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Arshad M, Noor N, Iqbal Z, Jaleel H. In silico analysis of missense SNPs in TNFR1a and their possible therapeutic or pathogenic role in immune diseases. Hum Immunol 2023; 84:609-617. [PMID: 37748952 DOI: 10.1016/j.humimm.2023.09.003] [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: 05/19/2023] [Revised: 09/12/2023] [Accepted: 09/19/2023] [Indexed: 09/27/2023]
Abstract
Tumor necrosis factor alpha (TNFa) is an inflammatory cytokine that is involved in the pathogenesis of various inflammatory disorders including rheumatoid arthritis. TNF-alpha receptor I (TNFR1a) is one of the receptors TNFa binds with for its activation. Any variation in this receptor might affect the role of TNFa in successive events. Amino acid residue substitutions might happen in TNFR1a through non-synonymous single nucleotide polymorphisms (nsSNPs) which may alter the functioning of TNFa, hence, identifying any such substitutions is of paramount significance. In this study, six nsSNPs at five different evolutionary conserved regions are predicted to be detrimental to the structure and/or function of TNFR1a by using numerous computational tools. Their 3D models are also proposed in this study. Besides, they were found to reduce the stability and affect the molecular mechanisms of this protein. Two contrasting possibilities might happen because of these substitutions. One, they might reduce the production of TNFa which is overexpressed in inflammatory diseases, hence can play therapeutic role in such diseases. Second, they might possibly hinder the apoptosis to occur which can effectuate the uncontrolled division of cells, hence can be pathogenic in diseases like cancer. Further investigations on these nsSNPs using animal models and at cellular level will open doors to understand the underlying mechanisms behind various diseases.
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Affiliation(s)
- Maria Arshad
- Department of Biochemistry and Molecular Biology, University of Iceland, Reykjavik, Iceland.
| | - Nabeel Noor
- Shalamar Medical & Dental College, Lahore, Pakistan
| | - Zunair Iqbal
- Shalamar Medical & Dental College, Lahore, Pakistan
| | - Hadiqa Jaleel
- Department of Research & Innovation, Shalamar Institute of Health Sciences, Lahore, Pakistan
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2
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Panda SP, Singh V. The Dysregulated MAD in Mad: A Neuro-theranostic Approach Through the Induction of Autophagic Biomarkers LC3B-II and ATG. Mol Neurobiol 2023; 60:5214-5236. [PMID: 37273153 DOI: 10.1007/s12035-023-03402-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 05/24/2023] [Indexed: 06/06/2023]
Abstract
The word mad has historically been associated with the psyche, emotions, and abnormal behavior. Dementia is a common symptom among psychiatric disorders or mad (schizophrenia, depression, bipolar disorder) patients. Autophagy/mitophagy is a protective mechanism used by cells to get rid of dysfunctional cellular organelles or mitochondria. Autophagosome/mitophagosome abundance in autophagy depends on microtubule-associated protein light chain 3B (LC3B-II) and autophagy-triggering gene (ATG) which functions as an autophagic biomarker for phagophore production and quick mRNA disintegration. Defects in either LC3B-II or the ATG lead to dysregulated mitophagy-and-autophagy-linked dementia (MAD). The impaired MAD is closely associated with schizophrenia, depression, and bipolar disorder. The pathomechanism of psychosis is not entirely known, which is the severe limitation of today's antipsychotic drugs. However, the reviewed circuit identifies new insights that may be especially helpful in targeting biomarkers of dementia. Neuro-theranostics can also be achieved by manufacturing either bioengineered bacterial and mammalian cells or nanocarriers (liposomes, polymers, and nanogels) loaded with both imaging and therapeutic materials. The nanocarriers must cross the BBB and should release both diagnostic agents and therapeutic agents in a controlled manner to prove their effectiveness against psychiatric disorders. In this review, we highlighted the potential of microRNAs (miRs) as neuro-theranostics in the treatment of dementia by targeting autophagic biomarkers LC3B-II and ATG. Focus was also placed on the potential for neuro-theranostic nanocells/nanocarriers to traverse the BBB and induce action against psychiatric disorders. The neuro-theranostic approach can provide targeted treatment for mental disorders by creating theranostic nanocarriers.
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Affiliation(s)
- Siva Prasad Panda
- Institute of Pharmaceutical Research, GLA University, Uttar Pradesh, Mathura, India.
| | - Vikrant Singh
- Research Scholar, Institute of Pharmaceutical Research, GLA University, Uttar Pradesh, Mathura, India
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3
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Zhang W, Zhou M, Chen C, Wu S, Wang L, Xia B, Liu J, Ma X, Pan T, Zhang H, Li L, Liu B. Identification of CD98 as a Novel Biomarker for HIV-1 Permissiveness and Latent Infection. mBio 2022; 13:e0249622. [PMID: 36214569 PMCID: PMC9765422 DOI: 10.1128/mbio.02496-22] [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: 09/09/2022] [Accepted: 09/21/2022] [Indexed: 11/20/2022] Open
Abstract
Human immunodeficiency virus type 1 (HIV-1) can integrate viral DNA into host cell chromosomes to establish a long-term stable latent reservoir, which is a major obstacle to cure HIV-1 infection. The characteristics of the HIV-1 latent reservoir have not been fully understood. Here, we identified 126 upregulated plasma membrane proteins in HIV-1 latently infected cells by a label-free liquid chromatography-tandem mass spectrometry analysis. The higher levels of CD98 expression in multiple HIV-1 latently infected cell lines and primary CD4+ T cells compared to uninfected cells were further confirmed by quantitative reverse transcription PCR (RT-qPCR) and flow cytometry analyses. In addition, CD98high CD4+ T cells displayed hyper-permissiveness to HIV-1 infection and possessed distinct immune phenotypic profiles associated with Th17 and peripheral follicular T helper (pTFH) characteristics. Notably, the CD98high resting memory CD4+ T cells harbored significantly higher cell-associated viral RNA and intact provirus than CD98low counterparts in HIV-1-infected individuals receiving combined antiretroviral therapy. Furthermore, CD98high CD4+ T cells exhibited a robust proliferative capacity and significantly contributed to the clonal expansion of the HIV-1 latent reservoir. Our study demonstrates that CD98 can be used as a novel biomarker of HIV-1 latently infected cells to indicate the effect of various strategies to reduce the viral reservoir. IMPORTANCE Identification of cellular biomarkers is the crucial challenge to eradicate the HIV-1 latent reservoir. In our study, we identified CD98 as a novel plasma membrane biomarker for HIV-1 permissiveness and latent infection. Importantly, CD98high CD4+ T cells exhibited a hyper-permissiveness to HIV-1 infection and significantly contributed to the clonal expansion of the HIV-1 latent reservoir. CD98 could be targeted to develop therapeutic strategies to reduce the HIV-1 latent reservoir in further research.
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Affiliation(s)
- Wanying Zhang
- Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
- Infectious Diseases Center, Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Mo Zhou
- Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Cancan Chen
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shiyu Wu
- Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Lilin Wang
- Shenzhen Blood Center, Shenzhen, Guangdong, China
| | - Baijin Xia
- Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jun Liu
- Qianyang Biomedical Research Institute, Guangzhou, Guangdong, China
| | - Xiancai Ma
- Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Ting Pan
- Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Hui Zhang
- Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Linghua Li
- Infectious Diseases Center, Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Bingfeng Liu
- Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
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4
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Xiao Y, Li M, Guo X, Zeng H, Shuai X, Guo J, Huang Q, Chu Y, Zhou B, Wen J, Liu J, Jiao H. Inflammatory Mechanism of Brucella Infection in Placental Trophoblast Cells. Int J Mol Sci 2022; 23:13417. [PMID: 36362199 PMCID: PMC9657658 DOI: 10.3390/ijms232113417] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 10/24/2022] [Accepted: 10/27/2022] [Indexed: 01/03/2024] Open
Abstract
Brucellosis is a severe zoonotic infectious disease caused by the infection of the Brucella, which is widespread and causes considerable economic losses in underdeveloped areas. Brucella is a facultative intracellular bacteria whose main target cells for infection are macrophages, placental trophoblast cells and dendritic cells. The main clinical signs of Brucella infection in livestock are reproductive disorders and abortion. At present, the pathogenesis of placentitis or abortion caused by Brucella in livestock is not fully understood, and further research on the effect of Brucella on placental development is still necessary. This review will mainly introduce the research progress of Brucella infection of placental trophoblast cells as well as the inflammatory response caused by it, explaining the molecular regulation mechanism of Brucella leading to reproductive system disorders and abortion, and also to provide the scientific basis for revealing the pathogenesis and infection mechanism of Brucella.
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Affiliation(s)
- Yu Xiao
- The College of Veterinary Medicine, Southwest University, Chongqing 400715, China
| | - Mengjuan Li
- The College of Veterinary Medicine, Southwest University, Chongqing 400715, China
| | - Xiaoyi Guo
- The College of Veterinary Medicine, Southwest University, Chongqing 400715, China
| | - Hui Zeng
- The College of Veterinary Medicine, Southwest University, Chongqing 400715, China
| | - Xuehong Shuai
- The College of Veterinary Medicine, Southwest University, Chongqing 400715, China
| | - Jianhua Guo
- The College of Veterinary Medicine, Southwest University, Chongqing 400715, China
| | - Qingzhou Huang
- The College of Veterinary Medicine, Southwest University, Chongqing 400715, China
| | - Yuefeng Chu
- State Key Laboratory of Veterinary Etiological Biology, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China
| | - Bo Zhou
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Yujinxiang Street 573, Changchun 130102, China
| | - Jake Wen
- Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA
| | - Jun Liu
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Yujinxiang Street 573, Changchun 130102, China
| | - Hanwei Jiao
- The College of Veterinary Medicine, Southwest University, Chongqing 400715, China
- The Immunology Research Center, Medical Research Institute, Southwest University, Chongqing 400715, China
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Hyaluronic Acid-Conjugated PLGA Nanoparticles Alleviate Ulcerative Colitis via CD44-Mediated Dual Targeting to Inflamed Colitis Tissue and Macrophages. Pharmaceutics 2022; 14:pharmaceutics14102118. [PMID: 36297553 PMCID: PMC9612393 DOI: 10.3390/pharmaceutics14102118] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/01/2022] [Accepted: 10/02/2022] [Indexed: 11/06/2022] Open
Abstract
Although various local anti-inflammatory therapies for ulcerative colitis have been developed, rapid drug elimination from inflamed colitis tissue and off-target side effects reduce their therapeutic efficacy. In this study, we synthesized curcumin (Cur)-loaded hyaluronic acid (HA)-conjugated nanoparticles (Cur-HA-PLGA-NPs) that target inflamed colitis tissue via HA-CD44 interaction with resident colonic epithelial cells and subsequently target activated macrophages for ulcerative colitis therapy. The synthesized spherical Cur-HA-PLGA-NPs showed physicochemical properties similar to those of non-HA-conjugated Cur-PLGA-NPs. HA-PLGA-NPs exhibited selective accumulation in inflamed colitis tissue with minimal accumulation in healthy colon tissue. HA functionalization enhanced targeted drug delivery to intestinal macrophages, significantly increasing HA-PLGA-NP cellular uptake. Importantly, the rectal administration of Cur-HA-PLGA-NPs exhibited better therapeutic efficacy than Cur-PLGA-NPs in animal studies. Histological examination revealed that Cur-HA-PLGA-NPs reduced inflammation with less inflammatory cell infiltration and accelerated recovery with re-epithelialization signs. Our results suggest that Cur-HA-PLGA-NPs are a promising delivery platform for treating ulcerative colitis.
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6
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Dang VD, Mohr E, Szelinski F, Le TA, Ritter J, Hinnenthal T, Stefanski AL, Schrezenmeier E, Ocvirk S, Hipfl C, Hardt S, Cheng Q, Hiepe F, Löhning M, Dörner T, Lino AC. CD39 and CD326 Are Bona Fide Markers of Murine and Human Plasma Cells and Identify a Bone Marrow Specific Plasma Cell Subpopulation in Lupus. Front Immunol 2022; 13:873217. [PMID: 35464469 PMCID: PMC9024045 DOI: 10.3389/fimmu.2022.873217] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 03/15/2022] [Indexed: 12/18/2022] Open
Abstract
Antibody-secreting cells (ASCs) contribute to immunity through production of antibodies and cytokines. Identification of specific markers of ASC would allow selective targeting of these cells in several disease contexts. Here, we performed an unbiased, large-scale protein screening, and identified twelve new molecules that are specifically expressed by murine ASCs. Expression of these markers, particularly CD39, CD81, CD130, and CD326, is stable and offers an improved resolution for ASC identification. We accessed their expression in germ-free conditions and in T cell deficient mice, showing that at least in part their expression is controlled by microbial- and T cell-derived signals. Further analysis of lupus mice revealed the presence of a subpopulation of LAG-3– plasma cells, co-expressing high amounts of CD39 and CD326 in the bone marrow. This population was IgM+ and correlated with IgM anti-dsDNA autoantibodies in sera. Importantly, we found that CD39, CD81, CD130, and CD326 are also expressed by human peripheral blood and bone marrow ASCs. Our data provide innovative insights into ASC biology and function in mice and human, and identify an intriguing BM specific CD39++CD326++ ASC subpopulation in autoimmunity.
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Affiliation(s)
- Van Duc Dang
- Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Berlin, Germany
- Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
- Faculty of Biology, VNU University of Science, Vietnam National University, Hanoi, Vietnam
| | - Elodie Mohr
- Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Berlin, Germany
| | - Franziska Szelinski
- Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Berlin, Germany
- Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Tuan Anh Le
- Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Berlin, Germany
- Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Jacob Ritter
- Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH), Berlin, Germany
| | - Timo Hinnenthal
- Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Berlin, Germany
| | - Ana-Luisa Stefanski
- Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Eva Schrezenmeier
- Berlin Institute of Health (BIH), Berlin, Germany
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Soeren Ocvirk
- Intestinal Microbiology Research Group, Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Christian Hipfl
- Centre for Musculoskeletal Surgery, Department of Orthopedics, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Sebastian Hardt
- Centre for Musculoskeletal Surgery, Department of Orthopedics, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Qingyu Cheng
- Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Berlin, Germany
- Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Falk Hiepe
- Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Berlin, Germany
- Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Max Löhning
- Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Berlin, Germany
- Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Thomas Dörner
- Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Berlin, Germany
- Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Andreia C. Lino
- Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Berlin, Germany
- Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
- *Correspondence: Andreia C. Lino,
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Lee Y, Kamada N, Moon JJ. Oral nanomedicine for modulating immunity, intestinal barrier functions, and gut microbiome. Adv Drug Deliv Rev 2021; 179:114021. [PMID: 34710529 PMCID: PMC8665886 DOI: 10.1016/j.addr.2021.114021] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 10/17/2021] [Accepted: 10/20/2021] [Indexed: 12/12/2022]
Abstract
The gastrointestinal tract (GIT) affects not only local diseases in the GIT but also various systemic diseases. Factors that can affect the health and disease of both GIT and the human body include 1) the mucosal immune system composed of the gut-associated lymphoid tissues and the lamina propria, 2) the intestinal barrier composed of mucus and intestinal epithelium, and 3) the gut microbiota. Selective delivery of drugs, including antigens, immune-modulators, intestinal barrier enhancers, and gut-microbiome manipulators, has shown promising results for oral vaccines, immune tolerance, treatment of inflammatory bowel diseases, and other systemic diseases, including cancer. However, physicochemical and biological barriers of the GIT present significant challenges for successful translation. With the advances of novel nanomaterials, oral nanomedicine has emerged as an attractive option to not only overcome these barriers but also to selectively deliver drugs to the target sites in GIT. In this review, we discuss the GIT factors and physicochemical and biological barriers in the GIT. Furthermore, we present the recent progress of oral nanomedicine for oral vaccines, immune tolerance, and anti-inflammation therapies. We also discuss recent advances in oral nanomedicine designed to fortify the intestinal barrier functions and modulate the gut microbiota and microbial metabolites. Finally, we opine about the future directions of oral nano-immunotherapy.
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Affiliation(s)
- Yonghyun Lee
- Department of Pharmacy, College of Pharmacy, Ewha Womans University, Seoul 03760, South Korea; Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, South Korea.
| | - Nobuhiko Kamada
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, USA
| | - James J Moon
- Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109 USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109 USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109 USA.
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Liu P, Gao C, Chen H, Vong CT, Wu X, Tang X, Wang S, Wang Y. Receptor-mediated targeted drug delivery systems for treatment of inflammatory bowel disease: Opportunities and emerging strategies. Acta Pharm Sin B 2021; 11:2798-2818. [PMID: 34589398 PMCID: PMC8463263 DOI: 10.1016/j.apsb.2020.11.003] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 10/01/2020] [Accepted: 10/14/2020] [Indexed: 02/08/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic intestinal disease with painful clinical manifestations and high risks of cancerization. With no curative therapy for IBD at present, the development of effective therapeutics is highly advocated. Drug delivery systems have been extensively studied to transmit therapeutics to inflamed colon sites through the enhanced permeability and retention (EPR) effect caused by the inflammation. However, the drug still could not achieve effective concentration value that merely utilized on EPR effect and display better therapeutic efficacy in the inflamed region because of nontargeted drug release. Substantial researches have shown that some specific receptors and cell adhesion molecules highly expresses on the surface of colonic endothelial and/or immune cells when IBD occurs, ligand-modified drug delivery systems targeting such receptors and cell adhesion molecules can specifically deliver drug into inflamed sites and obtain great curative effects. This review introduces the overexpressed receptors and cell adhesion molecules in inflamed colon sites and retrospects the drug delivery systems functionalized by related ligands. Finally, challenges and future directions in this field are presented to advance the development of the receptor-mediated targeted drug delivery systems for the therapy of IBD.
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Key Words
- ACQ, aggregation-caused quenching
- ADR, adverse drug reaction
- AIE, aggregation-induced emission
- Active target
- BSA, bovine serum albumin
- CAM, cell adhesion molecule
- CD, Crohn's disease
- CRD, cysteine-rich domain
- CS, chondroitin sulfate
- CT, computed tomography
- CTLD, c-type lectin-like domain
- Cell adhesion molecule
- Crohn's disease
- DCs, dendritic cells
- DSS, dextran sulfate sodium salt
- Drug delivery
- EGF, epidermal growth factor
- EPR, enhanced permeability and retention
- FNII, fibronectin type II domain
- FR, folate receptor
- FRET, fluorescence resonance energy transfer
- GIT, gastrointestinal tract
- HA, hyaluronic acid
- HUVEC, human umbilical vein endothelial cells
- IBD, inflammatory bowel disease
- ICAM, intercellular adhesion molecule
- Inflammatory bowel disease
- LMWC, low molecular weight chitosan
- LPS, lipopolysaccharide
- MAP4K4, mitogen-activated protein kinase kinase kinase kinase 4
- MGL, macrophage galactose lectin
- MPO, myeloperoxidase
- MPS, mononuclear phagocyte system
- MR, mannose receptor
- MRI, magnetic resonance imaging
- PAMAM, poly(amidoamine)
- PEI, polyethylenimine
- PSGL-1, P-selectin glycoprotein ligand-1
- PepT1, peptide transporter 1
- QDs, quantum dots
- RES, reticuloendothelial system
- Receptor-mediated target
- Targeted therapy
- TfR, transferrin receptor
- UC, ulcerative colitis
- Ulcerative colitis
- VCAM, vascular cell adhesion molecule
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Kovač Peić A, Šrajer Gajdošik M, Brilliant K, Callanan H, Hixson DC, Begić M, Josić D. Changes in the proteome of extracellular vesicles shed by rat liver after subtoxic exposure to acetaminophen. Electrophoresis 2021; 42:1388-1398. [PMID: 33837589 DOI: 10.1002/elps.202100020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 03/18/2021] [Accepted: 03/20/2021] [Indexed: 01/16/2023]
Abstract
To identify changes in extracellular vesicles (EVs) secreted by the liver following drug-induced liver injury (DILI), rats were treated with a subtoxic dose (500 mg/kg) of the analgesic drug, acetaminophen (APAP). EVs were collected by liver perfusion of sham and APAP-treated rats. Changes in EVs morphology were examined by transmission electron microscopic analysis of negatively stained vesicles. Results from morphometric analysis of EVs revealed striking differences in their size and distribution. Proteome composition of EVs collected by liver perfusion was determined by mass spectrometry using methods of sample preparation that enabled better detection of both highly hydrophobic proteins and proteins with complex post-translational modifications. The collection of EVs after liver perfusion is an approach that enables the isolation of EVs shed not only by isolated hepatocytes, but also by the entire complement of hepatic cells. EVs derived after DILI had a lower content of alpha-1-macroglobulin, ferritin, and members of cytochrome 450 family. Fibronectin, aminopeptidase N, metalloreductase STEAP4, integrin beta, and members of the annexin family were detected only in APAP-treated samples of EVs. These results show that the present approach can provide valuable insights into the response of the liver following drug-induced liver injury.
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Affiliation(s)
| | | | - Kate Brilliant
- Proteomics Core, COBRE CCRD, Rhode Island Hospital, Providence, RI, USA
| | - Helen Callanan
- Proteomics Core, COBRE CCRD, Rhode Island Hospital, Providence, RI, USA
| | - Douglas C Hixson
- Proteomics Core, COBRE CCRD, Rhode Island Hospital, Providence, RI, USA.,Warren Alpert Medical School, Brown University, Providence, RI, USA
| | - Marija Begić
- Faculty of Medicine, Juraj Dobrila University of Pula, Pula, Croatia
| | - Djuro Josić
- Proteomics Core, COBRE CCRD, Rhode Island Hospital, Providence, RI, USA.,Warren Alpert Medical School, Brown University, Providence, RI, USA
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10
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Charmsaz S, Gross N, Jaffee E, Ho WJ. A global live cell barcoding approach for multiplexed mass cytometry profiling of mouse tumors. JCI Insight 2021; 6:143283. [PMID: 33690223 PMCID: PMC8119183 DOI: 10.1172/jci.insight.143283] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 02/25/2021] [Indexed: 12/12/2022] Open
Abstract
With the advent of cancer immunology, mass cytometry has been increasingly employed to characterize the responses to cancer therapies and the tumor microenvironment (TME). One of its most notable applications is efficient multiplexing of samples into batches by dedicating a number of metal isotope channels to barcodes, enabling robust data acquisition and analysis. Barcoding is most effective when markers are present in all cells of interest. While CD45 has been shown to be a reliable marker for barcoding all immune cells in a given sample, a strategy to reliably barcode mouse cancer cells has not been demonstrated. To this end, we identified CD29 and CD98 as markers widely expressed by commonly used mouse cancer cell lines. We conjugated anti-CD29 and anti-CD98 antibodies to cadmium or indium metals and validated their utility in 10-plex barcoding of live cells. Finally, we established a potentially novel barcoding system incorporating the combination of CD29, CD98, and CD45 to multiplex 10 tumors from s.c. MC38 and KPC tumor models, while successfully recapitulating the known contrast in the PD1-PDL1 axis between the 2 models. The ability to barcode tumor cells along with immune cells empowers the interrogation of the tumor-immune interactions in mouse TME studies.
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Zhang Y, Thanou M, Vllasaliu D. Exploiting disease-induced changes for targeted oral delivery of biologics and nanomedicines in inflammatory bowel disease. Eur J Pharm Biopharm 2020; 155:128-138. [PMID: 32853696 DOI: 10.1016/j.ejpb.2020.08.017] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 07/21/2020] [Accepted: 08/18/2020] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic and progressive disorder with destructive inflammation in the gastrointestinal tract (GIT). Biologics have changed the management of IBD, but have serious limitations, which is associated with their systemic administration via injection. Oral administration is the most accepted route of drug administration. However, the physiological barriers of the GIT pose significant challenges for oral administration of biologics, making this route of administration currently unavailable. The status of tissue barriers to oral drug delivery is altered in IBD. This may bring more challenges, but also present opportunities for oral delivery of biologics. This article provides an overview of disease-induced alterations of GIT barriers in IBD and discusses challenges, opportunities and commonly-utilised strategies for oral delivery of complex therapeutics, including biologics and nanomedicines.
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Affiliation(s)
- Yunyue Zhang
- Institute of Pharmaceutical Science, School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, London SE1 9NH, United Kingdom.
| | - Maya Thanou
- Institute of Pharmaceutical Science, School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, London SE1 9NH, United Kingdom.
| | - Driton Vllasaliu
- Institute of Pharmaceutical Science, School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, London SE1 9NH, United Kingdom.
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12
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Bertoni S, Machness A, Tiboni M, Bártolo R, Santos HA. Reactive oxygen species responsive nanoplatforms as smart drug delivery systems for gastrointestinal tract targeting. Biopolymers 2019; 111:e23336. [PMID: 31724750 DOI: 10.1002/bip.23336] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 10/07/2019] [Accepted: 10/08/2019] [Indexed: 12/13/2022]
Abstract
The pharmacological therapy for gastrointestinal (GI) diseases, such as inflammatory bowel diseases, continues to present challenges in targeting efficacy. The need for maximal local drug exposure at the inflamed regions of the GI tract has led research to focus on a disease-targeted drug delivery approach. Smart nanomaterials responsive to the reactive oxygen species (ROS) concentrated in the inflamed areas, can be formulated into nanoplatforms to selectively release the active compounds, avoiding unspecific drug delivery to healthy tissues and limiting systemic absorption. Recent developments of ROS-responsive nanoplatforms include combination with other materials to obtain multi-responsive systems and modifications/derivatization to increase the interactions with biological tissues, cell uptake and targeting. This review describes the applications of ROS-responsive nanosystems for on-demand drug delivery to the GI tract.
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Affiliation(s)
- Serena Bertoni
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.,Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Ariella Machness
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.,Department of Materials Science and Engineering, University of California Los Angeles, Los Angeles, California, USA
| | - Mattia Tiboni
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.,Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy
| | - Raquel Bártolo
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Hélder A Santos
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.,Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
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13
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García-Méndez KB, Hielpos SM, Soler-Llorens PF, Arce-Gorvel V, Hale C, Gorvel JP, O'Callaghan D, Keriel A. Infection by Brucella melitensis or Brucella papionis modifies essential physiological functions of human trophoblasts. Cell Microbiol 2019; 21:e13019. [PMID: 30817085 DOI: 10.1111/cmi.13019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 02/14/2019] [Accepted: 02/15/2019] [Indexed: 12/01/2022]
Abstract
Brucellosis is a zoonosis caused by bacteria of the Brucella genus. In ruminants, brucellosis causes abortion, followed by chronic infection and secretion of bacteria in milk. In humans, it usually presents as flu-like symptoms, with serious complications if untreated. Epidemiological studies have only recently established that brucellosis can also cause pregnancy complications in women, but the pathogenic mechanisms are unknown. Pioneering studies in ruminants showed that Brucella infect trophoblasts and then colonise the placenta where they grow to high density. A recent study showed that the main zoonotic Brucella species can infect human cytotrophoblasts (CTB) and extravillous trophoblasts (EVT). In this work, we show that Brucella papionis (associated with stillbirth in primates) also infects human trophoblasts. However, it replicates actively in CTB, whereas its replication is very restricted within EVT. We also observed alteration of several trophoblastic functions upon infection by B. papionis or Brucella melitensis (the most prevalent species in human brucellosis). Infection altered the production of hormones, the ability of CTB to form syncytiotrophoblasts, and the invasion capacity of EVT. We also found that infection can spread between different types of trophoblasts. These findings constitute a new step in understanding how Brucella infection causes adverse pregnancy outcomes.
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Affiliation(s)
- Karellen B García-Méndez
- VBMI, INSERM, Université de Montpellier, Nîmes, France.,Centre National de Référence des Brucella, CHU de Nîmes, Nîmes, France
| | - Soledad M Hielpos
- VBMI, INSERM, Université de Montpellier, Nîmes, France.,Centre National de Référence des Brucella, CHU de Nîmes, Nîmes, France
| | | | | | - Christine Hale
- Microbial Pathogenesis, Wellcome Trust Sanger Institute, Hinxton, UK
| | | | - David O'Callaghan
- VBMI, INSERM, Université de Montpellier, Nîmes, France.,Centre National de Référence des Brucella, CHU de Nîmes, Nîmes, France
| | - Anne Keriel
- VBMI, INSERM, Université de Montpellier, Nîmes, France.,Centre National de Référence des Brucella, CHU de Nîmes, Nîmes, France
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14
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Peñaranda MMD, Jensen I, Tollersrud LG, Bruun JA, Jørgensen JB. Profiling the Atlantic Salmon IgM + B Cell Surface Proteome: Novel Information on Teleost Fish B Cell Protein Repertoire and Identification of Potential B Cell Markers. Front Immunol 2019; 10:37. [PMID: 30761128 PMCID: PMC6362898 DOI: 10.3389/fimmu.2019.00037] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 01/08/2019] [Indexed: 01/04/2023] Open
Abstract
Fish immunology research is at a pivotal point with the increasing availability of functional immunoassays and major advances in omics approaches. However, studies on fish B cells and their distinct subsets remain a challenge due to the limited availability of differentially expressed surface markers. To address this constraint, cell surface proteome of Atlantic salmon IgM+ B cells were analyzed by mass spectrometry and compared to surface proteins detected from two adherent salmon head kidney cell lines, ASK and SSP-9. Out of 21 cluster of differentiation (CD) molecules identified on salmon IgM+ B cells, CD22 and CD79A were shortlisted as potential markers based on the reported B cell-specific surface expression of their mammalian homologs. Subsequent RT-qPCR analyses of flow cytometry-sorted subpopulations from head kidney leukocytes confirmed that both cd22 and cd79a genes were highly expressed in IgM+ lymphoid cells but were observed in barely detectable levels in IgM- non-lymphoid suspension and adherent cells. Similarly, significantly high cd22 and cd79a mRNA levels were observed in IgM+ or IgT+ lymphoid cells from the spleen and peritoneal cavity, but not in their corresponding IgM- IgT- non-lymphoid fractions. This suggests that the B cell restrictive expression of CD22 and CD79A extend down to the transcription level, which was consistent across different lymphoid compartments and immunoglobulin isotypes, thus strongly supporting the potential of CD22 and CD79A as pan-B cell markers for salmon. In addition, this study provides novel information on the salmon B cell surface protein repertoire, as well as insights on B cell evolution. Further investigation of the identified salmon CD molecules, including development of immunological tools for detection, will help advance our understanding of the dynamics of salmon B cell responses such as during infection, vaccination, or immunostimulation.
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Affiliation(s)
- Ma Michelle D Peñaranda
- The Norwegian College of Fishery Science, Faculty of Biosciences, Fisheries and Economics, UiT The Arctic University of Norway, Tromsø, Norway
| | - Ingvill Jensen
- The Norwegian College of Fishery Science, Faculty of Biosciences, Fisheries and Economics, UiT The Arctic University of Norway, Tromsø, Norway
| | - Linn G Tollersrud
- The Norwegian College of Fishery Science, Faculty of Biosciences, Fisheries and Economics, UiT The Arctic University of Norway, Tromsø, Norway
| | - Jack-Ansgar Bruun
- Tromsø University Proteomics Platform, Institute of Medical Biology, UiT The Arctic University of Norway, Tromsø, Norway
| | - Jorunn B Jørgensen
- The Norwegian College of Fishery Science, Faculty of Biosciences, Fisheries and Economics, UiT The Arctic University of Norway, Tromsø, Norway
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15
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Salzberger W, Martrus G, Bachmann K, Goebels H, Heß L, Koch M, Langeneckert A, Lunemann S, Oldhafer KJ, Pfeifer C, Poch T, Richert L, Schramm C, Wahib R, Bunders MJ, Altfeld M. Tissue-resident NK cells differ in their expression profile of the nutrient transporters Glut1, CD98 and CD71. PLoS One 2018; 13:e0201170. [PMID: 30028872 PMCID: PMC6054388 DOI: 10.1371/journal.pone.0201170] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 07/10/2018] [Indexed: 12/20/2022] Open
Abstract
Metabolism is a critical basis for immune cell functionality. It was recently shown that NK cell subsets from peripheral blood modulate their expression of nutrient receptors following cytokine stimulation, demonstrating that NK cells can adjust to changes in metabolic requirements. As nutrient availability in blood and tissues can significantly differ, we examined NK cells isolated from paired blood-liver and blood-spleen samples and compared expression of the nutrient transporters Glut1, CD98 and CD71. CD56bright tissue-resident (CXCR6+) NK cells derived from livers and spleens expressed lower levels of Glut1 but higher levels of the amino acid transporter CD98 following stimulation than CD56bright NK cells from peripheral blood. In line with that, CD56dim NK cells, which constitute the main NK cell population in the peripheral blood, expressed higher levels of Glut1 and lower levels of CD98 and CD71 compared to liver CD56bright NK cells. Our results show that NK cells from peripheral blood differ from liver- and spleen-resident NK cells in the expression profile of nutrient transporters, consistent with a cell-adaptation to the different nutritional environment in these compartments.
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Affiliation(s)
- Wilhelm Salzberger
- Department of Viral Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Gloria Martrus
- Department of Viral Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Kai Bachmann
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg, Hamburg, Germany
| | - Hanna Goebels
- Department of Viral Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Leonard Heß
- Department of Viral Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Martina Koch
- Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg, Hamburg, Germany
| | - Annika Langeneckert
- Department of Viral Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Sebastian Lunemann
- Department of Viral Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Karl J. Oldhafer
- Department of General & Abdominal Surgery, Asklepios Hospital Barmbek, Semmelweis University of Medicine, Hamburg, Germany
| | - Caroline Pfeifer
- Department of Viral Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Tobias Poch
- First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Laura Richert
- INSERM U1219, INRIA SISTM, Bordeaux University, Bordeaux, France
| | - Christoph Schramm
- First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Martin Zeitz Centre for Rare Diseases, University Medical Center Hamburg, Hamburg, Germany
| | - Ramez Wahib
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg, Hamburg, Germany
| | - Madeleine J. Bunders
- Department of Viral Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Marcus Altfeld
- Department of Viral Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
- * E-mail:
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16
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Xiao B, Viennois E, Chen Q, Wang L, Han MK, Zhang Y, Zhang Z, Kang Y, Wan Y, Merlin D. Silencing of Intestinal Glycoprotein CD98 by Orally Targeted Nanoparticles Enhances Chemosensitization of Colon Cancer. ACS NANO 2018; 12:5253-5265. [PMID: 29860836 DOI: 10.1021/acsnano.7b08499] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Colon cancer is among the most widely occurring cancer types, leading to considerably high mortality rate. The current chemotherapy achieves only limited success, and more effective therapeutic strategies are urgently needed. Human colonic biopsy specimens indicate increased expression of CD98 in patients with colon cancer, suggesting that CD98 might be a potential therapeutic target and/or a receptor for targeted drug delivery in colon cancer treatment. Herein, we coloaded CD98 siRNA (siCD98) and camptothecin (CPT) into CD98 Fab'-functionalized nanoparticles (NPs). The resultant Fab'-siCD98/CPT-NPs showed good monodispersity with an average diameter of approximately 270 nm and a ζ-potential of around -24 mV. These NPs mediated efficient drug delivery to the target cancer cells and tumor tissues, producing much better anticancer and antimigration effects compared to other relevant NPs. Mouse models with orthotopic colon tumors were treated with NP-embedded hydrogel, which revealed that Fab'-siCD98/CPT-NPs exhibited a therapeutic efficacy significantly better than that of single drug-loaded NPs or nonfunctionalized siCD98/CPT-NPs. This study indicates that the Fab'-siCD98/CPT-NP/hydrogel system is able to realize specific release of NPs in the colonic lumen and enable drugs (siCD98 and CPT) to be internalized into target cells, demonstrating a notable potential for clinical applications in colon-cancer-targeted combination therapy.
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Affiliation(s)
- Bo Xiao
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Digestive Disease Research Group , Georgia State University , Atlanta , Georgia 30302 , United States
| | - Emilie Viennois
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Digestive Disease Research Group , Georgia State University , Atlanta , Georgia 30302 , United States
| | | | - Lixin Wang
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Digestive Disease Research Group , Georgia State University , Atlanta , Georgia 30302 , United States
- Atlanta Veterans Affairs Medical Center , Decatur , Georgia 30033 , United States
| | - Moon Kwon Han
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Digestive Disease Research Group , Georgia State University , Atlanta , Georgia 30302 , United States
| | - Yuchen Zhang
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Digestive Disease Research Group , Georgia State University , Atlanta , Georgia 30302 , United States
| | - Zhan Zhang
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Digestive Disease Research Group , Georgia State University , Atlanta , Georgia 30302 , United States
| | | | - Ying Wan
- College of Life Science and Technology , Huazhong University of Science and Technology , Wuhan , Hubei 430074 , P.R. China
| | - Didier Merlin
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Digestive Disease Research Group , Georgia State University , Atlanta , Georgia 30302 , United States
- Atlanta Veterans Affairs Medical Center , Decatur , Georgia 30033 , United States
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17
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Morel JD, Paatero AO, Wei J, Yewdell JW, Guenin-Macé L, Van Haver D, Impens F, Pietrosemoli N, Paavilainen VO, Demangel C. Proteomics Reveals Scope of Mycolactone-mediated Sec61 Blockade and Distinctive Stress Signature. Mol Cell Proteomics 2018; 17:1750-1765. [PMID: 29915147 DOI: 10.1074/mcp.ra118.000824] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Revised: 06/17/2018] [Indexed: 11/06/2022] Open
Abstract
Mycolactone is a bacteria-derived macrolide that blocks the biogenesis of a large array of secretory and integral transmembrane proteins (TMP) through potent inhibition of the Sec61 translocon. Here, we used quantitative proteomics to delineate the direct and indirect effects of mycolactone-mediated Sec61 blockade in living cells. In T lymphocytes, dendritic cells and sensory neurons, Sec61 substrates downregulated by mycolactone were in order of incidence: secretory proteins (with a signal peptide but no transmembrane domain), TMPs with a signal peptide (Type I) and TMPs without signal peptide and a cytosolic N terminus (Type II). TMPs without a signal peptide and the opposite N terminus topology (Type III) were refractory to mycolactone inhibition. This rule applied comparably to single- and multi-pass TMPs, and extended to exogenous viral proteins. Parallel to its broad-spectrum inhibition of Sec61-mediated protein translocation, mycolactone rapidly induced cytosolic chaperones Hsp70/Hsp90. Moreover, it activated an atypical endoplasmic reticulum stress response, differing from conventional unfolded protein response by the down-regulation of Bip. In addition to refining our mechanistic understanding of Sec61 inhibition by mycolactone, our findings thus reveal that Sec61 blockade induces proteostatic stress in the cytosol and the endoplasmic reticulum.
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Affiliation(s)
- Jean-David Morel
- From the ‡Immunobiology of Infection Unit, Institut Pasteur, 75015 Paris, France.,§INSERM, U1221, 75005 Paris, France
| | - Anja O Paatero
- ¶Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland
| | - Jiajie Wei
- ‖Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892
| | - Jonathan W Yewdell
- ‖Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892
| | - Laure Guenin-Macé
- From the ‡Immunobiology of Infection Unit, Institut Pasteur, 75015 Paris, France.,§INSERM, U1221, 75005 Paris, France
| | - Delphi Van Haver
- **VIB-UGent Center for Medical Biotechnology, 9000 Ghent, Belgium.,‡‡VIB Proteomics Core, 9000 Ghent, Belgium.,§§Department of Biochemistry, Ghent University, 9000 Ghent, Belgium
| | - Francis Impens
- **VIB-UGent Center for Medical Biotechnology, 9000 Ghent, Belgium.,‡‡VIB Proteomics Core, 9000 Ghent, Belgium.,§§Department of Biochemistry, Ghent University, 9000 Ghent, Belgium
| | - Natalia Pietrosemoli
- ¶¶Bioinformatics and Biostatistics Hub, Center of Bioinformatics, Biostatistics, and Integrative Biology, Institut Pasteur, Unité de Service et de Recherche 3756 Institut Pasteur CNRS, 75015 Paris, France
| | - Ville O Paavilainen
- ¶Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland
| | - Caroline Demangel
- From the ‡Immunobiology of Infection Unit, Institut Pasteur, 75015 Paris, France; .,§INSERM, U1221, 75005 Paris, France
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18
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Ghodrati F, Mehrabian M, Williams D, Halgas O, Bourkas MEC, Watts JC, Pai EF, Schmitt-Ulms G. The prion protein is embedded in a molecular environment that modulates transforming growth factor β and integrin signaling. Sci Rep 2018; 8:8654. [PMID: 29872131 PMCID: PMC5988664 DOI: 10.1038/s41598-018-26685-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 05/14/2018] [Indexed: 01/06/2023] Open
Abstract
At times, it can be difficult to discern if a lack of overlap in reported interactions for a protein-of-interest reflects differences in methodology or biology. In such instances, systematic analyses of protein-protein networks across diverse paradigms can provide valuable insights. Here, we interrogated the interactome of the prion protein (PrP), best known for its central role in prion diseases, in four mouse cell lines. Analyses made use of identical affinity capture and sample processing workflows. Negative controls were generated from PrP knockout lines of the respective cell models, and the relative levels of peptides were quantified using isobaric labels. The study uncovered 26 proteins that reside in proximity to PrP. All of these proteins are predicted to have access to the outer face of the plasma membrane, and approximately half of them were not reported to interact with PrP before. Strikingly, although several proteins exhibited profound co-enrichment with PrP in a given model, except for the neural cell adhesion molecule 1, no protein was highly enriched in all PrP-specific interactomes. However, Gene Ontology analyses revealed a shared association of the majority of PrP candidate interactors with cellular events at the intersection of transforming growth factor β and integrin signaling.
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Affiliation(s)
- Farinaz Ghodrati
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Centre, 6th Floor, 60 Leonard Avenue, Toronto, Ontario, M5T 0S8, Canada.,Department of Laboratory Medicine & Pathobiology, University of Toronto, Medical Sciences Building, 6th Floor, 1 King's College Circle, Toronto, Ontario, M5S 1A8, Canada
| | - Mohadeseh Mehrabian
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Centre, 6th Floor, 60 Leonard Avenue, Toronto, Ontario, M5T 0S8, Canada.,Department of Laboratory Medicine & Pathobiology, University of Toronto, Medical Sciences Building, 6th Floor, 1 King's College Circle, Toronto, Ontario, M5S 1A8, Canada
| | - Declan Williams
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Centre, 6th Floor, 60 Leonard Avenue, Toronto, Ontario, M5T 0S8, Canada
| | - Ondrej Halgas
- Department of Biochemistry, University of Toronto, Medical Sciences Building, 5th Floor, 1 King's College Circle, Toronto, Ontario, M5S 1A8, Canada
| | - Matthew E C Bourkas
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Centre, 6th Floor, 60 Leonard Avenue, Toronto, Ontario, M5T 0S8, Canada.,Department of Biochemistry, University of Toronto, Medical Sciences Building, 5th Floor, 1 King's College Circle, Toronto, Ontario, M5S 1A8, Canada
| | - Joel C Watts
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Centre, 6th Floor, 60 Leonard Avenue, Toronto, Ontario, M5T 0S8, Canada.,Department of Biochemistry, University of Toronto, Medical Sciences Building, 5th Floor, 1 King's College Circle, Toronto, Ontario, M5S 1A8, Canada
| | - Emil F Pai
- Department of Biochemistry, University of Toronto, Medical Sciences Building, 5th Floor, 1 King's College Circle, Toronto, Ontario, M5S 1A8, Canada.,Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, 101 College Street, Toronto, Ontario, M5G 1L7, Canada
| | - Gerold Schmitt-Ulms
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Centre, 6th Floor, 60 Leonard Avenue, Toronto, Ontario, M5T 0S8, Canada. .,Department of Laboratory Medicine & Pathobiology, University of Toronto, Medical Sciences Building, 6th Floor, 1 King's College Circle, Toronto, Ontario, M5S 1A8, Canada.
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19
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Canup BSB, Song H, Le Ngo V, Meng X, Denning TL, Garg P, Laroui H. CD98 siRNA-loaded nanoparticles decrease hepatic steatosis in mice. Dig Liver Dis 2017; 49:188-196. [PMID: 27939923 PMCID: PMC6475075 DOI: 10.1016/j.dld.2016.11.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 11/07/2016] [Accepted: 11/08/2016] [Indexed: 12/11/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid hepatic accumulation. Here, we investigated whether a reduction of CD98 expression mediated by CD98 siRNA-loaded nanoparticles (NPs) could attenuate liver disease markers in a mouse model of NAFLD. NPs were generated using a double emulsion/solvent evaporation technique. Mice fed a high fat diet for 8 weeks to induce fatty liver were treated with vein tail injections of CD98 siRNA-loaded NPs. In vitro, HepG2 treated with CD98 siRNA-loaded NPs showed significant downregulation of CD98 leading to a significant decrease of major pro-inflammatory cytokines and markers. In vivo, CD98 siRNA-loaded NPs strongly decreased all markers of NAFLD, including the blood levels of ALT and lipids accumulation, fibrosis evidence and pro-inflammatory cytokines. In conclusion, our results indicate that CD98 appears to function as a key actor/inducer in NAFLD, and that our NPs approach may offer a new targeted therapeutic for this disease.
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Affiliation(s)
- Brandon S B Canup
- Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA
| | - Heliang Song
- Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA
| | - Vu Le Ngo
- Department of Biology, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA
| | - Xiangxiao Meng
- Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA
| | - Timothy L Denning
- Department of Biology, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA
| | - Pallavi Garg
- Department of Biology, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA
| | - Hamed Laroui
- Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA; Department of Biology, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA.
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20
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Jia GZ, Zhai YL, Zhou S, Zhang B, Wu T, He XL, Qiao Q. Role of CD98 in invasion and metastasis of hepatocellular carcinoma cells. Shijie Huaren Xiaohua Zazhi 2016; 24:4788-4793. [DOI: 10.11569/wcjd.v24.i36.4788] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To knock down CD98 expression in human hepatocellular carcinoma (HCC) cells by RNA interference (RNAi) to explore the role of CD98 in HCC progression.
METHODS Down-regulation of CD98 expression in human HCC cell line (FHCC-98) was performed by RNAi and verified by Western blot analysis. The role of CD98 in the invasion and metastasis of FHCC-98 cells was investigated using cell adhesion assay, transwell invasion assay, and monolayer wound healing assay.
RESULTS After transient transfection with siRNA targeting CD98 for 48 h, the protein expression of CD98 in human HCC cells was significantly knocked down. Moreover, the numbers of attached cells and invaded cells, and wound closure rate were significantly decreased compared to cells transfected with the negative control siRNA.
CONCLUSION CD98 may promote tumor invasion and metastasis in HCC via enhancement of the abilities of tumor cells to adhere, invade and migrate. CD98 may be a novel therapeutic target for the treatment of HCC.
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21
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Zhang W, Pan Q, Serianni AS. A chemical synthesis of a multiply 13 C-labeled hexasaccharide: a high-mannose N-glycan fragment. J Labelled Comp Radiopharm 2016; 59:673-679. [PMID: 27387600 PMCID: PMC5177528 DOI: 10.1002/jlcr.3418] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 05/09/2016] [Accepted: 05/23/2016] [Indexed: 12/29/2022]
Abstract
As covalent modifiers of proteins, high-mannose N-glycans are important in maintaining protein structure and function in vivo. The conformations of these glycans can be studied by nuclear magnetic resonance spectroscopy using spin-spin couplings (J-couplings; scalar couplings) and other nuclear magnetic resonance parameters that are sensitive to the geometries of their constituent glycosidic linkages and other mobile elements in their structures. These analyses often require 13 C-labeling at specific carbon atoms, especially when measurements of 13 C-13 C J-couplings are of interest. The selection of particular 13 C isotopomers of a glycan depends on the type of question under scrutiny. A chemical synthesis of a mannose-containing hexasaccharide, α[1-13 C]Man(1→2)α[1,2-13 C2 ]Man(1→6)[α[1-13 C]Man(1→2)α[1,2-13 C2 ]Man(1→3)]α[1,2-13 C2 ]Man(1→6)βManOCH3 , which is a nested fragment of the high-mannose N-glycans of human glycoproteins and contains eight 13 C-enriched carbon sites, is described in this report. The selected 13 C isotopomer was chosen to maximize the measurement of J-couplings sensitive to linkage conformations. This work demonstrates that chemical syntheses of multiply 13 C-labeled oligosaccharides are technically feasible and practical using present synthetic methods. The availability of this and other multiply 13 C-labeled mannose-containing oligosaccharides will promote future studies of their conformations in solution and in the bound state.
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Affiliation(s)
- Wenhui Zhang
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556-5670 USA
| | - Qingfeng Pan
- Omicron Biochemicals, Inc., South Bend, IN 46617-2701 USA
| | - Anthony S. Serianni
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556-5670 USA
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CD98 signals controlling tumorigenesis. Int J Biochem Cell Biol 2016; 81:148-150. [PMID: 27840151 DOI: 10.1016/j.biocel.2016.11.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 11/07/2016] [Accepted: 11/09/2016] [Indexed: 11/23/2022]
Abstract
CD98 is implicated in a large number of cancers. CD98 regulates amino acid transport and integrin signaling, which are key drivers in tumor progression. The light chain in the CD98 heterodimer functions as an amino acid exchanger. Alongside the light chain, the heavy chain forms a heterocomplex at the plasma membrane to mediate signaling pathways. In this article, we review various approaches to blocking CD98 activity, which may lead to novel opportunities in cancer therapeutics.
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The novel c-Met inhibitor capmatinib mitigates diethylnitrosamine acute liver injury in mice. Toxicol Lett 2016; 261:13-25. [DOI: 10.1016/j.toxlet.2016.08.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Revised: 08/16/2016] [Accepted: 08/19/2016] [Indexed: 01/27/2023]
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Zhang Q, Tao H, Lin Y, Hu Y, An H, Zhang D, Feng S, Hu H, Wang R, Li X, Zhang J. A superoxide dismutase/catalase mimetic nanomedicine for targeted therapy of inflammatory bowel disease. Biomaterials 2016; 105:206-221. [DOI: 10.1016/j.biomaterials.2016.08.010] [Citation(s) in RCA: 112] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Revised: 08/02/2016] [Accepted: 08/05/2016] [Indexed: 12/19/2022]
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Xiao B, Zhang Z, Viennois E, Kang Y, Zhang M, Han MK, Chen J, Merlin D. Combination Therapy for Ulcerative Colitis: Orally Targeted Nanoparticles Prevent Mucosal Damage and Relieve Inflammation. Am J Cancer Res 2016; 6:2250-2266. [PMID: 27924161 PMCID: PMC5135446 DOI: 10.7150/thno.15710] [Citation(s) in RCA: 164] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 08/12/2016] [Indexed: 02/06/2023] Open
Abstract
Combination therapy is an emerging strategy that is under intensive preclinical investigation for the treatment of various diseases. CD98 is highly overexpressed on the surfaces of epithelial cells and macrophages in the colon tissue with ulcerative colitis (UC), which is usually associated with mucosal damage and inflammation. We previously proved that CD98 siRNA (siCD98)-induced down-regulation of CD98 in colitis tissue decreased the severity of UC to a certain extent. In an effort to further improve the therapeutic efficacy, we aim to simultaneously deliver siCD98 in combination with a potent anti-inflammatory agent, curcumin (CUR), using hyaluronic acid (HA)-functionalized polymeric nanoparticles (NPs). The resultant spherical HA-siCD98/CUR-NPs are featured by a desirable particle size (∼246 nm) and slightly negative zeta potential (∼-14 mV). The NPs functionalized with HA are able to guide the co-delivery of drugs to the targeted cells related to UC therapy (colonic epithelial cells and macrophages). Compared to either siCD98- or CUR-based monotherapy, co-delivery of siCD98 and CUR by HA-functionalized NPs can exert combinational effects against UC by protecting the mucosal layer and alleviating inflammation both in vitro and in vivo. This study shows the promising capability of the co-delivered siCD98 and CUR for boosting the conventional monotherapy via this novel nanotherapeutic agent, which offers a structurally simple platform for orally administered delivery of drugs to target cells in UC therapy.
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Xiao B, Ma P, Viennois E, Merlin D. Urocanic acid-modified chitosan nanoparticles can confer anti-inflammatory effect by delivering CD98 siRNA to macrophages. Colloids Surf B Biointerfaces 2016; 143:186-193. [PMID: 27011348 PMCID: PMC4856589 DOI: 10.1016/j.colsurfb.2016.03.035] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2015] [Revised: 02/18/2016] [Accepted: 03/10/2016] [Indexed: 01/17/2023]
Abstract
CD98 plays an important role in the development and progression of inflammation. Here, CD98 siRNA (siCD98) was complexed with urocanic acid-modified chitosan (UAC) to form nanoparticles (NPs), which were transfected into Raw 264.7 macrophages in an effort to convey anti-inflammatory effects. Characterization showed that the generated NPs had a desirable particle size (156.0-247.1nm), a slightly positive zeta potential (15.8-17.5mV), and no apparent cytotoxicity against Raw 264.7 macrophages and colon-26 cells compared to control NPs fabricated by Oligofectamine (OF) and siRNA. Cellular uptake experiments demonstrated that macrophages exhibited a time-dependent accumulation profile of UAC/siRNA NPs. Further in vitro gene silencing experiments revealed that UAC/siCD98 NPs with a weight ratio of 60:1 yielded the most efficient knockdowns of CD98 and the pro-inflammatory cytokine, TNF-α. Indeed, the RNAi efficiency obtained with our NPs was even higher than that of the positive control OF/siCD98 NPs. These results suggest that UAC/siCD98 NPs might be a safe, efficient and promising candidate for the treatment of inflammatory disease.
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Affiliation(s)
- Bo Xiao
- Institute for Clean Energy and Advanced Materials, Faculty for Materials and Energy, Southwest University, Chongqing 400715, PR China; Center for Diagnostics and Therapeutics, Institute for Biomedical Science, Georgia State University, Atlanta 30302, USA.
| | - Panpan Ma
- Institute for Clean Energy and Advanced Materials, Faculty for Materials and Energy, Southwest University, Chongqing 400715, PR China
| | - Emilie Viennois
- Center for Diagnostics and Therapeutics, Institute for Biomedical Science, Georgia State University, Atlanta 30302, USA; Atlanta Veterans Affairs Medical Center, Decatur 30033, USA
| | - Didier Merlin
- Center for Diagnostics and Therapeutics, Institute for Biomedical Science, Georgia State University, Atlanta 30302, USA; Atlanta Veterans Affairs Medical Center, Decatur 30033, USA
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Heteromeric amino acid transporters. In search of the molecular bases of transport cycle mechanisms1. Biochem Soc Trans 2016; 44:745-52. [DOI: 10.1042/bst20150294] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Indexed: 01/18/2023]
Abstract
Heteromeric amino acid transporters (HATs) are relevant targets for structural studies. On the one hand, HATs are involved in inherited and acquired human pathologies. On the other hand, these molecules are the only known examples of solute transporters composed of two subunits (heavy and light) linked by a disulfide bridge. Unfortunately, structural knowledge of HATs is scarce and limited to the atomic structure of the ectodomain of a heavy subunit (human 4F2hc-ED) and distant prokaryotic homologues of the light subunits that share a LeuT-fold. Recent data on human 4F2hc/LAT2 at nanometer resolution revealed 4F2hc-ED positioned on top of the external loops of the light subunit LAT2. Improved resolution of the structure of HATs, combined with conformational studies, is essential to establish the structural bases for light subunit recognition and to evaluate the functional relevance of heavy and light subunit interactions for the amino acid transport cycle.
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Hua S, Marks E, Schneider JJ, Keely S. Advances in oral nano-delivery systems for colon targeted drug delivery in inflammatory bowel disease: selective targeting to diseased versus healthy tissue. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2015; 11:1117-32. [PMID: 25784453 DOI: 10.1016/j.nano.2015.02.018] [Citation(s) in RCA: 344] [Impact Index Per Article: 34.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Revised: 02/02/2015] [Accepted: 02/25/2015] [Indexed: 12/15/2022]
Abstract
UNLABELLED Colon targeted drug delivery is an active area of research for local diseases affecting the colon, as it improves the efficacy of therapeutics and enables localized treatment, which reduces systemic toxicity. Targeted delivery of therapeutics to the colon is particularly advantageous for the treatment of inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease. Advances in oral drug delivery design have significantly improved the bioavailability of drugs to the colon; however in order for a drug to have therapeutic efficacy during disease, considerations must be made for the altered physiology of the gastrointestinal (GI) tract that is associated with GI inflammation. Nanotechnology has been used in oral dosage formulation design as strategies to further enhance uptake into diseased tissue within the colon. This review will describe some of the physiological challenges faced by orally administered delivery systems in IBD, the important developments in orally administered nano-delivery systems for colon targeting, and the future advances of this research. FROM THE CLINICAL EDITOR Inflammatory Bowel Disease (IBD) poses a significant problem for a large number of patients worldwide. Current medical therapy mostly aims at suppressing the active inflammatory episodes. In this review article, the authors described and discussed the various approaches current nano-delivery systems can offer in overcoming the limitations of conventional drug formulations.
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Affiliation(s)
- Susan Hua
- The School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia.
| | - Ellen Marks
- The School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia; Gastrointestinal Research Group, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Jennifer J Schneider
- The School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia
| | - Simon Keely
- The School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia; Gastrointestinal Research Group, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
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Membrane protein 4F2/CD98 is a cell surface receptor involved in the internalization and trafficking of human β-Defensin 3 in epithelial cells. ACTA ACUST UNITED AC 2015; 22:217-28. [PMID: 25641165 DOI: 10.1016/j.chembiol.2014.11.020] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Revised: 11/15/2014] [Accepted: 11/20/2014] [Indexed: 12/11/2022]
Abstract
Human β-defensins play a pivotal role in the innate immune response. Although expressed by and acting at epithelial surfaces, little is known about their specific interaction with epithelial structures. Here, we identify the transmembrane protein CD98 as a cell surface receptor involved in the internalization of human β-defensin 3 (hBD3) in human epithelial A549 cells. CD98 and hBD3 extensively colocalize on the basolateral domain of A549. While verifying their direct binding by fluorescence resonance energy transfer and surface plasmon resonance, we mapped the interaction to CD98 residues 304-414, i.e. to the region known to interact with the proteins of intestinal bacteria during colonic invasion. Treatment of A549 cells with hBD3 dramatically reduces CD98 expression and conversely, knockdown of CD98 expression impairs hBD3 cell surface binding and internalization. Competition for bacterial binding to CD98 and downregulation of CD98 expression may represent novel mechanisms for the antibacterial activity of hBD3.
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Keriel A, Botella E, Estrach S, Bragagnolo G, Vergunst AC, Feral CC, O'Callaghan D. Brucella Intracellular Life Relies on the Transmembrane Protein CD98 Heavy Chain. J Infect Dis 2014; 211:1769-78. [PMID: 25505297 DOI: 10.1093/infdis/jiu673] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Accepted: 12/01/2014] [Indexed: 01/01/2023] Open
Abstract
Brucella are intracellular bacterial pathogens that use a type IV secretion system (T4SS) to escape host defenses and create a niche in which they can multiply. Although the importance of Brucella T4SS is clear, little is known about its interactions with host cell structures. In this study, we identified the eukaryotic protein CD98hc as a partner for Brucella T4SS subunit VirB2. This transmembrane glycoprotein is involved in amino acid transport, modulation of integrin signaling, and cell-to-cell fusion. Knockdown of CD98hc expression in HeLa cells demonstrated that it is essential for Brucella infection. Using knockout dermal fibroblasts, we confirmed its role for Brucella but found that it is not required for Salmonella infection. CD98hc transiently accumulates around the bacteria during the early phases of infection and is required for both optimal bacterial uptake and intracellular multiplication of Brucella. These results provide new insights into the complex interplay between Brucella and its host.
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Affiliation(s)
- Anne Keriel
- INSERM, U1047 Université Montpellier 1, UFR de Médecine, Nîmes
| | - Eric Botella
- INSERM, U1047 Université Montpellier 1, UFR de Médecine, Nîmes
| | - Soline Estrach
- INSERM, U1081, CNRS, UMR7284, Institute for Research on Cancer and Aging, University of Nice Sophia Antipolis, France
| | | | | | - Chloe C Feral
- INSERM, U1081, CNRS, UMR7284, Institute for Research on Cancer and Aging, University of Nice Sophia Antipolis, France
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31
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Xiao B, Laroui H, Viennois E, Ayyadurai S, Charania MA, Zhang Y, Zhang Z, Baker MT, Zhang B, Gewirtz AT, Merlin D. Nanoparticles with surface antibody against CD98 and carrying CD98 small interfering RNA reduce colitis in mice. Gastroenterology 2014; 146:1289-300.e1-19. [PMID: 24503126 PMCID: PMC3992175 DOI: 10.1053/j.gastro.2014.01.056] [Citation(s) in RCA: 146] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Revised: 01/28/2014] [Accepted: 01/30/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Nanoparticles have been explored as carriers of small interfering RNAs (siRNAs) and might be developed to treat patients with inflammatory bowel disease (IBD). Overexpression of CD98 on the surface of colonic epithelial cells and macrophages promotes the development and progression of IBD. We developed an orally delivered hydrogel that releases nanoparticles with single-chain CD98 antibodies on their surface (scCD98 functionalized) and loaded with CD98 siRNA (siCD98). We tested the ability of the nanoparticles to reduce levels of CD98 in the colons of mice with colitis. METHODS scCD98-functionalized siCD98-loaded nanoparticles were fabricated using a complex coacervation technique. We investigated the cellular uptake and lysosome escape profiles of the nanoparticles in Colon-26 cells and RAW 264.7 macrophages using fluorescence microscopy. Colitis was induced by transfer of CD4(+)CD45RB(high) T cells to Rag(-/-) mice or administration of dextran sodium sulfate to C57BL/6 mice. Mice were then given hydrogel (chitosan and alginate) containing scCD98-functionalized nanoparticles loaded with siCD98 or scrambled siRNA (control) via gavage. RESULTS The scCD98-functionalized nanoparticles were approximately 200 nm in size and had high affinity for CD98-overexpressing cells. The scCD98-functionalized siCD98-loaded nanoparticles significantly reduced levels of CD98 in Colon-26 cells and RAW 264.7 macrophages, along with production of inflammatory cytokines (tumor necrosis factor α, interleukin-6, and interleukin-12). In mice with colitis, administration of the scCD98-functionalized siCD98-loaded nanoparticles reduced colon expression of CD98. Importantly, the severity of colitis was also reduced compared with controls (based on loss of body weight, myeloperoxidase activity, inflammatory cytokine production, and histological analysis). Approximately 24.1% of colonic macrophages (CD11b(+)CD11c(-)F4/80(+)) in the mice had taken up fluorescently labeled siRNA-loaded nanoparticles within 12 hours of administration. CONCLUSIONS Nanoparticles containing surface CD98 antibody and loaded with siCD98 reduce expression of this protein by colonic epithelial cells and macrophages, and oral administration decreases the severity of colitis in mice. This nanoparticle in hydrogel (chitosan/alginate) formulation might be developed to treat patients with IBD.
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Affiliation(s)
- Bo Xiao
- Center for Diagnostics and Therapeutics, Institute for Biomedical Science, Departments of Biology and Chemistry, Georgia State University, Atlanta.
| | - Hamed Laroui
- Center for Diagnostics and Therapeutics, Institute for Biomedical Science, Department of Biology and Department of Chemistry, Georgia State University, Atlanta, 30302, USA
| | - Emilie Viennois
- Center for Diagnostics and Therapeutics, Institute for Biomedical Science, Department of Biology and Department of Chemistry, Georgia State University, Atlanta, 30302, USA,Atlanta Veterans Affairs Medical Center, Decatur, 30033, USA
| | - Saravanan Ayyadurai
- Center for Diagnostics and Therapeutics, Institute for Biomedical Science, Department of Biology and Department of Chemistry, Georgia State University, Atlanta, 30302, USA
| | - Moiz A. Charania
- Center for Diagnostics and Therapeutics, Institute for Biomedical Science, Department of Biology and Department of Chemistry, Georgia State University, Atlanta, 30302, USA
| | - Yuchen Zhang
- Center for Diagnostics and Therapeutics, Institute for Biomedical Science, Department of Biology and Department of Chemistry, Georgia State University, Atlanta, 30302, USA
| | - Zhan Zhang
- Center for Inflammation, Immunity and Infection, Department of Biology, Georgia State University, Atlanta, 30302, USA
| | - Mark T. Baker
- Center for Diagnostics and Therapeutics, Institute for Biomedical Science, Department of Biology and Department of Chemistry, Georgia State University, Atlanta, 30302, USA
| | - Benyue Zhang
- Center for Inflammation, Immunity and Infection, Department of Biology, Georgia State University, Atlanta, 30302, USA
| | - Andrew T. Gewirtz
- Center for Inflammation, Immunity and Infection, Department of Biology, Georgia State University, Atlanta, 30302, USA,Department of Pathology, School of Medicine, Emory University, Atlanta, 30322, USA
| | - Didier Merlin
- Center for Diagnostics and Therapeutics, Institute for Biomedical Science, Department of Biology and Department of Chemistry, Georgia State University, Atlanta, 30302, USA,Atlanta Veterans Affairs Medical Center, Decatur, 30033, USA
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Li C, Liu VWS, Chiu PM, Yao KM, Ngan HYS, Chan DW. Reduced expression of AMPK-β1 during tumor progression enhances the oncogenic capacity of advanced ovarian cancer. Mol Cancer 2014; 13:49. [PMID: 24602453 PMCID: PMC4016028 DOI: 10.1186/1476-4598-13-49] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Accepted: 02/21/2014] [Indexed: 12/25/2022] Open
Abstract
AMP-activated protein kinase (AMPK) is a key energy sensor that is involved in regulating cell metabolism. Our previous study revealed that the subunits of the heterotimeric AMPK enzyme are diversely expressed during ovarian cancer progression. However, the impact of the variable expression of these AMPK subunits in ovarian cancer oncogenesis remains obscure. Here, we provide evidence to show that reduced expression of the AMPK-β1 subunit during tumor progression is associated with the increased oncogenic capacity of advanced ovarian cancer cells. Immunohistochemical analysis revealed that AMPK-β1 levels were reduced in advanced-stage (P = 0.008), high-grade (P = 0.013) and metastatic ovarian cancers (P = 0.008). Intriguingly, down-regulation of AMPK-β1 was progressively reduced from tumor stages 1 to 3 of ovarian cancer. Functionally, enforced expression of AMPK-β1 inhibited ovarian-cancer-cell proliferation, anchorage-independent cell growth, cell migration and invasion. Conversely, depletion of AMPK-β1 by siRNA enhanced the oncogenic capacities of ovarian cancer cells, suggesting that the loss of AMPK-β1 favors the aggressiveness of ovarian cancer. Mechanistically, enforced expression of AMPK-β1 increased AMPK activity, which, in turn, induced cell-cycle arrest via inhibition of AKT/ERK signaling activity as well as impaired cell migration/invasion through the suppression of JNK signaling in ovarian cancer cells. Taken together, these findings suggest that the reduced expression of AMPK-β1 confers lower AMPK activity, which enhances the oncogenic capacity of advanced-stage ovarian cancer.
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Affiliation(s)
| | | | | | | | - Hextan Y S Ngan
- Department of Obstetrics & Gynecology, The University of Hong Kong, 6th Floor, Professorial Block, Queen Mary Hospital, Pokfulam, Hong Kong, SAR, People's Republic of China.
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Maldonado-Báez L, Williamson C, Donaldson JG. Clathrin-independent endocytosis: a cargo-centric view. Exp Cell Res 2013; 319:2759-69. [PMID: 23954817 DOI: 10.1016/j.yexcr.2013.08.008] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Revised: 08/06/2013] [Accepted: 08/07/2013] [Indexed: 12/12/2022]
Abstract
Clathrin-independent endocytosis occurs in all cells and interest in this mode of cellular entry has grown. Although this form of endocytosis was first described for entry of bacterial toxins, here we focus our attention on the endogenous cell surface "cargo" proteins that enter cells by this mechanism. The cargo proteins entering by this mechanism are varied and include nutrient transporters, ion channels, cell adhesion molecules and proteins associated with the immune system. Despite the apparent lack of selection at the cell surface, we provide some examples of specific sorting of these cargo proteins after entry, leading to distinct itineraries and cellular fates.
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Affiliation(s)
- Lymarie Maldonado-Báez
- Cell Biology & Physiology Center, National Heart, Lung and Blood Institute, NIH, Bethesda, MD 20892, USA
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Raisch J, Darfeuille-Michaud A, Nguyen HTT. Role of microRNAs in the immune system, inflammation and cancer. World J Gastroenterol 2013; 19:2985-2996. [PMID: 23716978 PMCID: PMC3662938 DOI: 10.3748/wjg.v19.i20.2985] [Citation(s) in RCA: 155] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2013] [Accepted: 04/11/2013] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs, a key class of gene expression regulators, have emerged as crucial players in various biological processes such as cellular proliferation and differentiation, development and apoptosis. In addition, microRNAs are coming to light as crucial regulators of innate and adaptive immune responses, and their abnormal expression and/or function in the immune system have been linked to multiple human diseases including inflammatory disorders, such as inflammatory bowel disease, and cancers. In this review, we discuss our current understanding of microRNAs with a focus on their role and mode of action in regulating the immune system during inflammation and carcinogenesis.
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