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Xu X, Ying H, Wang X, Hong W, Zhang M. Identification of Angiogenesis-Related Gene Signatures and Prediction of Potential Therapeutic Targets in Ulcerative Colitis Using Integrated Bioinformatics. J Inflamm Res 2024; 17:11699-11717. [PMID: 39741751 PMCID: PMC11687120 DOI: 10.2147/jir.s478880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Accepted: 12/10/2024] [Indexed: 01/03/2025] Open
Abstract
Objective This study aims to clarify angiogenesis mechanisms in ulcerative colitis and identify potential therapeutic targets. Methods The Gene Expression Omnibus (GEO) database was used to obtain expression profiles and clinical data for UC and healthy colon tissues. Angiogenesis-related gene sets were acquired from GeneCards. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) identified UC-associated hub genes. The CIBERSORT algorithm assessed immune cell infiltration. Analyses of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed to determine biological mechanisms. External datasets were utilized to validate and characterize the angiogenesis-related genes in relation to biological agents. Additionally, an ulcerative colitis mouse model was constructed to verify the key genes' expression using real-time quantitative PCR. To predict potential therapeutic agents, we used the DGIdb database. Molecular docking modeled small molecule binding conformations to key gene targets. Results This study identified 1,247 DEGs enriched in inflammatory/immune pathways from UC and healthy colon samples. WGCNA indicated the black and light cyan modules were most relevant. Intersecting these with 89 angiogenesis genes revealed 5 UC-associated hub genes (pdgfrb, vegfc, angpt2, tnc, hgf). Validation via ROC analysis, differential expression, and a mouse model confirmed upregulation, supporting their potential as UC diagnostic biomarkers. Bioinformatics approaches like protein-protein interaction, enrichment analysis, and GSEA revealed involvement in PDGFR and PI3K-Akt signaling pathways. CIBERSORT analysis of immune cell infiltration showed positive correlations between the key genes and various immune cells, especially neutrophils, highlighting angiogenesis-inflammation interplay in UC. A ceRNA network was constructed. Drug prediction and molecular docking revealed potential UC therapies like sunitinib and imatinib targeting angiogenesis. Conclusion This study identified and validated five angiogenesis-related genes (pdgfrb, vegfc, angpt2, tnc, hgf) that may serve as diagnostic biomarkers and drug targets for UC.
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Affiliation(s)
- Xijuan Xu
- Department of Anus & Intestine Surgery, Taizhou First People’s Hospital, Taizhou, Zhejiang, People’s Republic of China
| | - Hongan Ying
- Department of Geriatrics, Taizhou First People’s Hospital, Taizhou, People’s Republic of China
| | - Xiaozhi Wang
- Department of Anus & Intestine Surgery, Taizhou First People’s Hospital, Taizhou, Zhejiang, People’s Republic of China
| | - Weiwen Hong
- Department of Anus & Intestine Surgery, Taizhou First People’s Hospital, Taizhou, Zhejiang, People’s Republic of China
| | - Meng Zhang
- Department of General Surgery, Taizhou First People’s Hospital, Taizhou, Zhejiang, People’s Republic of China
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Feng Y, Pan M, Li R, He W, Chen Y, Xu S, Chen H, Xu H, Lin Y. Recent developments and new directions in the use of natural products for the treatment of inflammatory bowel disease. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 132:155812. [PMID: 38905845 DOI: 10.1016/j.phymed.2024.155812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 05/13/2024] [Accepted: 06/06/2024] [Indexed: 06/23/2024]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) represents a significant global health challenge, and there is an urgent need to explore novel therapeutic interventions. Natural products have demonstrated highly promising effectiveness in the treatment of IBD. PURPOSE This study systematically reviews the latest research advancements in leveraging natural products for IBD treatment. METHODS This manuscript strictly adheres to the PRISMA guidelines. Relevant literature on the effects of natural products on IBD was retrieved from the PubMed, Web of Science and Cochrane Library databases using the search terms "natural product," "inflammatory bowel disease," "colitis," "metagenomics", "target identification", "drug delivery systems", "polyphenols," "alkaloids," "terpenoids," and so on. The retrieved data were then systematically summarized and reviewed. RESULTS This review assessed the different effects of various natural products, such as polyphenols, alkaloids, terpenoids, quinones, and others, in the treatment of IBD. While these natural products offer promising avenues for IBD management, they also face challenges in terms of clinical translation and drug discovery. The advent of metagenomics, single-cell sequencing, target identification techniques, drug delivery systems, and other cutting-edge technologies heralds a new era in overcoming these challenges. CONCLUSION This paper provides an overview of current research progress in utilizing natural products for the treatment of IBD, exploring how contemporary technological innovations can aid in discovering and harnessing bioactive natural products for the treatment of IBD.
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Affiliation(s)
- Yaqian Feng
- Fujian-Macao Science and Technology Cooperation Base of Traditional Chinese Medicine-Oriented Chronic Disease Prevention and Treatment, Innovation and Transformation Center, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China
| | - Mengting Pan
- Institute of Structural Pharmacology & TCM Chemical Biology, Fujian Key Laboratory of Chinese Materia Medica, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China
| | - Ruiqiong Li
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China
| | - Weishen He
- Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Yangyang Chen
- Institute of Structural Pharmacology & TCM Chemical Biology, Fujian Key Laboratory of Chinese Materia Medica, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China
| | - Shaohua Xu
- Institute of Structural Pharmacology & TCM Chemical Biology, Fujian Key Laboratory of Chinese Materia Medica, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China.
| | - Hui Chen
- Department of Gastroenterology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350004, China.
| | - Huilong Xu
- Institute of Structural Pharmacology & TCM Chemical Biology, Fujian Key Laboratory of Chinese Materia Medica, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China.
| | - Yao Lin
- Fujian-Macao Science and Technology Cooperation Base of Traditional Chinese Medicine-Oriented Chronic Disease Prevention and Treatment, Innovation and Transformation Center, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China.
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Atma Y, Murray BS, Sadeghpour A, Goycoolea FM. Encapsulation of short-chain bioactive peptides (BAPs) for gastrointestinal delivery: a review. Food Funct 2024; 15:3959-3979. [PMID: 38568171 DOI: 10.1039/d3fo04195f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/16/2024]
Abstract
The majority of known peptides with high bioactivity (BAPs) such as antihypertensive, antidiabetic, antioxidant, hypocholesterolemic, anti-inflammatory and antimicrobial actions, are short-chain sequences of less than ten amino acids. These short-chain BAPs of varying natural and synthetic origin must be bioaccessible to be capable of being adsorbed systemically upon oral administration to show their full range of bioactivity. However, in general, in vitro and in vivo studies have shown that gastrointestinal digestion reduces BAPs bioactivity unless they are protected from degradation by encapsulation. This review gives a critical analysis of short-chain BAP encapsulation and performance with regard to the oral delivery route. In particular, it focuses on short-chain BAPs with antihypertensive and antidiabetic activity and encapsulation methods via nanoparticles and microparticles. Also addressed are the different wall materials used to form these particles and their associated payloads and release kinetics, along with the current challenges and a perspective of the future applications of these systems.
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Affiliation(s)
- Yoni Atma
- School of Food Science and Nutrition, University of Leeds, Leeds, LS2 9JT, United Kingdom.
- Department of Food Science and Technology, Universitas Trilogi, Jakarta, 12760, Indonesia
| | - Brent S Murray
- School of Food Science and Nutrition, University of Leeds, Leeds, LS2 9JT, United Kingdom.
| | - Amin Sadeghpour
- School of Food Science and Nutrition, University of Leeds, Leeds, LS2 9JT, United Kingdom.
| | - Francisco M Goycoolea
- School of Food Science and Nutrition, University of Leeds, Leeds, LS2 9JT, United Kingdom.
- Department of Cell Biology and Histology, Faculty of Biology, University of Murcia, Campus de Espinardo, 30100, Murcia, Spain
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Li D, Shangguan J, Yu F, Lin G, Pan H, Zhang M, Lin H, Chen B, Xu H, Hu S. Growth Factors-Loaded Temperature-Sensitive Hydrogel as Biomimetic Mucus Attenuated Murine Ulcerative Colitis via Repairing the Mucosal Barriers. ACS APPLIED MATERIALS & INTERFACES 2024; 16:7686-7699. [PMID: 38289234 DOI: 10.1021/acsami.3c15684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/16/2024]
Abstract
The pathogenesis of ulcerative colitis (UC) is associated with the shedding of the gut mucus. Herein, inspired by the biological functions of mucus, growth factors-loaded in situ hydrogel (PHE-EK) was designed for UC treatment by integrating dihydrocaffeic acid-modified poloxamer as a thermosensitive material with hyaluronic acid (colitis-specific adhesive), epigallocatechin-3-gallate (antibacterial agent), and bioactive factors (KPV tripeptide and epidermal growth factor). PHE-EK presented good thermosensitive properties, as a flowable liquid at room temperature and gelled within 10 s when exposed to body temperature. PHE-EK hydrogel presented good mechanical strength with a strain of 77.8%. Moreover, PHE-EK hydrogel displayed antibacterial activity against Escherichia coli. Importantly, in vitro and in vivo adhesive tests showed that the PHE-EK hydrogel could specifically adhere to the inflamed colon via electrostatic interaction. When PHE-EK as a biomimetic mucus was rectally administrated to colitis rats, it effectively hindered the body weight loss, reduced the disease activity index and improved the colonic shorting. Moreover, the expression of pro-inflammatory cytokines (e.g., IL-1β, IL-6, and TNF-α) at the laminae propria or epitheliums of the colon for colitis rats was substantially inhibited by PHE-EK. Besides, the colonic epitheliums were well rearranged, and the tight junction proteins (Zonula-1 and Claudin-5) between them were greatly upregulated after PHE-EK treatment. Collectively, PHE-EK might be a promising therapy for UC.
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Affiliation(s)
- Dingwei Li
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province 325000, China
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Jianxun Shangguan
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Fengnan Yu
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Gaolong Lin
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Hanxiao Pan
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Mengjiao Zhang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Haoran Lin
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Ben Chen
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Helin Xu
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Sunkuan Hu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province 325000, China
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Yang J, Li D, Zhang M, Lin G, Hu S, Xu H. From the updated landscape of the emerging biologics for IBDs treatment to the new delivery systems. J Control Release 2023; 361:568-591. [PMID: 37572962 DOI: 10.1016/j.jconrel.2023.08.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 07/06/2023] [Accepted: 08/06/2023] [Indexed: 08/14/2023]
Abstract
Inflammatory bowel diseases (IBDs) treatments have shifted from small-molecular therapeutics to the oncoming biologics. The first-line biologics against the moderate-to-severe IBDs are mainly involved in antibodies against integrins, cytokines and cell adhesion molecules. Besides, other biologics including growth factors, antioxidative enzyme, anti-inflammatory peptides, nucleic acids, stem cells and probiotics have also been explored at preclinical or clinical studies. Biologics with variety of origins have their unique potentials in attenuating immune inflammation or gut mucosa healing. Great advances in use of biologics for IBDs treatments have been archived in recent years. But delivering issues for biologic have also been confronted due to their liable nature. In this review, we will focus on biologics for IBDs treatments in the recent publications; summarize the current landscapes of biologics and their promise to control disease progress. Alternatively, the confronted challenges for delivering biologics will also be analyzed. To combat these drawbacks, some new delivering strategies are provided: firstly, designing the functional materials with high affinity toward biologics; secondly, the delivering vehicle systems to encapsulate the liable biologics; thirdly, the topical adhering delivery systems as enema. To our knowledge, this review is the first study to summarize the updated usage of the oncoming biologics for IBDs, their confronted challenges in term of delivery and the potential combating strategies.
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Affiliation(s)
- Jiaojiao Yang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Dingwei Li
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Mengjiao Zhang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Gaolong Lin
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Sunkuan Hu
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province 325000, China
| | - Helin Xu
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China.
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Gravina AG, Pellegrino R, Durante T, Palladino G, Imperio G, D’Amico G, Trotta MC, Dallio M, Romeo M, D’Amico M, Federico A. The Melanocortin System in Inflammatory Bowel Diseases: Insights into Its Mechanisms and Therapeutic Potentials. Cells 2023; 12:1889. [PMID: 37508552 PMCID: PMC10378568 DOI: 10.3390/cells12141889] [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: 06/24/2023] [Revised: 07/08/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
The melanocortin system is a complex set of molecular mediators and receptors involved in many physiological and homeostatic processes. These include the regulation of melanogenesis, steroidogenesis, neuromodulation and the modulation of inflammatory processes. In the latter context, the system has assumed importance in conditions of chronic digestive inflammation, such as inflammatory bowel diseases (IBD), in which numerous experiences have been accumulated in mouse models of colitis. Indeed, information on how such a system can counteract colitis inflammation and intervene in the complex cytokine imbalance in the intestinal microenvironment affected by chronic inflammatory damage has emerged. This review summarises the evidence acquired so far and highlights that molecules interfering with the melanocortin system could represent new drugs for treating IBD.
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Affiliation(s)
- Antonietta Gerarda Gravina
- Hepatogastroenterology Unit, Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Raffaele Pellegrino
- Hepatogastroenterology Unit, Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Tommaso Durante
- Mental Health Department, S. Pio Hospital, Via dell’Angelo, 82100 Benevento, Italy
| | - Giovanna Palladino
- Hepatogastroenterology Unit, Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Giuseppe Imperio
- Hepatogastroenterology Unit, Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | | | - Maria Consiglia Trotta
- Department of Experimental Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Marcello Dallio
- Hepatogastroenterology Unit, Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Mario Romeo
- Hepatogastroenterology Unit, Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Michele D’Amico
- Department of Experimental Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Alessandro Federico
- Hepatogastroenterology Unit, Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
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Dodd J, Jordan R, Makhlina M, Barnett K, Roffel A, Spana C, Obr A, Dhingra P, Kayne PS. A novel oral formulation of the melanocortin-1 receptor agonist PL8177 resolves inflammation in preclinical studies of inflammatory bowel disease and is gut restricted in rats, dogs, and humans. Front Immunol 2023; 14:1083333. [PMID: 36891301 PMCID: PMC9986545 DOI: 10.3389/fimmu.2023.1083333] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 01/31/2023] [Indexed: 02/22/2023] Open
Abstract
Introduction PL8177 is a potent and selective agonist of the melanocortin 1 receptor (MC1R). PL8177 has shown efficacy in reversing intestinal inflammation in a cannulated rat ulcerative colitis model. To facilitate oral delivery, a novel, polymer-encapsulated formulation of PL8177 was developed. This formulation was tested in 2 rat ulcerative colitis models and evaluated for distribution, in vivo, in rats, dogs, and humans. Methods The rat models of colitis were induced by treatment with 2,4-dinitrobenzenesulfonic acid or dextran sulfate sodium. Single nuclei RNA sequencing of colon tissues was performed to characterize the mechanism of action. The distribution and concentration of PL8177 and the main metabolite within the GI tract after a single oral dose of PL8177 was investigated in rats and dogs. A phase 0 clinical study using a single microdose (70 µg) of [14C]-labeled PL8177 investigated the release of PL8177 in the colon of healthy men after oral administration. Results Rats treated with 50 µg oral PL8177 demonstrated significantly lower macroscopic colon damage scores and improvement in colon weight, stool consistency, and fecal occult blood vs the vehicle without active drug. Histopathology analysis resulted in the maintenance of intact colon structure and barrier, reduced immune cell infiltration, and increased enterocytes with PL8177 treatment. Transcriptome data show that oral PL8177 50 µg treatment causes relative cell populations and key gene expressions levels to move closer to healthy controls. Compared with vehicle, treated colon samples show negative enrichment of immune marker genes and diverse immune-related pathways. In rats and dogs, orally administered PL8177 was detected at higher amounts in the colon vs upper GI tract. [14C]-PL8177 and the main metabolite were detected in the feces but not in the plasma and urine in humans. This suggests that the parent drug [14C]-PL8177 was released from the polymer formulation and metabolized within the GI tract, where it would be expected to exert its effect. Conclusion Collectively, these findings support further research into the oral formulation of PL8177 as a possible therapeutic for GI inflammatory diseases in humans.
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Affiliation(s)
- John Dodd
- Palatin Technologies, Inc., Cranbury, NJ, United States
| | - Robert Jordan
- Palatin Technologies, Inc., Cranbury, NJ, United States
| | | | - Keith Barnett
- Palatin Technologies, Inc., Cranbury, NJ, United States
| | - Ad Roffel
- Consulting & Advisory Services – Clinical Pharmacology, ICON plc, Groningen, Netherlands
| | - Carl Spana
- Palatin Technologies, Inc., Cranbury, NJ, United States
| | - Alison Obr
- Palatin Technologies, Inc., Cranbury, NJ, United States
| | | | - Paul S. Kayne
- Palatin Technologies, Inc., Cranbury, NJ, United States
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Khodeneva N, Sugimoto MA, Davan-Wetton CSA, Montero-Melendez T. Melanocortin therapies to resolve fibroblast-mediated diseases. Front Immunol 2023; 13:1084394. [PMID: 36793548 PMCID: PMC9922712 DOI: 10.3389/fimmu.2022.1084394] [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: 10/30/2022] [Accepted: 11/28/2022] [Indexed: 02/01/2023] Open
Abstract
Stromal cells have emerged as central drivers in multiple and diverse diseases, and consequently, as potential new cellular targets for the development of novel therapeutic strategies. In this review we revise the main roles of fibroblasts, not only as structural cells but also as players and regulators of immune responses. Important aspects like fibroblast heterogeneity, functional specialization and cellular plasticity are also discussed as well as the implications that these aspects may have in disease and in the design of novel therapeutics. An extensive revision of the actions of fibroblasts on different conditions uncovers the existence of numerous diseases in which this cell type plays a pathogenic role, either due to an exacerbation of their 'structural' side, or a dysregulation of their 'immune side'. In both cases, opportunities for the development of innovative therapeutic approaches exist. In this regard, here we revise the existing evidence pointing at the melanocortin pathway as a potential new strategy for the treatment and management of diseases mediated by aberrantly activated fibroblasts, including scleroderma or rheumatoid arthritis. This evidence derives from studies involving models of in vitro primary fibroblasts, in vivo models of disease as well as ongoing human clinical trials. Melanocortin drugs, which are pro-resolving mediators, have shown ability to reduce collagen deposition, activation of myofibroblasts, reduction of pro-inflammatory mediators and reduced scar formation. Here we also discuss existing challenges, both in approaching fibroblasts as therapeutic targets, and in the development of novel melanocortin drug candidates, that may help advance the field and deliver new medicines for the management of diseases with high medical needs.
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Zhao Y, Xue P, Lin G, Tong M, Yang J, Zhang Y, Ran K, Zhuge D, Yao Q, Xu H. A KPV-binding double-network hydrogel restores gut mucosal barrier in an inflamed colon. Acta Biomater 2022; 143:233-252. [PMID: 35245681 DOI: 10.1016/j.actbio.2022.02.039] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 01/29/2022] [Accepted: 02/25/2022] [Indexed: 02/08/2023]
Abstract
Ulcerative colitis (UC) usually occurs in the superficial mucosa of the colorectum. Here, a double-network hydrogel (PMSP) was constructed from maleimided γ-polyglutamic acid and thiolated γ-polyglutamic acid through crosslinking of thiol-maleimide and self-oxidized thiols. PMSP with a negative charge specifically adhered to the inflamed mucosa with positively charged proteins rather than to the healthy mucosa. PMSP exhibited good mechanical strength with storage modulus (G') of 17.6 Pa and a linear viscoelastic region (LVR) of 107.2% strain. Moreover, PMSP showed a stronger bio-adhesive force toward the inflamed tissue-mimicking substrate than toward its healthy counterpart. In vivo imaging confirmed that PMSP specifically adhered to the inflamed colonic mucosa of rats with TNBS-induced UC. KPV (Lys-Pro-Val) as a model drug was easily captured by PMSP through electrostatic interactions, thus retaining its bioactivity for a longer time under high temperature conditions. Moreover, the alleviating effect of KPV on rats with TNBS-induced colitis was significantly improved by PMSP after intracolonic administration. The epithelial barrier of the colon also effectively recovered following PMSP-KPV treatment. PMSP-KPV also modulated the gut flora, markedly augmenting the abundance of beneficial microorganisms in gut homeostasis. The mechanism by which PMSP-KPV induces a therapeutic effect may be associated with the inhibition of oxidative stress. Conclusively, the PMSP hydrogel seems to be a promising rectal delivery system for the therapy of UC. STATEMENT OF SIGNIFICANCE: Ulcerative colitis (UC) is a chronic and relapsing disease of the gastrointestinal tract. A key therapeutic approach to treat UC is to repair the mucosal barriers. Here, a double-network hydrogel (PMSP) was constructed from maleimided and thiolated γ-polyglutamic acid through crosslinking of thiol-maleimide and self-oxidized thiols. The negatively charged PMSP specifically adhered to the inflamed colon rather than its healthy counterpart and was retained for a longer time. KPV as a model drug was easily captured by PMSP, which provided better stability to KPV when exposed to high temperature of 50 °C. The epithelial mucosal barrier of the colon was effectively recovered by the rectal administration of PMSP-KPV to rats with TNBS-induced UC. Moreover, PMSP-KPV modulated the gut flora of colitic rats, markedly augmenting the abundance of beneficial microorganisms. Conclusively, PMSP seems to be a promising rectal delivery system for UC therapy.
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Bai B, Li H, Han L, Mei Y, Hu C, Mei Q, Xu J, Liu X. Molecular mechanism of the TGF‑β/Smad7 signaling pathway in ulcerative colitis. Mol Med Rep 2022; 25:116. [PMID: 35137923 PMCID: PMC8855156 DOI: 10.3892/mmr.2022.12632] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 12/03/2021] [Indexed: 11/10/2022] Open
Abstract
Aberrant TGF‑β/Smad7 signaling has been reported to be an important mechanism underlying the pathogenesis of ulcerative colitis. Therefore, the present study aimed to investigate the effects of a number of potential anti‑colitis agents on intestinal epithelial permeability and the TGF‑β/Smad7 signaling pathway in an experimental model of colitis. A mouse model of colitis was first established before anti‑TNF‑α and 5‑aminosalicyclic acid (5‑ASA) were administered intraperitoneally and orally, respectively. Myeloperoxidase (MPO) activity, histological index (HI) of the colon and the disease activity index (DAI) scores were then detected in each mouse. Transmission electron microscopy (TEM), immunohistochemical and functional tests, including Evans blue (EB) and FITC‑dextran (FD‑4) staining, were used to evaluate intestinal mucosal permeability. The expression of epithelial phenotype markers E‑cadherin, occludin, zona occludens (ZO‑1), TGF‑β and Smad7 were measured. In addition, epithelial myosin light chain kinase (MLCK) expression and activity were measured. Anti‑TNF‑α and 5‑ASA treatments was both found to effectively reduce the DAI score and HI, whilst decreasing colonic MPO activity, plasma levels of FD‑4 and EB permeation of the intestine. Furthermore, anti‑TNF‑α and 5‑ASA treatments decreased MLCK expression and activity, reduced the expression of Smad7 in the small intestine epithelium, but increased the expression of TGF‑β. In mice with colitis, TEM revealed partial epithelial injury in the ileum, where the number of intercellular tight junctions and the expression levels of E‑cadherin, ZO‑1 and occludin were decreased, all of which were alleviated by anti‑TNF‑α and 5‑ASA treatment. In conclusion, anti‑TNF‑α and 5‑ASA both exerted protective effects on intestinal epithelial permeability in an experimental mouse model of colitis. The underlying mechanism may be mediated at least in part by the increase in TGF‑β expression and/or the reduction in Smad7 expression, which can inhibit epithelial MLCK activity and in turn reduce mucosal permeability during the pathogenesis of ulcerative colitis.
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Affiliation(s)
- Bingqing Bai
- Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
- The Key Laboratory of Digestive Diseases of Anhui Province, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Huihui Li
- The Key Laboratory of Digestive Diseases of Anhui Province, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
- Department of Gastroenterology, Fuyang Cancer Hospital, Fuyang, Anhui 236010, P.R. China
| | - Liang Han
- The Key Laboratory of Digestive Diseases of Anhui Province, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
- Department of Gastroenterology, Hangzhou Ninth People's Hospital, Hangzhou, Zhejiang 311225, P.R. China
| | - Yongyu Mei
- The Key Laboratory of Digestive Diseases of Anhui Province, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
- Department of Gastroenterology, Wuhu Second People's Hospital, Wuhu, Anhui 241000, P.R. China
| | - Cui Hu
- Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
- The Key Laboratory of Digestive Diseases of Anhui Province, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Qiao Mei
- Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
- The Key Laboratory of Digestive Diseases of Anhui Province, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Jianming Xu
- Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
- The Key Laboratory of Digestive Diseases of Anhui Province, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Xiaochang Liu
- Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
- The Key Laboratory of Digestive Diseases of Anhui Province, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
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11
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Resolution of Inflammation in Acute Graft-Versus-Host-Disease: Advances and Perspectives. Biomolecules 2022; 12:biom12010075. [PMID: 35053223 PMCID: PMC8773806 DOI: 10.3390/biom12010075] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/21/2021] [Accepted: 12/29/2021] [Indexed: 02/04/2023] Open
Abstract
Inflammation is an essential reaction of the immune system to infections and sterile tissue injury. However, uncontrolled or unresolved inflammation can cause tissue damage and contribute to the pathogenesis of various inflammatory diseases. Resolution of inflammation is driven by endogenous molecules, known as pro-resolving mediators, that contribute to dampening inflammatory responses, promoting the resolution of inflammation and the recovery of tissue homeostasis. These mediators have been shown to be useful to decrease inflammatory responses and tissue damage in various models of inflammatory diseases. Graft-versus-host disease (GVHD) is a major unwanted reaction following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is characterized by an exacerbated inflammatory response provoked by antigen disparities between transplant recipient and donor. There is no fully effective treatment or prophylaxis for GVHD. This review explores the effects of several pro-resolving mediators and discusses their potential use as novel therapies in the context of GVHD.
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12
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Sun J, Xue P, Liu J, Huang L, Lin G, Ran K, Yang J, Lu C, Zhao YZ, Xu HL. Self-Cross-Linked Hydrogel of Cysteamine-Grafted γ-Polyglutamic Acid Stabilized Tripeptide KPV for Alleviating TNBS-Induced Ulcerative Colitis in Rats. ACS Biomater Sci Eng 2021; 7:4859-4869. [PMID: 34547895 DOI: 10.1021/acsbiomaterials.1c00792] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
KPV (Lys-Pro-Val), which is a tripeptide derived from α-MSH (α-melanocyte-stimulating hormone), has an anti-inflammatory effect on colitis. However, KPV solution is very unstable when rectally administered, compromising its therapeutic efficacy. Herein, cysteamine-grafted γ-polyglutamic acid (SH-PGA) was synthesized by conjugating cysteamine with the carboxyl groups of γ-PGA. The synthesized SH-PGA has the thiol grafting amount of 4.5 ± 0.3 mmol/g. Without the use of the cross-linker, the SH-PGA hydrogel with 4% of the polymer was formed by self-cross-linking of thiol groups. Moreover, the formation of the SH-PGA hydrogel was not affected by KPV. The KPV/SH-PGA hydrogel presented higher elastic modulus (G') than the corresponding viscous modulus (G″) at 0.01-10 Hz, exhibiting good mechanical stability. The KPV/SH-PGA hydrogel presented a shear-thinning behavior, which was helpful for rectal administration. Only 30% of KPV was released from the KPV/SH-PGA hydrogel within 20 min, followed by a sustained-release behavior. Importantly, the stability of KPV in the SH-PGA hydrogel was obviously enhanced, which was presented by detecting its anti-inflammatory activity and promoting cell migration potential after 2 h of exposure to 37 °C. The enhanced therapeutic effect of the KPV/SH-PGA hydrogel on colitis was confirmed on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced ulcerative colitis rats. The colitis symptoms including body weight loss and the disease activity index score were obviously attenuated by rectally administering the KPV/SH-PGA hydrogel. Besides, the KPV/SH-PGA hydrogel treatment prevented the colon shortening of TNBS-infused rats and decreased the colonic myeloperoxidase level. The morphology of the colon including the epithelial barrier, crypt, and intact goblet cells was recovered after KPV/SH-PGA hydrogel treatment. Besides, the KPV/SH-PGA hydrogel decreased the expression of proinflammatory cytokines such as tumor necrosis factor α and interleukin 6. Collectively, the KPV/SH-PGA hydrogel may provide a promising strategy for the treatment of ulcerative colitis.
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Affiliation(s)
- Jie Sun
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Pengpeng Xue
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Jiayi Liu
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Lantian Huang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Gaolong Lin
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Kunjie Ran
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Jiaojiao Yang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Cuitao Lu
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Ying-Zheng Zhao
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - He-Lin Xu
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
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13
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Liu P, Gao C, Chen H, Vong CT, Wu X, Tang X, Wang S, Wang Y. Receptor-mediated targeted drug delivery systems for treatment of inflammatory bowel disease: Opportunities and emerging strategies. Acta Pharm Sin B 2021; 11:2798-2818. [PMID: 34589398 PMCID: PMC8463263 DOI: 10.1016/j.apsb.2020.11.003] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 10/01/2020] [Accepted: 10/14/2020] [Indexed: 02/08/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic intestinal disease with painful clinical manifestations and high risks of cancerization. With no curative therapy for IBD at present, the development of effective therapeutics is highly advocated. Drug delivery systems have been extensively studied to transmit therapeutics to inflamed colon sites through the enhanced permeability and retention (EPR) effect caused by the inflammation. However, the drug still could not achieve effective concentration value that merely utilized on EPR effect and display better therapeutic efficacy in the inflamed region because of nontargeted drug release. Substantial researches have shown that some specific receptors and cell adhesion molecules highly expresses on the surface of colonic endothelial and/or immune cells when IBD occurs, ligand-modified drug delivery systems targeting such receptors and cell adhesion molecules can specifically deliver drug into inflamed sites and obtain great curative effects. This review introduces the overexpressed receptors and cell adhesion molecules in inflamed colon sites and retrospects the drug delivery systems functionalized by related ligands. Finally, challenges and future directions in this field are presented to advance the development of the receptor-mediated targeted drug delivery systems for the therapy of IBD.
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Key Words
- ACQ, aggregation-caused quenching
- ADR, adverse drug reaction
- AIE, aggregation-induced emission
- Active target
- BSA, bovine serum albumin
- CAM, cell adhesion molecule
- CD, Crohn's disease
- CRD, cysteine-rich domain
- CS, chondroitin sulfate
- CT, computed tomography
- CTLD, c-type lectin-like domain
- Cell adhesion molecule
- Crohn's disease
- DCs, dendritic cells
- DSS, dextran sulfate sodium salt
- Drug delivery
- EGF, epidermal growth factor
- EPR, enhanced permeability and retention
- FNII, fibronectin type II domain
- FR, folate receptor
- FRET, fluorescence resonance energy transfer
- GIT, gastrointestinal tract
- HA, hyaluronic acid
- HUVEC, human umbilical vein endothelial cells
- IBD, inflammatory bowel disease
- ICAM, intercellular adhesion molecule
- Inflammatory bowel disease
- LMWC, low molecular weight chitosan
- LPS, lipopolysaccharide
- MAP4K4, mitogen-activated protein kinase kinase kinase kinase 4
- MGL, macrophage galactose lectin
- MPO, myeloperoxidase
- MPS, mononuclear phagocyte system
- MR, mannose receptor
- MRI, magnetic resonance imaging
- PAMAM, poly(amidoamine)
- PEI, polyethylenimine
- PSGL-1, P-selectin glycoprotein ligand-1
- PepT1, peptide transporter 1
- QDs, quantum dots
- RES, reticuloendothelial system
- Receptor-mediated target
- Targeted therapy
- TfR, transferrin receptor
- UC, ulcerative colitis
- Ulcerative colitis
- VCAM, vascular cell adhesion molecule
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14
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Dinparastisaleh R, Mirsaeidi M. Antifibrotic and Anti-Inflammatory Actions of α-Melanocytic Hormone: New Roles for an Old Player. Pharmaceuticals (Basel) 2021; 14:ph14010045. [PMID: 33430064 PMCID: PMC7827684 DOI: 10.3390/ph14010045] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Revised: 01/04/2021] [Accepted: 01/06/2021] [Indexed: 12/16/2022] Open
Abstract
The melanocortin system encompasses melanocortin peptides, five receptors, and two endogenous antagonists. Besides pigmentary effects generated by α-Melanocytic Hormone (α-MSH), new physiologic roles in sexual activity, exocrine secretion, energy homeostasis, as well as immunomodulatory actions, exerted by melanocortins, have been described recently. Among the most common and burdensome consequences of chronic inflammation is the development of fibrosis. Depending on the regenerative capacity of the affected tissue and the quality of the inflammatory response, the outcome is not always perfect, with the development of some fibrosis. Despite the heterogeneous etiology and clinical presentations, fibrosis in many pathological states follows the same path of activation or migration of fibroblasts, and the differentiation of fibroblasts to myofibroblasts, which produce collagen and α-SMA in fibrosing tissue. The melanocortin agonists might have favorable effects on the trajectories leading from tissue injury to inflammation, from inflammation to fibrosis, and from fibrosis to organ dysfunction. In this review we briefly summarized the data on structure, receptor signaling, and anti-inflammatory and anti-fibrotic properties of α-MSH and proposed that α-MSH analogues might be promising future therapeutic candidates for inflammatory and fibrotic diseases, regarding their favorable safety profile.
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Affiliation(s)
- Roshan Dinparastisaleh
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21218, USA;
| | - Mehdi Mirsaeidi
- Division of Pulmonary and Critical Care, University of Miami, Miami, FL 33146, USA
- Correspondence: ; Tel.: +1-305-243-1377
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15
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Can VC, Locke IC, Kaneva MK, Kerrigan MJP, Merlino F, De Pascale C, Grieco P, Getting SJ. Novel anti-inflammatory and chondroprotective effects of the human melanocortin MC1 receptor agonist BMS-470539 dihydrochloride and human melanocortin MC3 receptor agonist PG-990 on lipopolysaccharide activated chondrocytes. Eur J Pharmacol 2020; 872:172971. [PMID: 32004526 DOI: 10.1016/j.ejphar.2020.172971] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 01/15/2020] [Accepted: 01/27/2020] [Indexed: 12/01/2022]
Abstract
Human melanocortin MC1 and MC3 receptors expressed on C-20/A4 chondrocytes exhibit chondroprotective and anti-inflammatory effects when activated by melanocortin peptides. Nearly 9 million people in the UK suffer from osteoarthritis, and bacterial infections play a role in its development. Here, we evaluate the effect of a panel of melanocortin peptides with different selectivity for human melanocortin MC1 (α-MSH, BMS-470539 dihydrochloride) and MC3 ([DTrp8]-γ-MSH, PG-990) receptors and C-terminal peptide α-MSH11-13(KPV), on inhibiting LPS-induced chondrocyte death, pro-inflammatory mediators and induction of anti-inflammatory proteins. C-20/A4 chondrocytes were treated with a panel of melanocortin peptides prophylactically and therapeutically in presence of LPS (0.1 μg/ml). The chondroprotective properties of these peptides determined by cell viability assay, RT-PCR, ELISA for detection of changes in inflammatory markers (IL-6, IL-8 and MMP-1, -3 and -13) and western blotting for expression of the anti-inflammatory protein heme-oxygenase-1. C-20/A4 expressed human melanocortin MC1 and MC3 receptors and melanocortin peptides elevated cAMP. LPS stimulation caused a reduction in C-20/A4 viability, attenuated by the human melanocortin MC1 receptor agonist BMS-470539 dihydrochloride, and MC3 receptor agonists PG-990 and [DTrp8]-γ-MSH. Prophylactic and therapeutic regimes of [DTrp8]-γ-MSH significantly inhibited LPS-induced modulation of cartilage-damaging IL-6, IL-8, MMPs -1,-3 and -13 mediators both prophylactically and therapeutically, whilst human melanocortin MC1 and MC3 receptor agonists promoted an increase in HO-1 production. In the presence of LPS, activation of human melanocortin MC1 and MC3 receptors provided potent chondroprotection, upregulation of anti-inflammatory proteins and downregulation of inflammatory and proteolytic mediators involved in cartilage degradation, suggesting a new avenue for osteoarthritis treatment.
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Affiliation(s)
- Vedia C Can
- College of Liberal Arts and Sciences, School of Life Sciences, University of Westminster, 115 New Cavendish Street, London, W1W 6UW, UK
| | - Ian C Locke
- College of Liberal Arts and Sciences, School of Life Sciences, University of Westminster, 115 New Cavendish Street, London, W1W 6UW, UK
| | - Magdalena K Kaneva
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Mark J P Kerrigan
- Plymouth College of Art, Tavistock Place, Plymouth, Devon, PL4 8AT, UK
| | - Francesco Merlino
- Department of Pharmacy, University of Naples, Via D. Montesano, 49 - 80131, Naples, Italy
| | - Clara De Pascale
- College of Liberal Arts and Sciences, School of Life Sciences, University of Westminster, 115 New Cavendish Street, London, W1W 6UW, UK
| | - Paolo Grieco
- Department of Pharmacy, University of Naples, Via D. Montesano, 49 - 80131, Naples, Italy
| | - Stephen J Getting
- College of Liberal Arts and Sciences, School of Life Sciences, University of Westminster, 115 New Cavendish Street, London, W1W 6UW, UK.
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16
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Giron F, Pastó A, Tasciotti E, Abraham BP. Nanotechnology in the Treatment of Inflammatory Bowel Disease. Inflamm Bowel Dis 2019; 25:1871-1880. [PMID: 31560054 DOI: 10.1093/ibd/izz205] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Indexed: 12/12/2022]
Abstract
Due to the lack of cure for inflammatory bowel disease (IBD) and failure of current medical therapies in many patients with IBD, a need exists in finding novel ways to treat inflammation with a high benefit and the lowest risk possible. With current medical therapies, adverse events or risks of cancer/lymphoma and infections prevent patients-and sometimes providers-in using effective therapies for treatment. Some patients develop systemic side effects that preclude them from continuing a therapy that may have been efficacious, or in other cases, current medical therapies are not adequate to control disease. Nanotechnology is an emerging field where particles, in the size of nanometers, can be used to deliver medications directly to the area of inflammation thus avoiding drug-associated systemic side effects. When using nanoparticles (NPs), only a small amount of the drug is needed, and it can be delivered directly to the inflamed site without exposure to the rest of the body. Here we review conventional and unconventional therapies applied in the treatment of IBD underlying how the introduction of NPs has improved their safety and efficacy.
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Affiliation(s)
- Fanny Giron
- Universidad Católica de Honduras, San Pedro Sula, Honduras
| | - Anna Pastó
- Istituto Oncologico Veneto-IRCCS, Padova, Italy
| | - Ennio Tasciotti
- Underwood Center for Digestive Disorders, Houston Methodist Hospital, Houston, Texas.,Houston Methodist Research Institute, Houston Methodist Hospital, Houston, Texas
| | - Bincy P Abraham
- Underwood Center for Digestive Disorders, Houston Methodist Hospital, Houston, Texas.,Houston Methodist Research Institute, Houston Methodist Hospital, Houston, Texas
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17
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Wu Y, Sun M, Wang D, Li G, Huang J, Tan S, Bao L, Li Q, Li G, Si L. A PepT1 mediated medicinal nano-system for targeted delivery of cyclosporine A to alleviate acute severe ulcerative colitis. Biomater Sci 2019; 7:4299-4309. [PMID: 31408067 DOI: 10.1039/c9bm00925f] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/11/2023]
Abstract
To effectively alleviate acute severe ulcerative colitis (ASUC), we developed a colon-specific delivery system-PLGA-KPV/MMT/CS multifunctional medicinal nanoparticles loaded with cyclosporine A (CyA). The lysine-proline-valine (KPV) tripeptide, which possesses anti-inflammatory properties and high affinity to peptide transporter 1 (PepT1), can target therapy-related cells (colonic epithelial cells and macrophages) via overexpression of PepT1. Montmorillonite (MMT)/chitosan (CS) coating can reduce CyA leakage in the upper gastrointestinal tract (GIT) and enhance nanoparticle adhesion to the inflamed colon. The bio-distribution demonstrated that nanoparticles can specifically accumulate in the inflamed tissues and can be retained for up to 36 h. After being treated with the CyA-PLGA-KPV/MMT/CS nanoparticles (PKMCN), the mice with DSS-induced ulcerative colitis exhibited significant improvements in body weight, colon length, and disease activity index. Moreover, biochemistry and immunohistochemical analysis showed that the PKMCN treatment group performed as well as the healthy group. Intriguingly, PKMCN without CyA also presented marked therapeutic effects. Our results suggested that PKMCN could be a promising drug delivery system for ASUC therapy by targeting inflamed cells, prolonging curative time, and mitigating colitis.
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Affiliation(s)
- Ya Wu
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, PR China.
| | - Minghui Sun
- Department of Pharmacy, Affiliated Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, PR China
| | - Dan Wang
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, PR China.
| | - Genyun Li
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, PR China.
| | - Jiangeng Huang
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, PR China.
| | - Songwei Tan
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, PR China.
| | - Lin Bao
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, PR China.
| | - Qian Li
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, PR China.
| | - Gao Li
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, PR China.
| | - Luqin Si
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, PR China.
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18
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Barnig C, Bezema T, Calder PC, Charloux A, Frossard N, Garssen J, Haworth O, Dilevskaya K, Levi-Schaffer F, Lonsdorfer E, Wauben M, Kraneveld AD, Te Velde AA. Activation of Resolution Pathways to Prevent and Fight Chronic Inflammation: Lessons From Asthma and Inflammatory Bowel Disease. Front Immunol 2019; 10:1699. [PMID: 31396220 PMCID: PMC6664683 DOI: 10.3389/fimmu.2019.01699] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 07/08/2019] [Indexed: 12/15/2022] Open
Abstract
Formerly considered as a passive process, the resolution of acute inflammation is now recognized as an active host response, with a cascade of coordinated cellular and molecular events that promotes termination of the inflammatory response and initiates tissue repair and healing. In a state of immune fitness, the resolution of inflammation is contained in time and space enabling the restoration of tissue homeostasis. There is increasing evidence that poor and/or inappropriate resolution of inflammation participates in the pathogenesis of chronic inflammatory diseases, extending in time the actions of pro-inflammatory mechanisms, and responsible in the long run for excessive tissue damage and pathology. In this review, we will focus on how resolution can be the target for therapy in "Th1/Th17 cell-driven" immune diseases and "Th2 cell-driven" immune diseases, with inflammatory bowel diseases (IBD) and asthma, as relevant examples. We describe the main cells and mediators stimulating the resolution of inflammation and discuss how pharmacological and dietary interventions but also life style factors, physical and psychological conditions, might influence the resolution phase. A better understanding of the impact of endogenous and exogenous factors on the resolution of inflammation might open a whole area in the development of personalized therapies in non-resolving chronic inflammatory diseases.
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Affiliation(s)
- Cindy Barnig
- Department of Chest Disease, Strasbourg University Hospital, Strasbourg, France.,Equipe d'accueil 3072, University of Strasbourg, Strasbourg, France
| | | | - Philip C Calder
- Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.,National Institute for Health Research Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, United Kingdom
| | - Anne Charloux
- Department of Chest Disease, Strasbourg University Hospital, Strasbourg, France.,Equipe d'accueil 3072, University of Strasbourg, Strasbourg, France
| | - Nelly Frossard
- UMR 7200 CNRS/Université de Strasbourg, Laboratoire d'Innovation Thérapeutique and LabEx MEDALIS, Faculté de Pharmacie, Strasbourg, France
| | - Johan Garssen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands.,Nutricia Research, Utrecht, Netherlands
| | - Oliver Haworth
- Biochemical Pharmacology, William Harvey Research Institute, Bart's School of Medicine and Queen Mary University of London, London, United Kingdom
| | - Ksenia Dilevskaya
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands
| | - Francesca Levi-Schaffer
- Pharmacology and Experimental Therapeutics Unit, Faculty of Medicine, School of Pharmacy, Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Evelyne Lonsdorfer
- Department of Chest Disease, Strasbourg University Hospital, Strasbourg, France.,Equipe d'accueil 3072, University of Strasbourg, Strasbourg, France
| | - Marca Wauben
- Department of Biochemistry & Cell Biology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Aletta D Kraneveld
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands.,Institute for Risk Assessment Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Anje A Te Velde
- Amsterdam UMC, Tytgat Institute for Liver and Intestinal Research, University of Amsterdam, AGEM, Amsterdam, Netherlands
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19
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Böhm M, Luger T. Are melanocortin peptides future therapeutics for cutaneous wound healing? Exp Dermatol 2019; 28:219-224. [PMID: 30661264 DOI: 10.1111/exd.13887] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 10/29/2018] [Accepted: 11/20/2018] [Indexed: 12/11/2022]
Abstract
Cutaneous wound healing is a complex process divided into different phases, that is an inflammatory, proliferative and remodelling phase. During these phases, a variety of resident skin cell types but also cells of the immune system orchestrate the healing process. In the last year, it has been shown that the majority of cutaneous cell types express the melanocortin 1 receptor (MC1R) that binds α-melanocyte-stimulating hormone (α-MSH) with high affinity and elicits pleiotropic biological effects, for example modulation of inflammation and immune responses, cytoprotection, antioxidative defense and collagen turnover. Truncated α-MSH peptides such as Lys-Pro-Val (KPV) as well as derivatives like Lys-d-Pro-Thr (KdPT), the latter containing the amino acid sequence 193-195 of interleukin-1β, have been found to possess anti-inflammatory effects but to lack the pigment-inducing activity of α-MSH. We propose here that such peptides are promising future candidates for the treatment of cutaneous wounds and skin ulcers. Experimental approaches in silico, in vitro, ex vivo and in animal models are outlined. This is followed by an unbiased discussion of the pro and contra arguments of such peptides as future candidates for the therapeutic management of cutaneous wounds and a review of the so-far available data on melanocortin peptides and derivatives in wound healing.
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Affiliation(s)
- Markus Böhm
- Department of Dermatology, Laboratory for Neuroendocrinology of the Skin and Interdisciplinary Endocrinology, University of Münster, Münster, Germany
| | - Thomas Luger
- Department of Dermatology, Laboratory for Neuroendocrinology of the Skin and Interdisciplinary Endocrinology, University of Münster, Münster, Germany
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20
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Spana C, Taylor AW, Yee DG, Makhlina M, Yang W, Dodd J. Probing the Role of Melanocortin Type 1 Receptor Agonists in Diverse Immunological Diseases. Front Pharmacol 2019; 9:1535. [PMID: 30692924 PMCID: PMC6339910 DOI: 10.3389/fphar.2018.01535] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 12/17/2018] [Indexed: 12/12/2022] Open
Abstract
Background: The melanocortin α-melanocyte stimulating hormone (α-MSH), an endogenous peptide with high affinity for the melanocortin 1 receptor (MC1r), has demonstrated prevention and reversal of intestinal and ocular inflammation in animal models. Preclinical studies were performed to determine whether two MC1r receptor agonists, PL-8177 and PL-8331, exhibit actions and efficacy similar to α-MSH in preventing and reversing intestinal and ocular inflammation. Methods: Both PL-8177 and PL-8331 were assessed in a Eurofins LeadProfilingScreen selectivity panel including 72 in vitro assays. PL-8177 and PL-8331 were evaluated in an in vitro assay using human whole blood stimulated by lipopolysaccharide to determine inhibition of tumor necrosis factor alpha (TNF-α); for comparison, adrenocorticotropic hormone (ACTH) and α-MSH were used as positive controls. PL-8177, dosed at 0.5, 1.5, and 5.0 μg, was assessed in a cannulated rat model of dinitrobenzene sulfonic acid (DNBS)-induced bowel inflammation versus vehicle and oral sulfasalazine. PL-8177 was also dosed at 0.3 mg/kg/mouse injected intraperitoneally versus untreated controls and α-MSH treatment in mice with experimental autoimmune uveitis (EAU). PL-8331 at 3 doses, 3 times daily, was evaluated in a murine model of scopolamine-induced dry eye disease (SiccaSystemTM model), versus twice-daily Restasis® and Xiidra®. Results: Both PL-8177 and PL-8331 demonstrated no significant activity at the 1 μm concentration in any of the 72 in vitro assays. PL-8177 and PL-8331 inhibited lipopolysaccharide-induced TNF-α to a similar degree as ACTH and α-MSH. In the DNBS rat model of bowel inflammation, PL-8177 was significantly superior to untreated controls at all 3 doses (P < 0.05) in reducing bowel inflammation parameters, with effects similar to sulfasalazine. In the murine EAU model, PL-8177 significantly reduced retinal inflammation scores versus untreated controls (P = 0.0001) over 3–5 weeks, and to a similar degree as α-MSH. In the murine scopolamine-induced model of dry eye disease, PL-8331 reduced corneal fluorescein staining scores at all doses, significantly (P = 0.02) for the highest dose (1 × 10-5 mg⋅mL-1), and similarly to Restasis®; Xiidra® demonstrated no effect. Conclusion: The MC1r receptor agonists PL-8177 and PL-8331 exhibited actions similar to those of α-MSH in preventing and reversing intestinal and ocular inflammation in preclinical disease models.
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Affiliation(s)
- Carl Spana
- Palatin Technologies, Inc., Cranbury, NJ, United States
| | - Andrew W Taylor
- Department of Ophthalmology, Boston University School of Medicine, Boston, MA, United States
| | - David G Yee
- Department of Ophthalmology, Boston University School of Medicine, Boston, MA, United States
| | | | - Wei Yang
- Palatin Technologies, Inc., Cranbury, NJ, United States
| | - John Dodd
- Palatin Technologies, Inc., Cranbury, NJ, United States
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Wang W, Guo DY, Lin YJ, Tao YX. Melanocortin Regulation of Inflammation. Front Endocrinol (Lausanne) 2019; 10:683. [PMID: 31649620 PMCID: PMC6794349 DOI: 10.3389/fendo.2019.00683] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 09/19/2019] [Indexed: 12/18/2022] Open
Abstract
Adrenocorticotropic hormone (ACTH), and α-, β-, and γ-melanocyte-stimulating hormones (α-, β-, γ-MSH), collectively known as melanocortins, together with their receptors (melanocortin receptors), are components of an ancient modulatory system. The clinical use of ACTH in the treatment of rheumatoid arthritis started in 1949, originally thought that the anti-inflammatory action was through hypothalamus-pituitary-adrenal axis and glucocorticoid-dependent. Subsequent decades have witnessed extensive attempts in unraveling the physiology and pharmacology of the melanocortin system. It is now known that ACTH, together with α-, β-, and γ-MSHs, also possess glucocorticoid-independent anti-inflammatory and immunomodulatory effects by activating the melanocortin receptors expressed in the brain or peripheral immune cells. This review will briefly introduce the melanocortin system and highlight the action of melanocortins in the regulation of immune functions from in vitro, in vivo, preclinical, and clinical studies. The potential therapeutic use of melanocortins are also summarized.
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Affiliation(s)
- Wei Wang
- Department of Clinical Laboratory, Xiamen Huli Guoyu Clinic, Co., Ltd., Xiamen, China
| | - Dong-Yu Guo
- Department of Clinical Laboratory, Xiamen Huli Guoyu Clinic, Co., Ltd., Xiamen, China
- *Correspondence: Dong-Yu Guo
| | - Yue-Jun Lin
- Department of Clinical Laboratory, Xiamen Huli Guoyu Clinic, Co., Ltd., Xiamen, China
| | - Ya-Xiong Tao
- Department of Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States
- Ya-Xiong Tao
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Viennois E, Pujada A, Zen J, Merlin D. Function, Regulation, and Pathophysiological Relevance of the POT Superfamily, Specifically PepT1 in Inflammatory Bowel Disease. Compr Physiol 2018; 8:731-760. [PMID: 29687900 DOI: 10.1002/cphy.c170032] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Mammalian members of the proton-coupled oligopeptide transporter family are integral membrane proteins that mediate the cellular uptake of di/tripeptides and peptide-like drugs and couple substrate translocation to the movement of H+ , with the transmembrane electrochemical proton gradient providing the driving force. Peptide transporters are responsible for the (re)absorption of dietary and/or bacterial di- and tripeptides in the intestine and kidney and maintaining homeostasis of neuropeptides in the brain. These proteins additionally contribute to absorption of a number of pharmacologically important compounds. In this overview article, we have provided updated information on the structure, function, expression, localization, and activities of PepT1 (SLC15A1), PepT2 (SLC15A2), PhT1 (SLC15A4), and PhT2 (SLC15A3). Peptide transporters, in particular, PepT1 are discussed as drug-delivery systems in addition to their implications in health and disease. Particular emphasis has been placed on the involvement of PepT1 in the physiopathology of the gastrointestinal tract, specifically, its role in inflammatory bowel diseases. © 2018 American Physiological Society. Compr Physiol 8:731-760, 2018.
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Affiliation(s)
- Emilie Viennois
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia, USA
| | - Adani Pujada
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia, USA
| | - Jane Zen
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia, USA
| | - Didier Merlin
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia, USA.,Veterans Affairs Medical Center, Decatur, Georgia, USA
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Ilzarbe L, Fàbrega M, Quintero R, Bastidas A, Pintor L, García-Campayo J, Gomollón F, Ilzarbe D. Inflammatory Bowel Disease and Eating Disorders: A systematized review of comorbidity. J Psychosom Res 2017; 102:47-53. [PMID: 28992897 DOI: 10.1016/j.jpsychores.2017.09.006] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Revised: 08/27/2017] [Accepted: 09/13/2017] [Indexed: 12/18/2022]
Abstract
OBJECTIVE Research has shown that there is an association between Inflammatory Bowel Disease, anxiety and mood disorders, however little is known about their association with Eating Disorders. In this paper we will present a case of a young female with a comorbid diagnosis of Inflammatory Bowel Disease and Eating Disorder, and then discuss the results from a systematic review of the literature, describing published cases of patients with the same condition. METHODS A systematized review of the literature was conducted according to MOOSE guidelines. A computerized literature search of MEDLINE, PsycINFO and EMBASE, and a manual search through reference lists of selected original articles were performed to identify all published case-reports, case series and studies of Inflammatory Bowel Disease and Eating Disorders. RESULTS Fourteen articles were included, encompassing 219 cases, including ours. The vast majority were females ranging from 10 to 44years old. Anorexia Nervosa (n=156) and Crohn's Disease (n=129) was the most frequent combination (n=90) reported in the literature. These cases present a poor prognosis because of corticoid refusal, medication abandon and/or deliberate exacerbation of IBD symptoms, in the context of trying to lose weight. CONCLUSION Recent evidence suggests there is a possible association between Inflammatory Bowel Disease and Eating Disorders, although the mechanisms involved in its ethiopathogenesis are still unknown. To be aware of this association is important because a delayed diagnosis of this comorbidity may lead to worse prognosis. Further research and a multidisciplinary approach could facilitate earlier diagnosis and provide therapeutic interventions.
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Affiliation(s)
- L Ilzarbe
- Faculty of Medicine, Universidad de Zaragoza, Zaragoza, Spain
| | - M Fàbrega
- Department of Child and Adolescent Psychiatry, Imperial College London, London, United Kingdom.
| | - R Quintero
- Psychosomatic and Liason Psychiatry Unit, Department of Psychiatry and Psychology, Neuroscience Institute, Hospital Clínic de Barcelona, Barcelona, Spain.
| | - A Bastidas
- Acute Inpatient Unit, Department of Psychiatry and Psychology, Neuroscience Institute, Hospital Clínic de Barcelona, Barcelona, Spain.
| | - L Pintor
- Psychosomatic and Liason Psychiatry Unit, Department of Psychiatry and Psychology, Neuroscience Institute, Hospital Clínic de Barcelona, Barcelona, Spain.
| | - J García-Campayo
- Faculty of Medicine, Universidad de Zaragoza, Zaragoza, Spain; Department of Psychiatry, Hospital Universitario Miguel Servet, Zaragoza, Spain; Aragón Health Research Institute (IIS Aragón), Zaragoza, Spain; Network for Prevention and Health Promotion in Primary Care (RedIAPP), Madrid, Spain
| | - F Gomollón
- Faculty of Medicine, Universidad de Zaragoza, Zaragoza, Spain; Aragón Health Research Institute (IIS Aragón), Zaragoza, Spain; Inflammatory Bowel Disease Unit, Department of gastroenterology, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain; Centro de Investigación Biomédica en Red, Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - D Ilzarbe
- Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neurosciences, King's College London, London, United Kingdom; Faculty of Medicine, Universitat de Barcelona, Barcelona, Spain.
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Tripeptide K(D)PT Is Well Tolerated in Mild-to-moderate Ulcerative Colitis: Results from a Randomized Multicenter Study. Inflamm Bowel Dis 2017; 23:261-271. [PMID: 28092306 DOI: 10.1097/mib.0000000000001000] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND K(D)PT showed marked anti-inflammatory properties in preclinical studies and exhibited very low toxicity in phase I and preclinical trials. In this study, efficacy and safety of oral K(D)PT were evaluated in patients with mild-to-moderate active ulcerative colitis. METHODS A multicenter, randomized, double-blind, phase IIa trial was performed comparing add-on oral K(D)PT twice a day (20, 50, or 100 mg) with placebo in patients with mild-to-moderate active ulcerative colitis on baseline medication. The primary objective was to determine the difference in time to sustained improvement in colitis activity index (CAI) of ≥50% at week 8 between pooled K(D)PT group and placebo. Secondary endpoints included remission rates and CAI response at different time points. RESULTS Compared with placebo, K(D)PT (pooled group) resulted in significantly higher proportions of patients in remission at 2 and 4 weeks, (2 wk: P = 0.0349; 4 wk: P = 0.0278) and a significantly higher proportion of patients with CAI response at week 8 (P = 0.0434). K(D)PT (pooled group) met the primary endpoint after additional analyses. Because of high placebo response rates, subgroup analyses tried to identify patients with unquestionably active and more severe, but still moderate, disease (CAI score ≥9 or taking more than one concomitant medication). These subgroups showed earlier and statistically significant CAI responses to K(D)PT versus placebo. All doses of K(D)PT were well tolerated. CONCLUSIONS Despite a very high placebo rate after week 4, study data in this preliminary trial strongly suggest that add-on K(D)PT is efficacious in patients with mild-to-moderate ulcerative colitis. Moreover, K(D)PT showed an excellent safety profile.
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Xiao B, Xu Z, Viennois E, Zhang Y, Zhang Z, Zhang M, Han MK, Kang Y, Merlin D. Orally Targeted Delivery of Tripeptide KPV via Hyaluronic Acid-Functionalized Nanoparticles Efficiently Alleviates Ulcerative Colitis. Mol Ther 2017; 25:1628-1640. [PMID: 28143741 DOI: 10.1016/j.ymthe.2016.11.020] [Citation(s) in RCA: 125] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Revised: 10/23/2016] [Accepted: 11/27/2016] [Indexed: 12/22/2022] Open
Abstract
Overcoming adverse effects and selectively delivering drug to target cells are two major challenges in the treatment of ulcerative colitis (UC). Lysine-proline-valine (KPV), a naturally occurring tripeptide, has been shown to attenuate the inflammatory responses of colonic cells. Here, we loaded KPV into hyaluronic acid (HA)-functionalized polymeric nanoparticles (NPs). The resultant HA-KPV-NPs had a desirable particle size (∼272.3 nm) and a slightly negative zeta potential (∼-5.3 mV). These NPs successfully mediated the targeted delivery of KPV to key UC therapy-related cells (colonic epithelial cells and macrophages). In addition, these KPV-loaded NPs appear to be nontoxic and biocompatible with intestinal cells. Intriguingly, we found that HA-KPV-NPs exert combined effects against UC by both accelerating mucosal healing and alleviating inflammation. Oral administration of HA-KPV-NPs encapsulated in a hydrogel (chitosan/alginate) exhibited a much stronger capacity to prevent mucosa damage and downregulate TNF-α, thus they showed a much better therapeutic efficacy against UC in a mouse model, compared with a KPV-NP/hydrogel system. These results collectively demonstrate that our HA-KPV-NP/hydrogel system has the capacity to release HA-KPV-NPs in the colonic lumen and that these NPs subsequently penetrate into colitis tissues and enable KPV to be internalized into target cells, thereby alleviating UC.
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Affiliation(s)
- Bo Xiao
- Institute for Clean Energy and Advanced Materials, Faculty of Materials and Energy, Southwest University, Chongqing 400715, People's Republic of China; Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30302, USA.
| | - Zhigang Xu
- Institute for Clean Energy and Advanced Materials, Faculty of Materials and Energy, Southwest University, Chongqing 400715, People's Republic of China
| | - Emilie Viennois
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30302, USA
| | - Yuchen Zhang
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30302, USA
| | - Zhan Zhang
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30302, USA
| | - Mingzhen Zhang
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30302, USA
| | - Moon Kwon Han
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30302, USA
| | - Yuejun Kang
- Institute for Clean Energy and Advanced Materials, Faculty of Materials and Energy, Southwest University, Chongqing 400715, People's Republic of China
| | - Didier Merlin
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30302, USA; Atlanta Veterans Affairs Medical Center, Decatur, GA 30033, USA
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Shastri S, Vemuri R, Gueven N, D. Shastri M, Eri R. Molecular mechanisms of intestinal inflammation leading to colorectal cancer. AIMS BIOPHYSICS 2017. [DOI: 10.3934/biophy.2017.1.152] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
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Moronta J, Smaldini PL, Docena GH, Añón MC. Peptides of amaranth were targeted as containing sequences with potential anti-inflammatory properties. J Funct Foods 2016. [DOI: 10.1016/j.jff.2015.12.022] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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Viennois E, Ingersoll SA, Ayyadurai S, Zhao Y, Wang L, Zhang M, Han MK, Garg P, Xiao B, Merlin D. Critical role of PepT1 in promoting colitis-associated cancer and therapeutic benefits of the anti-inflammatory PepT1-mediated tripeptide KPV in a murine model. Cell Mol Gastroenterol Hepatol 2016; 2:340-357. [PMID: 27458604 PMCID: PMC4957955 DOI: 10.1016/j.jcmgh.2016.01.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS The human intestinal peptide transporter 1, hPepT1, is expressed in the small intestine at low levels in the healthy colon and upregulated during inflammatory bowel disease. hPepT1 plays a role in mouse colitis and human studies have demonstrated that chronic intestinal inflammation leads to colorectal cancer (colitis-associated cancer; CAC). Hence, we assessed here the role of PepT1 in CAC. METHODS Mice with hPepT1 overexpression in intestinal epithelial cells (TG) or PepT1 (PepT1-KO) deletion were used and CAC was induced by AOM/DSS. RESULTS TG mice had larger tumor sizes, increased tumor burdens, and increased intestinal inflammation compared to WT mice. Conversely, tumor number and size and intestinal inflammation were significantly decreased in PepT1-KO mice. Proliferating crypt cells were increased in TG mice and decreased in PepT1-KO mice. Analysis of human colonic biopsies revealed an increased expression of PepT1 in patients with colorectal cancer, suggesting that PepT1 might be targeted for the treatment of CAC. The use of an anti-inflammatory tripeptide KPV (Lys-Pro-Val) transported by PepT1 was able to prevent carcinogenesis in WT mice. When administered to PepT1-KO mice, KPV did not trigger any of the inhibitory effect on tumorigenesis observed in WT mice. CONCLUSIONS The observations that pepT1 was highly expressed in human colorectal tumor and that its overexpression and deletion in mice increased and decreased colitis associated tumorigenesis, respectively, suggest that PepT1 is a potential therapeutic target for the treatment of colitis associated tumorigenesis.
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Affiliation(s)
- Emilie Viennois
- Institute for Biomedical Sciences, Center Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia
- Veterans Affairs Medical Center, Decatur, Georgia
- Correspondence Address correspondence to: Emilie Viennois, PhD, Institute for Biomedical Sciences, Georgia State University, 100 Piedmont Avenue, PSC 757, Atlanta, Georgia 30303. fax: (404) 413-3580.Institute for Biomedical SciencesGeorgia State University100 Piedmont AvenuePSC 757AtlantaGeorgia 30303
| | - Sarah A. Ingersoll
- Institute for Biomedical Sciences, Center Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia
| | - Saravanan Ayyadurai
- Institute for Biomedical Sciences, Center Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia
| | - Yuan Zhao
- Institute for Biomedical Sciences, Center Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, China
| | - Lixin Wang
- Institute for Biomedical Sciences, Center Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia
- Veterans Affairs Medical Center, Decatur, Georgia
| | - Mingzhen Zhang
- Institute for Biomedical Sciences, Center Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia
| | - Moon K. Han
- Institute for Biomedical Sciences, Center Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia
| | - Pallavi Garg
- Institute for Biomedical Sciences, Center Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia
| | - Bo Xiao
- Institute for Biomedical Sciences, Center Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia
| | - Didier Merlin
- Institute for Biomedical Sciences, Center Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia
- Veterans Affairs Medical Center, Decatur, Georgia
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Takedatsu H, Mitsuyama K, Torimura T. Nanomedicine and drug delivery strategies for treatment of inflammatory bowel disease. World J Gastroenterol 2015; 21:11343-52. [PMID: 26525603 PMCID: PMC4616210 DOI: 10.3748/wjg.v21.i40.11343] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Revised: 05/28/2015] [Accepted: 08/29/2015] [Indexed: 02/06/2023] Open
Abstract
Crohn's disease and ulcerative colitis are two important categories of human inflammatory bowel disease (IBD). Because the precise mechanisms of the inflammation and immune responses in IBD have not been fully elucidated, the treatment of IBD primarily aims to inhibit the pathogenic factors of the inflammatory cascade. Inconsistencies exist regarding the response and side effects of the drugs that are currently used to treat IBD. Recent studies have suggested that the use of nanomedicine might be advantageous for the treatment of intestinal inflammation because nano-sized molecules can effectively penetrate epithelial and inflammatory cells. We reviewed nanomedicine treatments, such as the use of small interfering RNAs, antisense oligonucleotides, and anti-inflammatory molecules with delivery systems in experimental colitis models and clinical trials for IBD based on a systematic search. The efficacy and usefulness of the treatments reviewed in this manuscript have been demonstrated in experimental colitis models and clinical trials using various types of nanomedicine. Nanomedicine is expected to become a new therapeutic approach to the treatment of IBD.
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Olsen NJ, Decker DA, Higgins P, Becker PM, McAloose CA, Benko AL, Kovacs WJ. Direct effects of HP Acthar Gel on human B lymphocyte activation in vitro. Arthritis Res Ther 2015; 17:300. [PMID: 26507974 PMCID: PMC4624189 DOI: 10.1186/s13075-015-0823-y] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Accepted: 10/13/2015] [Indexed: 12/30/2022] Open
Abstract
Introduction Both clinical experience and experimental evidence have suggested that Adrenocorticotropic hormone (ACTH) might directly exert immunomodulatory effects not dependent on adrenal steroidogenesis. Methods The direct effects of H.P. Acthar Gel® (Acthar), a repository preparation containing a porcine ACTH analogue, on human B lymphocyte function were studied in vitro using peripheral blood B cells isolated using anti-CD19 coated magnetic beads and activated by interleukin 4 (IL-4) and CD40 ligand (CD40L). Analysis of expression of messenger RNA (mRNA) encoding activation-induced cytidine deaminase (AICDA) was carried out by quantitative real-time polymerase chain reaction (PCR). Cellular proliferation was assessed by a flow cytometric technique using intracellular staining with carboxyfluorescein succinimidyl ester (CFSE). Immunoglobulin G (IgG) production was measured in cell supernatants using an immunoassay. Results Acthar was found to exert acute, dose-dependent inhibitory effects on IL-4/CD40L–mediated induction of the expression of activation-induced cytidine deaminase (AICDA) after 24 hours, as well as sustained inhibition of B cell proliferation and IgG production during five more days of culture, without deleterious effects on B cell viability. Conclusions These experiments demonstrate that Acthar can exert direct effects on the humoral immune system independent of any role in the regulation of adrenal steroidogenesis. Although the impact of these findings on clinical disease was not evaluated in this study, these data support the therapeutic potential of Acthar for the management of autoimmune diseases characterized by B cell activation and aberrant humoral immune function.
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Affiliation(s)
- Nancy J Olsen
- Division of Rheumatology, The Pennsylvania State University, College of Medicine, 500 University Drive, Hershey, 17033, PA, USA.
| | - Dima A Decker
- Autoimmune and Rare Diseases Business, Mallinckrodt Pharmaceuticals, 6011 University Boulevard, Ellicott City, 21043, MD, USA.
| | - Paul Higgins
- Autoimmune and Rare Diseases Business, Mallinckrodt Pharmaceuticals, 6011 University Boulevard, Ellicott City, 21043, MD, USA.
| | - Patrice M Becker
- Autoimmune and Rare Diseases Business, Mallinckrodt Pharmaceuticals, 6011 University Boulevard, Ellicott City, 21043, MD, USA.
| | - Carl A McAloose
- Division of Rheumatology, The Pennsylvania State University, College of Medicine, 500 University Drive, Hershey, 17033, PA, USA.
| | - Ann L Benko
- Division of Endocrinology, Diabetes, and Metabolism, The Pennsylvania State University, College of Medicine, 500 University Drive, Hershey, PA, 17033, USA.
| | - William J Kovacs
- Division of Endocrinology, Diabetes, and Metabolism, The Pennsylvania State University, College of Medicine, 500 University Drive, Hershey, PA, 17033, USA.
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Pintér E, Pozsgai G, Hajna Z, Helyes Z, Szolcsányi J. Neuropeptide receptors as potential drug targets in the treatment of inflammatory conditions. Br J Clin Pharmacol 2015; 77:5-20. [PMID: 23432438 DOI: 10.1111/bcp.12097] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2012] [Accepted: 02/08/2013] [Indexed: 12/19/2022] Open
Abstract
Cross-talk between the nervous, endocrine and immune systems exists via regulator molecules, such as neuropeptides, hormones and cytokines. A number of neuropeptides have been implicated in the genesis of inflammation, such as tachykinins and calcitonin gene-related peptide. Development of their receptor antagonists could be a promising approach to anti-inflammatory pharmacotherapy. Anti-inflammatory neuropeptides, such as vasoactive intestinal peptide, pituitary adenylate cyclase-activating polypeptide, α-melanocyte-stimulating hormone, urocortin, adrenomedullin, somatostatin, cortistatin, ghrelin, galanin and opioid peptides, are also released and act on their own receptors on the neurons as well as on different inflammatory and immune cells. The aim of the present review is to summarize the most prominent data of preclinical animal studies concerning the main pharmacological effects of ligands acting on the neuropeptide receptors. Promising therapeutic impacts of these compounds as potential candidates for the development of novel types of anti-inflammatory drugs are also discussed.
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Affiliation(s)
- Erika Pintér
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Szigeti u. 12., H-7624, Pécs, Hungary; János Szentágothai Research Centre, University of Pécs, Ifjúság u. 20., H-7624, Pécs, Hungary
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Kaneva MK, Kerrigan MJ, Grieco P, Curley GP, Locke IC, Getting SJ. Melanocortin peptides protect chondrocytes from mechanically induced cartilage injury. Biochem Pharmacol 2014; 92:336-47. [DOI: 10.1016/j.bcp.2014.08.019] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Revised: 08/19/2014] [Accepted: 08/20/2014] [Indexed: 10/24/2022]
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Varga G, Ehrchen J, Brockhausen A, Weinhage T, Nippe N, Belz M, Tsianakas A, Ross M, Bettenworth D, Spieker T, Wolf M, Lippe R, Tenbrock K, Leenen PJM, Roth J, Sunderkötter C. Immune Suppression via Glucocorticoid-Stimulated Monocytes: A Novel Mechanism To Cope with Inflammation. THE JOURNAL OF IMMUNOLOGY 2014; 193:1090-9. [DOI: 10.4049/jimmunol.1300891] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Geiger BM, Gras-Miralles B, Ziogas DC, Karagiannis AKA, Zhen A, Fraenkel P, Kokkotou E. Intestinal upregulation of melanin-concentrating hormone in TNBS-induced enterocolitis in adult zebrafish. PLoS One 2013; 8:e83194. [PMID: 24376661 PMCID: PMC3869761 DOI: 10.1371/journal.pone.0083194] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2013] [Accepted: 11/11/2013] [Indexed: 12/22/2022] Open
Abstract
Background Melanin-concentrating hormone (MCH), an evolutionarily conserved appetite-regulating neuropeptide, has been recently implicated in the pathogenesis of inflammatory bowel disease (IBD). Expression of MCH is upregulated in inflamed intestinal mucosa in humans with colitis and MCH-deficient mice treated with trinitrobenzene-sulfonic acid (TNBS) develop an attenuated form of colitis compared to wild type animals. Zebrafish have emerged as a new animal model of IBD, although the majority of the reported studies concern zebrafish larvae. Regulation MCH expression in the adult zebrafish intestine remains unknown. Methods In the present study we induced enterocolitis in adult zebrafish by intrarectal administration of TNBS. Follow-up included survival analysis, histological assessment of changes in intestinal architecture, and assessment of intestinal infiltration by myeloperoxidase positive cells and cytokine transcript levels. Results Treatment with TNBS dose-dependently reduced fish survival. This response required the presence of an intact microbiome, since fish pre-treated with vancomycin developed less severe enterocolitis. At 6 hours post-challenge, we detected a significant influx of myeloperoxidase positive cells in the intestine and upregulation of both proinflammatory and anti-inflammatory cytokines. Most importantly, and in analogy to human IBD and TNBS-induced mouse experimental colitis, we found increased intestinal expression of MCH and its receptor in TNBS-treated zebrafish. Conclusions Taken together these findings not only establish a model of chemically-induced experimental enterocolitis in adult zebrafish, but point to effects of MCH in intestinal inflammation that are conserved across species.
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Affiliation(s)
- Brenda M Geiger
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Beatriz Gras-Miralles
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Dimitrios C Ziogas
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Apostolos K A Karagiannis
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Aileen Zhen
- Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Paula Fraenkel
- Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Efi Kokkotou
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
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Resolution of inflammation: mechanisms and opportunity for drug development. Pharmacol Ther 2013; 139:189-212. [PMID: 23583354 DOI: 10.1016/j.pharmthera.2013.04.006] [Citation(s) in RCA: 153] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2013] [Accepted: 04/01/2013] [Indexed: 12/12/2022]
Abstract
Inflammation is a beneficial host reaction to tissue damage and has the essential primary purpose of restoring tissue homeostasis. Inflammation plays a major role in containing and resolving infection and may also occur under sterile conditions. The cardinal signs of inflammation dolor, calor, tumor and rubor are intrinsically associated with events including vasodilatation, edema and leukocyte trafficking into the site of inflammation. If uncontrolled or unresolved, inflammation itself can lead to further tissue damage and give rise to chronic inflammatory diseases and autoimmunity with eventual loss of organ function. It is now evident that the resolution of inflammation is an active continuous process that occurs during an acute inflammatory episode. Successful resolution requires activation of endogenous programs with switch from production of pro-inflammatory towards pro-resolving molecules, such as specific lipid mediators and annexin A1, and the non-phlogistic elimination of granulocytes by apoptosis with subsequent removal by surrounding macrophages. These processes ensure rapid restoration of tissue homeostasis. Here, we review recent advances in the understanding of resolution of inflammation, highlighting the pharmacological strategies that may interfere with the molecular pathways which control leukocyte survival and clearance. Such strategies have proved beneficial in several pre-clinical models of inflammatory diseases, suggesting that pharmacological modulation of the resolution process may be useful for the treatment of chronic inflammatory diseases in humans.
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Liu X, Xu J, Mei Q, Han L, Huang J. Myosin light chain kinase inhibitor inhibits dextran sulfate sodium-induced colitis in mice. Dig Dis Sci 2013; 58:107-14. [PMID: 22777616 DOI: 10.1007/s10620-012-2304-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2011] [Accepted: 06/25/2012] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND AIMS Myosin light chain kinase (MLCK) plays a central role in the mechanisms of barrier dysfunction, and intestinal epithelial MLCK protein expression is upregulated in active ulcerative colitis (UC). ML-7, a MLCK inhibitor, has been used in many MLCK studies. However, the effect of ML-7 has never been estimated in colitis models. The aim of this study was to determine whether ML-7 can treat UC. METHODS Experimental colitis was induced and ML-7 was administered by intraperitoneal injection. The disease activity index (DAI) scores were evaluated and colon tissue was collected for the assessment of histological changes, myeloperoxidase (MPO) activity, and tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-13 and interleukin (IL)-17 levels. The small intestinal mucosa was ultrastructurally examined, epithelial MLCK protein expression and enzymatic activity were determined, and intestinal permeability was assayed using FITC-dextran 4000 (FD-4) and Evans blue (EB). RESULTS ML-7 was found to be significantly effective in reducing the DAI scores and histological index scores, and decreasing MPO activity and TNF-α, IFN-γ, IL-13 and IL-17 levels. The small intestinal epithelial MLCK protein expression and enzymatic activity were downregulated by ML-7. The epithelial cells and intercellular tight junctions were ameliorated, and the amount of FD-4 in blood and EB permeating into the intestine were decreased by ML-7 in colitis mice. CONCLUSIONS ML-7 has a significant anti-colitis effect in colitis mice. It is mainly associated with the inhibition of the epithelial MLCK protein expression, resulting in ameliorated intestinal mucosal permeability.
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Affiliation(s)
- Xiaochang Liu
- Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, The Key Laboratory of Digestive Diseases of Anhui Province, No. 218 Jixi Road, Hefei, Anhui, 230022, China
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Brzoska T, Böhm M, Lügering A, Loser K, Luger TA. Terminal signal: anti-inflammatory effects of α-melanocyte-stimulating hormone related peptides beyond the pharmacophore. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2012; 681:107-16. [PMID: 21222263 DOI: 10.1007/978-1-4419-6354-3_8] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
During the last two decades a significant number of investigations has established the fact that α-Melanocyte-stimulating hormone (α-MSH) is a potent anti-inflammatory mediator. The anti-inflammatory effects of α-MSH can be elicited via melanocortin receptors (MC-Rs) broadly expressed in a number of tissues ranging from the central nervous system to cells of the immune system and on resident somatic cells of peripheral tissues. α-MSH affects various pathways regulating inflammatory responses such as NF-κB activation, expression of adhesion molecules, inflammatory cytokines, chemokine receptors, T-cell proliferation and activity and inflammatory cell migration. In vivo α-MSH has been shown to be anti-inflammatory as well in animal models of fever, irritant and allergic contact dermatitis, cutaneous vasculitis, fibrosis, in ocular, gastrointestinal, brain and allergic airway inflammation and arthritis. A broad range of effects of α-MSH exerted beyond the field of inflammation, its pigmentory capacity being only the most visible aspect, has been one of the major impediments limiting the use of α-MSH in human inflammatory disorders. Interestingly KPV, C-terminal tripeptide of α-MSH, which lacks the entire sequence motif required for binding to any of the known MC-Rs, retains almost all of the anti-inflammatory capacity of the full hormone, but in its activities display a lack of any pigmentory action. While the exact signaling mechanism utilized by KPV and related peptides currently is unknown it has been demonstrated already that significant similarities between anti-inflammatory signaling of α-MSH and those short peptides exist. These α-MSH related tripeptides thus may be useful alternatives for anti-inflammatory peptide therapy. KdPT, a derivative of KPV corresponding to IL-1β(193-195), currently is emerging as another tripeptide with potent anti-inflammatory effects. A more limited spectrum of biologic activities, potentially advantageous physicochemical, pharmacokinetic and pharmacodynamic properties as well as the expectation of low costs for pharmaceutical production make these agents interesting candidates for the treatment of immune-mediated inflammatory skin and bowel diseases, allergic asthma and arthritis.
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Affiliation(s)
- Thomas Brzoska
- Department of Dermatology, University of Münster, Von Esmarch-Str. 58, D-48149 Münster, Germany.
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Bettenworth D, Buyse M, Böhm M, Mennigen R, Czorniak I, Kannengiesser K, Brzoska T, Luger TA, Kucharzik T, Domschke W, Maaser C, Lügering A. The tripeptide KdPT protects from intestinal inflammation and maintains intestinal barrier function. THE AMERICAN JOURNAL OF PATHOLOGY 2011; 179:1230-42. [PMID: 21741932 DOI: 10.1016/j.ajpath.2011.05.013] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/11/2010] [Revised: 05/13/2011] [Accepted: 05/23/2011] [Indexed: 12/20/2022]
Abstract
Treatment options for inflammatory bowel disease (IBD) are incompletely helpful, and surgery is often needed. One promising class of future therapeutic agents for IBD is melanocortin-related peptides, which exhibit potent immunomodulatory effects. We investigated KdPT, a tripeptide derivative of the C-terminus of α-melanocyte-stimulating hormone, as an anti-inflammatory small molecule in vivo and in vitro. Intestinal inflammation was studied after oral administration of dextran sodium sulfate and in IL-10 gene-deficient mice. The effects of KdPT on key colonic epithelial cell functions were studied in vitro and in vivo by evaluating proliferation, wound healing, transepithelial resistance, and expression of tight junction proteins. Melanin assays were performed to determine the melanotropic effects of KdPT. KdPT-treated animals showed markedly reduced severity of inflammation in both colitis models. In colonic epithelial cells, KdPT increased proliferation, accelerated closure of wounds, and improved transepithelial electrical resistance after stimulation with interferon-γ/tumor necrosis factor-α. Moreover, treatment with KdPT also prevented the loss of tight junction protein expression and improved barrier function in vivo. KdPT acted independently of IL-1 receptor type I in vivo and did not affect melanogenesis in vitro. KdPT is capable of attenuating the course of experimental colitis in different models and maintains epithelial cell function. Furthermore, KdPT does not induce pigmentation, emphasizing the potential of this small molecule for the future treatment of IBD.
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Montero-Melendez T, Patel HB, Seed M, Nielsen S, Jonassen TEN, Perretti M. The melanocortin agonist AP214 exerts anti-inflammatory and proresolving properties. THE AMERICAN JOURNAL OF PATHOLOGY 2011; 179:259-69. [PMID: 21703408 DOI: 10.1016/j.ajpath.2011.03.042] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2010] [Revised: 02/23/2011] [Accepted: 03/21/2011] [Indexed: 12/30/2022]
Abstract
Synthetic and natural melanocortin (MC) peptides afford inhibitory properties in inflammation and tissue injury, but characterization of receptor involvement is still elusive. We used the agonist AP214 to test MC-dependent anti-inflammatory effects. In zymosan peritonitis, treatment of mice with AP214 (400 to 800 μg/kg) inhibited cell infiltration, an effect retained in MC receptor type 1, or MC(1), mutant mice but lost in MC(3) null mice. In vitro, cytokine release from zymosan-stimulated macrophages was affected by AP214, with approximately 80%, 30%, and 40% reduction in IL-1β, tumor necrosis factor-α, and IL-6, respectively. Inhibition of IL-1β release was retained in MC(1) mutant cells but was lost in MC(3) null cells. Furthermore, AP214 augmented uptake of zymosan particles and human apoptotic neutrophils by wild-type macrophages: this proresolving property was lost in MC(3) null macrophages. AP214 displayed its pro-efferocytotic effect also in vivo. Finally, in a model of inflammatory arthritis, AP214 evoked significant reductions in the clinical score. These results indicate that AP214 elicits anti-inflammatory responses, with a preferential effect on IL-1β release. Furthermore, we describe for the first time a positive modulation of an MC agonist on the process of efferocytosis. In all cases, endogenous MC(3) is the receptor that mediates these novel properties of AP214. These findings might clarify the tissue-protective properties of AP214 in clinical settings and may open further development for novel MC agonists.
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MESH Headings
- Animals
- Apoptosis/drug effects
- Arthritis, Experimental/drug therapy
- Arthritis, Experimental/metabolism
- Arthritis, Experimental/pathology
- Blotting, Western
- Cytokines/genetics
- Cytokines/metabolism
- Disease Models, Animal
- Enzyme-Linked Immunosorbent Assay
- Humans
- Inflammation/drug therapy
- Inflammation/metabolism
- Inflammation/pathology
- Interleukin-1beta/genetics
- Interleukin-1beta/metabolism
- Interleukin-6/genetics
- Interleukin-6/metabolism
- Macrophages/cytology
- Macrophages/drug effects
- Macrophages/metabolism
- Macrophages, Peritoneal/cytology
- Macrophages, Peritoneal/drug effects
- Macrophages, Peritoneal/metabolism
- Male
- Melanocortins/agonists
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mutation/genetics
- Neutrophils/cytology
- Neutrophils/drug effects
- Neutrophils/metabolism
- Peritonitis/drug therapy
- Peritonitis/metabolism
- Peritonitis/pathology
- Phagocytosis
- RNA, Messenger/genetics
- Receptor, Melanocortin, Type 1/physiology
- Receptor, Melanocortin, Type 3/physiology
- Reverse Transcriptase Polymerase Chain Reaction
- Tumor Necrosis Factor-alpha/genetics
- Tumor Necrosis Factor-alpha/metabolism
- alpha-MSH/analogs & derivatives
- alpha-MSH/pharmacology
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Affiliation(s)
- Trinidad Montero-Melendez
- The William Harvey Research Institute, Barts, and The London School of Medicine, Queen Mary University of London, London, United Kingdom
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Laroui H, Dalmasso G, Nguyen HTT, Yan Y, Sitaraman SV, Merlin D. Drug-loaded nanoparticles targeted to the colon with polysaccharide hydrogel reduce colitis in a mouse model. Gastroenterology 2010; 138:843-53.e1-2. [PMID: 19909746 DOI: 10.1053/j.gastro.2009.11.003] [Citation(s) in RCA: 171] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2009] [Revised: 09/23/2009] [Accepted: 11/04/2009] [Indexed: 12/30/2022]
Abstract
BACKGROUND & AIMS One of the challenges to treating inflammatory bowel disease (IBD) is to target the site of inflammation. We engineered nanoparticles (NPs) to deliver an anti-inflammatory tripeptide Lys-Pro-Val (KPV) to the colon and assessed its therapeutic efficacy in a mouse model of colitis. METHODS NPs were synthesized by double-emulsion/solvent evaporation. KPV was loaded into the NPs during the first emulsion of the synthesis process. To target KPV to the colon, loaded NPs (NP-KPV) were encapsulated into a polysaccharide gel containing 2 polymers: alginate and chitosan. The effect of KPV-loaded NPs on inflammatory parameters was determined in vitro as well as in the dextran sodium sulfate-induced colitis mouse model. RESULTS NPs (400 nm) did not affect cell viability or barrier functions. A swelling degree study showed that alginate-chitosan hydrogel containing dextran-fluorescein isothiocyanate-labeled NPs collapsed in the colon. Once delivered, NPs quickly released KPV on or within the closed area of colonocytes. The inflammatory responses to lipopolysaccharide were reduced in Caco2-BBE (brush border enterocyte) cells exposed to NP-KPV compared with those exposed to NPs alone, in a dose-dependent fashion. Mice given dextran sodium sulfate (DSS) followed by NP-KPV were protected against inflammatory and histologic parameters, compared with mice given only DSS. CONCLUSIONS Nanoparticles are a versatile drug delivery system that can overcome physiologic barriers and target anti-inflammatory agents such as the peptide KPV to inflamed areas. By using NPs, KPV can be delivered at a concentration that is 12,000-fold lower than that of KPV in free solution, but with similar therapeutic efficacy. Administration of encapsulated drug-loaded NPs is a novel therapeutic approach for IBD.
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Affiliation(s)
- Hamed Laroui
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia 30322, USA
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Meyer K, Bodó E, Brzoska T, Abels C, Paus R. Immunomodulatory effects of the α-melanocyte-stimulating hormone-related tripeptide K(D)PT on human scalp hair follicles under proinflammatory conditions. Br J Dermatol 2009; 161:1400-3. [DOI: 10.1111/j.1365-2133.2009.09427.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Perroud B, Alvarado RJ, Espinal GM, Morado AR, Phinney BS, Warden CH. In vivo multiplex quantitative analysis of 3 forms of alpha melanocyte stimulating hormone in pituitary of prolyl endopeptidase deficient mice. Mol Brain 2009; 2:14. [PMID: 19490636 PMCID: PMC2698928 DOI: 10.1186/1756-6606-2-14] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2009] [Accepted: 06/02/2009] [Indexed: 12/20/2022] Open
Abstract
Background In vitro reactions are useful to identify putative enzyme substrates, but in vivo validation is required to identify actual enzyme substrates that have biological meaning. To investigate in vivo effects of prolyl endopeptidase (PREP), a serine protease, on alpha melanocyte stimulating hormone (α-MSH), we developed a new mass spectrometry based technique to quantitate, in multiplex, the various forms of α-MSH. Methods Using Multiple Reaction Monitoring (MRM), we analyzed peptide transitions to quantify three different forms of α-MSH. Transitions were first confirmed using standard peptides. Samples were then analyzed by mass spectrometry using a triple quadrupole mass spectrometer, after elution from a reverse phase C18 column by a gradient of acetonitrile. Results We first demonstrate in vitro that PREP digests biological active alpha melanocyte stimulating hormone (α-MSH1–13), by cleaving the terminal amidated valine and releasing a truncated alpha melanocyte stimulating hormone (α-MSH1–12) product – the 12 residues α-MSH form. We then use the technique in vivo to analyze the MRM transitions of the three different forms of α-MSH: the deacetylated α-MSH1–13, the acetylated α-MSH1–13 and the truncated form α-MSH1–12. For this experiment, we used a mouse model (PREP-GT) in which the serine protease, prolyl endopeptidase, is deficient due to a genetrap insertion. Here we report that the ratio between acetylated α-MSH1–13 and α-MSH1–12 is significantly increased (P-value = 0.015, N = 6) in the pituitaries of PREP-GT mice when compared to wild type littermates. In addition no significant changes were revealed in the relative level of α-MSH1–13 versus the deacetylated α-MSH1–13. These results combined with the demonstration that PREP digests α-MSH1–13 in vitro, strongly suggest that α-MSH1–13 is an in vivo substrate of PREP. Conclusion The multiplex targeted quantitative peptidomics technique we present in this study will be decidedly useful to monitor several neuropeptide enzymatic reactions in vivo under varying conditions.
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Affiliation(s)
- Bertrand Perroud
- Genome Center and Bioinformatics Program, University of California, Davis, California, USA.
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Azuma YT, Takeuchi T. [The emerging role of regulatory peptides as inflammatory mediators in inflammatory bowel disease]. Nihon Yakurigaku Zasshi 2009; 133:199-202. [PMID: 19367020 DOI: 10.1254/fpj.133.199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
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Lee HJ, Wang NX, Shao Y, Zheng J. Identification of tripeptides recognized by the PDZ domain of Dishevelled. Bioorg Med Chem 2009; 17:1701-8. [PMID: 19157887 PMCID: PMC2713185 DOI: 10.1016/j.bmc.2008.12.060] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2008] [Revised: 12/18/2008] [Accepted: 12/19/2008] [Indexed: 12/11/2022]
Abstract
The development of inhibitors of Dishevelled (Dvl) PDZ protein-protein interactions attracts attention due to a possible application in drug discovery and development. Using nuclear magnetic resonance (NMR) spectroscopy, we found that a tripeptide VVV binds to the PDZ domain of Dvl, which is a key component involved in Wnt signaling. Using a computational approach calculating the binding free energy of the complexes of the Dvl PDZ domain and each of the tripeptides VXV (X: any amino acid residue except Pro), we found that a tripeptide VWV had the highest binding affinity. Consistent with the computational result, experimental results showed that the binding of the tripeptide VWV to the Dvl PDZ domain was stronger than that of the tripeptide VVV. The binding affinity of the tripeptide VWV was comparable to that of the organic molecule NSC668036, which was the first identified Dvl PDZ inhibitor. The three-dimensional structure of the complex Dvl1 PDZ/VWV was determined to investigate the role of the energetically favorable W(-1) residue in binding. These interactions were also explored by using molecular dynamic simulation and the molecular mechanics Poisson-Boltzmann surface area method. Taken together, these two tripeptides may be used as modulators of Wnt signaling or as a scaffold to optimize an antagonist for targeting Dvl1 PDZ protein-protein interaction.
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Affiliation(s)
- Ho-Jin Lee
- Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
| | - Nick X. Wang
- Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
| | - Youming Shao
- Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
| | - Jie Zheng
- Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Department of Molecular Sciences, The University of Tennessee Health Science Center, Memphis, TN 38163, USA
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Brzoska T, Luger TA, Maaser C, Abels C, Böhm M. Alpha-melanocyte-stimulating hormone and related tripeptides: biochemistry, antiinflammatory and protective effects in vitro and in vivo, and future perspectives for the treatment of immune-mediated inflammatory diseases. Endocr Rev 2008; 29:581-602. [PMID: 18612139 DOI: 10.1210/er.2007-0027] [Citation(s) in RCA: 232] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Alpha-MSH is a tridecapeptide derived from proopiomelanocortin. Many studies over the last few years have provided evidence that alpha-MSH has potent protective and antiinflammatory effects. These effects can be elicited via centrally expressed melanocortin receptors that orchestrate descending neurogenic antiinflammatory pathways. alpha-MSH can also exert antiinflammatory and protective effects on cells of the immune system and on peripheral nonimmune cell types expressing melanocortin receptors. At the molecular level, alpha-MSH affects various pathways implicated in regulation of inflammation and protection, i.e., nuclear factor-kappaB activation, expression of adhesion molecules and chemokine receptors, production of proinflammatory cytokines and mediators, IL-10 synthesis, T cell proliferation and activity, inflammatory cell migration, expression of antioxidative enzymes, and apoptosis. The antiinflammatory effects of alpha-MSH have been validated in animal models of experimentally induced fever; irritant and allergic contact dermatitis, vasculitis, and fibrosis; ocular, gastrointestinal, brain, and allergic airway inflammation; and arthritis, but also in models of organ injury. One obstacle limiting the use of alpha-MSH in inflammatory disorders is its pigmentary effect. Due to its preserved antiinflammatory effect but lack of pigmentary action, the C-terminal tripeptide of alpha-MSH, KPV, has been delineated as an alternative for antiinflammatory therapy. KdPT, a derivative of KPV corresponding to amino acids 193-195 of IL-1beta, is also emerging as a tripeptide with antiinflammatory effects. The physiochemical properties and expected low costs of production render both agents suitable for the future treatment of immune-mediated inflammatory skin and bowel disease, fibrosis, allergic and inflammatory lung disease, ocular inflammation, and arthritis.
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Affiliation(s)
- Thomas Brzoska
- Department of Dermatology, University of Münster, Von Esmarch-Strasse 58, D-48149 Münster, Germany
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