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Abbas A, Di Fonzo DMP, Wetwittayakhlang P, Al-Jabri R, Lakatos PL, Bessissow T. Management of ulcerative colitis: where are we at and where are we heading? Expert Rev Gastroenterol Hepatol 2024; 18:567-574. [PMID: 39470444 DOI: 10.1080/17474124.2024.2422370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 10/14/2024] [Accepted: 10/24/2024] [Indexed: 10/30/2024]
Abstract
INTRODUCTION Remission rates for ulcerative colitis (UC) remain low despite significant progress in disease understanding and the introduction of novel therapeutic agents. Several challenges contribute to this, including the heterogeneity of the disease, suboptimal efficacy of current diagnostic and therapeutic tools, drug safety concerns, and limited access to newer treatment options. AREAS COVERED This review evaluates current treatment targets in UC, assessing the effectiveness of various therapies and management strategies in achieving remission. We explore the potential role of personalized medicine, which tailors treatment based on clinical predictors, genetic factors, and immunologic profiles. Personalized approaches show promise in improving remission rates by addressing the unique characteristics of each patient. We also discussed the feasibility of adapting such management models and suggested solutions to some of the challenges in their implementation. EXPERT OPINION Future efforts should prioritize the continued development of biologics, small molecules, and digital health solutions, alongside noninvasive monitoring techniques. These innovations could not only enhance patient outcomes by improving remission rates but also reduce healthcare costs by minimizing hospitalization and surgical interventions. Ultimately, a personalized, stratified approach to UC management is key to optimizing patient care and addressing the unmet needs in this field.
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Affiliation(s)
- Adnan Abbas
- Division of Gastroenterology and Hepatology, Department of Medicine, McGill University, Health Centre, Montreal, Canada
| | - David M P Di Fonzo
- Department of Medicine, McGill University Health Centre, Montreal, Canada
| | - Panu Wetwittayakhlang
- Division of Gastroenterology and Hepatology, Department of Medicine, McGill University, Health Centre, Montreal, Canada
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand
| | - Reem Al-Jabri
- Division of Gastroenterology and Hepatology, Department of Medicine, McGill University, Health Centre, Montreal, Canada
| | - Peter L Lakatos
- Division of Gastroenterology and Hepatology, Department of Medicine, McGill University, Health Centre, Montreal, Canada
- Department of Medicine, Semmelweis University, Budapest, Hungary
| | - Talat Bessissow
- Division of Gastroenterology and Hepatology, Department of Medicine, McGill University, Health Centre, Montreal, Canada
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Li MM, Huang Y, Sumathipala M, Liang MQ, Valdeolivas A, Ananthakrishnan AN, Liao K, Marbach D, Zitnik M. Contextual AI models for single-cell protein biology. Nat Methods 2024; 21:1546-1557. [PMID: 39039335 PMCID: PMC11310085 DOI: 10.1038/s41592-024-02341-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 06/10/2024] [Indexed: 07/24/2024]
Abstract
Understanding protein function and developing molecular therapies require deciphering the cell types in which proteins act as well as the interactions between proteins. However, modeling protein interactions across biological contexts remains challenging for existing algorithms. Here we introduce PINNACLE, a geometric deep learning approach that generates context-aware protein representations. Leveraging a multiorgan single-cell atlas, PINNACLE learns on contextualized protein interaction networks to produce 394,760 protein representations from 156 cell type contexts across 24 tissues. PINNACLE's embedding space reflects cellular and tissue organization, enabling zero-shot retrieval of the tissue hierarchy. Pretrained protein representations can be adapted for downstream tasks: enhancing 3D structure-based representations for resolving immuno-oncological protein interactions, and investigating drugs' effects across cell types. PINNACLE outperforms state-of-the-art models in nominating therapeutic targets for rheumatoid arthritis and inflammatory bowel diseases and pinpoints cell type contexts with higher predictive capability than context-free models. PINNACLE's ability to adjust its outputs on the basis of the context in which it operates paves the way for large-scale context-specific predictions in biology.
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Affiliation(s)
- Michelle M Li
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Yepeng Huang
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Marissa Sumathipala
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Man Qing Liang
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Alberto Valdeolivas
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Ashwin N Ananthakrishnan
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
| | - Katherine Liao
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA, USA
| | - Daniel Marbach
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Marinka Zitnik
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
- Kempner Institute for the Study of Natural and Artificial Intelligence, Harvard University, Allston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Harvard Data Science Initiative, Cambridge, MA, USA.
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Li MM, Huang Y, Sumathipala M, Liang MQ, Valdeolivas A, Ananthakrishnan AN, Liao K, Marbach D, Zitnik M. Contextual AI models for single-cell protein biology. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.07.18.549602. [PMID: 37503080 PMCID: PMC10370131 DOI: 10.1101/2023.07.18.549602] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
Understanding protein function and developing molecular therapies require deciphering the cell types in which proteins act as well as the interactions between proteins. However, modeling protein interactions across biological contexts remains challenging for existing algorithms. Here, we introduce Pinnacle, a geometric deep learning approach that generates context-aware protein representations. Leveraging a multi-organ single-cell atlas, Pinnacle learns on contextualized protein interaction networks to produce 394,760 protein representations from 156 cell type contexts across 24 tissues. Pinnacle's embedding space reflects cellular and tissue organization, enabling zero-shot retrieval of the tissue hierarchy. Pretrained protein representations can be adapted for downstream tasks: enhancing 3D structure-based representations for resolving immuno-oncological protein interactions, and investigating drugs' effects across cell types. Pinnacle outperforms state-of-the-art models in nominating therapeutic targets for rheumatoid arthritis and inflammatory bowel diseases, and pinpoints cell type contexts with higher predictive capability than context-free models. Pinnacle's ability to adjust its outputs based on the context in which it operates paves way for large-scale context-specific predictions in biology.
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Affiliation(s)
- Michelle M. Li
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Yepeng Huang
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Marissa Sumathipala
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Man Qing Liang
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Alberto Valdeolivas
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Ashwin N. Ananthakrishnan
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
| | - Katherine Liao
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, MA, USA
| | - Daniel Marbach
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Marinka Zitnik
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
- Kempner Institute for the Study of Natural and Artificial Intelligence, Harvard University, Allston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Harvard Data Science Initiative, Cambridge, MA, USA
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Patel SK, Billingsley MM, Mukalel AJ, Thatte AS, Hamilton AG, Gong N, El-Mayta R, Safford HC, Merolle M, Mitchell MJ. Bile acid-containing lipid nanoparticles enhance extrahepatic mRNA delivery. Theranostics 2024; 14:1-16. [PMID: 38164140 PMCID: PMC10750194 DOI: 10.7150/thno.89913] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 10/10/2023] [Indexed: 01/03/2024] Open
Abstract
Lipid nanoparticles (LNPs) have emerged as a viable, clinically-validated platform for the delivery of mRNA therapeutics. LNPs have been utilized as mRNA delivery systems for applications including vaccines, gene therapy, and cancer immunotherapy. However, LNPs, which are typically composed of ionizable lipids, cholesterol, helper lipids, and lipid-anchored polyethylene glycol, often traffic to the liver which limits the therapeutic potential of the platform. Several approaches have been proposed to resolve this tropism such as post-synthesis surface modification or the addition of synthetic cationic lipids. Methods: Here, we present a strategy for achieving extrahepatic delivery of mRNA involving the incorporation of bile acids, a naturally-occurring class of cholesterol analogs, during LNP synthesis. We synthesized a series of bile acid-containing C14-4 LNPs by replacing cholesterol with bile acids (cholic acid, chenodeoxycholic acid, deoxycholic acid, or lithocholic acid) at various ratios. Results: Bile acid-containing LNPs (BA-LNPs) were able to reduce delivery to liver cells in vitro and improve delivery in a variety of other cell types, including T cells, B cells, and epithelial cells. Our subsequent in vivo screening of selected LNP candidates injected intraperitoneally or intravenously identified a highly spleen tropic BA-LNP: CA-100, a four-component LNP containing cholic acid and no cholesterol. These screens also identified BA-LNP candidates demonstrating promise for other mRNA therapeutic applications such as for gastrointestinal or immune cell delivery. We further found that the substitution of cholic acid for cholesterol in an LNP formulation utilizing a different ionizable lipid, C12-200, also shifted mRNA delivery from the liver to the spleen, suggesting that this cholic acid replacement strategy may be generalizable. Conclusion: These results demonstrate the potential of a four-component BA-LNP formulation, CA-100, for extrahepatic mRNA delivery that could potentially be utilized for a range of therapeutic and vaccine applications.
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Affiliation(s)
- Savan K. Patel
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA
| | | | - Alvin J. Mukalel
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Ajay S. Thatte
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Alex G. Hamilton
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Ningqiang Gong
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Rakan El-Mayta
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Hannah C. Safford
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Maria Merolle
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Michael J. Mitchell
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Izco M, Schleef M, Schmeer M, Carlos E, Verona G, Alvarez-Erviti L. Targeted Extracellular Vesicle Gene Therapy for Modulating Alpha-Synuclein Expression in Gut and Spinal Cord. Pharmaceutics 2023; 15:pharmaceutics15041230. [PMID: 37111717 PMCID: PMC10145068 DOI: 10.3390/pharmaceutics15041230] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 04/05/2023] [Accepted: 04/07/2023] [Indexed: 04/29/2023] Open
Abstract
The development of effective disease-modifying therapies to halt Parkinson's disease (PD) progression is required. In a subtype of PD patients, alpha-synuclein pathology may start in the enteric nervous system (ENS) or autonomic peripheral nervous system. Consequently, strategies to decrease the expression of alpha-synuclein in the ENS will be an approach to prevent PD progression at pre-clinical stages in these patients. In the present study, we aimed to assess if anti-alpha-synuclein shRNA-minicircles (MC) delivered by RVG-extracellular vesicles (RVG-EV) could downregulate alpha-synuclein expression in the intestine and spinal cord. RVG-EV containing shRNA-MC were injected intravenously in a PD mouse model, and alpha-synuclein downregulation was evaluated by qPCR and Western blot in the cord and distal intestine. Our results confirmed the downregulation of alpha-synuclein in the intestine and spinal cord of mice treated with the therapy. We demonstrated that the treatment with anti-alpha-synuclein shRNA-MC RVG-EV after the development of pathology is effective to downregulate alpha-synuclein expression in the brain as well as in the intestine and spinal cord. Moreover, we confirmed that a multidose treatment is necessary to maintain downregulation for long-term treatments. Our results support the potential use of anti-alpha-synuclein shRNA-MC RVG-EV as a therapy to delay or halt PD pathology progression.
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Affiliation(s)
- Maria Izco
- Laboratory of Molecular Neurobiology, Center for Biomedical Research of La Rioja (CIBIR), Piqueras 98, 3th Floor, 26006 Logroño, Spain
| | | | - Marco Schmeer
- PlasmidFactory GmbH & Co. KG, 33607 Bielefeld, Germany
| | - Estefania Carlos
- Laboratory of Molecular Neurobiology, Center for Biomedical Research of La Rioja (CIBIR), Piqueras 98, 3th Floor, 26006 Logroño, Spain
| | - Guglielmo Verona
- Centre for Amyloidosis, UCL Medical School, Rowland Hill Street, London NW3 2PF, UK
| | - Lydia Alvarez-Erviti
- Laboratory of Molecular Neurobiology, Center for Biomedical Research of La Rioja (CIBIR), Piqueras 98, 3th Floor, 26006 Logroño, Spain
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Hartwig O, Shetab Boushehri MA, Shalaby KS, Loretz B, Lamprecht A, Lehr CM. Drug delivery to the inflamed intestinal mucosa - targeting technologies and human cell culture models for better therapies of IBD. Adv Drug Deliv Rev 2021; 175:113828. [PMID: 34157320 DOI: 10.1016/j.addr.2021.113828] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 06/09/2021] [Accepted: 06/10/2021] [Indexed: 12/19/2022]
Abstract
Current treatment strategies for inflammatory bowel disease (IBD) seek to alleviate the undesirable symptoms of the disorder. Despite the higher specificity of newer generation therapeutics, e.g. monoclonal antibodies, adverse effects still arise from their interference with non-specific systemic immune cascades. To circumvent such undesirable effects, both conventional and newer therapeutic options can benefit from various targeting strategies. Of course, both the development and the assessment of the efficiency of such targeted delivery systems necessitate the use of suitable in vivo and in vitro models representing relevant pathophysiological manifestations of the disorder. Accordingly, the current review seeks to provide a comprehensive discussion of the available preclinical models with emphasis on human in vitro models of IBD, along with their potentials and limitations. This is followed by an elaboration on the advancements in the field of biology- and nanotechnology-based targeted drug delivery systems and the potential rooms for improvement to facilitate their clinical translation.
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Affiliation(s)
- Olga Hartwig
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), D-66123 Saarbrücken, Germany; Department of Pharmacy, Saarland University, D-66123 Saarbrücken, Germany
| | | | - Karim S Shalaby
- Department of Pharmaceutics, University of Bonn, D-53121 Bonn, Germany; Department of Pharmaceutics and Industrial Pharmacy, Ain Shams University, Cairo, Egypt
| | - Brigitta Loretz
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), D-66123 Saarbrücken, Germany
| | - Alf Lamprecht
- Department of Pharmaceutics, University of Bonn, D-53121 Bonn, Germany.
| | - Claus-Michael Lehr
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), D-66123 Saarbrücken, Germany; Department of Pharmacy, Saarland University, D-66123 Saarbrücken, Germany.
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Verma P, Srivastava A, Srikanth CV, Bajaj A. Nanoparticle-mediated gene therapy strategies for mitigating inflammatory bowel disease. Biomater Sci 2021; 9:1481-1502. [PMID: 33404019 DOI: 10.1039/d0bm01359e] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Inflammatory bowel disease (IBD) is an autoimmune disorder of the gastrointestinal tract (GIT) where Ulcerative Colitis (UC) displays localized inflammation in the colon, and Crohn's Disease (CD) affects the entire GIT. Failure of current therapies and associated side-effects bring forth serious social, economic, and health challenges. The gut epithelium provides the best target for gene therapy delivery vehicles to combat IBD. Gene therapy involving the use of nucleic acid (NA) therapeutics faces major challenges due to the hydrophilic, negative-charge, and degradable nature of NAs. Recent success in the engineering of biomaterials for gene therapy and their emergence in clinical trials for various diseases is an inspiration for scientists to develop gene therapy vehicles that can be easily targeted to the desired tissues for IBD. Advances in nanotechnology have enabled the formulations of numerous nanoparticles for NA delivery to mitigate IBD that still faces challenges of stability in the GIT, poor therapeutic efficacy, and targetability. This review presents the challenges of gene therapeutics, gastrointestinal barriers, and recent advances in the engineering of nanoparticles for IBD treatment along with future directions for successful translation of nanoparticle-mediated gene therapeutics in clinics.
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Affiliation(s)
- Priyanka Verma
- Laboratory of Nanotechnology and Chemical Biology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone Faridabad-Gurgaon Expressway, Faridabad-121001, Haryana, India.
| | - Aasheesh Srivastava
- Department of Chemistry, Indian Institute of Science Education and Research Bhopal, By-pass Road, Bhauri, Bhopal-462030, India
| | - C V Srikanth
- Laboratory of Gut Inflammation and Infection Biology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone Faridabad- Gurgaon Expressway, Faridabad-121001, Haryana, India
| | - Avinash Bajaj
- Laboratory of Nanotechnology and Chemical Biology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone Faridabad-Gurgaon Expressway, Faridabad-121001, Haryana, India.
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Mishra R, Dhawan P, Srivastava AS, Singh AB. Inflammatory bowel disease: Therapeutic limitations and prospective of the stem cell therapy. World J Stem Cells 2020; 12:1050-1066. [PMID: 33178391 PMCID: PMC7596447 DOI: 10.4252/wjsc.v12.i10.1050] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 06/02/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD), consisting primarily of ulcerative colitis and Crohn’s disease, is a group of debilitating auto-immune disorders, which also increases the risk of colitis-associated cancer. However, due to the chronic nature of the disease and inconsistent treatment outcomes of current anti-IBD drugs (e.g., approximately 30% non-responders to anti-TNFα agents), and related serious side effects, about half of all IBD patients (in millions) turn to alternative treatment options. In this regard, mucosal healing is gaining acceptance as a measure of disease activity in IBD patients as recent studies have correlated the success of mucosal healing with improved prognosis. However, despite the increasing clinical realization of the significance of the concept of mucosal healing, its regulation and means of therapeutic targeting remain largely unclear. Here, stem-cell therapy, which uses hematopoietic stem cells or mesenchymal stem cells, remains a promising option. Stem cells are the pluripotent cells with ability to differentiate into the epithelial and/or immune-modulatory cells. The over-reaching concept is that the stem cells can migrate to the damaged areas of the intestine to provide curative help in the mucosal healing process. Moreover, by differentiating into the mature intestinal epithelial cells, the stem cells also help in restoring the barrier integrity of the intestinal lining and hence prevent the immunomodulatory induction, the root cause of the IBD. In this article, we elaborate upon the current status of the clinical management of IBD and potential role of the stem cell therapy in improving IBD therapy and patient’s quality of life.
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Affiliation(s)
- Rangnath Mishra
- Global Institute of Stem Cell Therapy and Research, San Diego, CA 92122, United States
| | - Punita Dhawan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68118, United States
- Fred and Pamela Buffett Cancer Center, Omaha, NE 68118, United States
- VA Nebraska-Western Iowa Health Care System, Omaha, NE 68118, United States
| | - Anand S Srivastava
- Global Institute of Stem Cell Therapy and Research, San Diego, CA 92122, United States
| | - Amar B Singh
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68118, United States
- Fred and Pamela Buffett Cancer Center, Omaha, NE 68118, United States
- VA Nebraska-Western Iowa Health Care System, Omaha, NE 68118, United States
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Crohn's Disease: Potential Drugs for Modulation of Autophagy. ACTA ACUST UNITED AC 2019; 55:medicina55060224. [PMID: 31146413 PMCID: PMC6630681 DOI: 10.3390/medicina55060224] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 02/26/2019] [Accepted: 05/23/2019] [Indexed: 12/12/2022]
Abstract
Autophagy is an intracellular process whereby cytoplasmic constituents are degraded within lysosomes. Autophagy functions to eliminate unwanted or damaged materials such as proteins and organelles as their accumulation would be harmful to the cellular system. Autophagy also acts as a defense mechanism against invading pathogens and plays an important role in innate and adaptive immunity. In physiological processes, autophagy is involved in the regulation of tissue development, differentiation and remodeling, which are essential for maintaining cellular homeostasis. Recent studies have demonstrated that autophagy is linked to various diseases and involved in pathophysiological roles, such as adaptation during starvation, anti-aging, antigen presentation, tumor suppression and cell death. The modulation of autophagy has shown greatest promise in Crohn’s disease as most of autophagy drugs involved in these diseases are currently under clinical trials and some has been approved by Food and Drug Administration. This review article discusses autophagy and potential drugs that are currently available for its modulation in Crohn’s disease.
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Yavvari PS, Verma P, Mustfa SA, Pal S, Kumar S, Awasthi AK, Ahuja V, Srikanth CV, Srivastava A, Bajaj A. A nanogel based oral gene delivery system targeting SUMOylation machinery to combat gut inflammation. NANOSCALE 2019; 11:4970-4986. [PMID: 30839018 DOI: 10.1039/c8nr09599j] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Poor success rates and challenges associated with the current therapeutic strategies of inflammatory bowel disease (IBD) have accelerated the emergence of gene therapy as an alternative treatment option with great promise. However, oral delivery of nucleic acids (NAs) to an inflamed colon is challenged by multiple barriers presented by the gastrointestinal, extracellular and intracellular compartments. Therefore, we screened a series of polyaspartic acid-derived amphiphilic cationic polymers with varied hydrophobicity for their ability to deliver NAs into mammalian cells. Using the most effective TAC6 polymer, we then engineered biocompatible and stable nanogels composed of polyplexes (TAC6, NA) and an anionic polymer, sodium polyaspartate, that were able to deliver the NAs across mammalian cells using caveolae-mediated cellular uptake. We then utilized these nanogels for oral delivery of PIAS1 (protein inhibitor of activated STAT1), a SUMO 3 ligase, encoding plasmid DNA since PIAS1 is a key nodal therapeutic target for IBD due to its ability to control NF-κB-mediated inflammatory signaling. We show that plasmid delivery using TAC6-derived nanogels diminished gut inflammation in a murine colitis model. Therefore, our study presents engineering of orally deliverable nanogels that can target SUMOylation machinery to combat gut inflammation with very high efficacy.
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Affiliation(s)
- Prabhu Srinivas Yavvari
- Department of Chemistry, Indian Institute of Science Education and Research, Bhopal By-pass Road, Bhauri, Bhopal-462030, India.
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Heck BE, Park JJ, Makani V, Kim EC, Kim DH. PPAR-δ Agonist With Mesenchymal Stem Cells Induces Type II Collagen-Producing Chondrocytes in Human Arthritic Synovial Fluid. Cell Transplant 2018; 26:1405-1417. [PMID: 28901183 PMCID: PMC5680970 DOI: 10.1177/0963689717720278] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Osteoarthritis (OA) is an inflammatory joint disease characterized by degeneration of articular cartilage within synovial joints. An estimated 27 million Americans suffer from OA, and the population is expected to reach 67 million in the United States by 2030. Thus, it is urgent to find an effective treatment for OA. Traditional OA treatments have no disease-modifying effect, while regenerative OA therapies such as autologous chondrocyte implantation show some promise. Nonetheless, current regenerative therapies do not overcome synovial inflammation that suppresses the differentiation of mesenchymal stem cells (MSCs) to chondrocytes and the expression of type II collagen, the major constituent of functional cartilage. We discovered a synergistic combination that overcame synovial inflammation to form type II collagen-producing chondrocytes. The combination consists of peroxisome proliferator–activated receptor (PPAR) δ agonist, human bone marrow (hBM)-derived MSCs, and hyaluronic acid (HA) gel. Interestingly, those individual components showed their own strong enhancing effects on chondrogenesis. GW0742, a PPAR-δ agonist, greatly enhanced MSC chondrogenesis and the expression of type II collagen and glycosaminoglycan (GAG) in hBM-MSC-derived chondrocytes. GW0742 also increased the expression of transforming growth factor β that enhances chondrogenesis and suppresses cartilage fibrillation, ossification, and inflammation. HA gel also increased MSC chondrogenesis and GAG production. However, neither GW0742 nor HA gel could enhance the formation of type II collagen-producing chondrocytes from hBM-MSCs within human OA synovial fluid. Our data demonstrated that the combination of hBM-MSCs, PPAR-δ agonist, and HA gel significantly enhanced the formation of type II collagen-producing chondrocytes within OA synovial fluid from 3 different donors. In other words, the novel combination of PPAR-δ agonist, hBM-MSCs, and HA gel can overcome synovial inflammation to form type II collagen cartilage within human OA synovial fluid. This novel articularly injectable formula could improve OA treatment in the future clinical application.
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Affiliation(s)
- Bruce E Heck
- 1 NWO Stem Cure, LLC, Findlay, OH, USA.,2 Northwest Ohio Orthopedics and Sports Medicine, Findlay, OH, USA
| | - Joshua J Park
- 3 Department of Neurosciences, University of Toledo College of Medicine and Life Science, Toledo, OH, USA
| | - Vishruti Makani
- 3 Department of Neurosciences, University of Toledo College of Medicine and Life Science, Toledo, OH, USA
| | - Eun-Cheol Kim
- 4 Department of Oral and Maxillofacial Pathology, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea
| | - Dong Hyun Kim
- 1 NWO Stem Cure, LLC, Findlay, OH, USA.,2 Northwest Ohio Orthopedics and Sports Medicine, Findlay, OH, USA.,5 Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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Hydrodynamic IL10 Gene Transfer in Human Colon: Results from an "EX VIVO" Study with Potential Clinical Application in Crohn's Disease. Inflamm Bowel Dis 2017; 23:1360-1370. [PMID: 28708803 DOI: 10.1097/mib.0000000000001197] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND The aim of this work is to evaluate the efficacy of hydrodynamic venous IL10 gene delivery to "ex vivo" human colon segments and to determine its potential interest in Crohn's disease treatment. METHODS Twenty human colon segments were obtained from surgical resections. Hydrodynamic transfection through the main vein of the pedicle with 50 mL of hIL10 plasmid (20 μg/mL) solution was performed on 13 of them. Tissue sections were cultured and DNA, RNA, and protein copies were determined after 1, 2, and 4 days. Data obtained were compared with 6 nontransfected specimens. Finally, 1 specimen was injected with gold nanoparticles, and their distribution was examined under electron microscope. RESULTS IL10 DNA levels were higher in treated tissues than in controls (P < 0.001), decreasing along time. The amount of hIL10 RNA was significantly increased in treated tissues when compared with controls (P = 0.001). The indexes of protein IL10 translation in treated groups were much higher (P < 0.001) than the basal production. The protein expression was higher in transfected tissue (10-50-fold, with respect to control tissue); this difference being established during the first hours and maintained during, at least, 4 days. With electron microscopy, we hardly observed large (15 nm) gold nanoparticles within the tissue, always in the submucosa. However, multiple small (4 nm) nanoparticles were observed within the cytoplasm of enterocytes in mucosa. CONCLUSIONS Hydrodynamic procedure efficiently delivers the IL10 gene to the human colon, achieving levels of tissue protein expression high enough to mediate pharmacological effects with interest in controlling immune response in patients with Crohn's disease.
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Yoshimoto T, Niimi K, Takahashi E. Tranexamic Acid and Supportive Measures to Treat Wasting Marmoset Syndrome. Comp Med 2016; 66:468-473. [PMID: 28304250 PMCID: PMC5157962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 06/12/2016] [Accepted: 07/10/2016] [Indexed: 06/06/2023]
Abstract
Wasting marmoset syndrome (WMS) has high incidence and mortality rates and is one of the most important problems in captive common marmoset (Callithrix jacchus) colonies. Despite several reports on WMS, little information is available regarding its reliable treatment. We previously reported that marmosets with WMS had high serum levels of matrix metalloproteinase 9 (MMP9). MMP9 is thought to be a key enzyme in the pathogenesis of inflammatory bowel disease, the main disease state of WMS, and is activated by plasmin, a fibrinolytic factor. In a previous study, treating mice with an antibody to inhibit plasmin prevented the progression of inflammatory bowel disease. Here we examined the efficacy of tranexamic acid, a commonly used plasmin inhibitor, for the treatment of WMS, with supportive measures including amino acid and iron formulations. Six colony marmosets with WMS received tranexamic acid therapy with supportive measures for 8 wk. The body weight, Hct, and serum albumin levels of these 6 marmosets were increased and serum MMP9 levels decreased after this regimen. Therefore, tranexamic acid therapy may be a new and useful treatment for WMS.
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Affiliation(s)
- Takuro Yoshimoto
- Research Resources Center, RIKEN Brain Science Institute, Saitama, Japan;,
| | - Kimie Niimi
- Research Resources Center, RIKEN Brain Science Institute, Saitama, Japan;,
| | - Eiki Takahashi
- Research Resources Center, RIKEN Brain Science Institute, Saitama, Japan
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Niu YT, Zhao YP, Jiao YF, Zheng J, Yang WL, Zhou R, Niu Y, Sun T, Li YX, Yu JQ. Protective effect of gentiopicroside against dextran sodium sulfate induced colitis in mice. Int Immunopharmacol 2016; 39:16-22. [DOI: 10.1016/j.intimp.2016.07.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2016] [Revised: 06/14/2016] [Accepted: 07/04/2016] [Indexed: 01/15/2023]
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YOSHIMOTO T, NIIMI K, TAKAHASHI E. Serum matrix metalloproteinase 9 (MMP9) as a biochemical marker for wasting marmoset syndrome. J Vet Med Sci 2016; 78:837-43. [PMID: 26876041 PMCID: PMC4905840 DOI: 10.1292/jvms.15-0675] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Accepted: 01/27/2016] [Indexed: 01/11/2023] Open
Abstract
Use of the common marmoset (Callithrix jacchus) as a non-human primate experimental animal has increased in recent years. Although wasting marmoset syndrome (WMS) is one of the biggest problems in captive marmoset colonies, the molecular mechanisms, biochemical markers for accurate diagnosis and a reliable treatment remain unknown. In this study, as a first step to finding biochemical marker(s) for the accurate diagnosis of WMS, we conducted blood cell counts, including hematocrit, hemoglobin and platelets, and examined serum chemistry values, including albumin, calcium and levels of serum matrix metalloproteinase 9 (MMP9), using a colony of marmosets with and without weight loss. MMP9 is thought to be an enzyme responsible for the degradation of extracellular matrix components and participates in the pathogenesis of inflammatory conditions, such as human and murine inflammatory bowel disease, which, like WMS, are characterized histologically by inflammatory cell infiltrations in the intestines. The values of hematocrit and hemoglobin and levels of serum albumin and calcium in the WMS group were significantly decreased versus the control group. The platelet values and serum MMP9 concentrations were increased significantly in the WMS group compared with the control group. MMP9 could be a new and useful marker for the diagnosis of WMS in addition to hematocrit, hemoglobin, serum albumin and calcium. Our results also indicate that MMP9 could be a useful molecular candidate for treatment.
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Affiliation(s)
- Takuro YOSHIMOTO
- Research Resources Center, RIKEN Brain Science Institute,
2–1 Hirosawa, Wako, Saitama 351–0198, Japan
| | - Kimie NIIMI
- Research Resources Center, RIKEN Brain Science Institute,
2–1 Hirosawa, Wako, Saitama 351–0198, Japan
| | - Eiki TAKAHASHI
- Research Resources Center, RIKEN Brain Science Institute,
2–1 Hirosawa, Wako, Saitama 351–0198, Japan
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Zhang J, Ding L, Wang B, Ren G, Sun A, Deng C, Wei X, Mani S, Wang Z, Dou W. Notoginsenoside R1 attenuates experimental inflammatory bowel disease via pregnane X receptor activation. J Pharmacol Exp Ther 2015; 352:315-24. [PMID: 25472953 PMCID: PMC4293438 DOI: 10.1124/jpet.114.218750] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 12/02/2014] [Indexed: 12/15/2022] Open
Abstract
Notoginsenoside R1 (R1) is the main bioactive component in Panax notoginseng, an old herb medicine widely used in Asian countries in the treatment of microcirculatory diseases. However, little is known about the effect of R1 on inflammatory bowel disease (IBD). The present study demonstrated that R1 alleviated the severity of dextran sulfate sodium-induced colitis in mice by decreasing the activity of myeloperoxidase, the production of cytokines, the expression of proinflammatory genes, and the phosphorylation of IκB kinase, IκBα, and p65 in the colon. Further studies indicated that R1 dose-dependently activated human/mouse pregnane X receptor (PXR), a known target for decreasing inflammation in IBD, and upregulated the expression of genes involved in xenobiotic metabolism in colorectal cells and the colon. Ligand pocket-filling mutant (S247W/C284W or S247W/C284W/S208W) of the human PXR abrogated the effect of R1 on PXR activation. Time-resolved fluorescence resonance energy transfer PXR competitive binding assay confirmed R1 (ligand) binding affinity. In addition, PXR overexpression inhibited nuclear factor-κB (NF-κB)-luciferase activity, which was potentiated by R1 treatment. PXR knockdown by small interfering RNA demonstrated the necessity of PXR in R1-induced upregulation of the expression of xenobiotic-metabolizing enzymes and downregulation of NF-κB activity. Finally, the anti-inflammatory effect of R1 was confirmed in trinitrobenzene sulfonic acid-induced colitis in mice. These findings suggest that R1 attenuates experimental IBD possibly via the activation of intestinal PXR signaling.
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Affiliation(s)
- Jingjing Zhang
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China (J.Z., L.D., G.R., A.S., C.D., X.W., Z.W., W.D.); Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (B.W.); and Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, New York (S.M.)
| | - Lili Ding
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China (J.Z., L.D., G.R., A.S., C.D., X.W., Z.W., W.D.); Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (B.W.); and Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, New York (S.M.)
| | - Baocan Wang
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China (J.Z., L.D., G.R., A.S., C.D., X.W., Z.W., W.D.); Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (B.W.); and Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, New York (S.M.)
| | - Gaiyan Ren
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China (J.Z., L.D., G.R., A.S., C.D., X.W., Z.W., W.D.); Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (B.W.); and Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, New York (S.M.)
| | - Aning Sun
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China (J.Z., L.D., G.R., A.S., C.D., X.W., Z.W., W.D.); Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (B.W.); and Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, New York (S.M.)
| | - Chao Deng
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China (J.Z., L.D., G.R., A.S., C.D., X.W., Z.W., W.D.); Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (B.W.); and Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, New York (S.M.)
| | - Xiaohui Wei
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China (J.Z., L.D., G.R., A.S., C.D., X.W., Z.W., W.D.); Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (B.W.); and Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, New York (S.M.)
| | - Sridhar Mani
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China (J.Z., L.D., G.R., A.S., C.D., X.W., Z.W., W.D.); Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (B.W.); and Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, New York (S.M.)
| | - Zhengtao Wang
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China (J.Z., L.D., G.R., A.S., C.D., X.W., Z.W., W.D.); Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (B.W.); and Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, New York (S.M.)
| | - Wei Dou
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China (J.Z., L.D., G.R., A.S., C.D., X.W., Z.W., W.D.); Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (B.W.); and Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, New York (S.M.)
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Lu S, Morris VB, Labhasetwar V. Codelivery of DNA and siRNA via arginine-rich PEI-based polyplexes. Mol Pharm 2015; 12:621-9. [PMID: 25591125 DOI: 10.1021/mp5006883] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In this study, we formulated polyplexes with different compositions for codelivery of DNA and small-interfering RNA (siRNA). Since DNA and siRNA have distinctive and complementary morphological characteristics (DNA is long and winding and siRNA is short and rigid), we hypothesized that their codelivery using polyplex would enhance each other's transfection. To test this hypothesis, cationic polymer branched polyethylenimine (bPEI) as a standard transfecting agent and its derivative arginine-rich oligopeptide-grafted bPEI modified with polyethylene glycol (P(SiDAAr)5P3), synthesized in our laboratory, were used as carriers for transfection. Polyplexes at different nucleic acid to polymer weight ratios were characterized for transfection in breast cancer sensitive (MCF-7) and resistant (MCF-7/Adr) cell lines. Gene silencing effect of polyplexes was determined in MDA-MB-231-luc-D3H2LN cell line. The results demonstrated that the polyplexes formed with derivative P(SiDAAr)5P3 show significantly lower toxicity compared to polyplexes formed using bPEI. Further, codelivery resulted in 20-fold higher DNA transfection and 2-fold higher siRNA transfection as compared to the respective single nucleotide delivery. DNA transfection was ∼100-fold lower in resistant MCF-7/Adr cells than in sensitive MCF-7 cells. Confocal imaging and flow cytometry data demonstrated that enhanced transfection does not solely depend on DNA's cellular uptake, suggesting that other mechanisms contribute to increased transfection. DNA-co-siRNA delivery could be a promising therapeutic approach to achieve synergistic effects because it can simultaneously target and interfere with multiple regulatory levels in a cell to halt and reverse disease progression.
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Affiliation(s)
- Shan Lu
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic , Cleveland, Ohio 44195, United States
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Dou W, Zhang J, Ren G, Ding L, Sun A, Deng C, Wu X, Wei X, Mani S, Wang Z. Mangiferin attenuates the symptoms of dextran sulfate sodium-induced colitis in mice via NF-κB and MAPK signaling inactivation. Int Immunopharmacol 2014; 23:170-8. [PMID: 25194678 DOI: 10.1016/j.intimp.2014.08.025] [Citation(s) in RCA: 112] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Revised: 08/06/2014] [Accepted: 08/26/2014] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder of the gastrointestinal (GI) tract, and currently no curative treatment is available. Mangiferin, a natural glucosylxanthone mainly from the fruit, leaves and stem bark of a mango tree, has a strong anti-inflammatory activity. We sought to investigate whether mangiferin attenuates inflammation in a mouse model of chemically induced IBD. Pre-administration of mangiferin significantly attenuated dextran sulfate sodium (DSS)-induced body weight loss, diarrhea, colon shortening and histological injury, which correlated with the decline in the activity of myeloperoxidase (MPO) and the level of tumor necrosis factor-α (TNF-α) in the colon. DSS-induced degradation of inhibitory κBα (IκBα) and the phosphorylation of nuclear factor-kappa B (NF-κB) p65 as well as the mRNA expression of pro-inflammatory mediators (inducible NO synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1), TNF-α, interleukin-1β (IL-1β) and IL-6) in the colon were also downregulated by mangiferin treatment. Additionally, the phosphorylation/activation of DSS-induced mitogen-activated protein kinase (MAPK) proteins was also inhibited by mangiferin treatment. In accordance with the in vivo results, mangiferin exposure blocked TNF-α-stimulated nuclear translocation of NF-κB in RAW264.7 mouse macrophage cells. Transient transfection gene reporter assay performed in TNF-α-stimulated HT-29 human colorectal adenocarcinoma cells indicated that mangiferin inhibits NF-κB transcriptional activity in a dose-dependent manner. The current study clearly demonstrates a protective role for mangiferin in experimental IBD through NF-κB and MAPK signaling inhibition. Since mangiferin is a natural compound with little toxicity, the results may contribute to the effective utilization of mangiferin in the treatment of human IBD.
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Affiliation(s)
- Wei Dou
- Shanghai Key Laboratory of Formulated Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jingjing Zhang
- Shanghai Key Laboratory of Formulated Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Gaiyan Ren
- Shanghai Key Laboratory of Formulated Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Lili Ding
- Shanghai Key Laboratory of Formulated Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Aning Sun
- Shanghai Key Laboratory of Formulated Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Chao Deng
- Shanghai Key Laboratory of Formulated Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiaojun Wu
- Shanghai Key Laboratory of Formulated Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiaohui Wei
- Shanghai Key Laboratory of Formulated Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Sridhar Mani
- Department of Medicine, Albert Einstein College of Medicine, NY 10461, USA
| | - Zhengtao Wang
- Shanghai Key Laboratory of Formulated Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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Dou W, Zhang J, Li H, Kortagere S, Sun K, Ding L, Ren G, Wang Z, Mani S. Plant flavonol isorhamnetin attenuates chemically induced inflammatory bowel disease via a PXR-dependent pathway. J Nutr Biochem 2014; 25:923-33. [PMID: 24913217 DOI: 10.1016/j.jnutbio.2014.04.006] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2014] [Revised: 03/25/2014] [Accepted: 04/08/2014] [Indexed: 12/13/2022]
Abstract
Isorhamnetin is an O-methylated flavonol present in fruit and vegetables. We recently reported the identification of isorhamnetin as an activator of the human pregnane X receptor (PXR), a known target for abrogating inflammation in inflammatory bowel disease (IBD). The current study investigated the role of isorhamnetin as a putative mouse PXR activator in ameliorating chemically induced IBD. Using two different models (ulcerative colitis like and Crohn's disease like) of experimental IBD in mice, we demonstrated that isorhamnetin abrogated inflammation through inhibiting the activity of myeloperoxidase, the levels of TNF-α and IL-6, the mRNA expression of proinflammatory mediators (iNOS, ICAM-1, COX2, TNF-α, IL-2 and IL-6) and the phosphorylation of IκBα and NF-κB p65. PXR gene overexpression inhibited NF-κB luciferase activity, and the inhibition was potentiated by isorhamnetin treatment. PXR knockdown by siRNA demonstrated the necessity for PXR in isorhamnetin-mediated up-regulation of xenobiotic metabolism genes. Ligand pocket-filling mutants (S247W/C284W and S247W/C284W/S208W) of human PXR weakened the effect of isorhamnetin on PXR activation. Molecular docking studies and time-resolved fluorescence resonance energy transfer competitive binding assays confirmed the ligand (isorhamnetin)-binding affinity. These results clearly demonstrated the ameliorating effect of isorhamnetin on experimental IBD via PXR-mediated up-regulation of xenobiotic metabolism and down-regulation of NF-κB signaling. The novel findings may contribute to the effective utilization of isorhamnetin or its derivatives as a PXR ligand in the treatment of human IBD.
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Affiliation(s)
- Wei Dou
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Jingjing Zhang
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Hao Li
- Departments of Medicine and Genetics, Albert Einstein College of Medicine, NY 10461, USA
| | - Sandhya Kortagere
- Department of Microbiology and Immunology, Drexel University College of Medicine, PA 19129, USA
| | - Katherine Sun
- Department of Pathology, Montefiore Medical Center, NY 10467, USA
| | - Lili Ding
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Gaiyan Ren
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Zhengtao Wang
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Sridhar Mani
- Departments of Medicine and Genetics, Albert Einstein College of Medicine, NY 10461, USA.
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Protective effect of naringenin against experimental colitis via suppression of Toll-like receptor 4/NF-κB signalling. Br J Nutr 2013; 110:599-608. [PMID: 23506745 DOI: 10.1017/s0007114512005594] [Citation(s) in RCA: 171] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Naringenin, one of the most abundant flavonoids in citrus, grapefruits and tomatoes, has been used as a traditional anti-inflammatory agent for centuries. However, the molecular mechanism of naringenin in intestinal inflammation remains unknown so far. The present study investigated a molecular basis for the protective effect of naringenin in dextran sulphate sodium-induced murine colitis. Pre-administration of naringenin significantly reduced the severity of colitis and resulted in down-regulation of pro-inflammatory mediators (inducible NO synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1), cyclo-oxygenase-2 (Cox2), TNF-α and IL-6 mRNA) in the colon mucosa. The decline in the production of pro-inflammatory cytokines, specifically TNF-α and IL-6, correlated with a decrease in mucosal Toll-like receptor 4 (TLR4) mRNA and protein. Phospho-NF-κB p65 protein was significantly decreased, which correlated with a similar decrease in phospho-IκBα protein. Consistent with the in vivo results, naringenin exposure blocked lipopolysaccharide-stimulated nuclear translocation of NF-κB p65 in mouse macrophage RAW264.7 cells. In addition, in vitro NF-κB reporter assays performed on human colonic HT-29 cells exposed to naringenin demonstrated a significant inhibition of TNF-α-induced NF-κB luciferase expression. Thus, for the first time, the present study indicates that targeted inhibition of the TLR4/NF-κB signalling pathway might be an important mechanism for naringenin in abrogating experimental colitis.
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Majowicz A, van der Marel S, te Velde AA, Meijer SL, Petry H, van Deventer SJ, Ferreira V. Murine CD4⁺CD25⁻ cells activated in vitro with PMA/ionomycin and anti-CD3 acquire regulatory function and ameliorate experimental colitis in vivo. BMC Gastroenterol 2012. [PMID: 23198878 PMCID: PMC3536706 DOI: 10.1186/1471-230x-12-172] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background Induced regulatory T (iTreg) lymphocytes show promise for application in the treatment of allergic, autoimmune and inflammatory disorders. iTreg cells demonstrate advantages over natural Treg (nTreg) cells in terms of increased number of starting population and greater potential to proliferate. Different activation methods to generate iTreg cells result in iTreg cells that are heterogeneous in phenotype and mechanisms of suppression. Therefore it is of interest to explore new techniques to generate iTreg cells and to determine their physiological relevance. Methods Using phorbol myristate acetate (PMA)/ionomycin and anti-CD3 activation of CD4+CD25- cells we generated in vitro functional CD4+CD25+ iTreg (TregPMA) cells. Functionality of the generated TregPMA cells was tested in vivo in a mouse model of inflammatory bowel disease (IBD) - CD45RB transfer colitis model. Results TregPMA cells expressed regulatory markers and proved to ameliorate the disease phenotype in murine CD45RB transfer colitis model. The body weight loss and disease activity scores for TregPMA treated mice were reduced when compared to diseased control group. Histological assessment of colon sections confirmed amelioration of the disease phenotype. Additionally, cytokine analysis showed decreased levels of proinflammatory colonic and plasma IL-6, colonic IL-1 β and higher levels of colonic IL-17 when compared to diseased control group. Conclusions This study identifies a new method to generate in vitro iTreg cells (TregPMA cells) which physiological efficacy has been demonstrated in vivo.
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Affiliation(s)
- Anna Majowicz
- Research and Development, uniQure BV, Meibergdreef 61, 1105 BA, Amsterdam, The Netherlands.
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Műzes G, Molnár B, Sipos F. Regulatory T cells in inflammatory bowel diseases and colorectal cancer. World J Gastroenterol 2012; 18:5688-5694. [PMID: 23155308 PMCID: PMC3484336 DOI: 10.3748/wjg.v18.i40.5688] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2012] [Revised: 04/06/2012] [Accepted: 04/12/2012] [Indexed: 02/06/2023] Open
Abstract
Regulatory T cells (T(regs)) are key elements in immunological self-tolerance. The number of T(regs) may alter in both peripheral blood and in colonic mucosa during pathological circumstances. The local cellular, microbiological and cytokine milieu affect immunophenotype and function of T(regs). Forkhead box P3+ T(regs) function shows altered properties in inflammatory bowel diseases (IBDs). This alteration of T(regs) function can furthermore be observed between Crohn's disease and ulcerative colitis, which may have both clinical and therapeutical consequences. Chronic mucosal inflammation may also influence T(regs) function, which together with the intestinal bacterial flora seem to have a supporting role in colitis-associated colorectal carcinogenesis. T(regs) have a crucial role in the immunoevasion of cancer cells in sporadic colorectal cancer. Furthermore, their number and phenotype correlate closely with the clinical outcome of the disease, even if their contribution to carcinogenesis has previously been controversial. Despite knowledge of the clinical relationship between IBD and colitis-associated colon cancer, and the growing number of immunological aspects encompassing sporadic colorectal carcinogenesis, the molecular and cellular links amongst T(regs), regulation of the inflammation, and cancer development are still not well understood. In this paper, we aimed to review the current data surrounding the role of T(regs) in the pathogenesis of IBD, colitis-associated colon cancer and sporadic colorectal cancer.
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Affiliation(s)
- Györgyi Műzes
- 2nd Department of Internal Medicine, Semmelweis University, 1088 Budapest, Hungary
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van der Marel S, Majowicz A, Kwikkers K, van Logtenstein R, te Velde AA, De Groot AS, Meijer SL, van Deventer SJ, Petry H, Hommes DW, Ferreira V. Adeno-associated virus mediated delivery of Tregitope 167 ameliorates experimental colitis. World J Gastroenterol 2012; 18:4288-99. [PMID: 22969191 PMCID: PMC3436043 DOI: 10.3748/wjg.v18.i32.4288] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2012] [Revised: 08/13/2012] [Accepted: 08/16/2012] [Indexed: 02/06/2023] Open
Abstract
AIM To explore the anti-inflammatory potential of adeno-associated virus-mediated delivery of Tregitope 167 in an experimental colitis model. METHODS The trinitrobenzene sulfonate (TNBS) model of induced colitis was used in Balb/c mice. Subsequently after intravenous adeno-associated virus-mediated regulatory T-cell epitopes (Tregitope) delivery, acute colitis was initiated by intra-rectal administration of 1.5 mg TNBS in 40% ethanol followed by a second treatment with TNBS (0.75 mg in 20% ethanol) 8 d later. Control groups included mice not treated with TNBS (healthy control group) and mice treated by TNBS only (diseased group). At the time of sacrifice colon weight, the disease activity index and histology damage score were determined. Immunohistochemical staining of the colonic tissues was performed to asses the cellular infiltrate and the presence of transcription factor forkhead Box-P3 (Foxp3). Thymus, mesenteric lymph nodes, liver and spleen tissue were collected and the corresponding lymphocyte populations were further assessed by flow cytometry analysis for the expression of CD4+ T cell and regulatory T cell associated markers. RESULTS The Tregitope 167 treated mice gained an average of 4% over their initial body weight at the time of sacrifice. In contrast, the mice treated with TNBS alone (no Tregitope) developed colitis, and lost 4% of their initial body weight at the time of sacrifice (P < 0.01). The body weight increase that had been observed in the mice pre-treated with Tregitope 167 was substantiated by a lower disease activity index and a decreased colon weight as compared to the diseased control group (P < 0.01 and P < 0.001, respectively). Immunohistochemical staining of the colonic tissues for CD4+ showed that inflammatory cell infiltrates were present in TNBS treated mice with or without administration with tregitope 167 and that these cellular infiltrates consisted mainly of CD4+ cells. For both TNBS treated groups CD4+ T cell infiltrates were observed in the sub-epithelial layer and the lamina propria. CD4+ T cell infiltrates were also present in the muscularis mucosa layer of the diseased control mice, but were absent in the Tregitope 167 treated group. Numerous Foxp3 positive cells were detected in the lamina propria and sub-epithelium of the colon sections from mice treated with Tregitope 167. Furthermore, the Foxp3 and glycoprotein A repetitions predominant markers were significantly increased in the CD4+ T lymphocyte population in the thymus of the mice pre-treated with adeno-associated virus serotype 5 (cytomegalovirus promoter-Tregitope 167), as cytomegalovirus promoter compared to lymphocyte populations in the thymus of diseased and the healthy control mice (P < 0.05 and P < 0.001, respectively). CONCLUSION This study identifies adeno-associated virus-mediated delivery of regulatory T-cell epitope 167 as a novel anti-inflammatory approach with the capacity to decrease intestinal inflammation and induce long-term remission in inflammatory bowel disease.
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