moro-Bari, 70126 Bari, Italy; (N.P.R.); (V.F.); (M.M.); (F.C.); (G.L.)
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Chen YH, Wu KH, Wu HP. Unraveling the Complexities of Toll-like Receptors: From Molecular Mechanisms to Clinical Applications. Int J Mol Sci 2024; 25:5037. [PMID: 38732254 PMCID: PMC11084218 DOI: 10.3390/ijms25095037] [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: 03/28/2024] [Revised: 05/02/2024] [Accepted: 05/03/2024] [Indexed: 05/13/2024] Open
Abstract
Toll-like receptors (TLRs) are vital components of the innate immune system, serving as the first line of defense against pathogens by recognizing a wide array of molecular patterns. This review summarizes the critical roles of TLRs in immune surveillance and disease pathogenesis, focusing on their structure, signaling pathways, and implications in various disorders. We discuss the molecular intricacies of TLRs, including their ligand specificity, signaling cascades, and the functional consequences of their activation. The involvement of TLRs in infectious diseases, autoimmunity, chronic inflammation, and cancer is explored, highlighting their potential as therapeutic targets. We also examine recent advancements in TLR research, such as the development of specific agonists and antagonists, and their application in immunotherapy and vaccine development. Furthermore, we address the challenges and controversies surrounding TLR research and outline future directions, including the integration of computational modeling and personalized medicine approaches. In conclusion, TLRs represent a promising frontier in medical research, with the potential to significantly impact the development of novel therapeutic strategies for a wide range of diseases.
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Affiliation(s)
- Yi-Hsin Chen
- Department of Nephrology, Taichung Tzu Chi Hospital, Taichung 427, Taiwan;
- School of Medicine, Tzu Chi University, Hualien 97004, Taiwan
- Department of Artificial Intelligence and Data Science, National Chung Hsing University, Taichung 40227, Taiwan
| | - Kang-Hsi Wu
- Department of Pediatrics, Chung Shan Medical University Hospital, Taichung 402, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
| | - Han-Ping Wu
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Pediatrics, Chiayi Chang Gung Memorial Hospital, Chiayi 613016, Taiwan
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Zhang Z, Zhang HL, Yang DH, Hao Q, Yang HW, Meng DL, Meindert de Vos W, Guan LL, Liu SB, Teame T, Gao CC, Ran C, Yang YL, Yao YY, Ding QW, Zhou ZG. Lactobacillus rhamnosus GG triggers intestinal epithelium injury in zebrafish revealing host dependent beneficial effects. IMETA 2024; 3:e181. [PMID: 38882496 PMCID: PMC11170971 DOI: 10.1002/imt2.181] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 02/22/2024] [Accepted: 02/26/2024] [Indexed: 06/18/2024]
Abstract
Lactobacillus rhamnosus GG (LGG), the well-characterized human-derived probiotic strain, possesses excellent properties in the maintenance of intestinal homeostasis, immunoregulation and defense against gastrointestinal pathogens in mammals. Here, we demonstrate that the SpaC pilin of LGG causes intestinal epithelium injury by inducing cell pyroptosis and gut microbial dysbiosis in zebrafish. Dietary SpaC activates Caspase-3-GSDMEa pathways in the intestinal epithelium, promotes intestinal pyroptosis and increases lipopolysaccharide (LPS)-producing gut microbes in zebrafish. The increased LPS subsequently activates Gaspy2-GSDMEb pyroptosis pathway. Further analysis reveals the Caspase-3-GSDMEa pyroptosis is initiated by the species-specific recognition of SpaC by TLR4ba, which accounts for the species-specificity of the SpaC-inducing intestinal pyroptosis in zebrafish. The observed pyroptosis-driven gut injury and microbial dysbiosis by LGG in zebrafish suggest that host-specific beneficial/harmful mechanisms are critical safety issues when applying probiotics derived from other host species and need more attention.
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Affiliation(s)
- Zhen Zhang
- Key Laboratory for Feed Biotechnology of the Ministry of Agriculture and Rural Affairs, Institute of Feed Research Chinese Academy of Agricultural Sciences Beijing China
- Faculty of Land and Food Systems The University of British Columbia Vancouver Canada
| | - Hong-Ling Zhang
- China-Norway Joint Lab on Fish Gut Microbiota, Institute of Feed Research Chinese Academy of Agricultural Sciences Beijing China
| | - Da-Hai Yang
- State Key Laboratory of Bioreactor Engineering East China University of Science and Technology Shanghai China
| | - Qiang Hao
- China-Norway Joint Lab on Fish Gut Microbiota, Institute of Feed Research Chinese Academy of Agricultural Sciences Beijing China
| | - Hong-Wei Yang
- China-Norway Joint Lab on Fish Gut Microbiota, Institute of Feed Research Chinese Academy of Agricultural Sciences Beijing China
| | - De-Long Meng
- China-Norway Joint Lab on Fish Gut Microbiota, Institute of Feed Research Chinese Academy of Agricultural Sciences Beijing China
| | - Willem Meindert de Vos
- Laboratory of Microbiology Wageningen University and Research Wageningen Netherlands
- Human Microbiome Research Program, Faculty of Medicine University of Helsinki Helsinki Finland
| | - Le-Luo Guan
- Faculty of Land and Food Systems The University of British Columbia Vancouver Canada
| | - Shu-Bin Liu
- China-Norway Joint Lab on Fish Gut Microbiota, Institute of Feed Research Chinese Academy of Agricultural Sciences Beijing China
| | - Tsegay Teame
- China-Norway Joint Lab on Fish Gut Microbiota, Institute of Feed Research Chinese Academy of Agricultural Sciences Beijing China
- Tigray Agricultural Research Institute Mekelle Ethiopia
| | - Chen-Chen Gao
- China-Norway Joint Lab on Fish Gut Microbiota, Institute of Feed Research Chinese Academy of Agricultural Sciences Beijing China
| | - Chao Ran
- Key Laboratory for Feed Biotechnology of the Ministry of Agriculture and Rural Affairs, Institute of Feed Research Chinese Academy of Agricultural Sciences Beijing China
| | - Ya-Lin Yang
- Key Laboratory for Feed Biotechnology of the Ministry of Agriculture and Rural Affairs, Institute of Feed Research Chinese Academy of Agricultural Sciences Beijing China
| | - Yuan-Yuan Yao
- Key Laboratory for Feed Biotechnology of the Ministry of Agriculture and Rural Affairs, Institute of Feed Research Chinese Academy of Agricultural Sciences Beijing China
| | - Qian-Wen Ding
- Key Laboratory for Feed Biotechnology of the Ministry of Agriculture and Rural Affairs, Institute of Feed Research Chinese Academy of Agricultural Sciences Beijing China
| | - Zhi-Gang Zhou
- China-Norway Joint Lab on Fish Gut Microbiota, Institute of Feed Research Chinese Academy of Agricultural Sciences Beijing China
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Yu H, Gu X, Wang D, Wang Z. Brucella infection and Toll-like receptors. Front Cell Infect Microbiol 2024; 14:1342684. [PMID: 38533384 PMCID: PMC10963510 DOI: 10.3389/fcimb.2024.1342684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 01/17/2024] [Indexed: 03/28/2024] Open
Abstract
Brucella consists of gram-negative bacteria that have the ability to invade and replicate in professional and non-professional phagocytes, and its prolonged persistence in the host leads to brucellosis, a serious zoonosis. Toll-like receptors (TLRs) are the best-known sensors of microorganisms implicated in the regulation of innate and adaptive immunity. In particular, TLRs are transmembrane proteins with a typical structure of an extracellular leucine-rich repeat (LRR) region and an intracellular Toll/interleukin-1 receptor (TIR) domain. In this review, we discuss Brucella infection and the aspects of host immune responses induced by pathogens. Furthermore, we summarize the roles of TLRs in Brucella infection, with substantial emphasis on the molecular insights into its mechanisms of action.
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Affiliation(s)
- Hui Yu
- Inner Mongolia Key Laboratory of Disease-Related Biomarkers, The Second Affiliated Hospital, Baotou Medical College, Baotou, China
- School of Basic Medicine, Baotou Medical College, Baotou, China
| | - Xinyi Gu
- The College of Medical Technology, Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Danfeng Wang
- The College of Medical Technology, Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Zhanli Wang
- Inner Mongolia Key Laboratory of Disease-Related Biomarkers, The Second Affiliated Hospital, Baotou Medical College, Baotou, China
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Peng J, Zhang S, Han F, Wang Z. C1QBP is a critical component in the immune response of large yellow croaker (Larimichthys crocea) against visceral white spot disease caused by Pseudomonas plecoglossicida. FISH & SHELLFISH IMMUNOLOGY 2024; 146:109372. [PMID: 38218420 DOI: 10.1016/j.fsi.2024.109372] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 12/27/2023] [Accepted: 01/10/2024] [Indexed: 01/15/2024]
Abstract
The large yellow croaker (Larimichthys crocea) stands as a cornerstone of mariculture in China due to its significant value. However, the threat of Pseudomonas plecoglossicida infection looms large, capable of triggering "visceral white spot disease" and subsequently inflicting severe economic ramifications. Through a prior genome-wide association analysis (GWAS) aimed at understanding the resistance of the large yellow croaker to this ailment, a pivotal player emerged: the complement component 1q binding protein, aptly named LcC1qbp. This protein assumes a crucial role in the activation of the complement system. This study delves deeper into the immune response by examining the expression patterns of LcC1QBP when confronted with P. plecoglossicida. The investigation into gene expression patterns reveals LcC1qbp's widespread presence, with its highest transcriptional abundance identified in the kidney tissues. Upon infection by P. plecoglossicida, the up-regulation of LcC1qbp in major immune organs manifests at both the transcriptional and translational levels. In the context of RNA interference, transcriptome analysis of C1qbp in HEK 293T cells uncovers 1327 differentially expressed genes (DEGs), featuring 41 significant immune genes. This includes pivotal components such as C1S and C3 of the complement system, along with IL11, IL12RB2, and Myd88, among others. The outcomes of enrichment analysis spotlight the prevalence of DEGs within key pathways like immune system development, myeloid leukocyte-mediated immunity, MAPK signaling, and other immune-related routes. By unveiling the immune response mechanisms of the large yellow croaker to P. plecoglossicida infection, this study bolsters our understanding. Furthermore, it lays the groundwork for pursuing effective strategies in both preventing and treating "visceral white spot disease" in the large yellow croaker.
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Affiliation(s)
- Jia Peng
- State Key Laboratory of Mariculture Breeding, Fujian Provincial Key Laboratory of Marine Fishery Resources and Eco-environment, Fisheries College, Jimei University, Xiamen, 361000, PR China
| | - Sen Zhang
- State Key Laboratory of Mariculture Breeding, Fujian Provincial Key Laboratory of Marine Fishery Resources and Eco-environment, Fisheries College, Jimei University, Xiamen, 361000, PR China
| | - Fang Han
- State Key Laboratory of Mariculture Breeding, Fujian Provincial Key Laboratory of Marine Fishery Resources and Eco-environment, Fisheries College, Jimei University, Xiamen, 361000, PR China.
| | - Zhiyong Wang
- State Key Laboratory of Mariculture Breeding, Fujian Provincial Key Laboratory of Marine Fishery Resources and Eco-environment, Fisheries College, Jimei University, Xiamen, 361000, PR China
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Jucá PM, de Almeida Duque É, Covre LHH, Mariano KAA, Munhoz CD. Microglia and Systemic Immunity. ADVANCES IN NEUROBIOLOGY 2024; 37:287-302. [PMID: 39207698 DOI: 10.1007/978-3-031-55529-9_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Microglia are specialized immune cells that reside in the central nervous system (CNS) and play a crucial role in maintaining the homeostasis of the brain microenvironment. While traditionally regarded as a part of the innate immune system, recent research has highlighted their role in adaptive immunity. The CNS is no longer considered an immune-privileged organ, and increasing evidence suggests bidirectional communication between the immune system and the CNS. Microglia are sensitive to systemic immune signals and can respond to systemic inflammation by producing various inflammatory cytokines and chemokines. This response is mediated by activating pattern recognition receptors (PRRs), which recognize pathogen- and danger-associated molecular patterns in the systemic circulation. The microglial response to systemic inflammation has been implicated in several neurological conditions, including depression, anxiety, and cognitive impairment. Understanding the complex interplay between microglia and systemic immunity is crucial for developing therapeutic interventions to modulate immune responses in the CNS.
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Affiliation(s)
- Paloma Marinho Jucá
- Department of Pharmacology, Universidade de Sao Paulo Instituto de Ciencias Biomedicas, São Paulo, Brazil
| | - Érica de Almeida Duque
- Department of Pharmacology, Universidade de Sao Paulo Instituto de Ciencias Biomedicas, São Paulo, Brazil
| | - Luiza Helena Halas Covre
- Department of Pharmacology, Universidade de Sao Paulo Instituto de Ciencias Biomedicas, São Paulo, Brazil
| | | | - Carolina Demarchi Munhoz
- Department of Pharmacology, Universidade de Sao Paulo Instituto de Ciencias Biomedicas, São Paulo, Brazil.
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Wu Z, Shih B, Macdonald J, Meunier D, Hogan K, Chintoan-Uta C, Gilhooley H, Hu T, Beltran M, Henderson NC, Sang HM, Stevens MP, McGrew MJ, Balic A. Development and function of chicken XCR1 + conventional dendritic cells. Front Immunol 2023; 14:1273661. [PMID: 37954617 PMCID: PMC10634274 DOI: 10.3389/fimmu.2023.1273661] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 10/06/2023] [Indexed: 11/14/2023] Open
Abstract
Conventional dendritic cells (cDCs) are antigen-presenting cells (APCs) that play a central role in linking innate and adaptive immunity. cDCs have been well described in a number of different mammalian species, but remain poorly characterised in the chicken. In this study, we use previously described chicken cDC specific reagents, a novel gene-edited chicken line and single-cell RNA sequencing (scRNAseq) to characterise chicken splenic cDCs. In contrast to mammals, scRNAseq analysis indicates that the chicken spleen contains a single, chemokine receptor XCR1 expressing, cDC subset. By sexual maturity the XCR1+ cDC population is the most abundant mononuclear phagocyte cell subset in the chicken spleen. scRNAseq analysis revealed substantial heterogeneity within the chicken splenic XCR1+ cDC population. Immature MHC class II (MHCII)LOW XCR1+ cDCs expressed a range of viral resistance genes. Maturation to MHCIIHIGH XCR1+ cDCs was associated with reduced expression of anti-viral gene expression and increased expression of genes related to antigen presentation via the MHCII and cross-presentation pathways. To visualise and transiently ablate chicken XCR1+ cDCs in situ, we generated XCR1-iCaspase9-RFP chickens using a CRISPR-Cas9 knockin transgenesis approach to precisely edit the XCR1 locus, replacing the XCR1 coding region with genes for a fluorescent protein (TagRFP), and inducible Caspase 9. After inducible ablation, the chicken spleen is initially repopulated by immature CD1.1+ XCR1+ cDCs. XCR1+ cDCs are abundant in the splenic red pulp, in close association with CD8+ T-cells. Knockout of XCR1 prevented this clustering of cDCs with CD8+ T-cells. Taken together these data indicate a conserved role for chicken and mammalian XCR1+ cDCs in driving CD8+ T-cells responses.
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Affiliation(s)
- Zhiguang Wu
- The Roslin Institute, University of Edinburgh, Midlothian, United Kingdom
| | - Barbara Shih
- The Roslin Institute, University of Edinburgh, Midlothian, United Kingdom
- Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, United Kingdom
| | - Joni Macdonald
- The Roslin Institute, University of Edinburgh, Midlothian, United Kingdom
| | - Dominique Meunier
- The Roslin Institute, University of Edinburgh, Midlothian, United Kingdom
| | - Kris Hogan
- The Roslin Institute, University of Edinburgh, Midlothian, United Kingdom
| | | | - Hazel Gilhooley
- The Roslin Institute, University of Edinburgh, Midlothian, United Kingdom
| | - Tuanjun Hu
- The Roslin Institute, University of Edinburgh, Midlothian, United Kingdom
| | - Mariana Beltran
- Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Neil C. Henderson
- Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
- Medical Research Council (MRC) Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
| | - Helen M. Sang
- The Roslin Institute, University of Edinburgh, Midlothian, United Kingdom
| | - Mark P. Stevens
- The Roslin Institute, University of Edinburgh, Midlothian, United Kingdom
| | - Michael J. McGrew
- The Roslin Institute, University of Edinburgh, Midlothian, United Kingdom
| | - Adam Balic
- The Roslin Institute, University of Edinburgh, Midlothian, United Kingdom
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia
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Di Ciaula A, Bonfrate L, Khalil M, Garruti G, Portincasa P. Contribution of the microbiome for better phenotyping of people living with obesity. Rev Endocr Metab Disord 2023; 24:839-870. [PMID: 37119391 PMCID: PMC10148591 DOI: 10.1007/s11154-023-09798-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/10/2023] [Indexed: 05/01/2023]
Abstract
Obesity has reached epidemic proportion worldwide and in all ages. Available evidence points to a multifactorial pathogenesis involving gene predisposition and environmental factors. Gut microbiota plays a critical role as a major interface between external factors, i.e., diet, lifestyle, toxic chemicals, and internal mechanisms regulating energy and metabolic homeostasis, fat production and storage. A shift in microbiota composition is linked with overweight and obesity, with pathogenic mechanisms involving bacterial products and metabolites (mainly endocannabinoid-related mediators, short-chain fatty acids, bile acids, catabolites of tryptophan, lipopolysaccharides) and subsequent alterations in gut barrier, altered metabolic homeostasis, insulin resistance and chronic, low-grade inflammation. Although animal studies point to the links between an "obesogenic" microbiota and the development of different obesity phenotypes, the translational value of these results in humans is still limited by the heterogeneity among studies, the high variation of gut microbiota over time and the lack of robust longitudinal studies adequately considering inter-individual confounders. Nevertheless, available evidence underscores the existence of several genera predisposing to obesity or, conversely, to lean and metabolically health phenotype (e.g., Akkermansia muciniphila, species from genera Faecalibacterium, Alistipes, Roseburia). Further longitudinal studies using metagenomics, transcriptomics, proteomics, and metabolomics with exact characterization of confounders are needed in this field. Results must confirm that distinct genera and specific microbial-derived metabolites represent effective and precision interventions against overweight and obesity in the long-term.
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Affiliation(s)
- Agostino Di Ciaula
- Clinica Medica “A. Murri”, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari Medical School, 70124 Bari, Italy
| | - Leonilde Bonfrate
- Clinica Medica “A. Murri”, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari Medical School, 70124 Bari, Italy
| | - Mohamad Khalil
- Clinica Medica “A. Murri”, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari Medical School, 70124 Bari, Italy
| | - Gabriella Garruti
- Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari Medical School, 70124 Bari, Italy
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari Medical School, 70124 Bari, Italy
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10
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Oseni SO, Naar C, Pavlović M, Asghar W, Hartmann JX, Fields GB, Esiobu N, Kumi-Diaka J. The Molecular Basis and Clinical Consequences of Chronic Inflammation in Prostatic Diseases: Prostatitis, Benign Prostatic Hyperplasia, and Prostate Cancer. Cancers (Basel) 2023; 15:3110. [PMID: 37370720 DOI: 10.3390/cancers15123110] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 05/23/2023] [Accepted: 05/31/2023] [Indexed: 06/29/2023] Open
Abstract
Chronic inflammation is now recognized as one of the major risk factors and molecular hallmarks of chronic prostatitis, benign prostatic hyperplasia (BPH), and prostate tumorigenesis. However, the molecular mechanisms by which chronic inflammation signaling contributes to the pathogenesis of these prostate diseases are poorly understood. Previous efforts to therapeutically target the upstream (e.g., TLRs and IL1-Rs) and downstream (e.g., NF-κB subunits and cytokines) inflammatory signaling molecules in people with these conditions have been clinically ambiguous and unsatisfactory, hence fostering the recent paradigm shift towards unraveling and understanding the functional roles and clinical significance of the novel and relatively underexplored inflammatory molecules and pathways that could become potential therapeutic targets in managing prostatic diseases. In this review article, we exclusively discuss the causal and molecular drivers of prostatitis, BPH, and prostate tumorigenesis, as well as the potential impacts of microbiome dysbiosis and chronic inflammation in promoting prostate pathologies. We specifically focus on the importance of some of the underexplored druggable inflammatory molecules, by discussing how their aberrant signaling could promote prostate cancer (PCa) stemness, neuroendocrine differentiation, castration resistance, metabolic reprogramming, and immunosuppression. The potential contribution of the IL1R-TLR-IRAK-NF-κBs signaling molecules and NLR/inflammasomes in prostate pathologies, as well as the prospective benefits of selectively targeting the midstream molecules in the various inflammatory cascades, are also discussed. Though this review concentrates more on PCa, we envision that the information could be applied to other prostate diseases. In conclusion, we have underlined the molecular mechanisms and signaling pathways that may need to be targeted and/or further investigated to better understand the association between chronic inflammation and prostate diseases.
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Affiliation(s)
- Saheed Oluwasina Oseni
- Department of Biological Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Corey Naar
- Department of Biological Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA
| | - Mirjana Pavlović
- Department of Computer and Electrical Engineering, Florida Atlantic University, Boca Raton, FL 33431, USA
| | - Waseem Asghar
- Department of Computer and Electrical Engineering, Florida Atlantic University, Boca Raton, FL 33431, USA
| | - James X Hartmann
- Department of Biological Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA
| | - Gregg B Fields
- Department of Chemistry & Biochemistry, and I-HEALTH, Florida Atlantic University, Boca Raton, FL 33431, USA
| | - Nwadiuto Esiobu
- Department of Biological Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA
| | - James Kumi-Diaka
- Department of Biological Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA
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11
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Qiao H, Morioka Y, Wang D, Liu K, Gao S, Wake H, Ousaka D, Teshigawara K, Mori S, Nishibori M. Protective effects of an anti-4-HNE monoclonal antibody against liver injury and lethality of endotoxemia in mice. Eur J Pharmacol 2023; 950:175702. [PMID: 37059372 DOI: 10.1016/j.ejphar.2023.175702] [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: 01/18/2023] [Revised: 03/28/2023] [Accepted: 03/29/2023] [Indexed: 04/16/2023]
Abstract
4-hydroxy-2-nonenal (4-HNE) is a lipid peroxidation product that is known to be elevated during oxidative stress. During systemic inflammation and endotoxemia, plasma levels of 4-HNE are elevated in response to lipopolysaccharide (LPS) stimulation. 4-HNE is a highly reactive molecule due to its generation of both Schiff bases and Michael adducts with proteins, which may result in modulation of inflammatory signaling pathways. In this study, we report the production of a 4-HNE adduct-specific monoclonal antibody (mAb) and the effectiveness of the intravenous injection of this mAb (1 mg/kg) in ameliorating LPS (10 mg/kg, i.v.)-induced endotoxemia and liver injury in mice. Endotoxic lethality in control mAb-treated group was suppressed by the administration of anti-4-HNE mAb (75 vs. 27%). After LPS injection, we observed a significant increase in the plasma levels of AST, ALT, IL-6, TNF-α and MCP-1, and elevated expressions of IL-6, IL-10 and TNF-α in the liver. All these elevations were inhibited by anti-4-HNE mAb treatment. As to the underlining mechanism, anti-4-HNE mAb inhibited the elevation of plasma high mobility group box-1 (HMGB1) levels, the translocation and release of HMGB1 in the liver and the formation of 4-HNE adducts themselves, suggesting a functional role of extracellular 4-HNE adducts in hypercytokinemia and liver injury associated with HMGB1 mobilization. In summary, this study reveals a novel therapeutic application of anti-4-HNE mAb for endotoxemia.
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Affiliation(s)
- Handong Qiao
- Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan
| | - Yuta Morioka
- Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan
| | - Dengli Wang
- Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan
| | - Keyue Liu
- Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan
| | - Shangze Gao
- Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan
| | - Hidenori Wake
- Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan
| | - Daiki Ousaka
- Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan
| | - Kiyoshi Teshigawara
- Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan
| | - Shuji Mori
- Department of Pharmacology, Shujitsu University, Okayama, 703-8516, Japan
| | - Masahiro Nishibori
- Department of Translational Research and Drug Development, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
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12
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Belhaouane I, Pochet A, Chatagnon J, Hoffmann E, Queval CJ, Deboosère N, Boidin-Wichlacz C, Majlessi L, Sencio V, Heumel S, Vandeputte A, Werkmeister E, Fievez L, Bureau F, Rouillé Y, Trottein F, Chamaillard M, Brodin P, Machelart A. Tirap controls Mycobacterium tuberculosis phagosomal acidification. PLoS Pathog 2023; 19:e1011192. [PMID: 36888688 PMCID: PMC9994722 DOI: 10.1371/journal.ppat.1011192] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 01/30/2023] [Indexed: 03/09/2023] Open
Abstract
Progression of tuberculosis is tightly linked to a disordered immune balance, resulting in inability of the host to restrict intracellular bacterial replication and its subsequent dissemination. The immune response is mainly characterized by an orchestrated recruitment of inflammatory cells secreting cytokines. This response results from the activation of innate immunity receptors that trigger downstream intracellular signaling pathways involving adaptor proteins such as the TIR-containing adaptor protein (Tirap). In humans, resistance to tuberculosis is associated with a loss-of-function in Tirap. Here, we explore how genetic deficiency in Tirap impacts resistance to Mycobacterium tuberculosis (Mtb) infection in a mouse model and ex vivo. Interestingly, compared to wild type littermates, Tirap heterozygous mice were more resistant to Mtb infection. Upon investigation at the cellular level, we observed that mycobacteria were not able to replicate in Tirap-deficient macrophages compared to wild type counterparts. We next showed that Mtb infection induced Tirap expression which prevented phagosomal acidification and rupture. We further demonstrate that the Tirap-mediated anti-tuberculosis effect occurs through a Cish-dependent signaling pathway. Our findings provide new molecular evidence about how Mtb manipulates innate immune signaling to enable intracellular replication and survival of the pathogen, thus paving the way for host-directed approaches to treat tuberculosis.
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Affiliation(s)
- Imène Belhaouane
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019—UMR 9017—CIIL—Center for Infection and Immunity of Lille, Lille, France
| | - Amine Pochet
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019—UMR 9017—CIIL—Center for Infection and Immunity of Lille, Lille, France
| | - Jonathan Chatagnon
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019—UMR 9017—CIIL—Center for Infection and Immunity of Lille, Lille, France
| | - Eik Hoffmann
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019—UMR 9017—CIIL—Center for Infection and Immunity of Lille, Lille, France
| | - Christophe J. Queval
- High Throughput Screening Laboratory, The Francis Crick Institute, London, United Kingdom
| | - Nathalie Deboosère
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019—UMR 9017—CIIL—Center for Infection and Immunity of Lille, Lille, France
| | - Céline Boidin-Wichlacz
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019—UMR 9017—CIIL—Center for Infection and Immunity of Lille, Lille, France
| | - Laleh Majlessi
- Pasteur-TheraVectys Joint Lab, Institut Pasteur, Université Paris Cité, Paris, France
| | - Valentin Sencio
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019—UMR 9017—CIIL—Center for Infection and Immunity of Lille, Lille, France
| | - Séverine Heumel
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019—UMR 9017—CIIL—Center for Infection and Immunity of Lille, Lille, France
| | - Alexandre Vandeputte
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019—UMR 9017—CIIL—Center for Infection and Immunity of Lille, Lille, France
| | - Elisabeth Werkmeister
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019—UMR 9017—CIIL—Center for Infection and Immunity of Lille, Lille, France
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41—UMS 2014—PLBS, Lille, France
| | - Laurence Fievez
- Laboratory of Cellular and Molecular Immunology, GIGA-Research, Liège, Belgium
| | - Fabrice Bureau
- Laboratory of Cellular and Molecular Immunology, GIGA-Research, Liège, Belgium
| | - Yves Rouillé
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019—UMR 9017—CIIL—Center for Infection and Immunity of Lille, Lille, France
| | - François Trottein
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019—UMR 9017—CIIL—Center for Infection and Immunity of Lille, Lille, France
| | - Mathias Chamaillard
- Laboratory of Cell Physiology, INSERM U1003, University of Lille, Lille, France
| | - Priscille Brodin
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019—UMR 9017—CIIL—Center for Infection and Immunity of Lille, Lille, France
- * E-mail: (PB); (AM)
| | - Arnaud Machelart
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019—UMR 9017—CIIL—Center for Infection and Immunity of Lille, Lille, France
- * E-mail: (PB); (AM)
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13
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Jiang C, Wang S. Identification and functional characterization of bactericidal permeability/increasing protein (BPI) from frog Nanorana yunnanensis (Paa yunnanensis). DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2022; 137:104517. [PMID: 36028172 DOI: 10.1016/j.dci.2022.104517] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 08/13/2022] [Accepted: 08/18/2022] [Indexed: 06/15/2023]
Abstract
Bactericidal permeability/increasing protein (BPI) and lipopolysaccharide-binding protein (LBP) have been most extensively studied in mammals, but little information is available regarding BPI and LBP in Amphibia. In this study we showed that the cDNA of BPI in the frog N. yunnanensis (P. yunnanensis) encoded a 490-amino-acid-long protein, the predicted tertiary structure appears closely similar to mammalian BPIs in terms of sequence and structure. Like mammalian BPI gene, the frog gene nybpi was widely expressed in various tissues and was inducible by challenge with LPS or Gram-negative bacterium. We also showed that recombinant NyBPI, resembling mammalian BPIs, specifically binds with LPS. In addition, the recombinant NyBPI displayed antibacterial activity against Gram-negative bacteria Vibrio anguillarum in a dose-dependent manner. These results indicate that NyBPI may play an important role in an immune response against bacteria in amphibians.
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Affiliation(s)
- Chengyan Jiang
- College of Biological and Agricultural Sciences, Honghe University, Mengzi, Yunnan, 661199, China.
| | - Shaolong Wang
- College of Biological and Agricultural Sciences, Honghe University, Mengzi, Yunnan, 661199, China
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14
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Cosme D, Soares-da-Silva P, Magro F. Effect of Toll-like receptor-2, -4, -5, -7, and NOD2 stimulation on potassium channel conductance in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 2022; 323:G410-G419. [PMID: 36040119 DOI: 10.1152/ajpgi.00139.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Disproportionate activation of pattern recognition receptors plays a role in inflammatory bowel disease (IBD) pathophysiology. Diarrhea is a hallmark symptom of IBD, resulting at least in part from an electrolyte imbalance that may be caused by changes in potassium channel activity. We evaluated the impact of Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain 2 (NOD2) stimulation on potassium conductance of the basolateral membrane in human intestinal epithelial cells (IECs) and the role of potassium channels through electrophysiological assays under short-circuit current in Ussing chambers. TLRs and NOD2 were stimulated using specific agonists, and potassium channels were selectively blocked using triarylmethane-34 (TRAM-34), adenylyl-imidodiphosphate (AMP-PNP), and BaCl2. Potassium conductance of the basolateral membrane decreased upon activation of TLR2, TLR4, and TLR7 in T84 cells (means ± SE, -11.2 ± 4.5, -40.4 ± 7.2, and -19.4 ± 5.9, respectively) and in Caco-2 cells (-13.1 ± 5.7, -55.7 ± 7.4, and -29.1 ± 7.2, respectively). In contrast, activation of TLR5 and NOD2 increased basolateral potassium conductance, both in T84 cells (18.0 ± 4.1 and 18.4 ± 2.8, respectively) and in Caco-2 cells (21.2 ± 8.4 and 16.0 ± 3.6, respectively). TRAM-34 and AMP-PNP induced a decrease in basolateral potassium conductance upon TLR4 stimulation in both cell lines. Both KCa3.1- and Kir6-channels appear to be important mediators of this effect in IECs and could be potential targets for therapeutic agent development.NEW & NOTEWORTHY This study highlights that PRRs stimulation directly influences K+-channel conductance in IECs. TLR-2, -4, -7 stimulation decreased K+ conductance, whereas TLR5 and NOD2 stimulation had the opposite effect, leading to an increase of it instead. This study reports for the first time that KCa3.1- and Kir6-channels play a role in K+ transport pathways triggered by TLR4 stimulation. These findings suggest that KCa3.1- and Kir6-channels modulation may be a potential target for new therapeutic agents in IBD.
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Affiliation(s)
- Dina Cosme
- Unit of Pharmacology and Therapeutics, Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal.,MedInUP, Center for Drug Discovery and Innovative Medicines, Porto, Portugal
| | - Patrício Soares-da-Silva
- Unit of Pharmacology and Therapeutics, Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal.,MedInUP, Center for Drug Discovery and Innovative Medicines, Porto, Portugal
| | - Fernando Magro
- Unit of Pharmacology and Therapeutics, Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal.,Department of Gastroenterology, São João Hospital University Centre, Porto, Portugal.,Center for Health Technology and Services Research, Porto, Portugal.,Clinical Pharmacology Unit, São João Hospital University Centre, Porto, Portugal.,Portuguese Inflammatory Bowel Disease Group, Porto, Portugal
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15
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Duan B, Liu R, Shi Y, Sun A, Tang Z, Wang C, Hu J. Lactobacillus plantarum synergistically regulates M1 macrophage polarization in resistance against Salmonella enterica serovar Typhimurium infection. Front Microbiol 2022; 13:933550. [PMID: 36325023 PMCID: PMC9620862 DOI: 10.3389/fmicb.2022.933550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 09/20/2022] [Indexed: 11/22/2022] Open
Abstract
Macrophage polarization affects the progression of pathogenic bacterial infections. Lactobacillus is widely used to interact with macrophages and to exert specific immunomodulatory activities. In this study, we investigated the regulation of macrophage polarization against Salmonella enterica serotype Typhimurium (STM) by Lactobacillus plantarum JL01 (LP), to explore prevention and treatment strategies for salmonellosis. We assessed the in vitro differential polarization of RAW 264.7 macrophages and mouse bone marrow macrophages (BMMs) by LP against STM, by measuring protein and cytokine levels, and bactericidal activity. In addition, we assessed the protective effects of LP against STM by evaluating weight loss, survival, the burden of STM in tissues, the polarization of macrophages in the spleen and mesenteric lymph nodes (MLNs), intestinal histopathology, and cytokine production. LP slightly affected the polarization of RAW 264.7, a slight M1-skewing. LP promoted the RAW 264.7 bactericidal activity against STM. In BMMs, M1 polarization induced by LP was significantly lower than the M1-positive phenotype. The combination of LP with M1 synergistically improved M1 polarization and bactericidal activity against STM compared to the individual effects. LP promoted the activation of the NF-κB signaling pathway. Supplementation with the NF-κB inhibitor decreased M1 polarization induced by LP. We observed the protective effect of LP against STM in C57BL/6 mice, through a decrease in weight loss, mortality, STM burden in the liver, and promotion of macrophage M1 and M2 polarization in the spleen and MLNs; though M1 was higher, it did not cause inflammatory damage. In summary, LP can synergistically promote M1 polarization in combination with the M1 phenotype through the NF-κB signaling pathway and increases resistance against S. Typhimurium infection. These findings will lay the foundation for the prevention and treatment of S. Typhimurium infections in the future.
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Affiliation(s)
- Bingjie Duan
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
- Jilin Provincial Key Laboratory of Animal Microecology and Health Breeding, Changchun, China
- Key Laboratory of Animal Production and Product Quality Safety of Ministry of Education, Changchun, China
| | - Ruihan Liu
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
- Jilin Provincial Key Laboratory of Animal Microecology and Health Breeding, Changchun, China
- Key Laboratory of Animal Production and Product Quality Safety of Ministry of Education, Changchun, China
| | - Yumeng Shi
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
- Jilin Provincial Key Laboratory of Animal Microecology and Health Breeding, Changchun, China
- Key Laboratory of Animal Production and Product Quality Safety of Ministry of Education, Changchun, China
| | - Anqi Sun
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
- Jilin Provincial Key Laboratory of Animal Microecology and Health Breeding, Changchun, China
- Key Laboratory of Animal Production and Product Quality Safety of Ministry of Education, Changchun, China
| | - Zhengxu Tang
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
- Jilin Provincial Key Laboratory of Animal Microecology and Health Breeding, Changchun, China
- Key Laboratory of Animal Production and Product Quality Safety of Ministry of Education, Changchun, China
| | - Chunfeng Wang
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
- Jilin Provincial Key Laboratory of Animal Microecology and Health Breeding, Changchun, China
- Key Laboratory of Animal Production and Product Quality Safety of Ministry of Education, Changchun, China
- Chunfeng Wang
| | - Jingtao Hu
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
- Jilin Provincial Key Laboratory of Animal Microecology and Health Breeding, Changchun, China
- Key Laboratory of Animal Production and Product Quality Safety of Ministry of Education, Changchun, China
- *Correspondence: Jingtao Hu
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16
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Signaling pathways in obesity: mechanisms and therapeutic interventions. Signal Transduct Target Ther 2022; 7:298. [PMID: 36031641 PMCID: PMC9420733 DOI: 10.1038/s41392-022-01149-x] [Citation(s) in RCA: 172] [Impact Index Per Article: 57.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/26/2022] [Accepted: 08/08/2022] [Indexed: 12/19/2022] Open
Abstract
Obesity is a complex, chronic disease and global public health challenge. Characterized by excessive fat accumulation in the body, obesity sharply increases the risk of several diseases, such as type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease, and is linked to lower life expectancy. Although lifestyle intervention (diet and exercise) has remarkable effects on weight management, achieving long-term success at weight loss is extremely challenging, and the prevalence of obesity continues to rise worldwide. Over the past decades, the pathophysiology of obesity has been extensively investigated, and an increasing number of signal transduction pathways have been implicated in obesity, making it possible to fight obesity in a more effective and precise way. In this review, we summarize recent advances in the pathogenesis of obesity from both experimental and clinical studies, focusing on signaling pathways and their roles in the regulation of food intake, glucose homeostasis, adipogenesis, thermogenesis, and chronic inflammation. We also discuss the current anti-obesity drugs, as well as weight loss compounds in clinical trials, that target these signals. The evolving knowledge of signaling transduction may shed light on the future direction of obesity research, as we move into a new era of precision medicine.
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17
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N-Palmitoyl-D-Glucosamine Inhibits TLR-4/NLRP3 and Improves DNBS-Induced Colon Inflammation through a PPAR-α-Dependent Mechanism. Biomolecules 2022; 12:biom12081163. [PMID: 36009057 PMCID: PMC9405927 DOI: 10.3390/biom12081163] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/19/2022] [Accepted: 08/20/2022] [Indexed: 02/07/2023] Open
Abstract
Similar to canine inflammatory enteropathy, inflammatory bowel disease (IBD) is a chronic idiopathic condition characterized by remission periods and recurrent flares in which diarrhea, visceral pain, rectal bleeding/bloody stools, and weight loss are the main clinical symptoms. Intestinal barrier function alterations often persist in the remission phase of the disease without ongoing inflammatory processes. However, current therapies include mainly anti-inflammatory compounds that fail to promote functional symptoms-free disease remission, urging new drug discoveries to handle patients during this step of the disease. ALIAmides (ALIA, autacoid local injury antagonism) are bioactive fatty acid amides that recently gained attention because of their involvement in the control of inflammatory response, prompting the use of these molecules as plausible therapeutic strategies in the treatment of several chronic inflammatory conditions. N-palmitoyl-D-glucosamine (PGA), an under-researched ALIAmide, resulted in being safe and effective in preclinical models of inflammation and pain, suggesting its potential engagement in the treatment of IBD. In our study, we demonstrated that micronized PGA significantly and dose-dependently reduces colitis severity, improves intestinal mucosa integrity by increasing the tight junction proteins expression, and downregulates the TLR-4/NLRP3/iNOS pathway via PPAR-α receptors signaling in DNBS-treated mice. The possibility of clinically exploiting micronized PGA as support for the treatment and prevention of inflammation-related changes in IBD patients would represent an innovative, effective, and safe strategy.
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18
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Abstract
The gut microbiota is now considered as one of the key elements contributing to the regulation of host health. Virtually all our body sites are colonised by microbes suggesting different types of crosstalk with our organs. Because of the development of molecular tools and techniques (ie, metagenomic, metabolomic, lipidomic, metatranscriptomic), the complex interactions occurring between the host and the different microorganisms are progressively being deciphered. Nowadays, gut microbiota deviations are linked with many diseases including obesity, type 2 diabetes, hepatic steatosis, intestinal bowel diseases (IBDs) and several types of cancer. Thus, suggesting that various pathways involved in immunity, energy, lipid and glucose metabolism are affected.In this review, specific attention is given to provide a critical evaluation of the current understanding in this field. Numerous molecular mechanisms explaining how gut bacteria might be causally linked with the protection or the onset of diseases are discussed. We examine well-established metabolites (ie, short-chain fatty acids, bile acids, trimethylamine N-oxide) and extend this to more recently identified molecular actors (ie, endocannabinoids, bioactive lipids, phenolic-derived compounds, advanced glycation end products and enterosynes) and their specific receptors such as peroxisome proliferator-activated receptor alpha (PPARα) and gamma (PPARγ), aryl hydrocarbon receptor (AhR), and G protein-coupled receptors (ie, GPR41, GPR43, GPR119, Takeda G protein-coupled receptor 5).Altogether, understanding the complexity and the molecular aspects linking gut microbes to health will help to set the basis for novel therapies that are already being developed.
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Affiliation(s)
- Willem M de Vos
- Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland,Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Matthias Van Hul
- Louvain Drug Research Institute (LDRI), Metabolism and Nutrition research group (MNUT), UCLouvain, Université catholique de Louvain, Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), Brussels, Belgium
| | - Patrice D Cani
- Louvain Drug Research Institute (LDRI), Metabolism and Nutrition research group (MNUT), UCLouvain, Université catholique de Louvain, Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), Brussels, Belgium
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19
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Abstract
The gut microbiota is now considered as one of the key elements contributing to the regulation of host health. Virtually all our body sites are colonised by microbes suggesting different types of crosstalk with our organs. Because of the development of molecular tools and techniques (ie, metagenomic, metabolomic, lipidomic, metatranscriptomic), the complex interactions occurring between the host and the different microorganisms are progressively being deciphered. Nowadays, gut microbiota deviations are linked with many diseases including obesity, type 2 diabetes, hepatic steatosis, intestinal bowel diseases (IBDs) and several types of cancer. Thus, suggesting that various pathways involved in immunity, energy, lipid and glucose metabolism are affected.In this review, specific attention is given to provide a critical evaluation of the current understanding in this field. Numerous molecular mechanisms explaining how gut bacteria might be causally linked with the protection or the onset of diseases are discussed. We examine well-established metabolites (ie, short-chain fatty acids, bile acids, trimethylamine N-oxide) and extend this to more recently identified molecular actors (ie, endocannabinoids, bioactive lipids, phenolic-derived compounds, advanced glycation end products and enterosynes) and their specific receptors such as peroxisome proliferator-activated receptor alpha (PPARα) and gamma (PPARγ), aryl hydrocarbon receptor (AhR), and G protein-coupled receptors (ie, GPR41, GPR43, GPR119, Takeda G protein-coupled receptor 5).Altogether, understanding the complexity and the molecular aspects linking gut microbes to health will help to set the basis for novel therapies that are already being developed.
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Affiliation(s)
- Willem M de Vos
- Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Matthias Van Hul
- Louvain Drug Research Institute (LDRI), Metabolism and Nutrition research group (MNUT), UCLouvain, Université catholique de Louvain, Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), Brussels, Belgium
| | - Patrice D Cani
- Louvain Drug Research Institute (LDRI), Metabolism and Nutrition research group (MNUT), UCLouvain, Université catholique de Louvain, Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), Brussels, Belgium
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20
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Zhao C, Chen H, Liang H, Zhao X, Tang W, Wei M, Li Y, Zhang J, Yu X, Chen G, Zhu H, Jiang L, Zhang X. Lactobacillus plantarum RS-09 Induces M1-Type Macrophage Immunity Against Salmonella Typhimurium Challenge via the TLR2/NF-κB Signalling Pathway. Front Pharmacol 2022; 13:832245. [PMID: 35355723 PMCID: PMC8959098 DOI: 10.3389/fphar.2022.832245] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 01/26/2022] [Indexed: 12/30/2022] Open
Abstract
Lactobacillus plantarum can interact with macrophages against bacterial enteropathy due to its potential ability to modulate macrophage polarization. However, this mechanism is not completely understood. TLR2 can recognize microbial components and trigger macrophage cytokine responses to different gram-positive strains. The aim of this study was to investigate whether probiotic Lactobacillus plantarum RS-09 can induce macrophage polarization against Salmonella Typhimurium infection via TLR2 signalling. BALB/c mice were preadministered RS-09 continuously for 7 days and then infected with Salmonella Typhimurium ATCC14028. Mouse RAW264.7 mononuclear macrophages were stimulated with RS-09 and coincubated with ATCC14028 or PBS controls. The results of the in vivo study indicated that RS-09 could relieve S. Typhimurium-induced splenomegaly, body weight loss and death rate. RS-09 also limited the colonization and translocation of S. Typhimurium in the gastrointestinal tract and thereby protected against infection. We also observed that RS-09 upregulated the production of M1 macrophage characteristics (e.g., CD11c and IL-6) against S. Typhimurium. Furthermore, RS-09 induced the expression of TLR2 in macrophages. In an in vitro study, treatment of RAW264.7 cells with RS-09 either concurrently with or before S. Typhimurium challenge enhanced the secretion of Reactive oxygen species and Nitric oxide. This effect was related to TLR2 and NF-κB activation. Based on these findings, Lactobacillus plantarum RS-09 was shown to modulate M1 macrophage polarization and induce TLR2-linked NF-κB signalling activity in the innate immune response to S. Typhimurium infection.
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Affiliation(s)
- Chenpei Zhao
- School of Life Sciences, Ludong University, Yantai, China
| | - Huan Chen
- School of Life Sciences, Ludong University, Yantai, China
| | - Hao Liang
- Department of Microbiology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiaoyu Zhao
- School of Life Sciences, Ludong University, Yantai, China
- Shandong Provincial Key Laboratory of Quality Safty Monitoring and Risk Assessment for Animal Products, Jinan, China
| | - Wenli Tang
- Shandong Provincial Key Laboratory of Quality Safty Monitoring and Risk Assessment for Animal Products, Jinan, China
| | - Maolian Wei
- Shandong Provincial Key Laboratory of Quality Safty Monitoring and Risk Assessment for Animal Products, Jinan, China
| | - Youzhi Li
- Shandong Provincial Key Laboratory of Quality Safty Monitoring and Risk Assessment for Animal Products, Jinan, China
| | - Jianlong Zhang
- School of Life Sciences, Ludong University, Yantai, China
- Shandong Provincial Key Laboratory of Quality Safty Monitoring and Risk Assessment for Animal Products, Jinan, China
| | - Xin Yu
- School of Life Sciences, Ludong University, Yantai, China
- Shandong Provincial Key Laboratory of Quality Safty Monitoring and Risk Assessment for Animal Products, Jinan, China
- Yantai Key Laboratory of Animal Pathogenetic Microbiology and Immunology, Yantai, China
| | - Guozhong Chen
- School of Life Sciences, Ludong University, Yantai, China
- Yantai Key Laboratory of Animal Pathogenetic Microbiology and Immunology, Yantai, China
- Shandong Aquaculture Environmental Control Engineering Laboratory, Yantai, China
| | - Hongwei Zhu
- School of Life Sciences, Ludong University, Yantai, China
- Shandong Provincial Key Laboratory of Quality Safty Monitoring and Risk Assessment for Animal Products, Jinan, China
- Shandong Aquaculture Environmental Control Engineering Laboratory, Yantai, China
| | - Linlin Jiang
- School of Life Sciences, Ludong University, Yantai, China
- Shandong Provincial Key Laboratory of Quality Safty Monitoring and Risk Assessment for Animal Products, Jinan, China
- Shandong Aquaculture Environmental Control Engineering Laboratory, Yantai, China
- *Correspondence: Linlin Jiang, ; Xingxiao Zhang,
| | - Xingxiao Zhang
- School of Life Sciences, Ludong University, Yantai, China
- Shandong Aquaculture Environmental Control Engineering Laboratory, Yantai, China
- *Correspondence: Linlin Jiang, ; Xingxiao Zhang,
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21
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Fakhri S, Moradi SZ, Yarmohammadi A, Narimani F, Wallace CE, Bishayee A. Modulation of TLR/NF-κB/NLRP Signaling by Bioactive Phytocompounds: A Promising Strategy to Augment Cancer Chemotherapy and Immunotherapy. Front Oncol 2022; 12:834072. [PMID: 35299751 PMCID: PMC8921560 DOI: 10.3389/fonc.2022.834072] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 01/26/2022] [Indexed: 12/12/2022] Open
Abstract
Background Tumors often progress to a more aggressive phenotype to resist drugs. Multiple dysregulated pathways are behind this tumor behavior which is known as cancer chemoresistance. Thus, there is an emerging need to discover pivotal signaling pathways involved in the resistance to chemotherapeutic agents and cancer immunotherapy. Reports indicate the critical role of the toll-like receptor (TLR)/nuclear factor-κB (NF-κB)/Nod-like receptor pyrin domain-containing (NLRP) pathway in cancer initiation, progression, and development. Therefore, targeting TLR/NF-κB/NLRP signaling is a promising strategy to augment cancer chemotherapy and immunotherapy and to combat chemoresistance. Considering the potential of phytochemicals in the regulation of multiple dysregulated pathways during cancer initiation, promotion, and progression, such compounds could be suitable candidates against cancer chemoresistance. Objectives This is the first comprehensive and systematic review regarding the role of phytochemicals in the mitigation of chemoresistance by regulating the TLR/NF-κB/NLRP signaling pathway in chemotherapy and immunotherapy. Methods A comprehensive and systematic review was designed based on Web of Science, PubMed, Scopus, and Cochrane electronic databases. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed to include papers on TLR/NF-κB/NLRP and chemotherapy/immunotherapy/chemoresistance by phytochemicals. Results Phytochemicals are promising multi-targeting candidates against the TLR/NF-κB/NLRP signaling pathway and interconnected mediators. Employing phenolic compounds, alkaloids, terpenoids, and sulfur compounds could be a promising strategy for managing cancer chemoresistance through the modulation of the TLR/NF-κB/NLRP signaling pathway. Novel delivery systems of phytochemicals in cancer chemotherapy/immunotherapy are also highlighted. Conclusion Targeting TLR/NF-κB/NLRP signaling with bioactive phytocompounds reverses chemoresistance and improves the outcome for chemotherapy and immunotherapy in both preclinical and clinical stages.
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Affiliation(s)
- Sajad Fakhri
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Seyed Zachariah Moradi
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Akram Yarmohammadi
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Fatemeh Narimani
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Carly E. Wallace
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, United States
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, United States
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22
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Chen R, Zhou D, Wang L, Zhu L, Ye X. MYD88L265P and CD79B double mutations type (MCD type) of diffuse large B-cell lymphoma: mechanism, clinical characteristics, and targeted therapy. Ther Adv Hematol 2022; 13:20406207211072839. [PMID: 35126963 PMCID: PMC8808040 DOI: 10.1177/20406207211072839] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 12/15/2021] [Indexed: 12/15/2022] Open
Abstract
MYD88/CD79B-mutated (MCD) genotype is a genetic subgroup of diffuse large B-cell lymphoma (DLBCL) with the co-occurrence of MYD88L265P and CD79B mutations. MCD genotype is characterized by poor prognosis and extranodal involvement especially in immune-privileged sites. MCD model is dominated by activated B-cell (ABC)-like subtype of DLBCLs. It is generally accepted that the pathogenesis of MCD DLBCL mainly includes chronic active B-cell receptor (BCR) signaling and oncogenic MYD88 mutations, which drives pathological nuclear factor kappa B (NF-κB) activation in MCD lymphoid malignancies. CD79B and MYD88L265P mutations are frequently and contemporaneously founded in B-cell malignancies. The collaboration of the two mutations may explain the unique biology of MCD. Meanwhile, standard immunochemotherapy combine with different targeted therapies worth further study to improve the prognosis of MCD, according to genetic, phenotypic, and clinical features of MCD type. In this review, we systematically described mechanism, clinical characteristics, and targeted therapy of MCD DLBCL.
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Affiliation(s)
- Rongrong Chen
- Program in Clinical Medicine, School of Medicine, Zhejiang University, Hangzhou, China
| | - De Zhou
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lulu Wang
- Program in Clinical Medicine, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lixia Zhu
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xiujin Ye
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China
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23
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Kociszewska D, Chan J, Thorne PR, Vlajkovic SM. The Link between Gut Dysbiosis Caused by a High-Fat Diet and Hearing Loss. Int J Mol Sci 2021; 22:13177. [PMID: 34947974 PMCID: PMC8708400 DOI: 10.3390/ijms222413177] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 12/02/2021] [Accepted: 12/06/2021] [Indexed: 12/17/2022] Open
Abstract
This review aims to provide a conceptual and theoretical overview of the association between gut dysbiosis and hearing loss. Hearing loss is a global health issue; the World Health Organisation (WHO) estimates that 2.5 billion people will be living with some degree of hearing loss by 2050. The aetiology of sensorineural hearing loss (SNHL) is complex and multifactorial, arising from congenital and acquired causes. Recent evidence suggests that impaired gut health may also be a risk factor for SNHL. Inflammatory bowel disease (IBD), type 2 diabetes, diet-induced obesity (DIO), and high-fat diet (HFD) all show links to hearing loss. Previous studies have shown that a HFD can result in microangiopathy, impaired insulin signalling, and oxidative stress in the inner ear. A HFD can also induce pathological shifts in gut microbiota and affect intestinal barrier (IB) integrity, leading to a leaky gut. A leaky gut can result in chronic systemic inflammation, which may affect extraintestinal organs. Here, we postulate that changes in gut microbiota resulting from a chronic HFD and DIO may cause a systemic inflammatory response that can compromise the permeability of the blood-labyrinth barrier (BLB) in the inner ear, thus inducing cochlear inflammation and hearing deficits.
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Affiliation(s)
| | | | | | - Srdjan M. Vlajkovic
- Department of Physiology and The Eisdell Moore Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, Auckland 1142, New Zealand; (D.K.); (J.C.); (P.R.T.)
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24
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Dull K, Fazekas F, Deák D, Kovács D, Póliska S, Szegedi A, Zouboulis CC, Törőcsik D. miR-146a modulates TLR1/2 and 4 induced inflammation and links it with proliferation and lipid production via the indirect regulation of GNG7 in human SZ95 sebocytes. Sci Rep 2021; 11:21510. [PMID: 34728702 PMCID: PMC8563942 DOI: 10.1038/s41598-021-00907-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 10/18/2021] [Indexed: 11/09/2022] Open
Abstract
Activation of Toll-like receptors (TLR) 1/2 and 4 are central in inducing inflammation in sebocytes by regulating the expression of protein coding mRNAs, however the microRNA (miRNA) profile in response to TLR activation and thus the possible role of miRNAs in modulating sebocyte functions has not been elucidated. In this work we identified miR-146a to have the highest induction in the TLR1/2 and 4 activated SZ95 sebocytes and found that its increased levels led to the down-regulation of IL-8 secretion, decreased the chemoattractant potential and stimulated the proliferation of sebocytes. Assessing the gene expression profile of SZ95 sebocytes treated with a miR-146a inhibitor, the induction of GNG7 was one of the highest, while when cells were treated with a miR-146a mimic, the expression of GNG7 was down-regulated. These findings correlated with our in situ hybridization results, that compared with control, miR-146a showed an increased, while GNG7 a decreased expression in sebaceous glands of acne samples. Further studies revealed, that when inhibiting the levels of GNG7 in SZ95 sebocytes, cells increased their lipid content and decreased their proliferation. Our findings suggest, that miR-146a could be a potential player in acne pathogenesis by regulating inflammation, inducing proliferation and, through the indirect down-regulation of GNG7, promoting the lipid production of sebocytes.
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Affiliation(s)
- Katalin Dull
- Department of Dermatology, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, Debrecen, 4032, Hungary
| | - Fruzsina Fazekas
- Department of Dermatology, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, Debrecen, 4032, Hungary
| | - Dávid Deák
- Department of Dermatology, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, Debrecen, 4032, Hungary
| | - Dóra Kovács
- Department of Dermatology, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, Debrecen, 4032, Hungary
| | - Szilárd Póliska
- Department of Biochemistry and Molecular Biology, Genomic Medicine and Bioinformatics Core Facility, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Andrea Szegedi
- Department of Dermatology, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, Debrecen, 4032, Hungary.,Division of Dermatological Allergology, Department of Dermatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Christos C Zouboulis
- Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Brandenburg Medical School Theodor Fontane and Faculty of Health Sciences Brandenburg, Dessau, Germany
| | - Dániel Törőcsik
- Department of Dermatology, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, Debrecen, 4032, Hungary.
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25
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Larrouy-Maumus G. Shotgun Bacterial Lipid A Analysis Using Routine MALDI-TOF Mass Spectrometry. Methods Mol Biol 2021; 2306:275-283. [PMID: 33954953 DOI: 10.1007/978-1-0716-1410-5_18] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/19/2023]
Abstract
Detection of bacterial lipids and particularly the lipid A, the lipid anchor of the lipopolysaccharide, can be very challenging and requires a certain level of expertise. Here, this chapter describes a straightforward and simple method for the analysis of bacterial lipid A. In addition, such approach, lipid fingerprint, has the potential to be applied to other bacteria such as mycobacteria.
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Affiliation(s)
- Gérald Larrouy-Maumus
- MRC Centre for Molecular Bacteriology and Infection, Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, London, UK.
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26
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Zhang Y, Yuan T, Li Y, Wu N, Dai X. Network Pharmacology Analysis of the Mechanisms of Compound Herba Sarcandrae (Fufang Zhongjiefeng) Aerosol in Chronic Pharyngitis Treatment. Drug Des Devel Ther 2021; 15:2783-2803. [PMID: 34234411 PMCID: PMC8254411 DOI: 10.2147/dddt.s304708] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 06/09/2021] [Indexed: 12/22/2022] Open
Abstract
Purpose This study aimed to investigate the molecular mechanisms of compound herba Sarcandrae aerosol, also known as the Fufang Zhongjiefeng (FFZJF) aerosol, in treating chronic pharyngitis (CP) using network pharmacology and in vivo experimental approaches. Methods Active compounds and putative targets of five herbs in FFZJF were identified from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, Chemistry Database, and Swiss Target Prediction databases. The therapeutic targets of CP were obtained from OMIM, Durgbank, DisGeNT, and GAD databases. The active compounds-target networks were constructed using Cytoscape 3.6.1. The overlapping targets of FFZJF active compounds and CP targets were further analyzed using the String database to construct protein–protein interaction (PPI) network. KEGG pathway and Gene Ontology enrichment analysis was performed using the Database for Annotation, Visualization, and Integrated Discovery. The predicted targets and pathways were validated in a group A β-hemolytic streptococcus-induced rat CP model. Results There were 45 active compounds identified from FFZJF and 11 potential protein targets identified for CP treatment. PPI network demonstrated that IL6, PTGS2, TLR-4, and TNF may serve as the key targets of FFZJF for the treatment of CP. The main functional pathways involving these key targets include cytokine secretion, inflammatory response, MyD88-dependent toll-like receptor signaling pathway, toll-like receptor signaling pathway, TNF signaling pathway, and NF-κB signaling pathway. In a rat CP model, the elevation of serum TNF-α, IL1β, and IL6 levels, as well as the upregulation of TLR-4, MyD88, NF-κB P65 in the pharyngeal mucosal tissues could be effectively reduced by FFZJF treatment in a dose-dependent manner. Conclusion Through a network pharmacology approach and animal study, we predicted and validated the active compounds of FFZJF and their potential targets for CP treatment. The results suggest that FFZJF can markedly alleviate GAS-induced chronic pharyngitis by modulating the TLR-4/MyD88/NF-κB signaling pathways.
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Affiliation(s)
- Yanping Zhang
- Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, People's Republic of China
| | - Taohua Yuan
- Guizhou Medical University, Guiyang, Guizhou, People's Republic of China
| | - Yunsong Li
- Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, People's Republic of China
| | - Ning Wu
- Guizhou Medical University, Guiyang, Guizhou, People's Republic of China
| | - Xiaotian Dai
- Department of Mathematics and Statistics, University of Calgary, Calgary, Alberta, Canada
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27
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Abstract
![]()
The development of
lipopeptides (lipidated peptides) for vaccines
is discussed, including their role as antigens and/or adjuvants. Distinct
classes of lipopeptide architectures are covered including simple
linear and ligated constructs and lipid core peptides. The design,
synthesis, and immunological responses of the important class of glycerol-based
Toll-like receptor agonist lipopeptides such as Pam3CSK4, which contains three palmitoyl chains and a CSK4 hexapeptide sequence, and many derivatives of this model immunogenic
compound are also reviewed. Self-assembled lipopeptide structures
including spherical and worm-like micelles that have been shown to
act as vaccine agents are also described. The work discussed includes
examples of lipopeptides developed with model antigens, as well as
for immunotherapies to treat many infectious diseases including malaria,
influenza, hepatitis, COVID-19, and many others, as well as cancer
immunotherapies. Some of these have proceeded to clinical development.
The research discussed highlights the huge potential of, and diversity
of roles for, lipopeptides in contemporary and future vaccine development.
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Affiliation(s)
- Ian W Hamley
- Department of Chemistry, University of Reading, Whiteknights, Reading RG6 6AD, U.K
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28
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Hu W, van Steijn L, Li C, Verbeek FJ, Cao L, Merks RMH, Spaink HP. A Novel Function of TLR2 and MyD88 in the Regulation of Leukocyte Cell Migration Behavior During Wounding in Zebrafish Larvae. Front Cell Dev Biol 2021; 9:624571. [PMID: 33659250 PMCID: PMC7917198 DOI: 10.3389/fcell.2021.624571] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 01/22/2021] [Indexed: 01/04/2023] Open
Abstract
Toll-like receptor (TLR) signaling via myeloid differentiation factor 88 protein (MyD88) has been indicated to be involved in the response to wounding. It remains unknown whether the putative role of MyD88 in wounding responses is due to a control of leukocyte cell migration. The aim of this study was to explore in vivo whether TLR2 and MyD88 are involved in modulating neutrophil and macrophage cell migration behavior upon zebrafish larval tail wounding. Live cell imaging of tail-wounded larvae was performed in tlr2 and myd88 mutants and their corresponding wild type siblings. In order to visualize cell migration following tissue damage, we constructed double transgenic lines with fluorescent markers for macrophages and neutrophils in all mutant and sibling zebrafish lines. Three days post fertilization (dpf), tail-wounded larvae were studied using confocal laser scanning microscopy (CLSM) to quantify the number of recruited cells at the wounding area. We found that in both tlr2-/- and myd88-/- groups the recruited neutrophil and macrophage numbers are decreased compared to their wild type sibling controls. Through analyses of neutrophil and macrophage migration patterns, we demonstrated that both tlr2 and myd88 control the migration direction of distant neutrophils upon wounding. Furthermore, in both the tlr2 and the myd88 mutants, macrophages migrated more slowly toward the wound edge. Taken together, our findings show that tlr2 and myd88 are involved in responses to tail wounding by regulating the behavior and speed of leukocyte migration in vivo.
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Affiliation(s)
- Wanbin Hu
- Institute of Biology, Leiden University, Leiden, Netherlands
| | | | - Chen Li
- Leiden Institute of Advanced Computer Science, Leiden University, Leiden, Netherlands
| | - Fons J Verbeek
- Institute of Biology, Leiden University, Leiden, Netherlands.,Leiden Institute of Advanced Computer Science, Leiden University, Leiden, Netherlands
| | - Lu Cao
- Leiden Institute of Advanced Computer Science, Leiden University, Leiden, Netherlands
| | - Roeland M H Merks
- Institute of Biology, Leiden University, Leiden, Netherlands.,Mathematical Institute, Leiden University, Leiden, Netherlands
| | - Herman P Spaink
- Institute of Biology, Leiden University, Leiden, Netherlands
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29
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Hosseini R, Lamers GEM, Bos E, Hogendoorn PCW, Koster AJ, Meijer AH, Spaink HP, Schaaf MJM. The adapter protein Myd88 plays an important role in limiting mycobacterial growth in a zebrafish model for tuberculosis. Virchows Arch 2021; 479:265-275. [PMID: 33559740 PMCID: PMC8364548 DOI: 10.1007/s00428-021-03043-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 01/19/2021] [Accepted: 01/22/2021] [Indexed: 11/27/2022]
Abstract
Tuberculosis (TB) is the most prevalent bacterial infectious disease in the world, caused by the pathogen Mycobacterium tuberculosis (Mtb). In this study, we have used Mycobacterium marinum (Mm) infection in zebrafish larvae as an animal model for this disease to study the role of the myeloid differentiation factor 88 (Myd88), the key adapter protein of Toll-like receptors. Previously, Myd88 has been shown to enhance innate immune responses against bacterial infections, and in the present study, we have investigated the effect of Myd88 deficiency on the granuloma morphology and the intracellular distribution of bacteria during Mm infection. Our results show that granulomas formed in the tail fin from myd88 mutant larvae have a more compact structure and contain a reduced number of leukocytes compared to the granulomas observed in wild-type larvae. These morphological differences were associated with an increased bacterial burden in the myd88 mutant. Electron microscopy analysis showed that the majority of Mm in the myd88 mutant are located extracellularly, whereas in the wild type, most bacteria were intracellular. In the myd88 mutant, intracellular bacteria were mainly present in compartments that were not electron-dense, suggesting that these compartments had not undergone fusion with a lysosome. In contrast, approximately half of the intracellular bacteria in wild-type larvae were found in electron-dense compartments. These observations in a zebrafish model for tuberculosis suggest a role for Myd88-dependent signalling in two important phenomena that limit mycobacterial growth in the infected tissue. It reduces the number of leukocytes at the site of infection and the acidification of bacteria-containing compartments inside these cells.
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Affiliation(s)
- Rohola Hosseini
- Institute of Biology Leiden, Leiden University, Leiden, Netherlands
| | - Gerda E M Lamers
- Institute of Biology Leiden, Leiden University, Leiden, Netherlands
| | - Erik Bos
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands
| | - Pancras C W Hogendoorn
- Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333, Leiden, ZA, Netherlands.
| | - Abraham J Koster
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands
| | | | - Herman P Spaink
- Institute of Biology Leiden, Leiden University, Leiden, Netherlands
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30
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Choi TY, Choi YP, Koo JW. Mental Disorders Linked to Crosstalk between The Gut Microbiome and The Brain. Exp Neurobiol 2020; 29:403-416. [PMID: 33139585 PMCID: PMC7788310 DOI: 10.5607/en20047] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 10/21/2020] [Accepted: 10/22/2020] [Indexed: 12/11/2022] Open
Abstract
Often called the second brain, the gut communicates extensively with the brain and vice versa. The conversation between these two organs affects a variety of physiological mechanisms that are associated with our mental health. Over the past decade, a growing body of evidence has suggested that the gut microbiome builds a unique ecosystem inside the gastrointestinal tract to maintain the homeostasis and that compositional changes in the gut microbiome are highly correlated with several mental disorders. There are ongoing efforts to treat or prevent mental disorders by regulating the gut microbiome using probiotics. These attempts are based on the seminal findings that probiotics can control the gut microbiome and affect mental conditions. However, some issues have yet to be conclusively addressed, especially the causality between the gut microbiome and mental disorders. In this review, we focus on the mechanisms by which the gut microbiome affects mental health and diseases. Furthermore, we discuss the potential use of probiotics as therapeutic agents for psychiatric disorders.
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Affiliation(s)
- Tae-Yong Choi
- Emotion, Cognition and Behavior Research Group, Korea Brain Research Institute (KBRI), Daegu 41062, Korea
| | - Young Pyo Choi
- Laboratory Animal Center, Korea Brain Research Institute (KBRI), Daegu 41062, Korea
| | - Ja Wook Koo
- Emotion, Cognition and Behavior Research Group, Korea Brain Research Institute (KBRI), Daegu 41062, Korea
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31
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Rea K, Dinan TG, Cryan JF. Gut Microbiota: A Perspective for Psychiatrists. Neuropsychobiology 2020; 79:50-62. [PMID: 31726457 DOI: 10.1159/000504495] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 10/31/2019] [Indexed: 11/19/2022]
Abstract
There is mounting evidence that the trillions of microbes that inhabit our gut are a substantial contributing factor to mental health and, equally, to the progression of neuropsychiatric disorders. The extraordinary complexity of the gut ecosystem, and how it interacts with the intestinal epithelium to manifest physiological changes in the brain to influence mood and behaviour, has been the subject of intense scientific scrutiny over the last 2 decades. To further complicate matters, we each harbour a unique microbiota community that is subject to change by a number of factors including diet, exercise, stress, health status, genetics, medication, and age, amongst others. The microbiota-gut-brain axis is a dynamic matrix of tissues and organs including the gastrointestinal (GI) microbiota, immune cells, gut tissue, glands, the autonomic nervous system (ANS), and the brain that communicate in a complex multidirectional manner through a number of anatomically and physiologically distinct systems. Long-term perturbations to this homeostatic environment may contribute to the progression of a number of disorders by altering physiological processes including hypothalamic-pituitary-adrenal axis activation, neurotransmitter systems, immune function, and the inflammatory response. While an appropriate, co-ordinated physiological response, such as an immune or stress response, is necessary for survival, a dysfunctional response can be detrimental to the host, contributing to the development of a number of central nervous system disorders.
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Affiliation(s)
- Kieran Rea
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Timothy G Dinan
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - John F Cryan
- APC Microbiome Ireland, University College Cork, Cork, Ireland, .,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland,
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Bistoletti M, Bosi A, Banfi D, Giaroni C, Baj A. The microbiota-gut-brain axis: Focus on the fundamental communication pathways. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2020; 176:43-110. [PMID: 33814115 DOI: 10.1016/bs.pmbts.2020.08.012] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Michela Bistoletti
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Annalisa Bosi
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Davide Banfi
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Cristina Giaroni
- Department of Medicine and Surgery, University of Insubria, Varese, Italy.
| | - Andreina Baj
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
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Song C, Gao X, Song W, Zeng D, Shan S, Yin Y, Li Y, Baranenko D, Lu W. Simulated spatial radiation impacts learning and memory ability with alterations of neuromorphology and gut microbiota in mice. RSC Adv 2020; 10:16196-16208. [PMID: 35493686 PMCID: PMC9052872 DOI: 10.1039/d0ra01017k] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 04/01/2020] [Indexed: 12/26/2022] Open
Abstract
Complex space environments, including microgravity and radiation, affect the body's central nervous system, endocrine system, circulatory system, and reproductive system. Radiation-induced aberration in the neuronal integrity and cognitive functions are particularly well known. Moreover, ionizing radiation is a likely contributor to alterations in the microbiome. However, there is a lacuna between radiation-induced memory impairment and gut microbiota. The present study was aimed at investigating the effects of simulated space-type radiation on learning and memory ability and gut microbiota in mice. Adult mice were irradiated by 60Co-γ rays at 4 Gy to simulate spatial radiation; behavioral experiments, pathological experiments, and transmission electron microscopy all showed that radiation impaired learning and memory ability and hippocampal neurons in mice, which was similar to the cognitive impairment in neurodegenerative diseases. In addition, we observed that radiation destroyed the colonic structure of mice, decreased the expression of tight junction proteins, and increased inflammation levels, which might lead to dysregulation of the intestinal microbiota. We found a correlation between the brain and colon in the changes in neurotransmitters associated with learning and memory. The 16S rRNA results showed that the bacteria associated with these neurotransmitters were also changed at the genus level and were significantly correlated. These results indicate that radiation-induced memory and cognitive impairment can be linked to gut microbiota through neurotransmitters.
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Affiliation(s)
- Chen Song
- Institute of Extreme Environment Nutrition and Protection, Harbin Institute of Technology Harbin China
- National Local Joint Laboratory of Extreme Environmental Nutritional Molecule Synthesis Transformation and Separation Harbin China
- School of Chemistry and Chemical Engineering, Harbin Institute of Technology Harbin China
| | - Xin Gao
- Institute of Extreme Environment Nutrition and Protection, Harbin Institute of Technology Harbin China
- National Local Joint Laboratory of Extreme Environmental Nutritional Molecule Synthesis Transformation and Separation Harbin China
- School of Chemistry and Chemical Engineering, Harbin Institute of Technology Harbin China
| | - Wei Song
- College of Food Science and Technology, Northwest University Xi'an 710069 China
- Laboratory of Nutritional and Healthy Food-Individuation Manufacturing Engineering Xi'an 710069 Shanxi China
| | - Deyong Zeng
- Institute of Extreme Environment Nutrition and Protection, Harbin Institute of Technology Harbin China
- National Local Joint Laboratory of Extreme Environmental Nutritional Molecule Synthesis Transformation and Separation Harbin China
- School of Chemistry and Chemical Engineering, Harbin Institute of Technology Harbin China
| | - Shan Shan
- Institute of Extreme Environment Nutrition and Protection, Harbin Institute of Technology Harbin China
- National Local Joint Laboratory of Extreme Environmental Nutritional Molecule Synthesis Transformation and Separation Harbin China
- School of Chemistry and Chemical Engineering, Harbin Institute of Technology Harbin China
| | - Yishu Yin
- Institute of Extreme Environment Nutrition and Protection, Harbin Institute of Technology Harbin China
- National Local Joint Laboratory of Extreme Environmental Nutritional Molecule Synthesis Transformation and Separation Harbin China
- School of Chemistry and Chemical Engineering, Harbin Institute of Technology Harbin China
| | - Yongzhi Li
- Institute of Extreme Environment Nutrition and Protection, Harbin Institute of Technology Harbin China
- China Astronaut Research and Training Centre Beijing China
| | - Denis Baranenko
- Biotechnologies of the Third Millennium, ITMO University Saint-Petersburg Russia
| | - Weihong Lu
- Institute of Extreme Environment Nutrition and Protection, Harbin Institute of Technology Harbin China
- National Local Joint Laboratory of Extreme Environmental Nutritional Molecule Synthesis Transformation and Separation Harbin China
- School of Chemistry and Chemical Engineering, Harbin Institute of Technology Harbin China
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Zhao CS, Fang DA, Xu DP. Toll-like receptors (TLRs) respond to tributyltin chloride (TBT-Cl) exposure in the river pufferfish (Takifugu obscurus): Evidences for its toxic injury function. FISH & SHELLFISH IMMUNOLOGY 2020; 99:526-534. [PMID: 32097718 DOI: 10.1016/j.fsi.2020.02.050] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 02/17/2020] [Accepted: 02/21/2020] [Indexed: 06/10/2023]
Abstract
Tributyltin chloride (TBT-Cl) residual in water body had become a noticeable ecological problem for aquatic ecosystems. Toll-like receptors (TLRs) are an ancient family of pattern recognition receptors that play key roles in detecting nonself antigens and immune system activation. In this study, we explored the effect of TBT-Cl exposure on four TLRs expression in river pufferfish, Takifugu obscurus. The four T. obscurus Toll-like receptors (To-TLRs) contained different types of domains such as leucine-rich repeats (LRRs), leucine-rich repeats, typical subfamily (LRR_TYP) and other special domains. The To-TLRs mRNA transcripts expressed in all tissues, also To-TLR2 was investigated with higher level in kidney, as well as To-TLR3 in kidney, while To-TLR18 in liver and To-TLR22 in intestine. After the acute and chronic exposure of TBT-Cl, To-TLR2 and To-TLR3 mRNA transcripts were significantly down-regulated in gill. However, To-TLR18 and To-TLR22 were significantly up-regulated in gill and liver. Moreover, the histology and immunohistochemistry (IHC) results showed the different injury degrees of TBT-Cl in liver and gill and implied the cytoplasm reorganization after TBT-Cl stress and the function of immunoregulation for To-TLRs to TBT-Cl exposure. All the results indicated that To-TLRs might involve in sensing and mediating innate immune responses caused by TBT-Cl for keeping detoxification homeostasis.
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Affiliation(s)
- Chang-Sheng Zhao
- Scientific Observing and Experimental Station of Fishery Resources and Environment in the Lower Reache of the Changjiang River, Ministry of Agriculture and Rural Affaris, Freshwater Fisheries Research Center, CAFS, WuXi, 214081, China
| | - Di-An Fang
- Scientific Observing and Experimental Station of Fishery Resources and Environment in the Lower Reache of the Changjiang River, Ministry of Agriculture and Rural Affaris, Freshwater Fisheries Research Center, CAFS, WuXi, 214081, China; College of Fisheries and Life Science, Shanghai Ocean University, 999 Huchenghuan Road, Shanghai, 201306, China
| | - Dong-Po Xu
- Scientific Observing and Experimental Station of Fishery Resources and Environment in the Lower Reache of the Changjiang River, Ministry of Agriculture and Rural Affaris, Freshwater Fisheries Research Center, CAFS, WuXi, 214081, China.
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Hu J, Wang W, Hao Q, Zhang T, Yin H, Wang M, Zhang C, Zhang C, Zhang L, Zhang X, Wang W, Cao X, Xiang J, Ye X. Suppressors of cytokine signalling (SOCS)-1 inhibits neuroinflammation by regulating ROS and TLR4 in BV2 cells. Inflamm Res 2020; 69:27-39. [PMID: 31707448 DOI: 10.1007/s00011-019-01289-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 09/26/2019] [Accepted: 09/30/2019] [Indexed: 02/01/2023] Open
Abstract
OBJECTIVE The suppressors of cytokine signaling (SOCS) proteins are physiological suppressors of cytokine signaling which have been identified as a negative feedback loop to weaken cytokine signaling. However, the underlying molecular mechanisms is unknown. This study was to investigate the role of SOCS1 in the oxygen-glucose deprivation and reoxygenation (OGDR) or LPS-induced inflammation in microglia cell line BV-2 cells. MATERIALS AND METHODS BV-2 microglial cells were used to construct inflammation model. A SOCS1 over-expression plasmid was constructed, and the SOCS1-deficient cells were generated by utilizing the CRISPR/CAS9 system. BV-2 microglial cells were pretreated with over-expression plasmid or SOCS1 CRISPR plasmid before OGDR and LPS stimulation. The effect of SOCS1 on proinflammatory cytokines, toll-like receptor 4 (TLR4), and reactive oxygen species (ROS) were evaluated. RESULTS We found that SOCS1 increased in OGDR or LPS-treated BV-2 microglial cells in vitro. SOCS1 over-expression significantly reduced the production of proinflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and IL-6, and CRISPR/CAS9-mediated SOCS1 knockout reversed this effect. Also we determined that SOCS1 over-expression reduced the level of reactive oxygen species (ROS) while the absence of SOCS1 increased the production of ROS after OGDR or LPS-stimulated inflammation. Furthermore, we found that OGDR and LPS induced the expression of toll-like receptor 4 (TLR4) in BV2 cells. Nevertheless, SOCS1 over-expression attenuated the expression of TLR4, while knockdown of SOCS1 upregulated TLR4. CONCLUSIONS Our study indicated that SOCS1 played a protective role under inflammatory conditions in OGDR or LPS treated BV-2 cells through regulating ROS and TLR4. These data demonstrated that SOCS1 served as a potential therapeutic target to alleviate inflammation after ischemic stroke.
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Affiliation(s)
- Jinxia Hu
- Institute of Stroke Center, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China.,School of Material Science and Engineering, China University of Mining and Technology, Xuzhou, 221116, Jiangsu, People's Republic of China
| | - Weiwei Wang
- Department of Rehabilitation Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, No. 99 West Huaihai Road, Xuzhou, 221006, Jiangsu, People's Republic of China.,Department of Rehabilitation Medicine, Linyi Cancer Hospital, Linyi, 276001, Shandong, People's Republic of China
| | - Qi Hao
- Institute of Stroke Center, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China
| | - Tao Zhang
- Institute of Stroke Center, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China
| | - Hanhan Yin
- Institute of Stroke Center, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China
| | - Miao Wang
- Institute of Stroke Center, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China
| | - Cheng Zhang
- Institute of Stroke Center, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China
| | - Conghui Zhang
- Institute of Stroke Center, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China
| | - Lijie Zhang
- Department of Rehabilitation Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, No. 99 West Huaihai Road, Xuzhou, 221006, Jiangsu, People's Republic of China
| | - Xiao Zhang
- Department of Rehabilitation Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, No. 99 West Huaihai Road, Xuzhou, 221006, Jiangsu, People's Republic of China
| | - Wei Wang
- Department of Rehabilitation Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, No. 99 West Huaihai Road, Xuzhou, 221006, Jiangsu, People's Republic of China
| | - Xichuan Cao
- School of Material Science and Engineering, China University of Mining and Technology, Xuzhou, 221116, Jiangsu, People's Republic of China
| | - Jie Xiang
- Department of Rehabilitation Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, No. 99 West Huaihai Road, Xuzhou, 221006, Jiangsu, People's Republic of China.
| | - Xinchun Ye
- Institute of Stroke Center, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China.
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Lu BL, Williams GM, Brimble MA. TLR2 agonists and their structure–activity relationships. Org Biomol Chem 2020; 18:5073-5094. [DOI: 10.1039/d0ob00942c] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
We review the structure–activity relationships and synthetic studies of TLR2 agonists – important chemical targets in immunotherapy.
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Affiliation(s)
- Benjamin L. Lu
- The School of Biological Sciences
- University of Auckland
- Auckland 1010
- New Zealand
- The School of Chemical Sciences
| | - Geoffrey M. Williams
- The School of Biological Sciences
- University of Auckland
- Auckland 1010
- New Zealand
- The School of Chemical Sciences
| | - Margaret A. Brimble
- The School of Biological Sciences
- University of Auckland
- Auckland 1010
- New Zealand
- The School of Chemical Sciences
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Marin M, Burucúa M, Rensetti D, Rosales JJ, Odeón A, Pérez S. Distinctive features of bovine alphaherpesvirus types 1 and 5 and the virus-host interactions that might influence clinical outcomes. Arch Virol 2019; 165:285-301. [PMID: 31845150 DOI: 10.1007/s00705-019-04494-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 11/09/2019] [Indexed: 12/14/2022]
Abstract
Bovine herpesvirus types 1 (BoHV-1) and 5 (BoHV-5) are two closely related alphaherpesviruses. BoHV-1 causes several syndromes in cattle, including respiratory disease and sporadic cases of encephalitis, whereas BoHV-5 is responsible for meningoencephalitis in calves. Although both viruses are neurotropic, they differ in their neuropathogenic potential. This review summarizes the findings on the specific mechanisms and pathways known to modulate the pathogenesis of BoHV-1 and BoHV-5, particularly in relation to respiratory and neurological syndromes, which characterize BoHV-1 and BoHV-5 infections, respectively.
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Affiliation(s)
- Maia Marin
- Instituto Nacional de Tecnología Agropecuaria (INTA), Estación Experimental Agropecuaria Balcarce, Ruta 226 Km 73.5, Balcarce, 7620, Buenos Aires, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Rivadavia 1917, C1033AAJ, Buenos Aires, Argentina
| | - Mercedes Burucúa
- Instituto Nacional de Tecnología Agropecuaria (INTA), Estación Experimental Agropecuaria Balcarce, Ruta 226 Km 73.5, Balcarce, 7620, Buenos Aires, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Rivadavia 1917, C1033AAJ, Buenos Aires, Argentina
| | - Daniel Rensetti
- Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires, Paraje Arroyo Seco S/N, 7000, Tandil, Argentina
| | - Juan José Rosales
- Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires, Paraje Arroyo Seco S/N, 7000, Tandil, Argentina.,Centro de Investigación Veterinaria de Tandil (CIVETAN)-CONICET, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires, Paraje Arroyo Seco S/N, 7000, Tandil, Argentina
| | - Anselmo Odeón
- Instituto Nacional de Tecnología Agropecuaria (INTA), Estación Experimental Agropecuaria Balcarce, Ruta 226 Km 73.5, Balcarce, 7620, Buenos Aires, Argentina
| | - Sandra Pérez
- Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires, Paraje Arroyo Seco S/N, 7000, Tandil, Argentina. .,Centro de Investigación Veterinaria de Tandil (CIVETAN)-CONICET, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires, Paraje Arroyo Seco S/N, 7000, Tandil, Argentina.
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Lim HJ, Jang HJ, Kim MH, Lee S, Lee SW, Lee SJ, Rho MC. Oleanolic Acid Acetate Exerts Anti-Inflammatory Activity via IKKα/β Suppression in TLR3-Mediated NF-κB Activation. Molecules 2019; 24:molecules24214002. [PMID: 31694243 PMCID: PMC6866124 DOI: 10.3390/molecules24214002] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 11/04/2019] [Accepted: 11/04/2019] [Indexed: 12/22/2022] Open
Abstract
Oleanolic acid acetate (OAA), a major triterpenoid compound of Vigna angularis (azuki bean, V. angularis), has been shown to downregulate inflammatory responses in macrophages. Here, we show the molecular basis for the effect of OAA on Toll-like receptor (TLR) downstream signaling. OAA treatment significantly inhibited the secretion of embryonic alkaline phosphatase (SEAP) induced by polyinosinic acid (poly(I), TLR3 ligand) in a dose-dependent manner and without cytotoxicity in THP1-XBlue cells. In addition, OAA downregulated the gene expression of poly(I) induced pro-inflammatory cytokines and chemokines genes such as MCP-1, IL-1β, IL-8, VCAM-1 and ICAM-1. Furthermore, we found that the inhibition activity of OAA was accompanied by decreased activation of not only nuclear factor-kappa B (NF-κB) signaling but also mitogen-activated protein kinase (MAPK) signaling upon stimulation with the TLR3 agonist. Interestingly, the interaction of OAA with IκB kinase α/β (IKKα/β) strongly attenuated the production of certain proteins and inflammatory cytokines in the TLR3 signaling pathway, such as nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IkBα), extracellular regulated kinases (ERK), and p38, in an in vitro model. The action of OAA was regulated by TLR3, demonstrating that TLR3 plays a critical role in mediating the physiologically-relevant anti-inflammatory action of OAA and that the interaction with IKKα/β is modulated through TLR3. These results reveal new insight into the understanding of the regulatory mechanisms of the downstream TLR3 signaling pathway and consequent inflammatory responses that are involved in the development and progression of inflammatory diseases.
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Affiliation(s)
- Hyung Jin Lim
- Immunoregulatory Material Research Center, Korea Research Institute of Bioscience and Biotechnology, 181 Ipsin-gil, Jeongeup-si 56212, Korea; (H.J.L.); (M.H.K.); (S.L.); (S.W.L.)
- Department of Bioactive Material Sciences, Chonbuk National University, Jeonju-si 54896, Korea
| | - Hyun-Jae Jang
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Cheongju-si 28116, Korea;
| | - Mi Hwa Kim
- Immunoregulatory Material Research Center, Korea Research Institute of Bioscience and Biotechnology, 181 Ipsin-gil, Jeongeup-si 56212, Korea; (H.J.L.); (M.H.K.); (S.L.); (S.W.L.)
| | - Soyoung Lee
- Immunoregulatory Material Research Center, Korea Research Institute of Bioscience and Biotechnology, 181 Ipsin-gil, Jeongeup-si 56212, Korea; (H.J.L.); (M.H.K.); (S.L.); (S.W.L.)
| | - Seung Woong Lee
- Immunoregulatory Material Research Center, Korea Research Institute of Bioscience and Biotechnology, 181 Ipsin-gil, Jeongeup-si 56212, Korea; (H.J.L.); (M.H.K.); (S.L.); (S.W.L.)
| | - Seung-Jae Lee
- Immunoregulatory Material Research Center, Korea Research Institute of Bioscience and Biotechnology, 181 Ipsin-gil, Jeongeup-si 56212, Korea; (H.J.L.); (M.H.K.); (S.L.); (S.W.L.)
- Correspondence: (S.-J.L.); (M.-C.R.); Tel.: +82-63-570-5267 (S.-J.L.); +82-63-570-5230 (M.-C.R.)
| | - Mun-Chual Rho
- Immunoregulatory Material Research Center, Korea Research Institute of Bioscience and Biotechnology, 181 Ipsin-gil, Jeongeup-si 56212, Korea; (H.J.L.); (M.H.K.); (S.L.); (S.W.L.)
- Correspondence: (S.-J.L.); (M.-C.R.); Tel.: +82-63-570-5267 (S.-J.L.); +82-63-570-5230 (M.-C.R.)
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Sasidharan R, Sreedharannair Leelabaiamma M, Mohanan R, Jose SP, Mathew B, Sukumaran S. Anti-inflammatory effect of synthesized indole-based chalcone (2E)-3-(4-bromophenyl)-1-(1 H-indol-3-yl) prop-2-en-1-one: an in vitro and in vivo studies. Immunopharmacol Immunotoxicol 2019; 41:568-576. [PMID: 31594421 DOI: 10.1080/08923973.2019.1672177] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Purpose: Chalcones are precursors of flavonoids with a wide range of pharmacological activities. This study evaluates the anti-inflammatory effect of indole based chalcone derivative (2E)-3-(4-bromophenyl)-1-(1H-indol-3-yl) prop-2-en-1-one (IC9) on lipopolysaccharide (LPS) activated murine macrophages RAW264.7 cells and carrageenan-induced acute model in rats.Materials and methods: LPS-treated RAW264.7 cell lines and carrageenan-induced animal model were employed to evaluate the anti-inflammatory activity of IC9. The cell cytotoxicity studies were carried out by MTT assay. Reactive oxygen species (ROS) production and other inflammatory markers such as prostaglandin E2 (PGE2), nitric oxide (NO) as well as cyclooxygenase-2 (COX-2) activity were determined using ELISA. The RT-PCR was performed to determine mRNA expressions in the case of inducible nitric oxide synthase (iNOS), COX-2, Toll-like receptor-4 (TLR-4) and also nuclear translocation of NF-κB activity.Results: LPS-activated RAW264.7 cells showed an increased level of ROS generation and other inflammatory markers such as PGE2, NO level and COX-2 activity. Expression of iNOS, COX- 2 and TLR-4 mRNA expression were also up-regulated along with nuclear translocation of NF-κB. On IC9 supplementation, all the above parameters of LPS-activated cells were found to be reversed, resembling the control group. Moreover, IC9 significantly inhibited paw swelling and exhibited maximum inhibition of 78.45% at low dose of 7.5 mg/kg.bwt.Conclusions: The targeting anti-inflammatory efficacy and profound NF-κB sensitive transcriptional regulatory mechanism of IC9 accounts for its effective anti-inflammatory action.
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Affiliation(s)
- Rani Sasidharan
- Department of Chemistry, School of Advanced Sciences, VIT University, Vellore, India
| | | | - Ratheesh Mohanan
- Departments of Biochemistry, St. Thomas College, Pala, Kottayam, India
| | - Svenia P Jose
- Departments of Biochemistry, St. Thomas College, Pala, Kottayam, India
| | - Bijo Mathew
- Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad, India
| | - Sandya Sukumaran
- Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore, India
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Cryan JF, O'Riordan KJ, Cowan CSM, Sandhu KV, Bastiaanssen TFS, Boehme M, Codagnone MG, Cussotto S, Fulling C, Golubeva AV, Guzzetta KE, Jaggar M, Long-Smith CM, Lyte JM, Martin JA, Molinero-Perez A, Moloney G, Morelli E, Morillas E, O'Connor R, Cruz-Pereira JS, Peterson VL, Rea K, Ritz NL, Sherwin E, Spichak S, Teichman EM, van de Wouw M, Ventura-Silva AP, Wallace-Fitzsimons SE, Hyland N, Clarke G, Dinan TG. The Microbiota-Gut-Brain Axis. Physiol Rev 2019; 99:1877-2013. [PMID: 31460832 DOI: 10.1152/physrev.00018.2018] [Citation(s) in RCA: 2692] [Impact Index Per Article: 448.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders. The microbiota and the brain communicate with each other via various routes including the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans. Many factors can influence microbiota composition in early life, including infection, mode of birth delivery, use of antibiotic medications, the nature of nutritional provision, environmental stressors, and host genetics. At the other extreme of life, microbial diversity diminishes with aging. Stress, in particular, can significantly impact the microbiota-gut-brain axis at all stages of life. Much recent work has implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson’s disease, and Alzheimer’s disease. Animal models have been paramount in linking the regulation of fundamental neural processes, such as neurogenesis and myelination, to microbiome activation of microglia. Moreover, translational human studies are ongoing and will greatly enhance the field. Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.
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Affiliation(s)
- John F. Cryan
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Kenneth J. O'Riordan
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Caitlin S. M. Cowan
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Kiran V. Sandhu
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Thomaz F. S. Bastiaanssen
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Marcus Boehme
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Martin G. Codagnone
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Sofia Cussotto
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Christine Fulling
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Anna V. Golubeva
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Katherine E. Guzzetta
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Minal Jaggar
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Caitriona M. Long-Smith
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Joshua M. Lyte
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Jason A. Martin
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Alicia Molinero-Perez
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Gerard Moloney
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Emanuela Morelli
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Enrique Morillas
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Rory O'Connor
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Joana S. Cruz-Pereira
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Veronica L. Peterson
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Kieran Rea
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Nathaniel L. Ritz
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Eoin Sherwin
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Simon Spichak
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Emily M. Teichman
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Marcel van de Wouw
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Ana Paula Ventura-Silva
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Shauna E. Wallace-Fitzsimons
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Niall Hyland
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Gerard Clarke
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Timothy G. Dinan
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
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Chen Y, Huang Z, Chen X, Ye H. Activation of the Toll‑like receptor 2 signaling pathway inhibits the proliferation of HCC cells in vitro. Oncol Rep 2019; 42:2267-2278. [PMID: 31578587 PMCID: PMC6826303 DOI: 10.3892/or.2019.7340] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 08/07/2019] [Indexed: 12/23/2022] Open
Abstract
Toll‑like receptor 2 (TLR2), is an important pattern recognition receptor which serves a role in chronic inflammation of the liver. However, the role of TLR2 in the progression of human hepatocellular carcinoma (HCC) remains unknown. The aim of the present study was to examine the effects of the activation of the TLR2 signaling pathway on biological functions, such as proliferation and apoptosis. TLR2 expression in HCC tissues was assayed by quantitative polymerase chain reaction, flow cytometry and western blotting. B76/Huh7 cells were transfected with overexpression plasmids, and cell proliferation was detected using a Cell Counting Kit‑8 assay and the secreted cytokines in the supernatant of transfected cells were measured by ELISA. The findings revealed that TLR2 expression was increased in the peritumoral groups compared with inner‑tumoral groups. Activation of the TLR2 signaling pathway through overexpression of pathway molecules inhibited the growth of B76/Huh7 cells and the secretion of interleukin‑6 and tumor necrosis factor‑α were reduced. Inhibition of the TLR2 signaling pathway resulted in a significant increase in the downstream signaling cascade, thus potentially increasing hepatocarcinogenesis and tumor progression. Activation of the TLR2 signaling pathway may be a potential target for therapeutic intervention in patients with HCC and downstream secreted cytokines are required for the functional biological effect. Therefore, modulation of the TLR2 signaling pathway may provide important insight into designing effective therapeutic regimens for treating patients with HCC.
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Affiliation(s)
- Yi Chen
- United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
| | - Zuxiong Huang
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
| | - Xuzheng Chen
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350108, P.R. China
| | - Hanhui Ye
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
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The Vertebrate TLR Supergene Family Evolved Dynamically by Gene Gain/Loss and Positive Selection Revealing a Host–Pathogen Arms Race in Birds. DIVERSITY-BASEL 2019. [DOI: 10.3390/d11080131] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The vertebrate toll-like receptor (TLRs) supergene family is a first-line immune defense against viral and non-viral pathogens. Here, comparative evolutionary-genomics of 79 vertebrate species (8 mammals, 48 birds, 11 reptiles, 1 amphibian, and 11 fishes) revealed differential gain/loss of 26 TLRs, including 6 (TLR3, TLR7, TLR8, TLR14, TLR21, and TLR22) that originated early in vertebrate evolution before the diversification of Agnatha and Gnathostomata. Subsequent dynamic gene gain/loss led to lineage-specific diversification with TLR repertoires ranging from 8 subfamilies in birds to 20 in fishes. Lineage-specific loss of TLR8-9 and TLR13 in birds and gains of TLR6 and TLR10-12 in mammals and TLR19-20 and TLR23-27 in fishes. Among avian species, 5–10% of the sites were under positive selection (PS) (omega 1.5–2.5) with radical amino-acid changes likely affecting TLR structure/functionality. In non-viral TLR4 the 20 PS sites (posterior probability PP > 0.99) likely increased ability to cope with diversified ligands (e.g., lipopolysaccharide and lipoteichoic). For viral TLR7, 23 PS sites (PP > 0.99) possibly improved recognition of highly variable viral ssRNAs. Rapid evolution of the TLR supergene family reflects the host–pathogen arms race and the coevolution of ligands/receptors, which follows the premise that birds have been important vectors of zoonotic pathogens and reservoirs for viruses.
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Jahanban‐Esfahlan R, Seidi K, Majidinia M, Karimian A, Yousefi B, Nabavi SM, Astani A, Berindan‐Neagoe I, Gulei D, Fallarino F, Gargaro M, Manni G, Pirro M, Xu S, Sadeghi M, Nabavi SF, Shirooie S. Toll‐like receptors as novel therapeutic targets for herpes simplex virus infection. Rev Med Virol 2019; 29:e2048. [DOI: 10.1002/rmv.2048] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 03/12/2019] [Accepted: 03/19/2019] [Indexed: 12/22/2022]
Affiliation(s)
- Rana Jahanban‐Esfahlan
- Department of Medical Biotechnology, Faculty of Advanced Medical SciencesTabriz University of Medical Sciences Tabriz Iran
- Drug Applied Research CenterTabriz University of Medical Sciences Tabriz Iran
| | - Khaled Seidi
- Immunology Research CenterTabriz University of Medical Sciences Tabriz Iran
| | - Maryam Majidinia
- Solid Tumor Research CenterUrmia University of Medical Sciences Urmia Iran
| | - Ansar Karimian
- Cellular and Molecular Biology Research Center, Health Research InstituteBabol University of Medical Sciences Babol Iran
| | - Bahman Yousefi
- Molecular Medicine Research CenterTabriz University of Medical Sciences Tabriz Iran
- Department of Biochemistry and Clinical Laboratories, Faculty of MedicineTabriz University of Medical Science Tabriz Iran
| | - Seyed Mohammad Nabavi
- Applied Biotechnology Research CenterBaqiyatallah University of Medical Sciences Tehran Iran
| | - Akram Astani
- Department of MicrobiologyShahid Sadoughi University of Medical Sciences Yazd Iran
| | - Ioana Berindan‐Neagoe
- MEDFUTURE ‐Research Center for Advanced Medicine“Iuliu‐Hatieganu” University of Medicine and Pharmacy Cluj‐Napoca Romania
- Research Centerfor Functional Genomics, Biomedicine and Translational Medicine“Iuliu‐Hatieganu” University of Medicine and Pharmacy Cluj‐Napoca Romania
- Department of Functional Genomics and Experimental PathologyThe Oncology Institute “Prof. Dr. Ion Chiricuţă” Cluj‐Napoca Romania
| | - Diana Gulei
- MEDFUTURE ‐Research Center for Advanced Medicine“Iuliu‐Hatieganu” University of Medicine and Pharmacy Cluj‐Napoca Romania
| | | | - Marco Gargaro
- Department of Experimental MedicineUniversity of Perugia Italy
| | - Giorgia Manni
- Department of Experimental MedicineUniversity of Perugia Italy
| | - Matteo Pirro
- Department of MedicineUniversity of Perugia Italy
| | - Suowen Xu
- Aab Cardiovascular Research InstituteUniversity of Rochester Rochester NY USA
| | - Mahmoud Sadeghi
- Department of Transplantation ImmunologyUniversity of Heidelberg Heidelberg Germany
| | - Seyed Fazel Nabavi
- Applied Biotechnology Research CenterBaqiyatallah University of Medical Sciences Tehran Iran
| | - Samira Shirooie
- Department of Pharmacology, Faculty of PharmacyKermanshah University of Medical Sciences Kermanshah Iran
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Alam S, Liu Q, Liu S, Liu Y, Zhang Y, Yang X, Liu G, Fan K, Ma J. Up-regulated cathepsin C induces macrophage M1 polarization through FAK-triggered p38 MAPK/NF-κB pathway. Exp Cell Res 2019; 382:111472. [PMID: 31229505 DOI: 10.1016/j.yexcr.2019.06.017] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 06/14/2019] [Accepted: 06/17/2019] [Indexed: 12/25/2022]
Abstract
Increasing evidence indicates that in response to environmental changes, macrophages can dynamically change into two main functional phenotypes, namely M1 and M2. Depending on these different phenotypes, macrophages can produce either pro-inflammatory or anti-inflammatory factors which may affect the outcome of inflammation. Mastering the switching of M1/M2 phenotypes may provide therapeutic approaches to chronic inflammatory disease, such as atherosclerosis, rheumatoid arthritis, even the metabolic disorders. Cathepsin C (CTSC), as a member of the papain family of cysteine proteases, is a key enzyme in the activation of granule serine proteases thereby involved in modulating the inflammatory responses. Moreover, abundant expression of CTSC has been found in M1 macrophages in plaques of atherosclerosis and related to the progression of disease. However, whether CTSC can regulate macrophage activation status in inflammatory responses has not been fully investigated. In the present study, using peritoneal macrophages (PMs) and mouse macrophage cell line RAW264.7 treated with LPS and active monomer of CTSC, we found that CTSC was not only expressed in macrophages in M1 activation status, but also facilitated macrophages towards M1 phenotype, suggesting a self-activation mechanism involved in this process which may lead to a vicious circle in chronic inflammation. Then we attempted to explore the underlying molecular mechanisms of CTSC resulting in M1 activation. Focal adhesion kinase (FAK) is one of the non-receptor cytoplasmic protein tyrosine kinases, serving as an upstream mediator that leads to transcription of many pro-inflammatory factors. We found FAK expression was up-regulated at both mRNA and protein levels following CTSC stimulation, and FAK phosphorylation level was also significantly increased. The p38MAPK/NF-κB pathway, as the downstream of FAK, were also found activated in CTSC-treated macrophages, suggesting that CTSC may promote macrophage towards M1 activation status through FAK-induced p38MAPK/NF-κB signaling pathway activation. Our study provides a new therapeutic target in the treatment of chronic inflammatory diseases.
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Affiliation(s)
- Shahid Alam
- Department of Anatomy, Dalian Medical University, No. 9 Lvshun South Road Western Section, Lvshun District, Dalian, 116044, PR China.
| | - Qing Liu
- Graduate School of Dalian Medical University, No. 9 Lvshun South Road Western Section, Lvshun District, Dalian, 116044, PR China.
| | - Shuang Liu
- Graduate School of Dalian Medical University, No. 9 Lvshun South Road Western Section, Lvshun District, Dalian, 116044, PR China.
| | - Yanna Liu
- Department of Anatomy, Dalian Medical University, No. 9 Lvshun South Road Western Section, Lvshun District, Dalian, 116044, PR China.
| | - Yanli Zhang
- Department of Anatomy, Dalian Medical University, No. 9 Lvshun South Road Western Section, Lvshun District, Dalian, 116044, PR China.
| | - Xiaohan Yang
- Liaoning Provincial Key Laboratory of Brain Diseases, Dalian Medical University, No. 9 Lvshun South Road Western Section, Lvshun District, Dalian, 116044, PR China.
| | - Gang Liu
- College ofBasic Medical Sciences, Dalian Medical University, No. 9 Lvshun South Road Western Section, Lvshun District, Dalian, 116044, PR China.
| | - Kai Fan
- Department of Anatomy, Dalian Medical University, No. 9 Lvshun South Road Western Section, Lvshun District, Dalian, 116044, PR China.
| | - Jianmei Ma
- Department of Anatomy, College of Basic Medical Sciences, National-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, No. 9 Lvshun South Road Western Section, Lvshun District, Dalian, 116044, PR China.
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Curtale G, Rubino M, Locati M. MicroRNAs as Molecular Switches in Macrophage Activation. Front Immunol 2019; 10:799. [PMID: 31057539 PMCID: PMC6478758 DOI: 10.3389/fimmu.2019.00799] [Citation(s) in RCA: 141] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 03/26/2019] [Indexed: 12/25/2022] Open
Abstract
The efficacy of macrophage- mediated inflammatory response relies on the coordinated expression of key factors, which expression is finely regulated at both transcriptional and post-transcriptional level. Several studies have provided compelling evidence that microRNAs play pivotal roles in modulating macrophage activation, polarization, tissue infiltration, and resolution of inflammation. In this review, we highlight the essential molecular mechanisms underlying the different phases of inflammation that are targeted by microRNAs to inhibit or accelerate restoration to tissue integrity and homeostasis. We further review the impact of microRNA-dependent regulation of tumor-associated macrophages and the relative implication for tumor biology.
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Affiliation(s)
- Graziella Curtale
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy.,Humanitas Clinical and Research Center - IRCCS, Rozzano, Italy
| | - Marcello Rubino
- Humanitas Clinical and Research Center - IRCCS, Rozzano, Italy
| | - Massimo Locati
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy.,Humanitas Clinical and Research Center - IRCCS, Rozzano, Italy
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Yong YH, Liu SF, Hua GH, Jia RM, Gooneratne R, Zhao YT, Liao M, Ju XH. Goose toll-like receptor 3 (TLR3) mediated IFN-γ and IL-6 in anti-H5N1 avian influenza virus response. Vet Immunol Immunopathol 2019; 197:31-38. [PMID: 29475504 DOI: 10.1016/j.vetimm.2018.01.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 12/29/2017] [Accepted: 01/19/2018] [Indexed: 12/13/2022]
Abstract
Induction of the innate immune pathways is critical for early anti-viral defense. How geese recognize viral molecules and activate these pathways is not well understood. In mammals, Toll-like receptor 3 (TLR3) recognizes double-stranded RNA. Activation of TLR3 induces the activation of NF-кB and the production of type-I interferon. In this study, the goose TLR3 gene was cloned using rapid amplification of cDNA ends. Goose TLR3 encoded an 896-amino-acid protein, containing a signal secretion peptide, 14 extracellular leucine-rich repeat domains, a transmembrane domain, a Toll/interleukin-1 receptor signaling domain, and shared 46.7-84.4% homology with other species. Tissue expression of goose TLR3 varied markedly and was highest in the pancreas and lowest in the skin. Human embryonic kidney 293 cells transfected with goose TLR3 and NF-κB-luciferase-containing plasmids responded significantly to poly i:c. The expression of TLR3, IL-6 and IFN-γ mRNA, but not IL-1 mRNA, was significantly upregulated after poly i:c or high pathogenic avian influenza virus (H5N1) stimulation in goose peripheral blood mononuclear cells cultured in vitro. Furthermore, geese infected with H5N1 showed significant upregulation of TLR3, especially in the lung and brain. We conclude that goose TLR3 is a functional TLR3 homologue of the protein in other species and plays an important role in virus recognition.
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Affiliation(s)
- Yan-Hong Yong
- Center of Modern Biochemistry, Guangdong Ocean University, Zhanjiang 524088, China.
| | - Shao-Feng Liu
- Department of Animal Science, Guangdong Ocean University, Zhanjiang 524088, China.
| | - Guo-Hong Hua
- Department of Animal Science, Guangdong Ocean University, Zhanjiang 524088, China.
| | - Ru-Min Jia
- Department of Animal Science, Guangdong Ocean University, Zhanjiang 524088, China.
| | - Ravi Gooneratne
- Faculty of Agriculture and Life Sciences, Lincoln University, Christchurch 7647, New Zealand.
| | - Yun-Tao Zhao
- MOA Key Laboratory for Animal Vaccine Development, Key Laboratory of Zoonoses Control and Prevention of Guangdong, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China.
| | - Ming Liao
- MOA Key Laboratory for Animal Vaccine Development, Key Laboratory of Zoonoses Control and Prevention of Guangdong, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China.
| | - Xiang-Hong Ju
- Department of Veterinary Medicine, Guangdong Ocean University, Zhanjiang 524088, China; MOA Key Laboratory for Animal Vaccine Development, Key Laboratory of Zoonoses Control and Prevention of Guangdong, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China.
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Effect of Low-Fat Diet in Obese Mice Lacking Toll-like Receptors. Nutrients 2018; 10:nu10101464. [PMID: 30304787 PMCID: PMC6213519 DOI: 10.3390/nu10101464] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 09/28/2018] [Accepted: 10/02/2018] [Indexed: 12/11/2022] Open
Abstract
Background: This study aimed at assessing the effect of a low-fat diet (LFD) in obese mice lacking toll–like receptors (Tlr) and understanding the expression and regulation of microRNAs during weight reduction. Methods: C57BL/6, Tlr5−/−, Tlr2−/− and Tlr4−/− mice were used in this study. A group of mice were fed with a high-fat diet (HFD) (58% kcal) for 12 weeks to induce obesity (diet-induced obesity, DIO). Another group that had been fed with HFD for eight weeks (obese mice) were switched to a low-fat diet (LFD) (10.5% kcal) for the next four weeks to reduce their body weight. The control mice were fed with a standard AIN-76A diet for the entire 12 weeks. The body weight of the mice was measured weekly. At the end of the experiment, epididymal fat weight and adipocyte size were measured. The differentially expressed miRNAs in the fat tissue was determined by next-generation sequencing with real-time quantitative reverse transcription polymerase chain reaction (RT–qPCR). Target prediction and functional annotation of miRNAs were performed using miRSystem database. Results: Switching to LFD significantly reduced the body weight and epididymal fat mass in the HFD-fed C57BL/6 and Tlr5−/− mice but not in Tlr2−/− and Tlr4−/− mice. Weight reduction significantly decreased the size of adipocytes in C57BL/6 but not in the Tlr knockout mice. In Tlr2−/− and Tlr4−/− mice, feeding with HFD and the subsequent weight reduction resulted in an aberrant miRNA expression in the epididymal fat tissue unlike in C57BL/6 and Tlr5−/−. However, target prediction and functional annotation by miRSystem database revealed that all the top 10 Kyoto Encyclopedia of Genes and Genomes (KEGG) database pathways of the dysregulated miRNAs during weight reduction in the C57BL/6 mice were also found in the regulated pathways of Tlr5−/−, Tlr2−/−, and Tlr4−/− strains. However, among these pathways, gene sets involved in arginine and proline metabolism and glutathione metabolism were mainly involved in the Tlr knockout mice but not in the C57BL/6 mice. Conclusions: In this study, we demonstrated that feeding of LFD leads to significant body weight reduction in C57BL/6 and Tlr5−/− mice, but not in Tlr2−/− and Tlr4−/− mice. Significant reduction in the size of adipocytes of epididymal fat was only found in C57BL/6, but not in Tlr5−/−, Tlr2−/−, and Tlr4−/− mice. The dysregulated miRNAs in Tlr2−/− and Tlr4−/− mice were different from those in C57BL/6 and Tlr5−/− strains. Among those miRNA-regulated pathways, arginine and proline metabolism as well as glutathione metabolism may have important roles in the Tlr knockout mice rather than in C57BL/6 mice.
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Chen CY, Kao CL, Liu CM. The Cancer Prevention, Anti-Inflammatory and Anti-Oxidation of Bioactive Phytochemicals Targeting the TLR4 Signaling Pathway. Int J Mol Sci 2018; 19:ijms19092729. [PMID: 30213077 PMCID: PMC6164406 DOI: 10.3390/ijms19092729] [Citation(s) in RCA: 211] [Impact Index Per Article: 30.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 09/04/2018] [Accepted: 09/10/2018] [Indexed: 12/22/2022] Open
Abstract
Toll-like receptors (TLRs) are a well-known family of pattern recognition receptors that play an important role in a host immune system. TLR triggering leads to the induction of pro-inflammatory cytokines and chemokines, driving the activation of both innate and adaptive immunity. Recently, an increasing number studies have shown the link between TLRs and cancer. Among them, the toll-like receptor 4 (TLR4) signaling pathway is associated with inflammatory response and cancer progression. Dietary phytochemicals are potential modulators of immunological status with various pharmacological properties including anti-cancer, anti-oxidant and anti-inflammatory. Curcumin, 6-gingerol, 6-shogaol, 1-dehydro-10-gingerdione, epigallocatechin gallate (EGCG), luteolin, quercetin, resveratrol, caffeic acid phenethyl ester, xanthohumol, genistein, berberine, and sulforaphane can inhibit TLR4 activation. The aim of the present review is to describe the role of the TLR4 signaling pathway between inflammatory response and cancer progression. We further introduce bioactive phytochemicals with potential anti-inflammation and chemoprevention by inhibiting TLR activation.
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Affiliation(s)
- Chung-Yi Chen
- School of Medical and Health Sciences, Fooyin University, Ta-Liao District, Kaohsiung 83102, Taiwan.
| | - Chiu-Li Kao
- Department of Nursing, Tzu Hui Institute of Technology, Pingtung County 92641, Taiwan.
| | - Chi-Ming Liu
- School of Medicine, Yichun University, Yuanzhou District, Yichun 336000, China.
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Chung J, Kim S, Lee HA, Park MH, Kim S, Song YR, Na HS. Trans-cinnamic aldehyde inhibitsAggregatibacter actinomycetemcomitans-induced inflammation in THP-1-derived macrophages via autophagy activation. J Periodontol 2018; 89:1262-1271. [DOI: 10.1002/jper.17-0727] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 04/17/2018] [Accepted: 04/17/2018] [Indexed: 12/31/2022]
Affiliation(s)
- Jin Chung
- Department of Oral Microbiology; School of Dentistry; Pusan National University; Yangsan South Korea
| | - Sumi Kim
- Department of Oral Microbiology; School of Dentistry; Pusan National University; Yangsan South Korea
| | - Hyun Ah Lee
- Department of Oral Microbiology; School of Dentistry; Pusan National University; Yangsan South Korea
| | - Mi Hee Park
- Department of Oral Microbiology; School of Dentistry; Pusan National University; Yangsan South Korea
| | - Seyeon Kim
- Department of Oral Microbiology; School of Dentistry; Pusan National University; Yangsan South Korea
| | - Yu Ri Song
- Department of Oral Microbiology; School of Dentistry; Pusan National University; Yangsan South Korea
| | - Hee Sam Na
- Department of Oral Microbiology; School of Dentistry; Pusan National University; Yangsan South Korea
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Cao S, Zhang P, Zou T, Fei S, Han D, Jin J, Liu H, Yang Y, Zhu X, Xie S. Replacement of fishmeal by spirulina Arthrospira platensis affects growth, immune related-gene expression in gibel carp (Carassius auratus gibelio var. CAS III), and its challenge against Aeromonas hydrophila infection. FISH & SHELLFISH IMMUNOLOGY 2018; 79:265-273. [PMID: 29775741 DOI: 10.1016/j.fsi.2018.05.022] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 05/04/2018] [Accepted: 05/11/2018] [Indexed: 06/08/2023]
Abstract
The present study examined the effect of dietary spirulina, Arthrospira platensis on growth performance, blood physiological indices, immune-related gene expressions and resistance of juvenile gibel carp against Aeromonas hydrophila infection. Four isonitrogenous (360 g kg-1) and isolipidic (90 g kg-1) diets were formulated with containing different levels of spirulina powder of 0 g (SP0, the control diet), 3.38 g (SP3.38), 6.76 g (SP6.76) and 13.52 g (SP13.52) per 100 g diet to replace 0%, 25%, 50% and 100% of fishmeal protein, respectively. And each diet was randomly assigned to triplicate tanks (150-L capacity per each) and each tank was stocked with 22 fish (15.37 ± 0.06 g). Fish were fed one of the tested diets up to satiation twice a day for 46 days. A challenge test was carried out after the feeding trial by injecting Aeromonas hydrophila intraperitoneally for 7 days. The results showed that fish growth, feeding rate in groups SP3.38 and SP6.76 were significantly higher than those of groups SP0 and SP13.52 (P < 0.05). Feed efficiency and protein retention rate had no significant difference among all tested groups. Plasma superoxide dismutase and phagocyte activity of blood leukocytes significantly increased in the spirulina-fed fish groups at 12-h post the bacterial challenge (P < 0.05). Both pre and post challenge test, plasma lysozyme activities in spirulina-fed groups were significantly higher than that in the control group (P < 0.05). Plasma malondialdehyde got the lowest value in the SP13.52 group before and after the challenge test. The transcriptional levels of TLR2 (Toll like receptor 2), myeloid differentiation factor 88 (MyD88), Toll/IL-1 receptor domain-containing adaptor protein (TIRAP), interleukin-1β (IL-1β) and tumor necrosis factor-α1 (TNF-α1) in spleen and kidney significantly increased post the bacterial challenge compared to the pre challenge. And the relative expressions of the immune-related genes of spirulina-fed fish groups were higher than those of the control group before and after the challenge test. The 7-day cumulative survival rate after the bacterial challenge was highest in the SP3.38 group (P < 0.05). The present results indicated that low dietary inclusion of spirulina significantly enhanced the immune response of gibel carp partly through TLR2 pathway and 3.38% of dietary spirulina was recommended for the juveniles based on the growth and immune response.
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Affiliation(s)
- Shenping Cao
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei 430072, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Peiyu Zhang
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei 430072, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Tao Zou
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei 430072, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Shuzhan Fei
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei 430072, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Dong Han
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei 430072, PR China
| | - Junyan Jin
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei 430072, PR China
| | - Haokun Liu
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei 430072, PR China
| | - Yunxia Yang
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei 430072, PR China
| | - Xiaoming Zhu
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei 430072, PR China.
| | - Shouqi Xie
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei 430072, PR China
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