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1
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Bakrania A, Mo Y, Zheng G, Bhat M. RNA nanomedicine in liver diseases. Hepatology 2025; 81:1847-1877. [PMID: 37725757 PMCID: PMC12077345 DOI: 10.1097/hep.0000000000000606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 09/08/2023] [Indexed: 09/21/2023]
Abstract
The remarkable impact of RNA nanomedicine during the COVID-19 pandemic has demonstrated the expansive therapeutic potential of this field in diverse disease contexts. In recent years, RNA nanomedicine targeting the liver has been paradigm-shifting in the management of metabolic diseases such as hyperoxaluria and amyloidosis. RNA nanomedicine has significant potential in the management of liver diseases, where optimal management would benefit from targeted delivery, doses titrated to liver metabolism, and personalized therapy based on the specific site of interest. In this review, we discuss in-depth the different types of RNA and nanocarriers used for liver targeting along with their specific applications in metabolic dysfunction-associated steatotic liver disease, liver fibrosis, and liver cancers. We further highlight the strategies for cell-specific delivery and future perspectives in this field of research with the emergence of small activating RNA, circular RNA, and RNA base editing approaches.
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Affiliation(s)
- Anita Bakrania
- Department of Medicine, Toronto General Hospital Research Institute, Toronto, Ontario, Canada
- Department of Medicine, Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Yulin Mo
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Gang Zheng
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Mamatha Bhat
- Department of Medicine, Toronto General Hospital Research Institute, Toronto, Ontario, Canada
- Department of Medicine, Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
- Department of Medicine, Division of Gastroenterology, University Health Network and University of Toronto, Toronto, Ontario, Canada
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2
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Lani R, Thariq IM, Suhaimi NS, Hassandarvish P, Abu Bakar S. From defense to offense: Modulating toll-like receptors to combat arbovirus infections. Hum Vaccin Immunother 2024; 20:2306675. [PMID: 38263674 PMCID: PMC11657068 DOI: 10.1080/21645515.2024.2306675] [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: 09/08/2023] [Revised: 01/08/2024] [Accepted: 01/14/2024] [Indexed: 01/25/2024] Open
Abstract
Arboviruses are a significant threat to global public health, with outbreaks occurring worldwide. Toll-like receptors (TLRs) play a crucial role in the innate immune response against these viruses by recognizing pathogen-associated molecular patterns and initiating an inflammatory response. Significantly, TLRs commonly implicated in the immune response against viral infections include TLR2, TLR4, TLR6, TLR3, TLR7, and TLR8; limiting or allowing them to replicate and spread within the host. Modulating TLRs has emerged as a promising approach to combat arbovirus infections. This review summarizes recent advances in TLR modulation as a therapeutic target in arbovirus infections. Studies have shown that the activation of TLRs can enhance the immune response against arbovirus infections, leading to increased viral clearance and protection against disease. Conversely, inhibition of TLRs can reduce the excessive inflammation and tissue damage associated with arbovirus infection. Modulating TLRs represents a potential therapeutic strategy to combat arbovirus infections.
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Affiliation(s)
- Rafidah Lani
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Ilya Maisarah Thariq
- Tropical Infectious Diseases Research and Education Centre, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Nuramira Syazreen Suhaimi
- Tropical Infectious Diseases Research and Education Centre, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Pouya Hassandarvish
- Tropical Infectious Diseases Research and Education Centre, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Sazaly Abu Bakar
- Tropical Infectious Diseases Research and Education Centre, Universiti Malaya, Kuala Lumpur, Malaysia
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3
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Alhamdan F, Bayarsaikhan G, Yuki K. Toll-like receptors and integrins crosstalk. Front Immunol 2024; 15:1403764. [PMID: 38915411 PMCID: PMC11194410 DOI: 10.3389/fimmu.2024.1403764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 05/24/2024] [Indexed: 06/26/2024] Open
Abstract
Immune system recognizes invading microbes at both pathogen and antigen levels. Toll-like receptors (TLRs) play a key role in the first-line defense against pathogens. Major functions of TLRs include cytokine and chemokine production. TLRs share common downstream signaling pathways with other receptors. The crosstalk revolving around TLRs is rather significant and complex, underscoring the intricate nature of immune system. The profiles of produced cytokines and chemokines via TLRs can be affected by other receptors. Integrins are critical heterodimeric adhesion molecules expressed on many different cells. There are studies describing synergetic or inhibitory interplay between TLRs and integrins. Thus, we reviewed the crosstalk between TLRs and integrins. Understanding the nature of the crosstalk could allow us to modulate TLR functions via integrins.
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Affiliation(s)
- Fahd Alhamdan
- Department of Anesthesiology, Critical Care and Pain Medicine, Cardiac Anesthesia, Boston Children’s Hospital, Boston, MA, United States
- Department of Anesthesia and Immunology, Harvard Medical School, Boston, MA, United States
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
| | - Ganchimeg Bayarsaikhan
- Department of Anesthesiology, Critical Care and Pain Medicine, Cardiac Anesthesia, Boston Children’s Hospital, Boston, MA, United States
- Department of Anesthesia and Immunology, Harvard Medical School, Boston, MA, United States
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
| | - Koichi Yuki
- Department of Anesthesiology, Critical Care and Pain Medicine, Cardiac Anesthesia, Boston Children’s Hospital, Boston, MA, United States
- Department of Anesthesia and Immunology, Harvard Medical School, Boston, MA, United States
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
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4
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Sioud M, Juzeniene A, Sæbøe-Larssen S. Exploring the Impact of mRNA Modifications on Translation Efficiency and Immune Tolerance to Self-Antigens. Vaccines (Basel) 2024; 12:624. [PMID: 38932353 PMCID: PMC11209393 DOI: 10.3390/vaccines12060624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 06/02/2024] [Accepted: 06/03/2024] [Indexed: 06/28/2024] Open
Abstract
Therapeutic modified mRNAs are being developed for a broad range of human diseases. However, the impact of potential miscoding of modified mRNAs on self-tolerance remains unknown. Additionally, more studies are needed to explore the effects of nucleoside alkylation on translation. While all six tested modifications are tolerated as substrates by T7 RNA polymerase and inhibited mRNA immunogenicity, the translation efficiency varied significantly depending on the type of modification. In contrast to methylation, ethylation at the N1 position of pseudouridine (Ψ) hindered translation, suggesting that the C5-C1' glycosidic bond alone is not a critical element for high translation. Inhibition of mRNA translation was also observed with 5-methoxyuridine modification. However, this inhibition was partially alleviated through the optimization of mRNA coding sequences. BALB/c mice immunized with syngeneic ψ-modified mRNA encoding for Wilms' tumor antigen-1 (WT1) developed a low but significant level of anti-WT1 IgG antibodies compared to those immunized with either unmodified or N1-methyl ψ-modified mRNA. Overall, the data indicate that adding a simple ethyl group (-CH2CH3) at the N1 position of ψ has a major negative effect on translation despite its reduced immunogenicity. Additionally, mRNA containing Ψ may alter translation fidelity at certain codons, which could lead to a breakdown of immune tolerance to self-antigens. This concern should be taken into account during gene replacement therapies, although it could benefit mRNA-based vaccines by generating a diverse repertoire of antigens.
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Affiliation(s)
- Mouldy Sioud
- Department of Cancer Immunology, Oslo University Hospital, Radiumhospitalet, Ullernchausseen 70, 0379 Oslo, Norway
| | - Asta Juzeniene
- Department of Radiation Biology, Oslo University Hospital, Radiumhospitalet, Ullernchausseen 70, 0379 Oslo, Norway;
| | - Stein Sæbøe-Larssen
- Department of cellular Therapy, Oslo University Hospital, Radiumhospitalet, Ullernchausseen 70, 0379 Oslo, Norway;
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5
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Wang T, Song D, Li X, Luo Y, Yang D, Liu X, Kong X, Xing Y, Bi S, Zhang Y, Hu T, Zhang Y, Dai S, Shao Z, Chen D, Hou J, Ballestar E, Cai J, Zheng F, Yang JY. MiR-574-5p activates human TLR8 to promote autoimmune signaling and lupus. Cell Commun Signal 2024; 22:220. [PMID: 38589923 PMCID: PMC11000404 DOI: 10.1186/s12964-024-01601-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Accepted: 03/28/2024] [Indexed: 04/10/2024] Open
Abstract
Endosomal single-stranded RNA-sensing Toll-like receptor-7/8 (TLR7/8) plays a pivotal role in inflammation and immune responses and autoimmune diseases. However, the mechanisms underlying the initiation of the TLR7/8-mediated autoimmune signaling remain to be fully elucidated. Here, we demonstrate that miR-574-5p is aberrantly upregulated in tissues of lupus prone mice and in the plasma of lupus patients, with its expression levels correlating with the disease activity. miR-574-5p binds to and activates human hTLR8 or its murine ortholog mTlr7 to elicit a series of MyD88-dependent immune and inflammatory responses. These responses include the overproduction of cytokines and interferons, the activation of STAT1 signaling and B lymphocytes, and the production of autoantigens. In a transgenic mouse model, the induction of miR-574-5p overexpression is associated with increased secretion of antinuclear and anti-dsDNA antibodies, increased IgG and C3 deposit in the kidney, elevated expression of inflammatory genes in the spleen. In lupus-prone mice, lentivirus-mediated silencing of miR-574-5p significantly ameliorates major symptoms associated with lupus and lupus nephritis. Collectively, these results suggest that the miR-574-5p-hTLR8/mTlr7 signaling is an important axis of immune and inflammatory responses, contributing significantly to the development of lupus and lupus nephritis.
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Affiliation(s)
- Tao Wang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'an, Xiamen, 361102, China
- The Key Laboratory of Urinary Tract Tumors and Calculi, Department of Urology, School of Medicine, The First Affiliated Hospital of Xiamen University, Xiamen University, Xiamen, 361003, China
| | - Dan Song
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'an, Xiamen, 361102, China
| | - Xuejuan Li
- Wuhu Hospital of East China Normal University, Wuhu, Anhui, 241000, China
- Kidney Health Institute, Health Science Center, East China Normal University, Minhang, Shanghai, 200241, China
- Department of Nephrology, The Second Hospital, Dalian Medical University, Dalian, 116144, China
| | - Yu Luo
- School of Nursing, The Third Military Medical University, Chongqing, 400038, China
| | - Dianqiang Yang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'an, Xiamen, 361102, China
| | - Xiaoyan Liu
- Department of Nephrology, The Second Hospital, Dalian Medical University, Dalian, 116144, China
| | - Xiaodan Kong
- Department of Rheumatology, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China
| | - Yida Xing
- Department of Rheumatology, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China
| | - Shulin Bi
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'an, Xiamen, 361102, China
| | - Yan Zhang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'an, Xiamen, 361102, China
| | - Tao Hu
- College of Medicine, Xiamen University, Xiang'an, Xiamen, 361102, China
| | - Yunyun Zhang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'an, Xiamen, 361102, China
| | - Shuang Dai
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'an, Xiamen, 361102, China
| | - Zhiqiang Shao
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'an, Xiamen, 361102, China
| | - Dahan Chen
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'an, Xiamen, 361102, China
| | - Jinpao Hou
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'an, Xiamen, 361102, China
| | - Esteban Ballestar
- Wuhu Hospital of East China Normal University, Wuhu, Anhui, 241000, China
- Kidney Health Institute, Health Science Center, East China Normal University, Minhang, Shanghai, 200241, China
- Epigenetics and Immune Disease Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, 08916, Spain
| | - Jianchun Cai
- Department of Gastrointestinal Surgery, Institute of Gastrointestinal Oncology, Zhongshan Hospital of Xiamen University, Medical College of Xiamen University, Xiamen, Fujian, 361005, China.
| | - Feng Zheng
- Wuhu Hospital of East China Normal University, Wuhu, Anhui, 241000, China.
- Kidney Health Institute, Health Science Center, East China Normal University, Minhang, Shanghai, 200241, China.
- Department of Nephrology, The Second Hospital, Dalian Medical University, Dalian, 116144, China.
- The Advanced Institute for Molecular Medicine, Dalian Medical University, Dalian, 116144, China.
| | - James Y Yang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'an, Xiamen, 361102, China.
- Wuhu Hospital of East China Normal University, Wuhu, Anhui, 241000, China.
- Kidney Health Institute, Health Science Center, East China Normal University, Minhang, Shanghai, 200241, China.
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Neary MT, Mulder LM, Kowalski PS, MacLoughlin R, Crean AM, Ryan KB. Nebulised delivery of RNA formulations to the lungs: From aerosol to cytosol. J Control Release 2024; 366:812-833. [PMID: 38101753 DOI: 10.1016/j.jconrel.2023.12.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 12/04/2023] [Accepted: 12/08/2023] [Indexed: 12/17/2023]
Abstract
In the past decade RNA-based therapies such as small interfering RNA (siRNA) and messenger RNA (mRNA) have emerged as new and ground-breaking therapeutic agents for the treatment and prevention of many conditions from viral infection to cancer. Most clinically approved RNA therapies are parenterally administered which impacts patient compliance and adds to healthcare costs. Pulmonary administration via inhalation is a non-invasive means to deliver RNA and offers an attractive alternative to injection. Nebulisation is a particularly appealing method due to the capacity to deliver large RNA doses during tidal breathing. In this review, we discuss the unique physiological barriers presented by the lung to efficient nebulised RNA delivery and approaches adopted to circumvent this problem. Additionally, the different types of nebulisers are evaluated from the perspective of their suitability for RNA delivery. Furthermore, we discuss recent preclinical studies involving nebulisation of RNA and analysis in in vitro and in vivo settings. Several studies have also demonstrated the importance of an effective delivery vector in RNA nebulisation therefore we assess the variety of lipid, polymeric and hybrid-based delivery systems utilised to date. We also consider the outlook for nebulised RNA medicinal products and the hurdles which must be overcome for successful clinical translation. In summary, nebulised RNA delivery has demonstrated promising potential for the treatment of several lung-related conditions such as asthma, COPD and cystic fibrosis, to which the mode of delivery is of crucial importance for clinical success.
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Affiliation(s)
- Michael T Neary
- SSPC, The SFI Research Centre for Pharmaceuticals, School of Pharmacy, University College Cork, Ireland; School of Pharmacy, University College Cork, Ireland
| | | | - Piotr S Kowalski
- School of Pharmacy, University College Cork, Ireland; APC Microbiome, University College Cork, Cork, Ireland
| | | | - Abina M Crean
- SSPC, The SFI Research Centre for Pharmaceuticals, School of Pharmacy, University College Cork, Ireland; School of Pharmacy, University College Cork, Ireland
| | - Katie B Ryan
- SSPC, The SFI Research Centre for Pharmaceuticals, School of Pharmacy, University College Cork, Ireland; School of Pharmacy, University College Cork, Ireland.
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7
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Chemical optimization of siRNA for safe and efficient silencing of placental sFLT1. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 29:135-149. [PMID: 35847173 PMCID: PMC9263991 DOI: 10.1016/j.omtn.2022.06.009] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 06/15/2022] [Indexed: 11/21/2022]
Abstract
Preeclampsia (PE) is a rising, potentially lethal complication of pregnancy. PE is driven primarily by the overexpression of placental soluble fms-like tyrosine kinase 1 (sFLT1), a validated diagnostic and prognostic marker of the disease when normalized to placental growth factor (PlGF) levels. Injecting cholesterol-conjugated, fully modified, small interfering RNAs (siRNAs) targeting sFLT1 mRNA into pregnant mice or baboons reduces placental sFLT1 and ameliorates clinical signs of PE, providing a strong foundation for the development of a PE therapeutic. siRNA delivery, potency, and safety are dictated by conjugate chemistry, siRNA duplex structure, and chemical modification pattern. Here, we systematically evaluate these parameters and demonstrate that increasing 2'-O-methyl modifications and 5' chemical stabilization and using sequence-specific duplex asymmetry and a phosphocholine-docosanoic acid conjugate enhance placental accumulation, silencing efficiency and safety of sFLT1-targeting siRNAs. The optimization strategy here provides a framework for the chemical optimization of siRNAs for PE as well as other targets and clinical indications.
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8
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Davodabadi F, Sarhadi M, Arabpour J, Sargazi S, Rahdar A, Díez-Pascual AM. Breast cancer vaccines: New insights into immunomodulatory and nano-therapeutic approaches. J Control Release 2022; 349:844-875. [PMID: 35908621 DOI: 10.1016/j.jconrel.2022.07.036] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 07/23/2022] [Accepted: 07/25/2022] [Indexed: 10/16/2022]
Abstract
Breast cancer (BC) is known to be a highly heterogeneous disease that is clinically subdivided into four primary molecular subtypes, each having distinct morphology and clinical implications. These subtypes are principally defined by hormone receptors and other proteins involved (or not involved) in BC development. BC therapeutic vaccines [including peptide-based vaccines, protein-based vaccines, nucleic acid-based vaccines (DNA/RNA vaccines), bacterial/viral-based vaccines, and different immune cell-based vaccines] have emerged as an appealing class of cancer immunotherapeutics when used alone or combined with other immunotherapies. Employing the immune system to eliminate BC cells is a novel therapeutic modality. The benefit of active immunotherapies is that they develop protection against neoplastic tissue and readjust the immune system to an anti-tumor monitoring state. Such immunovaccines have not yet shown effectiveness for BC treatment in clinical trials. In recent years, nanomedicines have opened new windows to increase the effectiveness of vaccinations to treat BC. In this context, some nanoplatforms have been designed to efficiently deliver molecular, cellular, or subcellular vaccines to BC cells, increasing the efficacy and persistence of anti-tumor immunity while minimizing undesirable side effects. Immunostimulatory nano-adjuvants, liposomal-based vaccines, polymeric vaccines, virus-like particles, lipid/calcium/phosphate nanoparticles, chitosan-derived nanostructures, porous silicon microparticles, and selenium nanoparticles are among the newly designed nanostructures that have been used to facilitate antigen internalization and presentation by antigen-presenting cells, increase antigen stability, enhance vaccine antigenicity and remedial effectivity, promote antigen escape from the endosome, improve cytotoxic T lymphocyte responses, and produce humoral immune responses in BC cells. Here, we summarized the existing subtypes of BC and shed light on immunomodulatory and nano-therapeutic strategies for BC vaccination. Finally, we reviewed ongoing clinical trials on BC vaccination and highlighted near-term opportunities for moving forward.
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Affiliation(s)
- Fatemeh Davodabadi
- Department of Biology, Faculty of Basic Science, Payame Noor University, Tehran, Iran
| | - Mohammad Sarhadi
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran
| | - Javad Arabpour
- Department of Microbiology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Saman Sargazi
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran.
| | - Abbas Rahdar
- Department of Physics, University of Zabol, Zabol 98613-35856, Iran.
| | - Ana M Díez-Pascual
- Universidad de Alcalá, Facultad de Ciencias, Departamento de Química Analítica, Química Física e Ingeniería Química, Ctra. Madrid-Barcelona, Km. 33.6, 28805 Alcalá de Henares, Madrid, Spain.
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9
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Sargazi S, Arshad R, Ghamari R, Rahdar A, Bakhshi A, Karkan SF, Ajalli N, Bilal M, Díez-Pascual AM. siRNA-based nanotherapeutics as emerging modalities for immune-mediated diseases: A preliminary review. Cell Biol Int 2022; 46:1320-1344. [PMID: 35830711 PMCID: PMC9543380 DOI: 10.1002/cbin.11841] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 06/01/2022] [Accepted: 06/09/2022] [Indexed: 11/21/2022]
Abstract
Immune‐mediated diseases (IMDs) are chronic conditions that have an immune‐mediated etiology. Clinically, these diseases appear to be unrelated, but pathogenic pathways have been shown to connect them. While inflammation is a common occurrence in the body, it may either stimulate a favorable immune response to protect against harmful signals or cause illness by damaging cells and tissues. Nanomedicine has tremendous promise for regulating inflammation and treating IMIDs. Various nanoparticles coated with nanotherapeutics have been recently fabricated for effective targeted delivery to inflammatory tissues. RNA interference (RNAi) offers a tremendous genetic approach, particularly if traditional treatments are ineffective against IMDs. In cells, several signaling pathways can be suppressed by using RNAi, which blocks the expression of particular messenger RNAs. Using this molecular approach, the undesirable effects of anti‐inflammatory medications can be reduced. Still, there are many problems with using short‐interfering RNAs (siRNAs) to treat IMDs, including poor localization of the siRNAs in target tissues, unstable gene expression, and quick removal from the blood. Nanotherapeutics have been widely used in designing siRNA‐based carriers because of the restricted therapy options for IMIDs. In this review, we have discussed recent trends in the fabrication of siRNA nanodelivery systems, including lipid‐based siRNA nanocarriers, liposomes, and cationic lipids, stable nucleic acid‐lipid particles, polymeric‐based siRNA nanocarriers, polyethylenimine (PEI)‐based nanosystems, chitosan‐based nanoformulations, inorganic material‐based siRNA nanocarriers, and hybrid‐based delivery systems. We have also introduced novel siRNA‐based nanocarriers to control IMIDs, such as pulmonary inflammation, psoriasis, inflammatory bowel disease, ulcerative colitis, rheumatoid arthritis, etc. This study will pave the way for new avenues of research into the diagnosis and treatment of IMDs.
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Affiliation(s)
- Saman Sargazi
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Rabia Arshad
- Department of Pharmacy, Quaid-i-Azam University Islamabad, Islamabad, Pakistan
| | - Reza Ghamari
- Department of Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Abbas Rahdar
- Department of Physics, University of Zabol, Zabol, Iran
| | - Ali Bakhshi
- School of Physics, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran
| | - Sonia Fathi Karkan
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences Tabriz University of Medical Sciences, Tabriz, Iran
| | - Narges Ajalli
- Department of Chemical Engineering, Faculty of Engineering, University of Tehran, Tehran, Iran
| | - Muhammad Bilal
- School of Life Science and Food Engineering, Huaiyin Institute of Technology, Huaian, China
| | - Ana M Díez-Pascual
- Universidad de Alcalá, Facultad de Ciencias, Departamento de Quimica Analítica, Química Física e Ingeniería Química, Ctra. Madrid-Barcelona, Alcalá de Henares, Madrid, Spain
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10
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Komal S, Komal N, Mujtaba A, Wang SH, Zhang LR, Han SN. Potential therapeutic strategies for myocardial infarction: the role of Toll-like receptors. Immunol Res 2022; 70:607-623. [PMID: 35608723 DOI: 10.1007/s12026-022-09290-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 05/06/2022] [Indexed: 11/27/2022]
Abstract
Myocardial infarction (MI) is a life-threatening condition among patients with cardiovascular diseases. MI increases the risk of stroke and heart failure and is a leading cause of morbidity and mortality worldwide. Several genetic and epigenetic factors contribute to the development of MI, suggesting that further understanding of the pathomechanism of MI might help in the early management and treatment of this disease. Toll-like receptors (TLRs) are well-known members of the pattern recognition receptor (PRR) family and contribute to both adaptive and innate immunity. Collectively, studies suggest that TLRs have a cardioprotective effect. However, prolonged TLR activation in the response to signals generated by damage-associated molecular patterns (DAMPs) results in the release of inflammatory cytokines and contributes to the development and exacerbation of myocardial inflammation, MI, ischemia-reperfusion injury, myocarditis, and heart failure. The objective of this review is to discuss and summarize the association of TLRs with MI, highlighting their therapeutic potential for the development of advanced TLR-targeted therapies for MI.
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Affiliation(s)
- Sumra Komal
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Nimrah Komal
- Department of Pharmacology, Mohi-Ud-Din Islamic Medical College, Azad Jammu & Kashmir, Mirpur, 10250, Pakistan
| | - Ali Mujtaba
- Department of Pharmacology, Mohi-Ud-Din Islamic Medical College, Azad Jammu & Kashmir, Mirpur, 10250, Pakistan
| | - Shu-Hui Wang
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Li-Rong Zhang
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Sheng-Na Han
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China.
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11
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Guo-Parke H, Linden D, Weldon S, Kidney JC, Taggart CC. Deciphering Respiratory-Virus-Associated Interferon Signaling in COPD Airway Epithelium. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:121. [PMID: 35056429 PMCID: PMC8781535 DOI: 10.3390/medicina58010121] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/08/2022] [Accepted: 01/11/2022] [Indexed: 01/08/2023]
Abstract
COPD is a chronic lung disorder characterized by a progressive and irreversible airflow obstruction, and persistent pulmonary inflammation. It has become a global epidemic affecting 10% of the population, and is the third leading cause of death worldwide. Respiratory viruses are a primary cause of COPD exacerbations, often leading to secondary bacterial infections in the lower respiratory tract. COPD patients are more susceptible to viral infections and associated severe disease, leading to accelerated lung function deterioration, hospitalization, and an increased risk of mortality. The airway epithelium plays an essential role in maintaining immune homeostasis, and orchestrates the innate and adaptive responses of the lung against inhaled and pathogen insults. A healthy airway epithelium acts as the first line of host defense by maintaining barrier integrity and the mucociliary escalator, secreting an array of inflammatory mediators, and initiating an antiviral state through the interferon (IFN) response. The airway epithelium is a major site of viral infection, and the interaction between respiratory viruses and airway epithelial cells activates host defense mechanisms, resulting in rapid virus clearance. As such, the production of IFNs and the activation of IFN signaling cascades directly contributes to host defense against viral infections and subsequent innate and adaptive immunity. However, the COPD airway epithelium exhibits an altered antiviral response, leading to enhanced susceptibility to severe disease and impaired IFN signaling. Despite decades of research, there is no effective antiviral therapy for COPD patients. Herein, we review current insights into understanding the mechanisms of viral evasion and host IFN antiviral defense signaling impairment in COPD airway epithelium. Understanding how antiviral mechanisms operate in COPD exacerbations will facilitate the discovery of potential therapeutic interventions to reduce COPD hospitalization and disease severity.
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Affiliation(s)
- Hong Guo-Parke
- Wellcome Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queens University Belfast, Belfast BT9 7AE, UK; (H.G.-P.); (D.L.); (S.W.)
| | - Dermot Linden
- Wellcome Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queens University Belfast, Belfast BT9 7AE, UK; (H.G.-P.); (D.L.); (S.W.)
| | - Sinéad Weldon
- Wellcome Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queens University Belfast, Belfast BT9 7AE, UK; (H.G.-P.); (D.L.); (S.W.)
| | - Joseph C. Kidney
- Department of Respiratory Medicine, Mater Hospital Belfast, Belfast BT14 6AB, UK;
| | - Clifford C. Taggart
- Wellcome Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queens University Belfast, Belfast BT9 7AE, UK; (H.G.-P.); (D.L.); (S.W.)
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12
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Naik R, Peden K. Regulatory Considerations on the Development of mRNA Vaccines. Curr Top Microbiol Immunol 2022; 440:187-205. [PMID: 32638114 DOI: 10.1007/82_2020_220] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Developing traditional viral vaccines for infectious diseases usually takes years, as these are usually produced either by chemical inactivation of the virus or attenuation of the pathogen, processes that can take considerable time to validate and also require the live pathogen. With the advent of nucleic-acid vaccines (DNA and mRNA), the time to vaccine design and production is considerably shortened, since once the platform has been established, all that is required is the sequence of the antigen gene, its synthesis and insertion into an appropriate expression vector; importantly, no infectious virus is required. mRNA vaccines have some advantages over DNA vaccines, such as expression in non-dividing cells and the absence of the perceived risk of integration into host genome. Also, generally lower doses are required to induce the immune response. Based on experience in recent clinical trials, mRNA-based vaccines are a promising novel platform that might be useful for the development of vaccines against emerging pandemic infectious diseases. This chapter discusses some of the specific issues that mRNA vaccines raise with respect to production, quality, safety and efficacy, and how they have been addressed so as to allow their evaluation in clinical trials.
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Affiliation(s)
- Ramachandra Naik
- Division of Vaccines and Related Products Applications, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Building 71, Room 3045, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA
| | - Keith Peden
- Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Building 52/72, Room 1220, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.
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13
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Chen Y, Lin J, Zhao Y, Ma X, Yi H. Toll-like receptor 3 (TLR3) regulation mechanisms and roles in antiviral innate immune responses. J Zhejiang Univ Sci B 2021; 22:609-632. [PMID: 34414698 PMCID: PMC8377577 DOI: 10.1631/jzus.b2000808] [Citation(s) in RCA: 109] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 04/09/2021] [Accepted: 04/09/2021] [Indexed: 01/08/2023]
Abstract
Toll-like receptor 3 (TLR3) is a member of the TLR family, mediating the transcriptional induction of type I interferons (IFNs), proinflammatory cytokines, and chemokines, thereby collectively establishing an antiviral host response. Studies have shown that unlike other TLR family members, TLR3 is the only RNA sensor that is utterly dependent on the Toll-interleukin-1 receptor (TIR)-domain-containing adaptor-inducing IFN-β (TRIF). However, the details of how the TLR3-TRIF signaling pathway works in an antiviral response and how it is regulated are unclear. In this review, we focus on recent advances in understanding the antiviral mechanism of the TRIF pathway and describe the essential characteristics of TLR3 and its antiviral effects. Advancing our understanding of TLR3 may contribute to disease diagnosis and could foster the development of novel treatments for viral diseases.
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Affiliation(s)
- Yujuan Chen
- College of Veterinary Medicine, Southwest University, Chongqing 402460, China
- Chongqing Veterinary Science Engineering Research Center, Chongqing 402460, China
| | - Junhong Lin
- College of Veterinary Medicine, Southwest University, Chongqing 402460, China
- Chongqing Veterinary Science Engineering Research Center, Chongqing 402460, China
| | - Yao Zhao
- College of Veterinary Medicine, Southwest University, Chongqing 402460, China
- Chongqing Veterinary Science Engineering Research Center, Chongqing 402460, China
| | - Xianping Ma
- College of Veterinary Medicine, Southwest University, Chongqing 402460, China
- Chongqing Veterinary Science Engineering Research Center, Chongqing 402460, China
| | - Huashan Yi
- College of Veterinary Medicine, Southwest University, Chongqing 402460, China.
- Chongqing Veterinary Science Engineering Research Center, Chongqing 402460, China.
- Immunology Research Center, Medical Research Institute, Southwest University, Chongqing 402460, China.
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14
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Gorabi AM, Kiaie N, Aslani S, Jamialahmadi T, Johnston TP, Sahebkar A. Prospects for the potential of RNA interference in the treatment of autoimmune diseases: Small interfering RNAs in the spotlight. J Autoimmun 2020; 114:102529. [PMID: 32782117 DOI: 10.1016/j.jaut.2020.102529] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 08/01/2020] [Accepted: 08/03/2020] [Indexed: 12/15/2022]
Abstract
The identification of RNA interference (RNAi) has caused a growing interest in harnessing its potential in the treatment of different diseases. Modulation of dysregulated genes through targeting by RNAi represents a potential approach with which to alter the biological pathways at a post-transcriptional level, especially as it pertains to autoimmunity and malignancy. Short hairpin RNAs (shRNA), short interfering RNAs (siRNA), and microRNAs (miRNA) are mainly involved as effector mechanisms in the targeting of RNAi biological pathways. The manipulation and delivery of these molecules in an efficient way promotes the specificity and stability of RNAi-based systems, while minimizing the unwanted adverse reactions by the immune system and reducing cytotoxicity and off-target effects. Advances made to date in identifying the etiopathogenesis of autoimmune diseases has prompted the utilization of RNAi-based systems in vitro and in vivo. Future investigations aimed at deciphering the molecular basis of RNAi and optimizing the delivery of RNAi-based targeting systems will hopefully promote the applicability of such regulatory mechanisms and, ultimately, transfer the acquired knowledge from bench-to-bedside to ameliorate human diseases. In this review, we seek to clarify the potential of RNAi, with a focus on siRNAs, in designing therapeutics for potential treatment of human autoimmune disorders.
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Affiliation(s)
- Armita Mahdavi Gorabi
- Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nasim Kiaie
- Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeed Aslani
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Tannaz Jamialahmadi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Food Science and Technology, Quchan Branch, Islamic Azad University, Quchan, Iran; Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Thomas P Johnston
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Amirhossein Sahebkar
- Halal Research Center of IRI, FDA, Tehran, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, 9177948564, Iran; Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland.
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15
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Harnessing the Complete Repertoire of Conventional Dendritic Cell Functions for Cancer Immunotherapy. Pharmaceutics 2020; 12:pharmaceutics12070663. [PMID: 32674488 PMCID: PMC7408110 DOI: 10.3390/pharmaceutics12070663] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 06/29/2020] [Accepted: 07/04/2020] [Indexed: 02/07/2023] Open
Abstract
The onset of checkpoint inhibition revolutionized the treatment of cancer. However, studies from the last decade suggested that the sole enhancement of T cell functionality might not suffice to fight malignancies in all individuals. Dendritic cells (DCs) are not only part of the innate immune system, but also generals of adaptive immunity and they orchestrate the de novo induction of tolerogenic and immunogenic T cell responses. Thus, combinatorial approaches addressing DCs and T cells in parallel represent an attractive strategy to achieve higher response rates across patients. However, this requires profound knowledge about the dynamic interplay of DCs, T cells, other immune and tumor cells. Here, we summarize the DC subsets present in mice and men and highlight conserved and divergent characteristics between different subsets and species. Thereby, we supply a resource of the molecular players involved in key functional features of DCs ranging from their sentinel function, the translation of the sensed environment at the DC:T cell interface to the resulting specialized T cell effector modules, as well as the influence of the tumor microenvironment on the DC function. As of today, mostly monocyte derived dendritic cells (moDCs) are used in autologous cell therapies after tumor antigen loading. While showing encouraging results in a fraction of patients, the overall clinical response rate is still not optimal. By disentangling the general aspects of DC biology, we provide rationales for the design of next generation DC vaccines enabling to exploit and manipulate the described pathways for the purpose of cancer immunotherapy in vivo. Finally, we discuss how DC-based vaccines might synergize with checkpoint inhibition in the treatment of malignant diseases.
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16
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Fischer A. Resistance of children to Covid-19. How? Mucosal Immunol 2020; 13:563-565. [PMID: 32467603 PMCID: PMC8851881 DOI: 10.1038/s41385-020-0303-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 05/08/2020] [Indexed: 02/04/2023]
Affiliation(s)
- Alain Fischer
- Collège de France, Paris, France,Immunology and Pediatric Hematology Department, Assistance Publique-Hôpitaux de Paris, Paris, France,INSERM UMR 1163, Institut Imagine, Paris, France
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17
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Lou F, Sun Y, Xu Z, Niu L, Wang Z, Deng S, Liu Z, Zhou H, Bai J, Yin Q, Cai X, Sun L, Wang H, Li Q, Wu Z, Chen X, Gu J, Shi YL, Tao W, Ginhoux F, Wang H. Excessive Polyamine Generation in Keratinocytes Promotes Self-RNA Sensing by Dendritic Cells in Psoriasis. Immunity 2020; 53:204-216.e10. [PMID: 32553276 DOI: 10.1016/j.immuni.2020.06.004] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Revised: 02/25/2020] [Accepted: 06/01/2020] [Indexed: 12/12/2022]
Abstract
Psoriasis is a chronic inflammatory disease whose etiology is multifactorial. The contributions of cellular metabolism to psoriasis are unclear. Here, we report that interleukin-17 (IL-17) downregulated Protein Phosphatase 6 (PP6) in psoriatic keratinocytes, causing phosphorylation and activation of the transcription factor C/EBP-β and subsequent generation of arginase-1. Mice lacking Pp6 in keratinocytes were predisposed to psoriasis-like skin inflammation. Accumulation of arginase-1 in Pp6-deficient keratinocytes drove polyamine production from the urea cycle. Polyamines protected self-RNA released by psoriatic keratinocytes from degradation and facilitated the endocytosis of self-RNA by myeloid dendritic cells to promote toll-like receptor-7 (TLR7)-dependent RNA sensing and IL-6 production. An arginase inhibitor improved skin inflammation in murine and non-human primate models of psoriasis. Our findings suggest that urea cycle hyperreactivity and excessive polyamine generation in psoriatic keratinocytes promote self-RNA sensation and PP6 deregulation in keratinocytes is a pivotal event that amplifies the inflammatory circuits in psoriasis.
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Affiliation(s)
- Fangzhou Lou
- Shanghai Institute of Immunology, Translational Medicine Center, Shanghai General Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yang Sun
- Shanghai Institute of Immunology, Translational Medicine Center, Shanghai General Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Zhenyao Xu
- Shanghai Institute of Immunology, Translational Medicine Center, Shanghai General Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Liman Niu
- Shanghai Institute of Immunology, Translational Medicine Center, Shanghai General Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Zhikai Wang
- Shanghai Institute of Immunology, Translational Medicine Center, Shanghai General Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Siyu Deng
- Shanghai Institute of Immunology, Translational Medicine Center, Shanghai General Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Zhaoyuan Liu
- Shanghai Institute of Immunology, Translational Medicine Center, Shanghai General Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Hong Zhou
- Shanghai Institute of Immunology, Translational Medicine Center, Shanghai General Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jing Bai
- Shanghai Institute of Immunology, Translational Medicine Center, Shanghai General Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Qianqian Yin
- Shanghai Institute of Immunology, Translational Medicine Center, Shanghai General Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xiaojie Cai
- Shanghai Institute of Immunology, Translational Medicine Center, Shanghai General Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Libo Sun
- Shanghai Institute of Immunology, Translational Medicine Center, Shanghai General Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Hong Wang
- Shanghai Institute of Immunology, Translational Medicine Center, Shanghai General Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Qun Li
- Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200020, China
| | - Zhouwei Wu
- Department of Dermatology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Jun Gu
- Department of Dermatology, Shanghai Tenth People's Hospital, Institute of Psoriasis, Tongji University School of Medicine, Shanghai 200072, China
| | - Yu-Ling Shi
- Department of Dermatology, Shanghai Tenth People's Hospital, Institute of Psoriasis, Tongji University School of Medicine, Shanghai 200072, China
| | - Wufan Tao
- State Key Laboratory of Genetic Engineering and Institute of Developmental Biology and Molecular Medicine, Fudan University, Shanghai 200433, China
| | - Florent Ginhoux
- Shanghai Institute of Immunology, Translational Medicine Center, Shanghai General Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore.
| | - Honglin Wang
- Shanghai Institute of Immunology, Translational Medicine Center, Shanghai General Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
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18
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Cheng K, Kang Q, Zhao X. Biogenic nanoparticles as immunomodulator for tumor treatment. WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY 2020; 12:e1646. [DOI: 10.1002/wnan.1646] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 04/26/2020] [Accepted: 04/28/2020] [Indexed: 12/24/2022]
Affiliation(s)
- Keman Cheng
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology (NCNST) Beijing China
- Department of Biomaterials, Key Laboratory of Biomedical Engineering of Fujian Province College of Materials, Xiamen University Xiamen Fujian China
| | - Qinglin Kang
- School of Chemistry and Molecular Biosciences The University of Queensland Brisbane Queensland Australia
| | - Xiao Zhao
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology (NCNST) Beijing China
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19
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Mohsen MO, Speiser DE, Knuth A, Bachmann MF. Virus-like particles for vaccination against cancer. WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY 2019; 12:e1579. [PMID: 31456339 PMCID: PMC6916610 DOI: 10.1002/wnan.1579] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 05/31/2019] [Accepted: 07/16/2019] [Indexed: 12/21/2022]
Abstract
Active immunotherapy of cancer aims to treat the disease by inducing effective cellular and humoral immune responses. Virus‐like particle‐based vaccines have evolved dramatically over the last few decades, greatly reducing morbidity and mortality of several infectious diseases and expectedly preventing cervical cancer caused by human papilloma virus. In contrast to these broad successes of disease prevention, therapeutic cancer vaccines remain to demonstrate clinical benefit. Yet, several preclinical and clinical trials have revealed promising results and are paving the way for medical breakthroughs. This study reviews and discusses the recent preclinical development and clinical trials in this field. This article is categorized under: Biology‐Inspired Nanomaterials > Protein and Virus‐Based Structures Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
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Affiliation(s)
- Mona O Mohsen
- The Interim Translational Research Institute "iTRI", National Center for Cancer Care & Research (NCCCR), Doha, Qatar.,Department of BioMedical Research, Immunology RIA, University of Bern, Bern, Switzerland
| | - Daniel E Speiser
- Department of Oncology, University of Lausanne, Lausanne, Switzerland
| | - Alexander Knuth
- The Interim Translational Research Institute "iTRI", National Center for Cancer Care & Research (NCCCR), Doha, Qatar
| | - Martin F Bachmann
- Department of BioMedical Research, Immunology RIA, University of Bern, Bern, Switzerland.,Nuffield Department of Medicine, Jenner Institute, University of Oxford, Oxford, UK
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20
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Type of RNA Packed in VLPs Impacts IgG Class Switching-Implications for an Influenza Vaccine Design. Vaccines (Basel) 2019; 7:vaccines7020047. [PMID: 31167472 PMCID: PMC6630894 DOI: 10.3390/vaccines7020047] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 05/22/2019] [Accepted: 05/24/2019] [Indexed: 12/20/2022] Open
Abstract
Nucleic acid packed within virus-like particles (VLPs) is shown to shape the immune response and to induce stronger B cell responses in different immunisation models. Here, using a VLP displaying the highly conserved extracellular domain of the M2 protein (M2e) from the influenza viruses as an antigen, we demonstrate that the type of RNA packaged into VLPs can alter the quality of the induced humoral response. By comparing prokaryotic RNA (pRNA), eukaryotic RNA (eRNA) and transfer RNA (tRNA), we find that pRNA induces the most protective IgG subclasses using a murine influenza model. We provide evidence that this process is predominantly dependent on endosomal Toll-like receptor (TLR7), and rule out a role for cytoplasmic mitochondrial antiviral signalling protein (MAVS) and its upstream retinoic acid-inducible gene-I-like receptors (RIG-I). Our findings provide considerations for the rational design of VLP-based vaccines and the immunomodulation exerted by TLR7 ligands packaged within the particles. Based on this work, we conclude that VLPs packing prokaryotic RNA must be preferred whenever a response dominated by IgG2 is desired, while eukaryotic RNA should be employed in order to induce a response dominated by IgG1.
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21
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Tröscher AR, Wimmer I, Quemada-Garrido L, Köck U, Gessl D, Verberk SGS, Martin B, Lassmann H, Bien CG, Bauer J. Microglial nodules provide the environment for pathogenic T cells in human encephalitis. Acta Neuropathol 2019; 137:619-635. [PMID: 30663001 PMCID: PMC6426829 DOI: 10.1007/s00401-019-01958-5] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 01/03/2019] [Accepted: 01/03/2019] [Indexed: 02/07/2023]
Abstract
Microglia nodule formation is a common feature in inflammatory brain diseases mediated by T lymphocytes such as viral and paraneoplastic encephalitis, multiple sclerosis, and Rasmussen encephalitis (RE). However, its role has not been fully understood yet. We hypothesized that, in RE, microglial nodules provide an environment for the initiation of the later dominating T-cell cytotoxicity. In RE stage 0, small primary microglia nodules could be identified in the absence of T cells. These primary nodules showed inflammasome activation and endosomal Toll-like receptor upregulation. In stage 1, T cells migrate into the parenchyma and intermingle with microglial cells, thereby forming secondary nodules in which neurons are destroyed. Whole-genome transcriptome analysis at this point showed upregulation of several inflammatory pathways including interferon signaling and major histocompatibility complex-I signaling. Inflammatory profiles, like the ones observed in RE, could be induced upon TLR3 stimulation in neonatal microglial cell cultures. Taken together, our results point towards activation of endosomal TLRs, resulting in increased interferon signaling, inflammasome activation, and chemokine upregulation as early steps in RE pathogenesis. This activity sets the scene for subsequent infiltration of T cells and destruction of neurons. Similar to RE, this microglial microenvironment might be a crucial step in other T-cell-mediated inflammatory brain diseases.
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Affiliation(s)
- Anna R Tröscher
- Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090, Vienna, Austria
| | - Isabella Wimmer
- Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090, Vienna, Austria
| | - Lucía Quemada-Garrido
- Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090, Vienna, Austria
| | - Ulrike Köck
- Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090, Vienna, Austria
| | - Denise Gessl
- Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090, Vienna, Austria
| | - Sanne G S Verberk
- Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090, Vienna, Austria
| | - Bethany Martin
- Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090, Vienna, Austria
| | - Hans Lassmann
- Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090, Vienna, Austria
| | - Christian G Bien
- Epilepsy Center Bethel, Krankenhaus Mara, Bielefeld, Germany
- Laboratory Krone, Bad Salzuflen, Germany
| | - Jan Bauer
- Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090, Vienna, Austria.
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22
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Post-PEGylated and crosslinked polymeric ssRNA nanocomplexes as adjuvants targeting lymph nodes with increased cytolytic T cell inducing properties. J Control Release 2018; 284:73-83. [DOI: 10.1016/j.jconrel.2018.06.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 06/04/2018] [Accepted: 06/05/2018] [Indexed: 01/04/2023]
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23
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Hong E, Halman JR, Shah AB, Khisamutdinov EF, Dobrovolskaia MA, Afonin KA. Structure and Composition Define Immunorecognition of Nucleic Acid Nanoparticles. NANO LETTERS 2018; 18:4309-4321. [PMID: 29894623 PMCID: PMC6540121 DOI: 10.1021/acs.nanolett.8b01283] [Citation(s) in RCA: 96] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
Nucleic acid nanoparticles (NANPs) have evolved as a new class of therapeutics with the potential to detect and treat diseases. Despite tremendous advancements in NANP development, their immunotoxicity, one of the major impediments in clinical translation of traditional therapeutic nucleic acids (TNAs), has never been fully characterized. Here, we describe the first systematically studied immunological recognition of 25 representative RNA and DNA NANPs selected to have different design principles and physicochemical properties. We discover that, unlike traditional TNAs, NANPs used without a delivery carrier are immunoquiescent. We show that interferons (IFNs) are the key cytokines triggered by NANPs after their internalization by phagocytic cells, which agrees with predictions based on the experiences with TNAs. However, in addition to type I IFNs, type III IFNs also serve as reliable biomarkers of NANPs, which is usually not characteristic of TNAs. We show that overall immunostimulation relies on NANP shapes, connectivities, and compositions. We demonstrate that, like with traditional TNAs, plasmacytoid dendritic cells serve as the primary interferon producers among all peripheral blood mononuclear cells treated with NANPs, and scavenger receptor-mediated uptake and endosomal Toll-like receptor signaling are essential for NANP immunorecognition. The TLR involvement, however, is different from that expected for traditional TNA recognition. Based on these results, we suggest that NANP technology may serve as a prototype of auxiliary molecular language for communication with the immune system and the modulation of immune responses.
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Affiliation(s)
- Enping Hong
- Nanotechnology Characterization Lab, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, Maryland 21702, United States
| | - Justin R. Halman
- Nanoscale Science Program, Department of Chemistry, The University of North Carolina at Charlotte, Charlotte, North Carolina 28223, United States
| | - Ankit B. Shah
- Nanotechnology Characterization Lab, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, Maryland 21702, United States
| | - Emil F. Khisamutdinov
- Department of Chemistry, Ball State University, Muncie, Indiana 47306, United States
| | - Marina A. Dobrovolskaia
- Nanotechnology Characterization Lab, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, Maryland 21702, United States
| | - Kirill A. Afonin
- Nanoscale Science Program, Department of Chemistry, The University of North Carolina at Charlotte, Charlotte, North Carolina 28223, United States
- The Center for Biomedical Engineering and Science, The University of North Carolina at Charlotte, Charlotte, North Carolina 28223, United States
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24
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Chen Y, Yousaf MN, Mehal WZ. Role of sterile inflammation in fatty liver diseases. LIVER RESEARCH 2018. [DOI: 10.1016/j.livres.2018.02.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Mobergslien A, Peng Q, Vasovic V, Sioud M. Cancer cell-binding peptide fused Fc domain activates immune effector cells and blocks tumor growth. Oncotarget 2018; 7:75940-75953. [PMID: 27713158 PMCID: PMC5342789 DOI: 10.18632/oncotarget.12445] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 09/24/2016] [Indexed: 01/29/2023] Open
Abstract
Therapeutic strategies aiming at mobilizing immune effector cells to kill tumor cells independent of tumor mutational load and MHC expression status are expected to benefit cancer patients. Recently, we engineered various peptide-Fc fusion proteins for directing Fcg receptor-bearing immune cells toward tumor cells. Here, we investigated the immunostimulatory and anti-tumor effects of one of the engineered Fc fusion proteins (WN-Fc). In contrast to the Fc control, soluble WN-Fc-1 fusion protein activated innate immune cells (e.g. monocytes, macrophages, dendritic cells, NK cells), resulting in cytokine production and surface display of the lytic granule marker CD107a on NK cells. An engineered Fc-fusion variant carrying two peptide sequences (WN-Fc-2) also activated immune cells and bound to various cancer cell types with high affinity, including the murine 4T1 breast carcinoma cells. When injected into 4T1 tumor-bearing BALB/c mice, both peptide-Fc fusions accumulated in tumor tissues as compared to other organs such as the lungs. Moreover, treatment of 4T1 tumor-bearing BALB/c mice by means of two intravenous injections of the WN-Fc fusion proteins inhibited tumor growth with WN-Fc-2 being more effective than WN-Fc-1. Treatment resulted in tumor infiltration by T cells and NK cells. These new engineered WN-Fc fusion proteins may be a promising alternative to existing immunotherapies for cancer.
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Affiliation(s)
- Anne Mobergslien
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, N-0310 Oslo, Norway
| | - Qian Peng
- Department of Pathology, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, N-0310 Oslo, Norway
| | - Vlada Vasovic
- Department of Pathology, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, N-0310 Oslo, Norway
| | - Mouldy Sioud
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, N-0310 Oslo, Norway
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26
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Wei J, Chen S, Xue S, Zhu Q, Liu S, Cui L, Hua X, Wang Y. Blockade of Inflammation and Apoptosis Pathways by siRNA Prolongs Cold Preservation Time and Protects Donor Hearts in a Porcine Model. MOLECULAR THERAPY. NUCLEIC ACIDS 2017; 9:428-439. [PMID: 29246321 PMCID: PMC5701800 DOI: 10.1016/j.omtn.2017.10.020] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Revised: 10/28/2017] [Accepted: 10/28/2017] [Indexed: 02/08/2023]
Abstract
In donor hearts from mini pigs, overtime cold preservation and ischemia-reperfusion injury cause poor graft quality and impaired heart function. Blockage of complement, apoptosis, and inflammation is considered a strategy for attenuating ischemia-reperfusion injury and protecting cardiac function. Minipig donor hearts were perfused and preserved in Celsior solution or transfection reagent containing Celsior solution with scramble siRNA or siRNAs targeting complement 3, caspase-8, caspase-3, and nuclear factor κB-p65 genes at 4°C and subsequently hemo-reperfused ex vivo (38°C) or transplanted into recipients. The protective effect of the siRNA solution was evaluated by measuring cell apoptosis, structural alteration, protein markers for tissue damage and oxidative stress, and cardiac function. We found a reduction in cell apoptosis, myocardial damage, and tissue inflammation by reduced biochemistry and markers and protein expression of proinflammatory cytokines and improvement in cardiac function, as shown by the improved hemodynamic indices in 12-hr-preserved siRNA-treated hearts of both ex vivo and orthotopic transplantation models. These findings demonstrate that blockade of inflammation and apoptosis pathways using siRNA can prolong cold preservation time and better protect donor heart function in cardiac transplantation of large animals, which may be beneficial for human heart preservation.
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Affiliation(s)
- Jia Wei
- Shanghai Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiaotong University, Shanghai 200240, China
| | - Shiyou Chen
- Department of Physiology and Pharmacology, University of Georgia, Athens, GA 30602, USA
| | - Song Xue
- Department of Cardiac Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
| | - Qiangru Zhu
- CCI Facility, Covidien (Shanghai) Management Consulting Co. Ltd., Shanghai 200233, China
| | - Sha Liu
- CCI Facility, Covidien (Shanghai) Management Consulting Co. Ltd., Shanghai 200233, China
| | - Li Cui
- Shanghai Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiaotong University, Shanghai 200240, China
| | - Xiuguo Hua
- Shanghai Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiaotong University, Shanghai 200240, China.
| | - Yongyi Wang
- Department of Cardiac Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
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Gomes AC, Mohsen M, Bachmann MF. Harnessing Nanoparticles for Immunomodulation and Vaccines. Vaccines (Basel) 2017; 5:E6. [PMID: 28216554 PMCID: PMC5371742 DOI: 10.3390/vaccines5010006] [Citation(s) in RCA: 101] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 01/23/2017] [Accepted: 01/25/2017] [Indexed: 12/13/2022] Open
Abstract
The first successful use of nanoparticles (NPs) for vaccination was reported almost 40 years ago with a virus-like particle-based vaccine against Hepatitis B. Since then, the term NP has been expanded to accommodate a large number of novel nano-sized particles engineered from a range of materials. The great interest in NPs is likely not only a result of the two successful vaccines against hepatitis B and Human Papilloma Virus (HPV) that use this technology, but also due to the versatility of those small-sized particles, as indicated by the wide range of applications reported so far, ranging from medicinal and cosmetics to purely technical applications. In this review, we will focus on the use of NPs, especially virus-like particles (VLPs), in the field of vaccines and will discuss their employment as vaccines, antigen display platforms, adjuvants and drug delivery systems.
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Affiliation(s)
- Ariane C Gomes
- The Jenner Institute, Oxford University, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
| | - Mona Mohsen
- The Jenner Institute, Oxford University, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
| | - Martin F Bachmann
- The Jenner Institute, Oxford University, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
- Inselspital, Universitatsspital, Sahlihaus 1, 3010 Bern, Switzerland.
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Tsan MF, Gao B. Review: Pathogen-associated molecular pattern contamination as putative endogenous ligands of Toll-like receptors. ACTA ACUST UNITED AC 2016; 13:6-14. [PMID: 17621541 DOI: 10.1177/0968051907078604] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Extensive work in recent years has suggested that a number of endogenous molecules, their derivatives or degradation products may be potent activators of the innate immune system capable of inducing pro-inflammatory cytokine production by the monocyte—macrophage system and the activation and maturation of dendritic cells. The cytokine-like effects of these endogenous molecules are mediated via Toll-like receptor (TLR) signal transduction pathways in a manner similar to pathogen-associated molecular patterns (PAMPs). However, recent evidence suggests that the reported cytokine effects of some of these putative endogenous ligands are in fact due to contaminating PAMPs. The reasons for the failure to recognize PAMP contaminants being responsible for the putative TLR ligands of these endogenous molecules include: (i) failure to use highly purified preparations free of PAMP contamination; (ii) failure to recognize the heat sensitivity of lipopolysaccharide (LPS); and (iii) failure to consider contaminant(s) other than LPS. Strategies are proposed to avoid future designation of PAMP contamination as putative endogenous ligands of TLRs.
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Affiliation(s)
- Min-Fu Tsan
- Department of Veterans Affairs, Research Service, VA Medical Center, Washington, DC 20422, USA.
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29
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Xin Y, Huang Q, Tang JQ, Hou XY, Zhang P, Zhang LZ, Jiang G. Nanoscale drug delivery for targeted chemotherapy. Cancer Lett 2016; 379:24-31. [DOI: 10.1016/j.canlet.2016.05.023] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2016] [Revised: 05/19/2016] [Accepted: 05/20/2016] [Indexed: 12/16/2022]
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Kolter J, Feuerstein R, Spoeri E, Gharun K, Elling R, Trieu-Cuot P, Goldmann T, Waskow C, Chen ZJ, Kirschning CJ, Deshmukh SD, Henneke P. Streptococci Engage TLR13 on Myeloid Cells in a Site-Specific Fashion. THE JOURNAL OF IMMUNOLOGY 2016; 196:2733-41. [PMID: 26873993 DOI: 10.4049/jimmunol.1501014] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Accepted: 01/14/2016] [Indexed: 12/11/2022]
Abstract
Streptococci are common human colonizers with a species-specific mucocutaneous distribution. At the same time, they are among the most important and most virulent invasive bacterial pathogens. Thus, site-specific cellular innate immunity, which is predominantly executed by resident and invading myeloid cells, has to be adapted with respect to streptococcal sensing, handling, and response. In this article, we show that TLR13 is the critical mouse macrophage (MΦ) receptor in the response to group B Streptococcus, both in bone marrow-derived MΦs and in mature tissue MΦs, such as those residing in the lamina propria of the colon and the dermis, as well as in microglia. In contrast, TLR13 and its chaperone UNC-93B are dispensable for a potent cytokine response of blood monocytes to group B Streptococcus, although monocytes serve as the key progenitors of intestinal and dermal MΦs. Furthermore, a specific role for TLR13 with respect to MΦ function is supported by the response to staphylococci, where TLR13 and UNC-93B limit the cytokine response in bone marrow-derived MΦs and microglia, but not in dermal MΦs. In summary, TLR13 is a critical and site-specific receptor in the single MΦ response to β-hemolytic streptococci.
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Affiliation(s)
- Julia Kolter
- Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, 79106 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
| | - Reinhild Feuerstein
- Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, 79106 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
| | - Evelyne Spoeri
- Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Kourosh Gharun
- Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, 79106 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
| | - Roland Elling
- Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, 79106 Freiburg, Germany; Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655
| | - Patrick Trieu-Cuot
- Institute Pasteur, Unité de Biologie des Bactéries Pathogènes à Gram-Positif, CNRS ERL3526, 75724 Paris Cedex 15, France
| | - Tobias Goldmann
- Institute of Neuropathology, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Claudia Waskow
- Regeneration in Hematopoiesis and Animal Models of Hematopoiesis, Faculty of Medicine, Technical University, 01307 Dresden, Germany
| | - Zhijian J Chen
- Southwestern Medical School, University of Texas, Dallas, TX 75390
| | - Carsten J Kirschning
- Institute of Medical Microbiology, Medical Center, University of Essen, 45147 Essen, Germany
| | - Sachin D Deshmukh
- Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, 79106 Freiburg, Germany; Center for Sepsis Control and Care, Medical Center, University of Jena, 07747 Jena, Germany; and
| | - Philipp Henneke
- Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, 79106 Freiburg, Germany; Center for Pediatrics and Adolescent Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
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31
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Zandieh Z, Amjadi F, Ashrafi M, Aflatoonian A, Fazeli A, Aflatoonian R. The Effect of Estradiol and Progesterone on Toll Like Receptor Gene Expression in A Human Fallopian Tube Epithelial Cell Line. CELL JOURNAL 2016; 17:678-91. [PMID: 26862527 PMCID: PMC4746418 DOI: 10.22074/cellj.2016.3840] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Accepted: 10/21/2014] [Indexed: 11/09/2022]
Abstract
Objective Toll like receptors (TLRs) are one of the main components of the innate im-
mune system. It has been reported that expression of these receptors are altered in the
female reproductive tract (FRT) during menstrual cycle. Here we used a fallopian tube
epithelial cell line (OE-E6/E7) to evaluate the effect of two sex hormones in modulating
TLR expression.
Materials and Methods In this experimental study, initially TLR gene expression in OE-
E6/E7 cells was evaluated and compared with that of fallopian tube tissue using quanti-
tative real time-polymerase chain reaction (qRT-PCR) and immunostaining. Thereafter,
OE-E6/E7 cells were cultured with different concentrations of estradiol and progesterone,
and combination of both. qRT-PCR was performed to reveal any changes in expression of
TLR genes as a result of hormonal treatment.
Results TLR1-10 genes were expressed in human fallopian tube tissue. TLR1-6 genes
and their respective proteins were expressed in the OE-E6/E7 cell line. Although estradiol
and progesterone separately had no significant effect on TLR expression, their combined
treatment altered the expression of TLRs in this cell line. Also, the pattern of TLR expres-
sion in preovulation (P), mensturation (M) and window of implantation (W) were the same
for all TLRs with no significant differences between P, M and W groups.
Conclusion These data show the significant involvement of the combination of es-
tradiol and progesterone in modulation of TLR gene expression in this human fal-
lopian tube cell line. Further experiments may reveal the regulatory mechanism and
signalling pathway behind the effect of sex hormones in modulating TLRs in the hu-
man FRT.
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Affiliation(s)
- Zahra Zandieh
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Fatemehsadat Amjadi
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mahnaz Ashrafi
- Department of Obstetrics and Gynecology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Abbas Aflatoonian
- Research and Clinical Center for Infertility, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Alireza Fazeli
- Academic Unit of Reproductive and Developmental Medicine, The University of Sheffield, Sheffield, United Kingdom
| | - Reza Aflatoonian
- Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
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Zhang Z, Wang F, Ding J, Zhang H, Zhu J, Sun Z, Zhang Y. Cationic dendron-bearing lipid/CD151 siRNA complex inhibits osteosarcoma metastasis by down-regulating matrix metalloproteinase-9. RSC Adv 2016; 6:59601-59609. [DOI: 10.1039/c6ra08376e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/14/2025] Open
Abstract
Cationic dendron-bearing lipid safely and effectively delivers CD151 siRNA complex for inhibition of osteosarcoma metastasis by down-regulating matrix metalloproteinase-9.
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Affiliation(s)
- Zhiyu Zhang
- Department of Orthopedics
- The Fourth Affiliated Hospital of China Medical University
- Shenyang 110032
- People's Republic of China
| | - Feng Wang
- Department of Orthopedics
- The Fourth Affiliated Hospital of China Medical University
- Shenyang 110032
- People's Republic of China
| | - Jianxun Ding
- Key Laboratory of Polymer Ecomaterials
- Changchun Institute of Applied Chemistry
- Chinese Academy of Sciences
- Changchun 130022
- People's Republic of China
| | - Haifei Zhang
- Department of Orthopedics
- The Fourth Affiliated Hospital of China Medical University
- Shenyang 110032
- People's Republic of China
| | - Jiajun Zhu
- Department of Orthopedics
- The Fourth Affiliated Hospital of China Medical University
- Shenyang 110032
- People's Republic of China
| | - Zhenguo Sun
- Department of Orthopedics
- The Fourth Affiliated Hospital of China Medical University
- Shenyang 110032
- People's Republic of China
| | - Yu Zhang
- Key Laboratory of Polymer Ecomaterials
- Changchun Institute of Applied Chemistry
- Chinese Academy of Sciences
- Changchun 130022
- People's Republic of China
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Li XP, Sun L. TLR7 is required for optimal immune defense against bacterial infection in tongue sole (Cynoglossus semilaevis). FISH & SHELLFISH IMMUNOLOGY 2015; 47:93-99. [PMID: 26327112 DOI: 10.1016/j.fsi.2015.08.025] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Revised: 07/28/2015] [Accepted: 08/26/2015] [Indexed: 06/04/2023]
Abstract
In mammals as well as in teleost, toll-like receptor 7 (TLR7) is known to be involved in antiviral immunity by recognizing viral RNA. However, the antibacterial potential of fish TLR7 is unclear. In this study, we analyzed the TLR7 of tongue sole (Cynoglossus semilaevis), CsTLR7, and examined its potential involvement in antibacterial immunity. CsTLR7 is composed of 1052 amino acid residues and shares 64.0%-75.9% overall sequence identities with known teleost TLR7. CsTLR7 possesses a toll/interleukin-1 receptor domain and six leucine-rich repeats. Constitutive expression of CsTLR7 occurred in relatively high levels in kidney, spleen and liver. Bacterial infection upregulated CsTLR7 expression, whereas viral infection downregulated CsTLR7 expression. Knockdown of CsTLR7 significantly enhanced bacterial dissemination in the tissues of tongue sole. Treatment of tongue sole with the imidazoquinoline compound R848 (TLR7 activator) and the endosomal acidification inhibitor chloroquine (TLR7 inhibitor) caused enhanced and reduced resistance against bacterial infection respectively. These results indicate that CsTLR7 plays an essential role in the antibacterial immunity of tongue sole.
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Affiliation(s)
- Xue-peng Li
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; University of Chinese Academy of Sciences, Beijing 100049, China; Function Laboratory for Marine Biology and Biotechnology, Qingdao National Oceanography Laboratory, Qingdao, China
| | - Li Sun
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; Function Laboratory for Marine Biology and Biotechnology, Qingdao National Oceanography Laboratory, Qingdao, China.
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U1-RNP and Toll-like receptors in the pathogenesis of mixed connective tissue diseasePart II. Endosomal TLRs and their biological significance in the pathogenesis of mixed connective tissue disease. Reumatologia 2015; 53:143-51. [PMID: 27407241 PMCID: PMC4847297 DOI: 10.5114/reum.2015.53136] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Accepted: 06/11/2015] [Indexed: 12/20/2022] Open
Abstract
Mixed connective tissue disease (MCTD) is a chronic autoimmune immunopathological disease of unknown etiology, which is characterized by the presence of various clinical symptoms and the presence of autoantibodies against U1-RNP particles. The U1-RNP component engages immune cells and their receptors in a complex network of interactions that ultimately lead to autoimmunity, inflammation, and tissue injury. The anti-U1-RNP autoantibodies form an immune complex with self-RNA, present in MCTD serum, which can act as endosomal Toll-like receptor (TLR) ligands. Inhibition of TLRs by nucleic acids is a promising area of research for the development of novel therapeutic strategies against pathogenic infection, tumorigenesis and autoimmunity. In this review we summarize current knowledge of endogenous TLRs and discuss their biological significance in the pathogenesis of MCTD. In part I we described the structure, biological function and significance of the U1-RNP complex in MCTD.
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Madeddu S, Woods TA, Mukherjee P, Sturdevant D, Butchi NB, Peterson KE. Identification of Glial Activation Markers by Comparison of Transcriptome Changes between Astrocytes and Microglia following Innate Immune Stimulation. PLoS One 2015. [PMID: 26214311 PMCID: PMC4516330 DOI: 10.1371/journal.pone.0127336] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
The activation of astrocytes and microglia is often associated with diseases of the central nervous system (CNS). Understanding how activation alters the transcriptome of these cells may offer valuable insight regarding how activation of these cells mediate neurological damage. Furthermore, identifying common and unique pathways of gene expression during activation may provide new insight into the distinct roles these cells have in the CNS during infection and inflammation. Since recent studies indicate that TLR7 recognizes not only viral RNA but also microRNAs that are released by damaged neurons and elevated during neurological diseases, we first examined the response of glial cells to TLR7 stimulation using microarray analysis. Microglia were found to generate a much stronger response to TLR7 activation than astrocytes, both in the number of genes induced as well as fold induction. Although the primary pathways induced by both cell types were directly linked to immune responses, microglia also induced pathways associated with cellular proliferation, while astrocytes did not. Targeted analysis of a subset of the upregulated genes identified unique mRNA, including Ifi202b which was only upregulated by microglia and was found to be induced during both retroviral and bunyavirus infections in the CNS. In addition, other genes including Birc3 and Gpr84 as well as two expressed sequences AW112010 and BC023105 were found to be induced in both microglia and astrocytes and were upregulated in the CNS following virus infection. Thus, expression of these genes may a useful measurement of glial activation during insult or injury to the CNS.
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Affiliation(s)
- Silvia Madeddu
- Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Hamilton, Montana, United States of America
| | - Tyson A. Woods
- Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Hamilton, Montana, United States of America
| | - Piyali Mukherjee
- Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Hamilton, Montana, United States of America
| | - Dan Sturdevant
- Research Technologies Branch, RML, NIAID, NIH, Hamilton, Montana, United States of America
| | | | - Karin E. Peterson
- Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Hamilton, Montana, United States of America
- * E-mail:
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Modified 2'-ribose small RNAs function as Toll-like receptor-7/8 antagonists. Methods Mol Biol 2015; 1218:483-9. [PMID: 25319669 DOI: 10.1007/978-1-4939-1538-5_28] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
A subset of Toll-like receptors (TLRs) senses microbial nucleic acids in endosomal compartments. Furthermore, under certain conditions TLRs can recognize self-RNAs leading to the induction and/or perpetuation of inflammatory diseases. Recent studies have shown that the incorporation of modified nucleotides into small interfering RNA suppressed unwanted immunostimulation. Interestingly, RNA harboring 2'-ribose modifications, particularly 2'-O-methyl not only evaded immune activation but also suppressed TLR signaling triggered in-trans by immunostimulatory RNAs. This new generation of TLR antagonists may have utility as inhibitors of pathogenic inflammatory reactions mediated by TLR activation. Beyond their structural role, natural modifications in native eukaryotic RNAs may function as endogenous TLR antagonists as well. This chapter describes the characterization of short synthetic small RNAs that suppress immunostimulatory activity in-trans.
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Martínez T, Jiménez AI, Pañeda C. Short-interference RNAs: becoming medicines. EXCLI JOURNAL 2015; 14:714-46. [PMID: 26648823 PMCID: PMC4669907 DOI: 10.17179/excli2015-297] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Accepted: 05/12/2015] [Indexed: 12/30/2022]
Abstract
RNA interference is a cellular mechanism by which small molecules of double stranded RNA modulate gene expression acting on the concentration and/or availability of a given messenger RNA. Almost 10 years after Fire and Mello received the Nobel Prize for the discovery of this mechanism in flat worms, RNA interference is on the edge of becoming a new class of therapeutics. With various phase III studies underway, the following years will determine whether RNAi-therapeutics can rise up to the challenge and become mainstream medicines. The present review gives a thorough overview of the current status of this technology focusing on the path to the clinic of this new class of compounds.
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Affiliation(s)
- Tamara Martínez
- Sylentis, R&D department c/Santiago Grisolía, Tres Cantos, Madrid, Spain
| | - Ana Isabel Jiménez
- Sylentis, R&D department c/Santiago Grisolía, Tres Cantos, Madrid, Spain
| | - Covadonga Pañeda
- Sylentis, R&D department c/Santiago Grisolía, Tres Cantos, Madrid, Spain
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38
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Gentile F, Deriu MA, Licandro G, Prunotto A, Danani A, Tuszynski JA. Structure Based Modeling of Small Molecules Binding to the TLR7 by Atomistic Level Simulations. Molecules 2015; 20:8316-40. [PMID: 26007168 PMCID: PMC6272798 DOI: 10.3390/molecules20058316] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2015] [Revised: 04/17/2015] [Accepted: 04/30/2015] [Indexed: 12/15/2022] Open
Abstract
Toll-Like Receptors (TLR) are a large family of proteins involved in the immune system response. Both the activation and the inhibition of these receptors can have positive effects on several diseases, including viral pathologies and cancer, therefore prompting the development of new compounds. In order to provide new indications for the design of Toll-Like Receptor 7 (TLR7)-targeting drugs, the mechanism of interaction between the TLR7 and two important classes of agonists (imidazoquinoline and adenine derivatives) was investigated through docking and Molecular Dynamics simulations. To perform the computational analysis, a new model for the dimeric form of the receptors was necessary and therefore created. Qualitative and quantitative differences between agonists and inactive compounds were determined. The in silico results were compared with previous experimental observations and employed to define the ligand binding mechanism of TLR7.
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Affiliation(s)
- Francesco Gentile
- Department of Physics, University of Alberta, Edmonton, AB T6G 2E1, Canada.
| | - Marco A Deriu
- Institute of Computer Integrated Manufacturing for Sustainable Innovation, Department of Innovative Technologies, University of Applied Sciences and Arts of Southern Switzerland (SUPSI), Manno CH-6928, Switzerland.
| | - Ginevra Licandro
- Institute of Computer Integrated Manufacturing for Sustainable Innovation, Department of Innovative Technologies, University of Applied Sciences and Arts of Southern Switzerland (SUPSI), Manno CH-6928, Switzerland.
| | - Alessio Prunotto
- Institute of Computer Integrated Manufacturing for Sustainable Innovation, Department of Innovative Technologies, University of Applied Sciences and Arts of Southern Switzerland (SUPSI), Manno CH-6928, Switzerland.
| | - Andrea Danani
- Institute of Computer Integrated Manufacturing for Sustainable Innovation, Department of Innovative Technologies, University of Applied Sciences and Arts of Southern Switzerland (SUPSI), Manno CH-6928, Switzerland.
| | - Jack A Tuszynski
- Department of Physics, University of Alberta, Edmonton, AB T6G 2E1, Canada.
- Cross Cancer Institute, Department of Oncology, University of Alberta, Edmonton, AB T6G 1Z2, Canada.
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Elawadli I, Brisbin JT, Mallard BA, Griffiths MW, Corredig M, Sharif S. Differential effects of lactobacilli on activation and maturation of mouse dendritic cells. Benef Microbes 2015; 5:323-34. [PMID: 24913839 DOI: 10.3920/bm2013.0066] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Lactic acid bacteria (LAB) are of interest because of their potential to modulate immune responses. The effects of LAB range from regulation to stimulation of the immune system. A series of studies were performed in vitro to study the effects of six lactic acid bacteria (LAB), Lactobacillus helveticus LH-2, Lactobacillus acidophilus La-5, La-115, La-116 and La-14, and Lactobacillus salivarius, on maturation and activation of mouse dendritic cells. Production of tumour necrosis factor (TNF)-?, interleukin (IL)-6 and IL-10 by dendritic cells (DCs) was determined after treating cells with live LAB. The expression of DC maturation markers, CD80 and CD40, was also measured using flow cytometry after stimulation with LAB. In addition, the expression of Toll-like receptors (TLRs) 2, 4 and 9 by DCs stimulated with LAB was measured. Our results revealed that LAB act differentially on pro-inflammatory and anti-inflammatory cytokine production and induction of co-stimulatory molecules by DCs. Specifically, L. salivarius was found to be the most effective LAB to induce pro-inflammatory cytokine production and expression of co-stimulatory molecules. Moreover, La-14, La-116 and La-5 induced moderate maturation and activation of DCs. On the other hand, LH-2 and La-115 were the least effective lactobacilli to induce DC responses. The present study also revealed that L. salivarius was able to induce the expression of TLR2, 4 and 9 by DCs. In conclusion, various strains and species of LAB can differentially regulate DC activation and maturation, providing further evidence that these bacteria may have the ability to influence and steer immune responses in vivo.
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Affiliation(s)
- I Elawadli
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, 419 Gordon Street, Guelph, Ontario, N1G 2W1 Canada
| | - J T Brisbin
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, 419 Gordon Street, Guelph, Ontario, N1G 2W1 Canada
| | - B A Mallard
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, 419 Gordon Street, Guelph, Ontario, N1G 2W1 Canada
| | - M W Griffiths
- Department of Food Science, Ontario Agricultural College, University of Guelph, 43 McGilvray Street, Guelph, Ontario, N1G 2W1 Canada
| | - M Corredig
- Department of Food Science, Ontario Agricultural College, University of Guelph, 43 McGilvray Street, Guelph, Ontario, N1G 2W1 Canada
| | - S Sharif
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, 419 Gordon Street, Guelph, Ontario, N1G 2W1 Canada
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40
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Gao D, Liu Y, Diao Y, Gao N, Wang Z, Jiang W, Jin G. Synthesis and Evaluation of Conjugates of Novel TLR7 Inert Ligands as Self-Adjuvanting Immunopotentiators. ACS Med Chem Lett 2015; 6:249-53. [PMID: 25815141 DOI: 10.1021/ml5003647] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2014] [Accepted: 01/30/2015] [Indexed: 01/21/2023] Open
Abstract
During the design and synthesis of a series of 8-hydroxy-2-(2-methoxyethoxy)-adenine derivatives bearing various substituted -RCOOH groups at the 9-position, we identified a TLR7-inert ligand, which does not activate TLR7 signaling pathway. Of interest, the coupling of weakly immunogenic antigens via the -RCOOH group was able to significantly enhance the immunogenicity of the antigens. Herein, an inert ligand, 9-(3-carboxypropyl)-8-hydroxy-2-(2-methoxyethoxy)-adenine (5, GD2), was synthesized and conjugated to 5 different weakly immunogenic antigens (BSA, OVA, MSA, MG7, and thymosin). Compared with the GD2 and the potent agonist UC-1 V150, all conjugates demonstrated potent immunogenicity in vitro and in vivo. All conjugates induced prolonged increases, while UC-1 V150 showed a rapid decline in the levels of proinflammatory cytokines following initial increases. These data indicate that the immunostimulatory activity of TLR7-inert ligands could be amplified and prolonged by conjugation to antigens, thus broadening the potential therapeutic application of these agents.
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Affiliation(s)
- Dong Gao
- Shenzhen University Cancer Research Center, Institute of Otorhinolaryngology, Shenzhen 518060, China
- Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Yu Liu
- Shenzhen University Cancer Research Center, Institute of Otorhinolaryngology, Shenzhen 518060, China
- Key Laboratory of Optoelectronic Devices
and Systems of Ministry of Education, College of Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, China
| | - Yuwen Diao
- Shenzhen University Cancer Research Center, Institute of Otorhinolaryngology, Shenzhen 518060, China
| | - Ningning Gao
- Shenzhen University Cancer Research Center, Institute of Otorhinolaryngology, Shenzhen 518060, China
| | - Zhulin Wang
- Shenzhen University Cancer Research Center, Institute of Otorhinolaryngology, Shenzhen 518060, China
| | - Wenqi Jiang
- Shenzhen University Cancer Research Center, Institute of Otorhinolaryngology, Shenzhen 518060, China
- Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Guangyi Jin
- Shenzhen University Cancer Research Center, Institute of Otorhinolaryngology, Shenzhen 518060, China
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41
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Huang L, Fan Y, Zhou Y, Jiang N, Liu W, Meng Y, Zeng L. Cloning, sequence analysis and expression profiles of Toll-like receptor 7 from Chinese giant salamander Andrias davidianus. Comp Biochem Physiol B Biochem Mol Biol 2015; 184:52-7. [PMID: 25754925 DOI: 10.1016/j.cbpb.2015.02.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2014] [Revised: 02/17/2015] [Accepted: 02/26/2015] [Indexed: 02/02/2023]
Abstract
The Chinese giant salamander, Andrias davidianus, is the largest extant amphibian species in the world, which is of significance due to its specific position in the evolutionary history of vertebrates. Currently, limited information about the innate immune system of this animal is known. In this study, the toll-like receptor 7 (TLR7), designated CgsTLR7, was cloned from Chinese giant salamander, A. davidianus. The full-length cDNA of CgsTLR7 is 3747 bp, with an open reading frame of 3150 bp, encoding 1049 amino acids. The TLR family motifs, including the leucine-rich repeat (LRR) and Toll/interleukin (IL)-1 receptor (TIR) domain are conserved in CgsTLR7, which includes 19 LRRs and a TIR domain. The predicted amino acid sequence of CgsTLR7 has 71%, 65%, 63% and 55% identity with turtle, chicken, human and fugu TLR7 homologues, respectively. Phylogenetic analysis showed that CgsTLR7 is closest to that of frog TLR7 among the examined species. Quantitative real-time PCR analysis revealed broad expression of CgsTLR7 in tissues from apparently healthy Chinese giant salamanders with the highest expression in the liver and the lowest expression in the intestine. The mRNA expression was up-regulated and reached a peak level in the kidney, liver and spleen at 12 h, 24 h and 48 h after infecting the animals with the giant salamander iridovirus (GSIV), respectively. These results suggest that CgsTLR7 has a conserved gene structure and might play an important role in immune regulation against viral infections in the Chinese giant salamander.
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Affiliation(s)
- Lili Huang
- College of Fisheries and Biosciences, Shanghai Ocean University, Shanghai 201306, China
| | - Yuding Fan
- Yangtze River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Wuhan, Hubei 430223, China
| | - Yong Zhou
- Yangtze River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Wuhan, Hubei 430223, China
| | - Nan Jiang
- Yangtze River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Wuhan, Hubei 430223, China
| | - Wenzhi Liu
- Yangtze River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Wuhan, Hubei 430223, China
| | - Yan Meng
- Yangtze River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Wuhan, Hubei 430223, China
| | - Lingbing Zeng
- College of Fisheries and Biosciences, Shanghai Ocean University, Shanghai 201306, China; Yangtze River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Wuhan, Hubei 430223, China.
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42
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Zandieh Z, Ashrafi M, Jameie B, Amanpour S, Mosaffa N, Salman Yazdi R, Pacey A, Aflatoonian R. Evaluation of immunological interaction between spermatozoa and fallopian tube epithelial cells. Andrologia 2015; 47:1120-30. [DOI: 10.1111/and.12391] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/22/2014] [Indexed: 12/12/2022] Open
Affiliation(s)
- Z. Zandieh
- Anatomy Department; School of Medicine; Iran University of Medical Sciences; Tehran Iran
| | - M. Ashrafi
- Obstetrics and Gynecology Department; School of Medicine; Iran University of Medical Sciences; Tehran Iran
| | - B. Jameie
- Anatomy Department; School of Medicine; Iran University of Medical Sciences; Tehran Iran
| | - S. Amanpour
- Valie-Asr Reproductive Health Research Center; Tehran University of Medical Sciences; Tehran Iran
| | - N. Mosaffa
- Department of Immunology; Faculty of Medicine; Shaheed Beheshti University of Medical Sciences; Tehran Iran
| | - R. Salman Yazdi
- Department of Andrology at Reproductive Biomedicine Research Center; Royan Institute for Reproductive Biomedicine; ACECR; Tehran Iran
| | - A. Pacey
- Academic Unit of Reproductive and Developmental Medicine; University of Sheffield; Sheffield UK
| | - R. Aflatoonian
- Department of Endocrinology and Female Infertility at Reproductive Biomedicine Research Center; Royan Institute for Reproductive Biomedicine; ACECR; Tehran Iran
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43
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Iversen PO, Sioud M. Engineering therapeutic cancer vaccines that activate antitumor immunity. Methods Mol Biol 2015; 1218:263-268. [PMID: 25319656 DOI: 10.1007/978-1-4939-1538-5_15] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Vaccination represents one the most effective methods of preventing disease. Because dendritic cells (DCs) are the most efficient antigen presenting cells, exploiting their plasticity is likely to yield improved therapeutic vaccines. Herein, we applied a novel DC-based vaccine (i.e., DC loaded with leukemia antigens that have been transfected with an IL-10 siRNA capable of coordinately activating DCs via TLR7/8) in a rat model of acute myeloid leukemia. Leukemic rats treated with this new vaccine had less leukemic cell mass in their bone marrows and less extramedullar dissemination of the leukemic disease examined postmortem compared with rats given the control vaccine. Collectively, the new strategy demonstrates the possible usefulness of dual siRNAs as an immunomodulatory drug with antileukemic properties.
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MESH Headings
- Animals
- Antigens, Neoplasm/genetics
- Antigens, Neoplasm/immunology
- Bone Marrow/immunology
- Bone Marrow/pathology
- Cancer Vaccines/administration & dosage
- Cancer Vaccines/genetics
- Cancer Vaccines/immunology
- Cytotoxicity, Immunologic
- Dendritic Cells/immunology
- Dendritic Cells/transplantation
- Disease Models, Animal
- Gene Expression Regulation, Leukemic
- Genetic Engineering/methods
- Humans
- Immunotherapy/methods
- Interleukin-10/agonists
- Interleukin-10/genetics
- Interleukin-10/immunology
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/immunology
- Leukemia, Myeloid, Acute/mortality
- Leukemia, Myeloid, Acute/prevention & control
- RNA, Small Interfering/genetics
- RNA, Small Interfering/immunology
- Rats
- Survival Analysis
- Toll-Like Receptor 7/genetics
- Toll-Like Receptor 7/immunology
- Toll-Like Receptor 8/genetics
- Toll-Like Receptor 8/immunology
- Transfection
- Vaccination
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Affiliation(s)
- Per Ole Iversen
- Department of Nutrition, Oslo University Hospital, Norway, Montebello, 0310, Norway
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44
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Sioud M. Overcoming the challenges of siRNA activation of innate immunity: design better therapeutic siRNAs. Methods Mol Biol 2015; 1218:301-319. [PMID: 25319660 DOI: 10.1007/978-1-4939-1538-5_19] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
RNA interference (RNAi) is a conserved regulatory mechanism of posttranscriptional gene silencing triggered by either endogenously (e.g. microRNAs) or exogenously double-stranded RNA as small interfering (si) RNAs. To date, the use of siRNA (21-nt) has become a standard laboratory tool to silence gene expression in mammalian cells in-vitro and in-vivo. The methodology also holds promise for treating a diversity of human diseases. However, one of the challenges of making siRNAs as therapeutic drugs includes the activation of innate immunity and silencing of unwanted genes. Therefore, the use of siRNAs in functional genomics and human therapies depends on the development of strategies to overcome siRNA unwanted effects. This chapter highlights some efficient strategies aimed at separating gene silencing from immunostimulation and improving siRNA gene silencing specificity.
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MESH Headings
- Antigens, Neoplasm/genetics
- Antigens, Neoplasm/immunology
- Cancer Vaccines/administration & dosage
- Cancer Vaccines/genetics
- Cancer Vaccines/immunology
- Dendritic Cells/immunology
- Dendritic Cells/transplantation
- Gene Expression Regulation, Neoplastic
- Genetic Engineering/methods
- Humans
- Immunity, Innate
- Immunotherapy/methods
- Neoplasms/genetics
- Neoplasms/immunology
- Neoplasms/therapy
- RNA, Double-Stranded
- RNA, Small Interfering/chemical synthesis
- RNA, Small Interfering/genetics
- RNA, Small Interfering/immunology
- Receptors, Retinoic Acid/genetics
- Receptors, Retinoic Acid/immunology
- Ribose/metabolism
- Toll-Like Receptor 7/genetics
- Toll-Like Receptor 7/immunology
- Toll-Like Receptor 8/genetics
- Toll-Like Receptor 8/immunology
- Toll-Like Receptors/genetics
- Toll-Like Receptors/immunology
- Transfection
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Affiliation(s)
- Mouldy Sioud
- Department of Immunology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, N-310, Norway,
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45
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Zewge D, Gosselin F, Kenski DM, Li J, Jadhav V, Yuan Y, Nerurkar SS, Tellers DM, Flanagan WM, Davies IW. High-throughput chemical modification of oligonucleotides for systematic structure-activity relationship evaluation. Bioconjug Chem 2014; 25:2222-32. [PMID: 25398098 DOI: 10.1021/bc500453q] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Chemical modification of siRNA is achieved in a high-throughput manner (96-well plate format) by copper catalyzed azide-alkyne cycloadditions. This transformation can be performed in one synthetic operation at up to four positions with complete specificity, good yield, and acceptable purity. As demonstrated here, this approach extends the current synthetic options for oligonucleotide modifications and simultaneously facilitates the systematic, rapid biological evaluation of modified siRNA.
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Affiliation(s)
- Daniel Zewge
- Department of Process Chemistry, Merck Research Laboratories , Rahway, New Jersey 07065, United States
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46
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Gao D, Liu Y, Li W, Zhong F, Zhang X, Diao Y, Gao N, Wang X, Jiang W, Jin G. Synthesis and immunoregulatory activities of conjugates of a Toll-like receptor 7 inert ligand. Bioorg Med Chem Lett 2014; 24:5792-5795. [PMID: 25453821 DOI: 10.1016/j.bmcl.2014.10.034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Revised: 08/26/2014] [Accepted: 10/09/2014] [Indexed: 01/12/2023]
Abstract
In the synthesis and modification of the analogs of an adenine type of Toll-like receptor (TLR) 7 agonists, we found a special compound, 9-propionyloxy-8-hydroxy-2-(2-methoxyethoxy)-adenine (6). It is a synthesized TLR7 inert ligand, which does not respond to TLR7 itself. However, it can be coupled with protein or peptide antigens via propionyloxy functional group to promote their immunogenicity significantly. The compound was covalently coupled to protein and peptide to get the conjugates. The inductivity of cytokine production by the conjugates was 872.4-fold compared with the unconjugated antigens in vitro by mouse splenocyte. These data show that the immunostimulatory activity of inert TLR7 ligand can be endowed, and the activity of antigens can be amplified by conjugation with various proteins and peptides, thus broadening the potential therapeutic application and reducing the risk of TLR7 agonists' side effects.
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Affiliation(s)
- Dong Gao
- Shenzhen University Cancer Research Center, Institute of Otorhinolaryngology, Shenzhen 518060, China; Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Yu Liu
- Shenzhen University Cancer Research Center, Institute of Otorhinolaryngology, Shenzhen 518060, China
| | - Wang Li
- Shenzhen University Cancer Research Center, Institute of Otorhinolaryngology, Shenzhen 518060, China
| | - Fangshu Zhong
- Shenzhen University Cancer Research Center, Institute of Otorhinolaryngology, Shenzhen 518060, China
| | - Xiaoli Zhang
- Shenzhen University Cancer Research Center, Institute of Otorhinolaryngology, Shenzhen 518060, China
| | - Yuwen Diao
- Shenzhen University Cancer Research Center, Institute of Otorhinolaryngology, Shenzhen 518060, China
| | - Ningning Gao
- Shenzhen University Cancer Research Center, Institute of Otorhinolaryngology, Shenzhen 518060, China
| | - Xiaodong Wang
- Shenzhen University Cancer Research Center, Institute of Otorhinolaryngology, Shenzhen 518060, China
| | - Wenqi Jiang
- Shenzhen University Cancer Research Center, Institute of Otorhinolaryngology, Shenzhen 518060, China; Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
| | - Guangyi Jin
- Shenzhen University Cancer Research Center, Institute of Otorhinolaryngology, Shenzhen 518060, China.
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47
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Yang C, Zhao T, Zhao Z, Jia Y, Li L, Zhang Y, Song M, Rong R, Xu M, Nicholson ML, Zhu T, Yang B. Serum-stabilized naked caspase-3 siRNA protects autotransplant kidneys in a porcine model. Mol Ther 2014; 22:1817-28. [PMID: 24930602 DOI: 10.1038/mt.2014.111] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Accepted: 06/11/2014] [Indexed: 11/09/2022] Open
Abstract
The naked small interfering RNA (siRNA) of caspase-3, a key player in ischemia reperfusion injury, was effective in cold preserved and hemoreperfused kidneys, but not autotransplanted kidneys in our porcine models. Here, chemically modified serum stabilized caspase-3 siRNAs were further evaluated. The left kidney was retrieved and infused by University of Wisconsin solution with/without 0.3 mg caspase-3 or negative siRNA into the renal artery for 24-hour cold storage (CS). After an intravenous injection of 0.9 mg siRNA and right-uninephrectomy, the left kidney was autotransplanted for 2 weeks. The effectiveness of caspase-3 siRNA was confirmed by caspase-3 knockdown in the post-CS and/or post-transplant kidneys with reduced apoptosis and inflammation, while the functional caspase-3 siRNA in vivo was proved by detected caspase-3 mRNA degradation intermediates. HMGB1 protein was also decreased in the post-transplanted kidneys; correlated positively with renal IL-1β mRNA, but negatively with serum IL-10 or IL-4. The minimal off-target effects of caspase-3 siRNA were seen with favorable systemic responses. More importantly, renal function, associated with active caspase-3, HMGB1, apoptosis, inflammation, and tubulointerstitial damage, was improved by caspase-3 siRNA. Taken together, the 2-week autotransplanted kidneys were protected when caspase-3 siRNA administrated locally and systemically, which provides important evidence for future clinical trials.
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Affiliation(s)
- Cheng Yang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Tian Zhao
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Zitong Zhao
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Yichen Jia
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Long Li
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Yufang Zhang
- Department of Nephrology, Affiliated Hospital of Nantong University, Medical Research Centre, Medical School, University of Nantong, Nantong, China
| | - Mangen Song
- 1] Department of Urology, Zhongshan Hospital, Fudan University, Shanghai Key Laboratory of Organ Transplantation, Shanghai, China [2] Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ruiming Rong
- 1] Department of Urology, Zhongshan Hospital, Fudan University, Shanghai Key Laboratory of Organ Transplantation, Shanghai, China [2] Department of Transfusion, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ming Xu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Michael L Nicholson
- Transplant Group, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester General Hospital, University Hospitals of Leicester, Leicester, UK
| | - Tongyu Zhu
- 1] Department of Urology, Zhongshan Hospital, Fudan University, Shanghai Key Laboratory of Organ Transplantation, Shanghai, China [2] Qingpu Branch Zhongshan Hospital, Fudan University, Shanghai, China
| | - Bin Yang
- 1] Department of Urology, Zhongshan Hospital, Fudan University, Shanghai Key Laboratory of Organ Transplantation, Shanghai, China [2] Department of Nephrology, Affiliated Hospital of Nantong University, Medical Research Centre, Medical School, University of Nantong, Nantong, China
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Wen Y, Meng WS. Recent In Vivo Evidences of Particle-Based Delivery of Small-Interfering RNA (siRNA) into Solid Tumors. J Pharm Innov 2014; 9:158-173. [PMID: 25221632 PMCID: PMC4161233 DOI: 10.1007/s12247-014-9183-4] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Small-interfering RNA (siRNA) is both a powerful tool in research and a promising therapeutic platform to modulate expression of disease-related genes. Malignant tumors are attractive disease targets for nucleic acid-based therapies. siRNA directed against oncogenes, and genes driving metastases or angiogenesis have been evaluated in animal models and in some cases, in humans. The outcomes of these studies indicate that drug delivery is a significant limiting factor. This review provides perspectives on in vivo validated nanoparticle-based siRNA delivery systems. Results of recent advances in liposomes and polymeric and inorganic formulations illustrate the need for mutually optimized attributes for performance in systemic circulation, tumor interstitial space, plasma membrane, and endosomes. Physiochemical properties conducive to efficient siRNA delivery are summarized and directions for future research are discussed.
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Affiliation(s)
- Yi Wen
- Division of Pharmaceutical Sciences, Duquesne University, 600, Forbes Avenue, Pittsburgh, PA 15282, USA
| | - Wilson S. Meng
- Division of Pharmaceutical Sciences, Duquesne University, 600, Forbes Avenue, Pittsburgh, PA 15282, USA
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49
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Funk E, Kottilil S, Gilliam B, Talwani R. Tickling the TLR7 to cure viral hepatitis. J Transl Med 2014; 12:129. [PMID: 24884741 PMCID: PMC4039542 DOI: 10.1186/1479-5876-12-129] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Accepted: 04/16/2014] [Indexed: 01/01/2023] Open
Abstract
Chronic hepatitis B and C are the leading causes of liver disease and liver transplantation worldwide. Ability to mount an effective immune response against both HBV and HCV is associated with spontaneous clearance of both infections, while an inability to do so leads to chronicity of both infections. To mount an effective immune response, both innate and adaptive immune responses must work in tandem. Hence, developing protective immunity to hepatitis viruses is an important goal in order to reduce the global burden of these two infections and prevent development of long-term complications. In this regard, the initial interactions between the pathogen and immune system are pivotal in determining the effectiveness of immune response and subsequent elimination of pathogens. Toll-like receptors (TLRs) are important regulators of innate and adaptive immune responses to various pathogens and are often involved in initiating and augmenting effective antiviral immunity. Immune-based therapeutic strategies that specifically induce type I interferon responses are associated with functional cure for both chronic HBV and HCV infections. Precisely, TLR7 stimulation mediates an endogenous type I interferon response, which is critical in development of a broad, effective and protective immunity against hepatitis viruses. This review focuses on anti-viral strategies that involve targeting TLR7 that may lead to development of protective immunity and eradication of hepatitis B.
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Affiliation(s)
- Emily Funk
- Critical Care Medicine Department, Clinical Research Center, National Institutes of Health, Bethesda, MD 20892, USA
| | - Shyam Kottilil
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Bruce Gilliam
- Institute of Human Virology at the University of Maryland School of Medicine, 725 West Lombard St. N151, Baltimore, MD 21201, USA
| | - Rohit Talwani
- Institute of Human Virology at the University of Maryland School of Medicine, 725 West Lombard St. N151, Baltimore, MD 21201, USA
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Carter E, Lau CY, Tosh D, Ward SG, Mrsny RJ. Cell penetrating peptides fail to induce an innate immune response in epithelial cells in vitro: implications for continued therapeutic use. Eur J Pharm Biopharm 2014; 85:12-9. [PMID: 23958314 DOI: 10.1016/j.ejpb.2013.03.024] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Revised: 03/16/2013] [Accepted: 03/19/2013] [Indexed: 12/28/2022]
Abstract
Cell penetrating peptides (CPPs) offer the exciting potential of effectively delivering macromolecules to the cytoplasm of a cell that are otherwise impermeable to the plasma membrane. Although the use of these peptides has so far been well tolerated in clinical trials, it is important to remember that some of these CPPs were originally derived from pathogenic material. We therefore sought to determine if three of the most widely studied CPPs; HIV-TAT, Antennapedia and Transportan, initiated an immune response in epithelial cells. Using conditions where these peptides efficiently delivered a rhodamine tagged BSA cargo to the interior of epithelial cells, we failed to observe an effect on cell viability as determined by MTT assay (P>0.05). Further, CPP-mediated delivery of this protein cargo failed to activate NFκB, which would be indicative of toll-like receptor signalling. Finally, no significant increase in the release of the inflammatory cytokines interleukin (IL)-8 and IL-6 was detected in epithelial cells exposed to CPP complexes for 72 h (P>0.05). Together, these results indicate that these commonly used CPPs are passive carriers that do not initiate epithelial cell-associated 'danger signals' during the process of cytoplasmic delivery of a model protein cargo.
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Affiliation(s)
- Edward Carter
- Department of Pharmacy and Pharmacology, University of Bath, Bath, UK; Department of Biology and Biochemistry, University of Bath, Bath, UK
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