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Akhzari N, Amani J, Tajadod G, Karizi SZ, Arbabian S. Construction and evaluation of a novel Stx2a-based immunotoxin against epidermal growth factor receptor (EGFR). Biologicals 2025; 91:101833. [PMID: 40315796 DOI: 10.1016/j.biologicals.2025.101833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 02/17/2025] [Accepted: 04/22/2025] [Indexed: 05/04/2025] Open
Abstract
Immunotoxins (ITs) are chimeric proteins that combine the targeting specificity of a monoclonal antibody or antibody fragment with the cytotoxic properties of a toxin. They offer a promising strategy for cancer therapy by selectively delivering cytotoxic payloads to tumor cells. The epidermal growth factor receptor (EGFR) is frequently overexpressed in various cancers, making it an attractive target for IT-based therapies. In this study, we designed and constructed a novel IT composed of a single-chain variable fragment (scFv) derived from Panitumumab, a humanized monoclonal antibody targeting EGFR, and the Shiga toxin A subunit 2 (Stx2a), a potent cytotoxic agent. The IT was designed using computational tools to optimize the linker region between the scFv and Stx2a domains. The recombinant IT was expressed in a prokaryotic host and purified to homogeneity. The cytotoxic activity of the IT was evaluated in vitro against human colorectal carcinoma (HCT-116) and human embryonic kidney (HEK293) cells. The IT demonstrated significant cytotoxicity against HCT-116 cells, while exhibiting minimal toxicity to non-target cells. To enhance the delivery and efficacy of the IT, we encapsulated it in chitosan nanoparticles. The nanoparticle-based formulation showed improved cellular uptake and enhanced cytotoxicity compared to the free IT. Our findings suggest that the designed IT has the potential to be a promising therapeutic agent against EGFR-expressing cancers. Further studies are warranted to evaluate its efficacy in vivo and to optimize its formulation for clinical applications.
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Affiliation(s)
- Negar Akhzari
- Department of Cell Biology, North Tehran Branch, Islamic Azad University, Tehran, Iran.
| | - Jafar Amani
- Applied Microbiology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Golnaz Tajadod
- Islamic Azad University, North Tehran Branch, Tehran, Iran.
| | - Shohreh Zare Karizi
- Department of Biology, Varamin Pishva Branch, Islamic Azad University, Pishva, Varamin, Iran.
| | - Sedigheh Arbabian
- Department of Cell Biology, Faculty of Science, North Tehran Branch, Islamic Azad University, Tehran, Iran.
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2
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Vieujean S, Jairath V, Peyrin-Biroulet L, Dubinsky M, Iacucci M, Magro F, Danese S. Understanding the therapeutic toolkit for inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2025:10.1038/s41575-024-01035-7. [PMID: 39891014 DOI: 10.1038/s41575-024-01035-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/19/2024] [Indexed: 02/03/2025]
Abstract
Inflammatory bowel disease (IBD), encompassing ulcerative colitis and Crohn's disease, is a group of chronic, immune-mediated disorders of the gastrointestinal tract that present substantial clinical challenges owing to their complex pathophysiology and tendency to relapse. A treat-to-target approach is recommended, involving iterative treatment adjustments to achieve clinical response, reduce inflammatory markers and achieve long-term goals such as mucosal healing. Lifelong medication is often necessary to manage the disease, maintain remission and prevent complications. The therapeutic landscape for IBD has evolved substantially; however, a ceiling on therapeutic efficacy remains and surgery is sometimes required (owing to uncontrolled disease activity or complications). Effective IBD management involves comprehensive care, including medication adherence and a collaborative clinician-patient relationship. This Review discusses current therapeutic options for IBD, detailing mechanisms of action, efficacy, safety profiles and guidelines for use of each drug class. We also explore emerging therapies and the role of surgery. Additionally, the importance of a multidisciplinary team and personalized care in managing IBD is emphasized, advocating for patient empowerment and involvement in treatment decisions. By synthesizing current knowledge and emerging trends, this Review aims to equip healthcare professionals with a thorough understanding of therapeutic options for IBD, enhancing informed, evidence-based decisions in clinical practice.
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Affiliation(s)
- Sophie Vieujean
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
- Department of Gastroenterology, INFINY Institute, CHRU Nancy, Vandœuvre-lès-Nancy, France
| | - Vipul Jairath
- Division of Gastroenterology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, INFINY Institute, CHRU Nancy, Vandœuvre-lès-Nancy, France
- Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Marla Dubinsky
- Department of Paediatrics, Susan and Leonard Feinstein IBD Center, Icahn School of Medicine, Mount Sinai, New York, NY, USA
| | - Marietta Iacucci
- APC Microbiome Ireland, College of Medicine and Health, University College of Cork, Cork, Ireland
| | - Fernando Magro
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milano, Italy.
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3
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Słoka J, Strzałka-Mrozik B, Kubica S, Nowak I, Kruszniewska-Rajs C. Influence of Mesalazine on Ferroptosis-Related Gene Expression in In Vitro Colorectal Cancer Culture. Biomedicines 2025; 13:219. [PMID: 39857803 PMCID: PMC11762154 DOI: 10.3390/biomedicines13010219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 01/13/2025] [Accepted: 01/15/2025] [Indexed: 01/27/2025] Open
Abstract
Background/Objectives: Colorectal cancer (CRC) is one of the most common oncological disorders. Its fundamental treatments include surgery and chemotherapy, predominantly utilizing 5-fluorouracil (5-FU). Despite medical advances, CRC continues to present a high risk of recurrence, metastasis and low survival rates. Consequently, significant emphasis has been directed towards exploring novel types of cell death, particularly ferroptosis. Ferroptosis is characterized by iron imbalance and the accumulation of lipid peroxides and reactive oxygen species (ROS), leading to cellular damage and death. Thus, the discovery of safe inducers of ferroptosis, offering new hope in the struggle against CRC, remains crucial. In this study, we applied the concept of drug repositioning, selecting mesalazine (MES), a non-steroidal anti-inflammatory drug (NSAID), for investigation. Methods: The study was conducted on the colon cancer cell line DLD-1 and normal intestinal epithelial cells from the CCD 841 CoN cell line. Both cell lines were treated with MES solutions at concentrations of 10, 20, 30, 40, and 50 mM. Cytotoxicity was assessed using the MTT assay, while ferroptosis-related gene expression analysis was performed using oligonucleotide microarrays, with RT-qPCR used for validation. Results: MES effectively reduces the viability of DLD-1 cells while minimally affecting normal intestinal cells. Subsequent oligonucleotide microarray analysis revealed that MES significantly alters the expression of 56 genes associated with ferroptosis. Conclusions: Our results suggest that MES may induce ferroptosis in CRC, providing a foundation for further research in this area.
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Affiliation(s)
| | - Barbara Strzałka-Mrozik
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland; (J.S.); (S.K.); (I.N.); (C.K.-R.)
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4
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Fousekis FS, Mpakogiannis K, Filis P, Skamnelos A, Christodoulou DK, Mauri D, Katsanos KH. Exploring Chemoprevention in Colorectal Cancer for Patients with Inflammatory Bowel Disease: Mechanisms of Action and Clinical Aspects. Cancers (Basel) 2025; 17:229. [PMID: 39858011 PMCID: PMC11764170 DOI: 10.3390/cancers17020229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 01/09/2025] [Accepted: 01/10/2025] [Indexed: 01/27/2025] Open
Abstract
Background: Inflammatory bowel diseases (IBDs) have been associated with a higher risk of colorectal cancer (CRC) development and chronic colonic inflammation seems to have a critical role in the pathogenesis of CRC in patients suffering from IBD. In respect to that, surveillance colonoscopy at regular intervals is recommended in patients with colitis. Objective: This review aims to explore the chemopreventive potential of a range of agents, including mesalazine, thiopurines, anti-TNF agents, statins, ursodeoxycholic acid, aspirin, folic acid, and nutraceuticals. Results: These agents target inflammation, oxidative stress, and oncogenic pathways, thereby offering the potential to reduce the risk of CRC in patients with IBD. Anti-TNF agents, such as infliximab and adalimumab, not only reduce colonic inflammation, but also play a protective role against CRC by lessening the carcinogenic effects associated with prolonged inflammatory processes. Furthermore, mesalazine and thiopurines have demonstrated established efficacy, while newer biologics, including interleukin inhibitors, show promising advancements. Although nutraceuticals and dietary interventions require further clinical validation, they offer additional possibilities for non-pharmacological prevention. Conclusion: Despite progress, knowledge gaps persist regarding the long-term safety, optimal dosing, and combined use of these agents. A significant reduction in the incidence of CRC in patients with IBD could be achieved by advancing chemoprevention and personalizing strategies.
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Affiliation(s)
- Fotios S. Fousekis
- Department of Gastroenterology, University Hospital of Ioannina, 455 00 Ioannina, Greece; (K.M.); (A.S.); (D.K.C.); (K.H.K.)
| | - Konstantinos Mpakogiannis
- Department of Gastroenterology, University Hospital of Ioannina, 455 00 Ioannina, Greece; (K.M.); (A.S.); (D.K.C.); (K.H.K.)
| | - Panagiotis Filis
- Department of Medical Oncology, School of Health Sciences, Faculty of Medicine, University of Ioannina, 455 00 Ioannina, Greece (D.M.)
| | - Alexandros Skamnelos
- Department of Gastroenterology, University Hospital of Ioannina, 455 00 Ioannina, Greece; (K.M.); (A.S.); (D.K.C.); (K.H.K.)
| | - Dimitrios K. Christodoulou
- Department of Gastroenterology, University Hospital of Ioannina, 455 00 Ioannina, Greece; (K.M.); (A.S.); (D.K.C.); (K.H.K.)
| | - Davide Mauri
- Department of Medical Oncology, School of Health Sciences, Faculty of Medicine, University of Ioannina, 455 00 Ioannina, Greece (D.M.)
| | - Konstantinos H. Katsanos
- Department of Gastroenterology, University Hospital of Ioannina, 455 00 Ioannina, Greece; (K.M.); (A.S.); (D.K.C.); (K.H.K.)
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5
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Wang T, Huang Y, Jiang P, Yuan X, Long Q, Yan X, Huang Y, Wang Z, Li C. Research progress on anti-inflammatory drugs for preventing colitis-associated colorectal cancer. Int Immunopharmacol 2025; 144:113583. [PMID: 39580861 DOI: 10.1016/j.intimp.2024.113583] [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: 08/28/2024] [Revised: 11/04/2024] [Accepted: 11/05/2024] [Indexed: 11/26/2024]
Abstract
Colorectal cancer (CRC) is the third most prevalent malignancy worldwide. Inflammatory bowel diseases (IBD) encompass a group of chronic intestinal inflammatory disorders, including ulcerative colitis (UC) and Crohn's disease (CD). As a chronic inflammatory bowel disease, UC may persist and elevate the risk of malignancy, thereby contributing to the development of colorectal cancer, known as colitis-associated colorectal cancer (CAC). Chronic intestinal inflammation is a significant risk factor for colorectal cancer, and the incidence of colitis-associated colorectal cancer continues to rise. Current studies indicate that therapeutic agents targeting inflammation and key molecules or signaling pathways involved in the inflammatory process may effectively prevent and treat CAC. Mechanistically, drugs with anti-inflammatory or modulatory effects on inflammation-related pathways may exert preventive or therapeutic roles in CAC through multiple molecules or signaling pathways implicated in tumor development. Moreover, the development or discovery of novel drugs with anti-inflammatory properties to prevent or delay CAC progression is becoming an emerging field in fighting against CRC. Therefore, this review aims to summarize drugs that prevent or delay CAC through modulating anti-inflammatory pathways. First, we categorize the published studies exploring the role of anti-inflammatory in CAC prevention. Second, we highlight the specific molecular mechanisms underlying the anti-inflammatory effect of the above-mentioned drugs. Finally, we discuss the potential and challenges associated with clinical application of these drugs. It is hoped that this review offers new insights for further drug development and mechanism exploration.
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Affiliation(s)
- Tong Wang
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College, Chengdu, Sichuan 610052, PR China
| | | | - Peng Jiang
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College, Chengdu, Sichuan 610052, PR China
| | - Xin Yuan
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College, Chengdu, Sichuan 610052, PR China
| | - Qian Long
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College, Chengdu, Sichuan 610052, PR China
| | - Xiaochen Yan
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College, Chengdu, Sichuan 610052, PR China
| | - Yuwei Huang
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College, Chengdu, Sichuan 610052, PR China
| | - Zongkui Wang
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College, Chengdu, Sichuan 610052, PR China.
| | - Changqing Li
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College, Chengdu, Sichuan 610052, PR China.
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Fadlallah H, El Masri J, Fakhereddine H, Youssef J, Chemaly C, Doughan S, Abou-Kheir W. Colorectal cancer: Recent advances in management and treatment. World J Clin Oncol 2024; 15:1136-1156. [PMID: 39351451 PMCID: PMC11438855 DOI: 10.5306/wjco.v15.i9.1136] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 06/11/2024] [Accepted: 07/29/2024] [Indexed: 08/29/2024] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide, and the second most common cause of cancer-related death. In 2020, the estimated number of deaths due to CRC was approximately 930000, accounting for 10% of all cancer deaths worldwide. Accordingly, there is a vast amount of ongoing research aiming to find new and improved treatment modalities for CRC that can potentially increase survival and decrease overall morbidity and mortality. Current management strategies for CRC include surgical procedures for resectable cases, and radiotherapy, chemotherapy, and immunotherapy, in addition to their combination, for non-resectable tumors. Despite these options, CRC remains incurable in 50% of cases. Nonetheless, significant improvements in research techniques have allowed for treatment approaches for CRC to be frequently updated, leading to the availability of new drugs and therapeutic strategies. This review summarizes the most recent therapeutic approaches for CRC, with special emphasis on new strategies that are currently being studied and have great potential to improve the prognosis and lifespan of patients with CRC.
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Affiliation(s)
- Hiba Fadlallah
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Jad El Masri
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Hiam Fakhereddine
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Joe Youssef
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Chrystelle Chemaly
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Samer Doughan
- Department of Surgery, American University of Beirut Medical Center, Beirut 1107-2020, Lebanon
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
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7
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Ho J, Puoplo N, Pokharel N, Hirdaramani A, Hanyaloglu AC, Cheng CW. Nutrigenomic underpinnings of intestinal stem cells in inflammatory bowel disease and colorectal cancer development. Front Genet 2024; 15:1349717. [PMID: 39280096 PMCID: PMC11393785 DOI: 10.3389/fgene.2024.1349717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 08/12/2024] [Indexed: 09/18/2024] Open
Abstract
Food-gene interaction has been identified as a leading risk factor for inflammatory bowel disease (IBD) and colorectal cancer (CRC). Accordingly, nutrigenomics emerges as a new approach to identify biomarkers and therapeutic targets for these two strongly associated gastrointestinal diseases. Recent studies in stem cell biology have further shown that diet and nutrition signal to intestinal stem cells (ISC) by altering nutrient-sensing transcriptional activities, thereby influencing barrier integrity and susceptibility to inflammation and tumorigenesis. This review recognizes the dietary factors related to both CRC and IBD and investigates their impact on the overlapping transcription factors governing stem cell activities in homeostasis and post-injury responses. Our objective is to provide a framework to study the food-gene regulatory network of disease-contributing cells and inspire new nutrigenomic approaches for detecting and treating diet-related IBD and CRC.
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Affiliation(s)
- Jennifer Ho
- Institute of Human Nutrition, Columbia University Irving Medical Center, New York City, NY, United States
- Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York City, NY, United States
| | - Nicholas Puoplo
- Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York City, NY, United States
- Division of Neonatology-Perinatology, Department of Pediatrics, Columbia University Irving Medical Center, New York City, NY, United States
| | - Namrata Pokharel
- Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York City, NY, United States
| | - Aanya Hirdaramani
- Department of Metabolism, Digestion and Reproduction, Division of Digestive Diseases, Section of Nutrition, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Aylin C Hanyaloglu
- Department of Metabolism, Digestion and Reproduction, Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Chia-Wei Cheng
- Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York City, NY, United States
- Department of Genetics and Development, Columbia University Irving Medical Center, New York City, NY, United States
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8
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Li X, Zan X, Liu T, Dong X, Zhang H, Li Q, Bao Z, Lin J. Integrated edge information and pathway topology for drug-disease associations. iScience 2024; 27:110025. [PMID: 38974972 PMCID: PMC11226970 DOI: 10.1016/j.isci.2024.110025] [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: 01/31/2024] [Revised: 04/06/2024] [Accepted: 05/15/2024] [Indexed: 07/09/2024] Open
Abstract
Drug repurposing is a promising approach to find new therapeutic indications for approved drugs. Many computational approaches have been proposed to prioritize candidate anticancer drugs by gene or pathway level. However, these methods neglect the changes in gene interactions at the edge level. To address the limitation, we develop a computational drug repurposing method (iEdgePathDDA) based on edge information and pathway topology. First, we identify drug-induced and disease-related edges (the changes in gene interactions) within pathways by using the Pearson correlation coefficient. Next, we calculate the inhibition score between drug-induced edges and disease-related edges. Finally, we prioritize drug candidates according to the inhibition score on all disease-related edges. Case studies show that our approach successfully identifies new drug-disease pairs based on CTD database. Compared to the state-of-the-art approaches, the results demonstrate our method has the superior performance in terms of five metrics across colorectal, breast, and lung cancer datasets.
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Affiliation(s)
- Xianbin Li
- School of Computer and Big Data Science, Jiujiang University, Jiujiang, Jiangxi 332000, China
- Department of Digital Media Technology, Hangzhou Dianzi University, Hangzhou, Zhejiang 310018, China
| | - Xiangzhen Zan
- Institute of Computational Science and Technology, Guangzhou University, Guangzhou, Guangdong 520000, China
| | - Tao Liu
- School of Computer and Big Data Science, Jiujiang University, Jiujiang, Jiangxi 332000, China
| | - Xiwei Dong
- School of Computer and Big Data Science, Jiujiang University, Jiujiang, Jiangxi 332000, China
| | - Haqi Zhang
- Department of Digital Media Technology, Hangzhou Dianzi University, Hangzhou, Zhejiang 310018, China
| | - Qizhang Li
- Innovative Drug R&D Center, School of Life Sciences, Huaibei Normal University, Huaibei, Anhui 235000, China
| | - Zhenshen Bao
- College of Information Engineering, Taizhou University, Taizhou 225300, Jiangsu, China
| | - Jie Lin
- Department of Pharmacy, the Third Affiliated Hospital of Wenzhou Medical University, Wenzhou 325200, Zhejiang Province, China
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9
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Faghfuri E, Gholizadeh P. The role of Akkermansia muciniphila in colorectal cancer: A double-edged sword of treatment or disease progression? Biomed Pharmacother 2024; 173:116416. [PMID: 38471272 DOI: 10.1016/j.biopha.2024.116416] [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: 12/09/2023] [Revised: 03/04/2024] [Accepted: 03/06/2024] [Indexed: 03/14/2024] Open
Abstract
Colorectal cancer (CRC) is the second most cancer-related death worldwide. In recent years, probiotics have been used to reduce the potential risks of CRC and tumors with various mechanisms. Different bacteria have been suggested to play different roles in the progression, prevention, or treatment of CRC. Akkermansia muciniphila is considered a next-generation probiotic for preventing and treating some diseases. Therefore, in this review article, we aimed to describe and discuss different mechanisms of A. muciniphila as an intestinal microbiota or probiotic in CRC. Some studies suggested that the abundance of A. muciniphila was higher or increased in CRC patients compared to healthy individuals. However, the decreased abundance of A. muciniphila was associated with severe symptoms of CRC, indicating that A. muciniphila did not play a role in the development of CRC. In addition, A. muciniphila administration elevates gene expression of proliferation-associated molecules such as S100A9, Dbf4, and Snrpd1, or markers for cell proliferation. Some other studies suggested that inflammation and tumorigenesis in the intestine might promoted by A. muciniphila. Overall, the role of A. muciniphila in CRC development or inhibition is still unclear and controversial. Various methods of bacterial supplementation, such as viability, bacterial number, and abundance, could all influence the colonization effect of A. muciniphila administration and CRC progression. Overall, A. mucinipila has been revealed to modulate the therapeutic potential of immune checkpoint inhibitors. Preliminary human data propose that oral consumption of A. muciniphila is safe, but its efficacy needs to be confirmed in more human clinical studies.
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Affiliation(s)
- Elnaz Faghfuri
- Digestive Disease Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Pourya Gholizadeh
- Digestive Disease Research Center, Ardabil University of Medical Sciences, Ardabil, Iran; Zoonoses Research Center, Ardabil University of Medical Sciences, Ardabil, Iran.
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10
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Abdollahy A, Salehi M, Mahami S, Bernkop-Schnürch A, Vahedi H, Gharravi AM, Mehrabi M. Therapeutic effect of 5-ASA and hesperidin-loaded chitosan/Eudragit® S100 nanoparticles as a pH-sensitive carrier for local targeted drug delivery in a rat model of ulcerative colitis. Int J Pharm 2024; 652:123838. [PMID: 38266937 DOI: 10.1016/j.ijpharm.2024.123838] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 01/20/2024] [Accepted: 01/20/2024] [Indexed: 01/26/2024]
Abstract
Ulcerative colitis (UC) is an idiopathic disease characterized by colonic mucosal tissue destruction secondary to an excessive immune response. We synthesized pH-sensitive cross-linked chitosan/Eudragit® S100 nanoparticles (EU S100/CS NPs) as carriers for 5-aminosalicylic acid (5-ASA) and hesperidin (HSP), then conducted in-vitro and in-vivo studies and evaluated the therapeutic effects. In-vitro analysis revealed that the 5-ASA-loaded EU S100/CS NPs and the HSP-loaded EU S100/CS NPs had smooth and curved surfaces and ranged in size between 250 and 300 nm, with a zeta potential of 32 to 34 mV. FTIR analysis demonstrated that the drugs were loaded on the nanoparticles without significant alterations. The loading capacity and encapsulation efficiency of loading 5-ASA onto EU S100/CS NPs were 25.13 % and 60.81 %, respectively. Regarding HSP, these values were 38.34 % and 77.84 %, respectively. Drug release did not occur in simulated gastric fluid (SGF), while a slow-release pattern was recorded for both drugs in simulated intestinal fluid (SIF). In-vivo macroscopic and histopathological examinations revealed that both NPs containing drugs significantly relieved the symptoms of acetic acid (AA)-induced UC in Wistar rats. We conclude that the synthesized pH-sensitive 5-ASA/EU S100/CS NPs and HSP/EU S100/CS NPs offer promise in treating UC.
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Affiliation(s)
- Armana Abdollahy
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran; Department of Medical Nanotechnology, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Majid Salehi
- Department of Tissue Engineering, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran; Tissue Engineering and Stem Cells Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Solmaz Mahami
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran; Department of Medical Nanotechnology, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Andreas Bernkop-Schnürch
- Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
| | - Hamid Vahedi
- Clinical Research Development Unit, Imam Hossein Hospital, Shahroud University of Medical Sciences, Shahroud, Iran; Department of Gastroenterology, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Anneh Mohammad Gharravi
- Tissue Engineering and Stem Cells Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Mohsen Mehrabi
- Department of Medical Nanotechnology, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran.
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11
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Liu M, Gu L, Zhang Y, Zhou H, Wang Y, Xu ZX. A real-world disproportionality analysis of mesalazine data mining of the public version of FDA adverse event reporting system. Front Pharmacol 2024; 15:1290975. [PMID: 38357304 PMCID: PMC10864552 DOI: 10.3389/fphar.2024.1290975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 01/18/2024] [Indexed: 02/16/2024] Open
Abstract
Background: Mesalazine, a preparation of 5-aminosalicylic acid, is a medication widely used in clinical practice as a first-line therapy in the treatment of mild and moderate inflammatory bowel disease. However, the long-term safety of mesalazine in large sample population was unknown. The current study was to assess mesalazine -related adverse events of real-world through data mining of the US Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio the Bayesian confidence propagation neural network and the multi-item gamma Poisson shrinker (MGPS) algorithms were employed to quantify the signals of mesalazine -associated AEs. Results: Out of 14,149,980 reports collected from the FDA Adverse Event Reporting System database, 24,284 reports of mesalazine -associated AEs were identified. A total of 170 significant disproportionality preferred terms conforming to the four algorithms simultaneously were retained. The most common AEs included colitis ulcerative, diarrhoea, condition aggravated, crohn's disease, fatigue, abdominal pain, nausea, haematochezia, which were corresponding to those reported in the specification and clinical trials. Unexpected significant AEs as dizziness, drug ineffective, drug hypersensitivity, infection, off label use, weight decreased, decreased appetite, arthralgia, rash might also occur. The median onset time of mesalazine -related AEs was 1,127 days (interquartile range [IQR] 1,127-1,674 days), and most of the cases occurred 2 years later (n = 610, 70.93%) and within the first 1 month (n = 89, 10.35%) after mesalazine initiation. Conclusion: Results of our study were consistent with clinical observations. We also found potential new and unexpected AEs signals for mesalazine, suggesting prospective clinical studies were needed to confirm these results and illustrate their relationship. Our results could provide valuable evidence for further safety studies of mesalazine.
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Affiliation(s)
- Mingdi Liu
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, Jilin, China
| | - Liting Gu
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, Jilin, China
| | - Yuning Zhang
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, Jilin, China
| | - Honglan Zhou
- Department of Urology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yishu Wang
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, Jilin, China
| | - Zhi-Xiang Xu
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, Jilin, China
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12
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Imbrizi M, Magro F, Coy CSR. Pharmacological Therapy in Inflammatory Bowel Diseases: A Narrative Review of the Past 90 Years. Pharmaceuticals (Basel) 2023; 16:1272. [PMID: 37765080 PMCID: PMC10537095 DOI: 10.3390/ph16091272] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/23/2023] [Accepted: 09/04/2023] [Indexed: 09/29/2023] Open
Abstract
Inflammatory Bowel Diseases had their first peak in incidence in countries in North America, Europe, and Oceania and are currently experiencing a new acceleration in incidence, especially in Latin America and Asia. Despite technological advances, 90 years after the development of the first molecule for the treatment of IBD, we still do not have drugs that promote disease remission in a generalized way. We carried out a narrative review on therapeutic advances in the treatment of IBD, the mechanisms of action, and the challenges facing the therapeutic goals in the treatment of IBD. Salicylates are still used in the treatment of Ulcerative Colitis. Corticosteroids have an indication restricted to the period of therapeutic induction due to frequent adverse events, while technologies with less systemic action have been developed. Most immunomodulators showed a late onset of action, requiring a differentiated initial strategy to control the disease. New therapeutic perspectives emerged with biological therapy, initially with anti-TNF, followed by anti-integrins and anti-interleukins. Despite the different mechanisms of action, there are similarities between the general rates of effectiveness. These similar results were also evidenced in JAK inhibitors and S1p modulators, the last therapeutic classes approved for the treatment of IBD.
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Affiliation(s)
- Marcello Imbrizi
- Department of Surgery, Faculty of Medical Sciences, University of Campinas, Cidade Universitária Zeferino Vaz-Barão Geraldo, Campinas 13083-970, SP, Brazil
| | - Fernando Magro
- Unit of Pharmacology and Therapeutics, Department of Biomedicine, Faculty of Medicine, University of Porto, 4200-450 Porto, Portugal
| | - Claudio Saddy Rodrigues Coy
- Department of Surgery, Faculty of Medical Sciences, University of Campinas, Cidade Universitária Zeferino Vaz-Barão Geraldo, Campinas 13083-970, SP, Brazil
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13
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Cao Z, Liu Y, Chen S, Wang W, Yang Z, Chen Y, Jiao S, Huang W, Chen L, Sun L, Li Z, Zhang L. Discovery of novel carboxylesterase 2 inhibitors for the treatment of delayed diarrhea and ulcerative colitis. Biochem Pharmacol 2023; 215:115742. [PMID: 37567318 DOI: 10.1016/j.bcp.2023.115742] [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: 08/06/2023] [Accepted: 08/08/2023] [Indexed: 08/13/2023]
Abstract
Human carboxylesterase 2 (hCES2) is an enzyme that metabolizes irinotecan to SN-38, a toxic metabolite considered a significant source of side effects (lethal delayed diarrhea). The hCES2 inhibitors could block the hydrolysis of irinotecan in the intestine and thus reduce the exposure of intestinal SN-38, which may alleviate irinotecan-associated diarrhea. However, existing hCES2 inhibitors (except loperamide) are not used in clinical applications due to lack of validity or acceptable safety. Therefore, developing more effective and safer drugs for treating delayed diarrhea is urgently needed. This study identified a lead compound 1 with a novel scaffold by high-throughput screening in our in-house library. After a comprehensive structure-activity relationship study, the optimal compound 24 was discovered as an efficient and highly selective hCES2 inhibitor (hCES2: IC50 = 6.72 μM; hCES1: IC50 > 100 μM). Further enzyme kinetics study indicated that compound 24 is a reversible inhibitor of hCES2 with competitive inhibition mode (Ki = 6.28 μM). The cell experiments showed that compound 24 could reduce the level of hCES2 in living cells (IC50 = 6.54 μM). The modeling study suggested that compound 24 fitted very well with the binding pocket of hCES2 by forming multiple interactions. Notably, compound 24 can effectively treat irinotecan-induced delayed diarrhea and DSS-induced ulcerative colitis, and its safety has also been verified in subtoxic studies. Based on the overall pharmacological and preliminary safety profiles, compound 24 is worthy of further evaluation as a novel agent for irinotecan-induced delayed diarrhea.
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Affiliation(s)
- Zhijun Cao
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, PR China
| | - Yuxia Liu
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China
| | - Siliang Chen
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China
| | - Wenxin Wang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China
| | - Zhongcheng Yang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China
| | - Ya Chen
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China
| | - Shixuan Jiao
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, PR China
| | - Wanqiu Huang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, PR China
| | - Lianru Chen
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China
| | - Lidan Sun
- Department of Pharmaceutics, Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, PR China.
| | - Zheng Li
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Guangdong Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangzhou 510006, PR China.
| | - Luyong Zhang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Guangdong Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
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14
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Valvano M, Fabiani S, Monaco S, Calabrò M, Mancusi A, Frassino S, Rolandi C, Mosca M, Faenza S, Sgamma E, Cesaro N, Latella G. Old and New Adjunctive Therapies in Celiac Disease and Refractory Celiac Disease: A Review. Int J Mol Sci 2023; 24:12800. [PMID: 37628981 PMCID: PMC10454405 DOI: 10.3390/ijms241612800] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 07/13/2023] [Accepted: 08/12/2023] [Indexed: 08/27/2023] Open
Abstract
Celiac disease (CD) is a chronic enteropathy caused by the ingestion of gluten in a genetically susceptible individual. Currently, a gluten-free diet (GFD) is the only recommended treatment. However, unintentional gluten ingestion or a persistent villous atrophy with malabsorption (regardless of a strict GFD) as in the case of Refractory Celiac Disease (RCD) represents a major issue. In this review, we have analysed and discussed data from both randomized controlled trials and observational studies concerning adjunctive therapies as well as novel therapies for the treatment of CD and RCD. The literature search was carried out through Medline and Scopus. In total, 2268 articles have been identified and 49 were included in this review (36 studies resulting from the search strategy and 13 from other sources). Today, GFD remains the only effective treatment, although steroids, mesalamine, and more recently biological therapies have found space in the complex management of RCD. Currently, studies evaluating the effectiveness of novel therapies are still limited and preliminary results have been controversial.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Giovanni Latella
- Gastroenterology Unit, Division of Gastroenterology, Hepatology and Nutrition, Department of Life, Health and Environmental Sciences, University of L’Aquila, Piazzale Salvatore Tommasi 1, 67100 L’Aquila, Italy; (M.V.); (S.F.); (S.M.); (M.C.); (A.M.); (S.F.); (C.R.); (M.M.); (S.F.); (E.S.); (N.C.)
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