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Ma D, Hu S, Wang C, Ai J, Ma J, Gao T, Hong Y, Wu Z, Gu M, Tang X, Chang Y, Chen Q, Chen S, Yu Q, Yang J, Zhang C, Li C, Liu X, Shi J, Liu X, Liu Y, Liu M. Discovery of Potent and Balanced Dual RIPK2 and 3 Inhibitors as a New Strategy for the Treatment of Inflammatory Bowel Diseases. J Med Chem 2025; 68:7539-7559. [PMID: 40131099 DOI: 10.1021/acs.jmedchem.4c03226] [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: 03/26/2025]
Abstract
Receptor-interacting serine/threonine protein kinase 2 (RIPK2) and RIPK3 have been demonstrated to be promising targets for treating multiple inflammatory diseases, including inflammatory bowel diseases (IBDs). Due to the complexity of IBD pathogenesis, on the basis of synergy strategies, we herein describe the discovery and optimization of a series of N,7-diaryl-quinazolin-4-amine derivatives as dual RIPK2 and RIPK3 inhibitors. Based on a step-by-step process involving three rounds of structural modifications, compound 29 was identified as the most one, exhibiting balanced potency against RIPK2 (IC50 = 12 nM) and RIPK3 (IC50 = 18 nM), as well as demonstrating good selectivity over other kinase targets. Further biological evaluation confirmed that compound 29 could bind directly to RIPK2 and RIPK3, effectively suppressing NOD-induced cytokine production and cellular necroptosis. Notably, compound 29 displayed significant therapeutic effects in a DSS-induced colitis mouse model, with no detectable toxicity, indicating its promising therapeutic potential as RIPK2/RIPK3 dual inhibitors for treatment of IBD.
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Affiliation(s)
- Duo Ma
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Shuang Hu
- Department of Pharmacy, Eye & ENT Hospital of Fudan University, Shanghai 200031, China
| | - Chun Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Jiaxin Ai
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Jiahai Ma
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Tianwen Gao
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China
- Department of Pharmacy, Fuyang Hospital of Anhui Medical University, Fuyang 236112, China
| | - Yaling Hong
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Zhengxing Wu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Mingzhen Gu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - XiaoXin Tang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - YanTai Chang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - QiHang Chen
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Shuo Chen
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Qing Yu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - JunJie Yang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Chen Zhang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Chong Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Xuesong Liu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Jingbo Shi
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Xinhua Liu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Yuhai Liu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Anhui Medical University, The First People's Hospital of Hefei, Binhu Hospital District, Hefei 230041, China
| | - Mingming Liu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China
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Gao C, Yang Z, Song R, Sheng H, Zhu L. Nanotechnology-based drug delivery system for targeted therapy of ulcerative colitis from traditional Chinese medicine: A review. Int J Pharm 2025; 673:125375. [PMID: 39965734 DOI: 10.1016/j.ijpharm.2025.125375] [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: 12/01/2024] [Revised: 01/27/2025] [Accepted: 02/15/2025] [Indexed: 02/20/2025]
Abstract
Ulcerative colitis (UC) is a chronic autoimmune disease and seriously affects the normal life of patients. Conventional therapeutic drugs are difficult to meet clinical needs. Traditional Chinese medicine (TCM) ingredients could effectively alleviate the symptoms of UC by anti-inflammatory, anti-oxidative, regulating the gut microbiota, and repairing the colonic epithelial barrier, but their low solubility and bioavailability severely limit their clinical application. Nano-drug delivery systems (NDDS) combined with TCM ingredients is a promising option for treating UC, and they could significantly enhance the stability, solubility, and bioavailability of TCM ingredients. The review describes the anti-UC mechanisms of TCM ingredients, systematically summarizes various kinds of NDDS for TCM ingredients according to different routes of administration, and highlights the advantages of NDDS for TCM ingredients in the treatmentof UC. In addition, we discuss the limitations of existing NDDS for TCM ingredients and the development direction in the future. This review will provide a basis for the future development of anti-UC NDDS for TCM ingredients.
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Affiliation(s)
- Chengcheng Gao
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Zerun Yang
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Ruirui Song
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Huagang Sheng
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
| | - Liqiao Zhu
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
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Gazit I, Wussuki-Lior O, Tauber T, Morad Y. Systemic Treatment With Cyclosporine A in Children With Severe Vernal Keratoconjunctivitis. Cornea 2025; 44:282-285. [PMID: 38950071 DOI: 10.1097/ico.0000000000003613] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 05/22/2024] [Indexed: 07/03/2024]
Abstract
PURPOSE To report our experience with systemic cyclosporine as a treatment for severe vernal keratoconjunctivitis (VKC) in pediatric patients who did not respond to previous treatments. METHODS We analyzed the medical records of 6 patients, aged 4 to 15 years, with severe VKC treated with systemic cyclosporine for VKC at Shamir Medical Center in Zerifin, Israel, between the years 2000 and 2023. The average treatment duration was 18 months. In all patients, previous treatments with antihistamines, mast cells stabilizers, topical steroids and topical cyclosporine, and systemic steroids did not result in sufficient improvement. The severity of inflammation was evaluated during clinical examinations and the patients' subjective assessment of their quality of life. RESULTS In all 6 patients, signs and symptoms showed significant improvement within 2 to 4 weeks of initiating systemic cyclosporine treatment. All patients were able to discontinue regular steroids use and reported a significant improvement in their quality of life. No significant side effects were observed in any of the patients. CONCLUSIONS Systemic cyclosporine is a safe and effective treatment for severe VKC. It is a steroid-sparing treatment that allows good quality of life, while keeping the disease latent.
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Affiliation(s)
- Inbal Gazit
- Department of Ophthalmology, Shamir Medical Center, Zerifin, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Orly Wussuki-Lior
- Department of Ophthalmology, Shamir Medical Center, Zerifin, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Tsivia Tauber
- Department of Pediatrics, Shamir Medical Center, Zerifin, Israel; and
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yair Morad
- Department of Ophthalmology, Shamir Medical Center, Zerifin, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Gong B, Zhang C, Hu S, Zhang X, Zou H, Li J, Wang J, Kao Y, Liu F. Network pharmacology and experimental verification in vivo reveal the mechanism of Zhushao Granules against ulcerative colitis. Biol Proced Online 2025; 27:7. [PMID: 39953430 PMCID: PMC11827476 DOI: 10.1186/s12575-025-00268-3] [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: 09/24/2024] [Accepted: 01/28/2025] [Indexed: 02/17/2025] Open
Abstract
BACKGROUND Zhushao Granules (ZSG) had exhibited beneficial effects in the treatment of ulcerative colitis (UC) as an effective herbal prescription in Traditional Chinese Medicine. However, the underlying anti-inflammatory mechanism of ZSG remains unclear. This study aimed to decipher the mechanism of ZSG against UC combining network pharmacology and animal-based experiments. METHODS Network pharmacology was employed to identify active components and therapeutic targets of ZSG against UC. The protein-protein interaction (PPI) network was constructed among the therapeutic targets using the STRING database, and GO and pathway analyses were carried out using DAVID. Then, the "herb-component-target-pathway" network based on therapeutic targets was established and the topological parameters were subsequently calculated to identify hub active components, targets and pathways by Cytoscape. Finally, the therapeutic function and the special pathway of ZSG against UC were validated using a TNBS-induced UC model in BABL/c mice. RESULTS Ninety-four active components of ZSG and 460 potential targets were acquired from the Encyclopedia of Traditional Chinese Medicine and Tradition Chinese Medicine Systems Pharmacology Database and Analysis Platform. 884 potential targets of UC were obtained from OMIM and HINT. Sixty-two overlapping potential targets were identified as therapeutic targets of ZSG against UC. PPI network filtered out 61 therapeutic targets. GO and pathway analyses extracted 48, 25, and 98 terms corresponding to biological processes, molecular functions and Reactome pathways, respectively. Enrichment analysis suggested that the therapeutic targets were mainly involved in immune regulation, especially RIP-mediated NF-κB activation via ZBP1. Topological analysis of the "herb-component-target-pathway" network recognized 9 hub components, 20 hub targets and 18 hub pathways. The animal-based experiments revealed that ZSG ameliorated symptoms and histological changes in TNBS-induced colitis by significantly inhibiting the ZBP1/RIP/NF-κB pathway. CONCLUSIONS ZSG might alleviate the mucosal damage and ameliorate colitis via targeting ZBP1/RIP/NF-κB pathway, which laid the theoretical foundation for the clinical application and further study of ZSG and provided new insights into UC treatment.
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Affiliation(s)
- Benjiao Gong
- Central Laboratory, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Chenglin Zhang
- Central Laboratory, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Shaofei Hu
- Department of Pharmacy, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Xueying Zhang
- Life Science and Technology College, Shandong Second Medical University, Weifang, China
| | - Hui Zou
- Department of Spleen and Stomach Diseases, Yantai Hospital of Traditional Chinese Medicine, Yantai, China
| | - Jiayao Li
- Central Laboratory, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Jiahui Wang
- Central Laboratory, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China.
| | - Yanlei Kao
- Department of Spleen and Stomach Diseases, Yantai Hospital of Traditional Chinese Medicine, Yantai, China.
| | - Fujun Liu
- Central Laboratory, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China.
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Sammari H, Abidi A, Jedidi S, Dhawefi N, Sebai H. Antioxidant activity and protective effect of phyto-active compounds of Crataegus azarolus berries decoction extract against acetic acid-induced hepatorenal injuries in male rats. Physiol Rep 2025; 13:e70240. [PMID: 39924696 PMCID: PMC11807846 DOI: 10.14814/phy2.70240] [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: 08/21/2024] [Revised: 01/27/2025] [Accepted: 01/27/2025] [Indexed: 02/11/2025] Open
Abstract
The present study evaluated the hepato-nephronal protective properties of Crataegus azarolus berries decoction extract (CAB-DE) on acetic acid (AA)-induced oxidative stress and metabolic disorders in rats. Animals (60 rats) were randomly divided into six groups (n = 10), with groups 1 and 2 being controls and groups 3, 4, and 5 given increasing doses of CAB-DE, group 6 were given gallic acid until ulcerative colitis was induced and then intoxicated by an acute intra-rectal infusion of AA. Our results showed that CAB-DE-oral administration had no signs of toxicity or abnormal behavior in rats, with a LD50 higher than 3500 mg/kg bw. In addition, CAB-DE protected against AA-induced nephropathy and hepatic damage in rats, as determined by an increase in organ weights and an alteration in the renal and liver parameters and functions. Moreover, extract co-administration reduced AA-induced liver and kidney lipoperoxidation, maintained non-enzymatic contents such as sulfhydryl groups (-SH) and reduced glutathione (GSH), and restored antioxidant enzyme activities, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Finally, CAB-DE might have a possible protective effect against AA-oxidative stress and dysfunction in the rat liver and kidney, suggesting that Crataegus azarolus berries may be beneficial for people suffering from liver issues and nephropathy.
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Affiliation(s)
- Houcem Sammari
- Laboratory of Functional Physiology and Valorization of Bio‐Resources, Department of Animal PhysiologyUniversity of Jendouba, Higher Institute of Biotechnology of BejaBejaTunisia
| | - Anouar Abidi
- Laboratory of Functional Physiology and Valorization of Bio‐Resources, Department of Animal PhysiologyUniversity of Jendouba, Higher Institute of Biotechnology of BejaBejaTunisia
| | - Saber Jedidi
- Laboratory of Functional Physiology and Valorization of Bio‐Resources, Department of Animal PhysiologyUniversity of Jendouba, Higher Institute of Biotechnology of BejaBejaTunisia
| | - Nourhen Dhawefi
- Laboratory of Functional Physiology and Valorization of Bio‐Resources, Department of Animal PhysiologyUniversity of Jendouba, Higher Institute of Biotechnology of BejaBejaTunisia
| | - Hichem Sebai
- Laboratory of Functional Physiology and Valorization of Bio‐Resources, Department of Animal PhysiologyUniversity of Jendouba, Higher Institute of Biotechnology of BejaBejaTunisia
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Zhang Y, Cao P, Qin D, Zhao Y, Chen X, Ma P. Anti-inflammatory, anti-colitis, and antioxidant effects of columbianadin against DSS-induced ulcerative colitis in rats via alteration of HO-1/Nrf2 and TLR4-NF-κB signaling pathway. Inflammopharmacology 2025; 33:341-352. [PMID: 39757276 DOI: 10.1007/s10787-024-01630-9] [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: 08/25/2024] [Accepted: 12/04/2024] [Indexed: 01/07/2025]
Abstract
BACKGROUND Ulcerative colitis (UC) is a significant inflammatory bowel disease (IBD) that typically arises from chronic inflammation of the intestinal tract. Report suggest that anti-inflammatory drug plays a crucial role in the protection of UC. The recent study demonstrated that columbianadin has a protective effect against UC induced by dextran sulfate sodium (DSS) in rats through the modulation of HO-1/Nrf2 and TLR4-NF-κB signaling pathways. MATERIAL AND METHODS In this study, Swiss Wistar rats were utilized, and UC was induced using 2% DSS. The treatment regimen included oral administration of columbianadin (5, 10 and 15 mg/kg) and sulfasalazine to the rats. The body weight, spleen index, disease activity index (DAI), colon length, food and water intake were estimated. Moreover, antioxidant, cytokines, inflammatory and apoptosis parameters were determined. mRNA expression levels were also quantitatively analyzed. RESULTS Columbianadin treatment significantly (P < 0.001) boosted the body weight and suppressed the DAI. Columbianadin significantly (P < 0.001) enhanced the colon length and repressed the spleen index along with enhanced food and water intake. Columbianadin significantly (P < 0.001) suppressed the level of lactate dehydrogenase (LDH), myeloperoxidase (MPO) and altered the level of oxidative stress parameters such as catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPx), malonaldehyde (MDA), nitric oxide (NO), SA; cytokines level such as interleukin (IL)-1, 1β, 6, 10, 17, 18, TNF-α; inflammatory parameters viz., cyclooxygenase-2 (COX-2), prostaglandin (PGE2), inducible nitric oxide synthetase (iNOS), nuclear factor kappa B (NF-κB), transforming growth factor (TGF-β); apoptosis parameters include Bax, Bcl-2, Bcl-2/Bax ratio, caspase-1 and A-caspase-3 activity, respectively. Columbianadin significantly altered the mRNA expression of IFN-γ, IL-6, IL-1β, IL-8, TNF-α, NF-κB, TLR4, Bcl-2, caspase-9, Bax, p38, ASC, MCP-1, ZO-1, and Ocln. While this study focused on COX-2 modulation as a marker of inflammatory response, no direct measurements or inferences were made regarding leukotriene activity, which involves a separate lipoxygenase pathway. CONCLUSION Columbianadin exhibited the protective effect against DSS-induced UC via alteration of HO-1/Nrf2 and TLR4-NF-κB signaling pathway.
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Affiliation(s)
- Yanping Zhang
- Department of Gastroenterology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, No.99 Longcheng street, Xiao dian District, Taiyuan, 030032, China
- Faculty of Graduate Studies, Shanxi Medical University, NO.56 Road, NO. Xinjiannan Yingze District, Taiyuan, 030000, China
| | - Ping Cao
- Department of Gastroenterology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, No.99 Longcheng street, Xiao dian District, Taiyuan, 030032, China
| | - Dongyuan Qin
- Department of Gastroenterology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, No.99 Longcheng street, Xiao dian District, Taiyuan, 030032, China
| | - Ying Zhao
- Department of Gastroenterology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, No.99 Longcheng street, Xiao dian District, Taiyuan, 030032, China
| | - Xing Chen
- Early Gastrointestinal Cancer Diagnosis and Treatment Research Center, First Hospital of Shanxi Medical University, NO.85 Xinjian nan Road, Yingze District, Taiyuan, 030000, China.
- Department of Gastroenterology, First Hospital of Shanxi Medical University, NO.56 Jiefangnan Road, Taiyuan, 030000, China.
| | - Peng Ma
- General Surgery Department, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China.
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Nguyen PT, Seo Y, Ahn JS, Oh SJ, Park HJ, Yu JH, Kim SH, Lee Y, Yang JW, Cho J, Kang MJ, Park JH, Kim HS. De novo interleukin-10 production primed by Lactobacillus sakei CVL-001 amplifies the immunomodulatory abilities of mesenchymal stem cells to alleviate colitis. Biomed Pharmacother 2025; 182:117745. [PMID: 39705909 DOI: 10.1016/j.biopha.2024.117745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 12/06/2024] [Accepted: 12/08/2024] [Indexed: 12/23/2024] Open
Abstract
Mesenchymal stem cells (MSCs) hold therapeutic promise for treating inflammatory bowel disease (IBD) owing to their immunomodulatory properties. Currently, pre-conditioning strategies with several beneficial agents have been applied to enhance the efficacy of MSCs in treating IBDs. Probiotics are increasingly acknowledged as supplemental therapy for IBD; however, their potential benefits in MSCs-based therapy remain largely unexplored. In this study, we hypothesized that pretreating MSCs with Lactobacillus sakei CVL-001 (L. sakei CVL-001), a representative probiotic strain, could improve their therapeutic effectiveness for IBD. In line with this hypothesis, we noted that pretreatment with L. sakei CVL-001 significantly induced IL-10 secretion in MSCs via the activation of the STAT3 signaling pathway. These primed MSCs reduced pro-inflammatory cytokine production in LPS/IFN-γ-treated macrophages and promoted an M2 phenotype, associated with immunoregulation and tissue repair, in undifferentiated macrophages. In addition, their conditioned media significantly reduced the proliferation capacity of Jurkat T cells and splenocytes, while the neutralization of IL-10 reversed these phenomena. Furthermore, MSCs treated with L. sakei CVL-001 mitigated inflammatory responses and promoted epithelial regeneration, leading to accelerated recovery from disease symptoms and improved survival rates compared to naive MSCs in a DSS-induced colitis mouse model. In conclusion, our findings suggest that probiotics, such as L. sakei CVL-001, can improve the therapeutic efficacy of MSCs for treating IBD.
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Affiliation(s)
- Phuong Thao Nguyen
- Department of Oral Biochemistry; Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Yoojin Seo
- Department of Oral Biochemistry; Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Ji-Su Ahn
- Department of Oral Biochemistry; Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Su-Jeong Oh
- Department of Oral Biochemistry; Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Hee-Jeong Park
- Department of Oral Biochemistry; Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Jeong Hyun Yu
- Department of Oral Biochemistry; Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Seong Hui Kim
- Department of Oral Biochemistry; Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Yunji Lee
- Department of Oral Biochemistry; Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Ji Won Yang
- Department of Oral Biochemistry; Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Jaejin Cho
- Department of Dental Regenerative Biotechnology, School of Dentistry, Seoul National University, Seoul 03080, Republic of Korea; Dental Research Institute, Seoul National University, Seoul 03080, Republic of Korea
| | - Min-Jung Kang
- Department of Oral Biochemistry; Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea.
| | - Jong-Hwan Park
- Laboratory Animal Medicine, College of Veterinary Medicine, Animal Medical Institute, Chonnam National University, Gwangju 61186, Republic of Korea; NODCURE, Inc, 77 Yongbong-ro, Buk-gu, Gwangju 61186, Republic of Korea.
| | - Hyung-Sik Kim
- Department of Oral Biochemistry; Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Republic of Korea.
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Zhao J, Zhang Q, Hao X. Syringin ameliorates dextran sulphate colitis via alteration oxidative stress, inflammation NF-κB signalling pathway and gut microbiota. Basic Clin Pharmacol Toxicol 2025; 136:e14105. [PMID: 39548740 DOI: 10.1111/bcpt.14105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 09/24/2024] [Accepted: 10/29/2024] [Indexed: 11/18/2024]
Abstract
BACKGROUND The objective of the current study was to investigate the potential effects of syringin against dextran sulphate colitis (DSS)-induced ulcerative colitis (UC) in mice. MATERIAL AND METHODS In vitro study was performed on the RAW 264.7 cells and cytokines and inflammatory level were estimated. The oxidative stress, inflammatory cytokines, apoptosis and inflammatory parameters were estimated. The mRNA expression and faecal samples were estimated in the colon tissue. RESULTS Syringin treatment enhanced the body weight, colon length and reduced the disease activity index (DAI), spleen index. Syringin treatment remarkably suppressed the level of nitric oxide (NO), myeloperoxidase (MPO), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) along with alteration of antioxidant parameters. Syringin treatment also altered level of cytokines in the serum and colon tissue; inflammatory parameters viz., platelet-activating factor (PAF), cyclooxygenase-2 (COX-2), prostaglandin (PGE2), inducible nitric oxide synthetase (iNOS), nuclear factor κ-B (NF-κB); matrix metalloproteinases (MMP) level. Syringin significantly (p < 0.001) enhanced the level of nuclear factor erythroid 2-related factor (Nrf2) and heme oxygenase-1 (HO-1). Syringin remarkably altered the relative abundance of gut microbiota like Firmicutes, Bacteroidetes, F/B ratio, Verrucomicrobia and Actinobacteria. CONCLUSION Syringin exhibited the protective effect against DSS-induced UC in mice via alteration of NF-κB signalling pathway.
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Affiliation(s)
- Juhui Zhao
- Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an City, China
| | - Qingqing Zhang
- Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an City, China
| | - Xudong Hao
- Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an City, China
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Zhao J, Zhang X, Li F, Lei X, Ge L, Li H, Zhao N, Ming J. The Effects of Interventions with Glucosinolates and Their Metabolites in Cruciferous Vegetables on Inflammatory Bowel Disease: A Review. Foods 2024; 13:3507. [PMID: 39517291 PMCID: PMC11544840 DOI: 10.3390/foods13213507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 10/29/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract which affects millions of individuals worldwide. Despite advancements in treatment options, there is increasing interest in exploring natural interventions with minimal side effects. Cruciferous vegetables, such as broccoli, cabbage, and radishes, contain bioactive compounds known as glucosinolates (GLSs), which have shown promising effects in alleviating IBD symptoms. This review aims to provide a comprehensive overview of the physiological functions and mechanisms of cruciferous GLSs and their metabolites in the context of IBD. Reviewed studies demonstrated that GLSs attenuated all aspects of IBD, including regulating the intestinal microbiota composition, exerting antioxidant and anti-inflammatory effects, restoring intestinal barrier function, and regulating epigenetic mechanisms. In addition, a few interventions with GLS supplementation in clinical studies were also discussed. However, there are still several challenges and remaining knowledge gaps, including variations in animals' experimental outcomes, the bioavailability of certain compounds, and few clinical trials to validate their effectiveness in human subjects. Addressing these issues will contribute to a better understanding of the therapeutic potential of cruciferous GLSs and their metabolites in the management of IBD.
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Affiliation(s)
- Jichun Zhao
- College of Food Science, Southwest University, Chongqing 400715, China; (J.Z.)
- Chongqing Key Laboratory of Speciality Food Co-Built by Sichuan and Chongqing, Chongqing 400715, China
- Research Center for Fruits and Vegetables Logistics Preservation and Nutritional Quality Control, Southwest University, Chongqing 400715, China
| | - Xiaoqin Zhang
- College of Food Science, Southwest University, Chongqing 400715, China; (J.Z.)
| | - Fuhua Li
- College of Food Science, Southwest University, Chongqing 400715, China; (J.Z.)
- Chongqing Key Laboratory of Speciality Food Co-Built by Sichuan and Chongqing, Chongqing 400715, China
- Research Center for Fruits and Vegetables Logistics Preservation and Nutritional Quality Control, Southwest University, Chongqing 400715, China
| | - Xiaojuan Lei
- College of Food Science, Southwest University, Chongqing 400715, China; (J.Z.)
- Chongqing Key Laboratory of Speciality Food Co-Built by Sichuan and Chongqing, Chongqing 400715, China
- Research Center for Fruits and Vegetables Logistics Preservation and Nutritional Quality Control, Southwest University, Chongqing 400715, China
| | - Lihong Ge
- College of Life Science, Sichuan Normal University, Chengdu 610101, China
| | - Honghai Li
- College of Food Science, Southwest University, Chongqing 400715, China; (J.Z.)
- Chongqing Key Laboratory of Speciality Food Co-Built by Sichuan and Chongqing, Chongqing 400715, China
- Research Center for Fruits and Vegetables Logistics Preservation and Nutritional Quality Control, Southwest University, Chongqing 400715, China
| | - Nan Zhao
- Institute of Agro-products Processing Science and Technology, Sichuan Academy of Agricultural Sciences, Chengdu 610066, China
| | - Jian Ming
- College of Food Science, Southwest University, Chongqing 400715, China; (J.Z.)
- Chongqing Key Laboratory of Speciality Food Co-Built by Sichuan and Chongqing, Chongqing 400715, China
- Research Center for Fruits and Vegetables Logistics Preservation and Nutritional Quality Control, Southwest University, Chongqing 400715, China
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10
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Huang Y, Wu Q, Li S, Lin X, Yang S, Zhu R, Fu C, Zhang Z. Harnessing nature's pharmacy: investigating natural compounds as novel therapeutics for ulcerative colitis. Front Pharmacol 2024; 15:1394124. [PMID: 39206263 PMCID: PMC11349575 DOI: 10.3389/fphar.2024.1394124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 07/01/2024] [Indexed: 09/04/2024] Open
Abstract
Backgrounds Ulcerative colitis (UC) is a form of chronic inflammatory bowel disease, and UC diagnosis rates continue to rise throughout the globe. The research and development of new drugs for the treatment of UC are urgent, and natural compounds are an important source. However, there is a lack of systematic summarization of natural compounds and their mechanisms for the treatment of UC. Methods We reviewed the literature in the databases below from their inception until July 2023: Web of Science, PubMed, China National Knowledge Infrastructure, and Wanfang Data, to obtain information on the relationship between natural compounds and UC. Results The results showed that 279 natural compounds treat UC through four main mechanisms, including regulating gut microbiota and metabolites (Mechanism I), protecting the intestinal mucosal barrier (Mechanism II), regulating intestinal mucosal immune response (Mechanism III), as well as regulating other mechanisms (Mechanism Ⅳ) such as cellular autophagy modulation and ferroptosis inhibition. Of these, Mechanism III is regulated by all natural compounds. The 279 natural compounds, including 62 terpenoids, 57 alkaloids, 52 flavonoids, 26 phenols, 19 phenylpropanoids, 9 steroids, 9 saponins, 8 quinonoids, 6 vitamins, and 31 others, can effectively ameliorate UC. Of these, terpenoids, alkaloids, and flavonoids have the greatest potential for treating UC. It is noteworthy to highlight that a total of 54 natural compounds exhibit their therapeutic effects by modulating Mechanisms I, II, and III. Conclusion This review serves as a comprehensive resource for the pharmaceutical industry, researchers, and clinicians seeking novel therapeutic approaches to combat UC. Harnessing the therapeutic potential of these natural compounds may significantly contribute to the improvement of the quality of life of patients with UC and promotion of disease-modifying therapies in the future.
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Affiliation(s)
- You Huang
- School of Pharmacy/School of Modern Chinese Medicine Industry, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qiuhong Wu
- School of Pharmacy/School of Modern Chinese Medicine Industry, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Sha Li
- School of Pharmacy/School of Modern Chinese Medicine Industry, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xia Lin
- School of Pharmacy/School of Modern Chinese Medicine Industry, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shasha Yang
- School of Pharmacy/School of Modern Chinese Medicine Industry, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Rui Zhu
- School of Pharmacy/School of Modern Chinese Medicine Industry, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chaomei Fu
- School of Pharmacy/School of Modern Chinese Medicine Industry, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhen Zhang
- School of Pharmacy/School of Modern Chinese Medicine Industry, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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11
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Zhang B, Ren D, Yang C, Zhao Y, Zhang X, Tian X, Yang X. Intracellular Polysaccharides of Eurotium cristatum Exhibited Anticolitis Effects in Association with Gut Tryptophan Metabolism. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:16347-16358. [PMID: 38982686 DOI: 10.1021/acs.jafc.4c04024] [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: 07/11/2024]
Abstract
This study is to investigate the protective effects of Eurotium cristatum intracellular polysaccharides (ECIP) on dextran sodium sulfate (DSS)-induced ulcerative colitis (UC). The oral administration of ECIP could downregulate the disease activity index (DAI) and ameliorate the colonic shortening, immune stress, and damage caused by DSS. In addition, ECIP treatment increased the colonic contents of SCFAs including acetic, propionic, and butyric acids in UC mice. Targeted and untargeted metabolic analysis suggested that ECIP dramatically altered the tryptophan metabolism in the feces of UC mice and promoted the conversion of tryptophan into indole metabolites including indolepyruvate and indole-3-acetic acid (IAA) and indolealdehyde (IAId). Moreover, ECIP observably increased the content of colonic IL-22 and stimulated the relative concentration and relative expression of tight junction molecules in mRNA and proteins levels. Conclusively, consumption of ECIP can improve colon damage and its related effects of UC by promoting the production of IAA and IAId to reinforce intestinal barriers.
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Affiliation(s)
- Bo Zhang
- Shaanxi Engineering Laboratory for Food Green Processing and Safety Control, Shaanxi Normal University, Xi'an 710119, China
- Shaanxi Key Laboratory for Hazard Factors Assessment in Processing and Storage of Agricultural Products, Shaanxi Normal University, Xi'an 710119, China
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China
| | - Daoyuan Ren
- Shaanxi Engineering Laboratory for Food Green Processing and Safety Control, Shaanxi Normal University, Xi'an 710119, China
- Shaanxi Key Laboratory for Hazard Factors Assessment in Processing and Storage of Agricultural Products, Shaanxi Normal University, Xi'an 710119, China
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China
| | - Chengcheng Yang
- Shaanxi Engineering Laboratory for Food Green Processing and Safety Control, Shaanxi Normal University, Xi'an 710119, China
- Shaanxi Key Laboratory for Hazard Factors Assessment in Processing and Storage of Agricultural Products, Shaanxi Normal University, Xi'an 710119, China
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China
| | - Yan Zhao
- Shaanxi Engineering Laboratory for Food Green Processing and Safety Control, Shaanxi Normal University, Xi'an 710119, China
- Shaanxi Key Laboratory for Hazard Factors Assessment in Processing and Storage of Agricultural Products, Shaanxi Normal University, Xi'an 710119, China
- Key Laboratory of Ministry of Education for Medicinal Resource and Natural Pharmaceutical Chemistry, College of Life Sciences, Shaanxi Normal University, Xi'an 710119, China
| | - Xiangnan Zhang
- Shaanxi Engineering Laboratory for Food Green Processing and Safety Control, Shaanxi Normal University, Xi'an 710119, China
- Shaanxi Key Laboratory for Hazard Factors Assessment in Processing and Storage of Agricultural Products, Shaanxi Normal University, Xi'an 710119, China
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China
| | - Xinwei Tian
- Shaanxi Engineering Laboratory for Food Green Processing and Safety Control, Shaanxi Normal University, Xi'an 710119, China
- Shaanxi Key Laboratory for Hazard Factors Assessment in Processing and Storage of Agricultural Products, Shaanxi Normal University, Xi'an 710119, China
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China
| | - Xingbin Yang
- Shaanxi Engineering Laboratory for Food Green Processing and Safety Control, Shaanxi Normal University, Xi'an 710119, China
- Shaanxi Key Laboratory for Hazard Factors Assessment in Processing and Storage of Agricultural Products, Shaanxi Normal University, Xi'an 710119, China
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China
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12
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Zhang MQ, Huang LH, Gong MC, Hong WM, Xie R, Wang J, Zhou LL, Chen ZH. Dual targeting total saponins of Pulsatilla of natural polymer crosslinked gel beads with multiple therapeutic effects for ulcerative colitis. Eur J Pharm Biopharm 2024; 199:114309. [PMID: 38704102 DOI: 10.1016/j.ejpb.2024.114309] [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: 02/15/2024] [Revised: 04/18/2024] [Accepted: 05/01/2024] [Indexed: 05/06/2024]
Abstract
Oral colon targeted drug delivery system (OCTDDS) is desirable for the treatment of ulcerative colitis (UC). In this study, we designed a partially oxidized sodium alginate-chitosan crosslinked microsphere for UC treatment. Dissipative particle dynamics (DPD) was used to study the formation and enzyme response of gel beads from a molecular perspective. The formed gel beads have a narrow particle size distribution, a compact structure, low cytotoxicity and great colon targeting in vitro and in vivo. Animal experiments demonstrated that gel beads promoted colonic epithelial barrier integrity, decreased the level of pro-inflammatory factors, accelerated the recovery of intestinal microbial homeostasis in UC rats and restored the intestinal metabolic disorders. In conclusion, our gel bead is a promising approach for the treatment of UC and significant for the researches on the pathogenesis and treatment mechanism of UC.
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Affiliation(s)
- Min-Quan Zhang
- Jiangxi Province Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang 330013, PR China
| | - Liang-Hui Huang
- Jiangxi Province Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang 330013, PR China
| | - Min-Cheng Gong
- Jiangxi Pharmaceutical School, Nanchang 330001, PR China
| | - Wei-Man Hong
- Jiangxi Province Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang 330013, PR China
| | - Rong Xie
- Jiangxi Province Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang 330013, PR China
| | - Jin Wang
- Jiangxi Province Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang 330013, PR China
| | - Liang-Liang Zhou
- Jiangxi Province Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang 330013, PR China; Engineering Center of Jiangxi University for Fine Chemicals, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
| | - Zhen-Hua Chen
- Jiangxi Province Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang 330013, PR China.
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13
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Huang D, Wang Y, Xu C, Zou M, Ming Y, Luo F, Xu Z, Miao Y, Wang N, Lin Z, Weng Z. Colon-targeted hydroxyethyl starch-curcumin microspheres with high loading capacity ameliorate ulcerative colitis via alleviating oxidative stress, regulating inflammation, and modulating gut microbiota. Int J Biol Macromol 2024; 266:131107. [PMID: 38527677 DOI: 10.1016/j.ijbiomac.2024.131107] [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: 01/10/2024] [Revised: 03/08/2024] [Accepted: 03/21/2024] [Indexed: 03/27/2024]
Abstract
Curcumin (CUR) is a natural polyphenol that holds promise for treating ulcerative colitis (UC), yet oral administration of CUR exhibits limited bioavailability and existing formulations for oral delivery of CUR often suffer from unsatisfactory loading capacity. This study presents hydroxyethyl starch-curcumin microspheres (HC-MSs) with excellent CUR loading capacity (54.52 %), and the HC-MSs can further encapsulate anti-inflammatory drugs dexamethasone (DEX) to obtain a combination formulation (DHC-MSs) with high DEX loading capacity (19.91 %), for combination therapy of UC. The microspheres were successfully engineered, retaining the anti-oxidative and anti-inflammatory activities of parental CUR and demonstrating excellent biocompatibility and controlled release properties, notably triggered by α-amylase, facilitating targeted drug delivery to inflamed sites. In a mouse UC model induced by dextran sulfate sodium, the microspheres effectively accumulated in inflamed colons and both HC-MSs and DHC-MSs exhibited superior therapeutic efficacy in alleviating UC symptoms compared to free DEX. Moreover, mechanistic exploration uncovered the multifaceted therapeutic mechanisms of these formulations, encompassing anti-inflammatory actions, mitigation of spleen enlargement, and modulation of gut microbiota composition. These findings underscore the potential of HC-MSs and DHC-MSs as promising formulations for UC, with implications for advancing treatment modalities for various inflammatory bowel disorders.
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Affiliation(s)
- Da Huang
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian 350108, China
| | - Yongming Wang
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian 350108, China
| | - Chenlan Xu
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian 350108, China
| | - Minglang Zou
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian 350108, China
| | - Yangcan Ming
- Department of Pediatrics, Wuhan NO.1 Hospital, Wuhan, Hubei 430022, China
| | - Fang Luo
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian 350108, China; Ministry of Education Key Laboratory for Analytical Science of Food Safety and Biology, Fujian Provincial Key Laboratory of Analysis and Detection for Food Safety, College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China
| | - Zhenjin Xu
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian 350108, China
| | - Ying Miao
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian 350108, China
| | - Na Wang
- Department of Pediatrics, Wuhan NO.1 Hospital, Wuhan, Hubei 430022, China.
| | - Zhenyu Lin
- Ministry of Education Key Laboratory for Analytical Science of Food Safety and Biology, Fujian Provincial Key Laboratory of Analysis and Detection for Food Safety, College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China
| | - Zuquan Weng
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian 350108, China; Ministry of Education Key Laboratory for Analytical Science of Food Safety and Biology, Fujian Provincial Key Laboratory of Analysis and Detection for Food Safety, College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China.
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14
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Liu C, Qi X, Liu X, Sun Y, Mao K, Shen G, Ma Y, Li Q. Anti-inflammatory probiotics HF05 and HF06 synergistically alleviate ulcerative colitis and secondary liver injury. Food Funct 2024; 15:3765-3777. [PMID: 38506656 DOI: 10.1039/d3fo04419j] [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: 03/21/2024]
Abstract
Given the limited efficacy and adverse effects associated with conventional drugs, probiotics are emerging as a promising therapeutic strategy for mitigating the chronic nature of ulcerative colitis (UC) and its consequential secondary liver injury (SLI). Limosilactobacillus fermentum HF06 and Lactiplatibacillus plantarum HF05 are strains we screened with excellent anti-inflammatory and probiotic properties in vitro. In this study, the intervention of HF06 and HF05 in combination (MIXL) was found to be more effective in alleviating intestinal inflammation and secondary liver injury in UC mice compared to supplementing with the two strains individually. Results demonstrated that MIXL effectively attenuated colon shortening and weight loss, downregulated the expression of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 mRNA in the intestines, mitigated SLI, and augmented the enzymatic activities of SOD, CAT, and GSH-Px in the liver. MIXL enhances the intestinal barrier in UC mice, regulates the structure and composition of the gut microbiota, promotes the abundance of Lactobacillus, and suppresses the abundance of bacteria associated with inflammation and liver injury, including Clostridium_Sensu_Stricto_1, Escherichia, Shigella, Enterococcus, Corynebacterium, Desulfovibrio, and norank_f__Oscillospiraceae. This study demonstrated the synergistic effect of HF06 and HF05, providing a reliable foundation for the alleviation of UC.
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Affiliation(s)
| | - Xiaofen Qi
- Harbin Institute of Technology, Harbin, China.
| | - Xiaolin Liu
- Harbin Institute of Technology, Harbin, China.
| | - Yue Sun
- Harbin Institute of Technology, Harbin, China.
| | - Kaidong Mao
- Jiangsu HOWYOU Biotechnology Co., Ltd, Qidong, China
| | - Guiqi Shen
- Jiangsu HOWYOU Biotechnology Co., Ltd, Qidong, China
| | - Ying Ma
- Harbin Institute of Technology, Harbin, China.
| | - Qingming Li
- New Hope Dairy Company Limited, China.
- Sichuan Engineering Laboratory for High-quality Dairy Product Preparation and Quality Control Technology, China
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15
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Wu Q, Luo Y, Lu H, Xie T, Hu Z, Chu Z, Luo F. The Potential Role of Vitamin E and the Mechanism in the Prevention and Treatment of Inflammatory Bowel Disease. Foods 2024; 13:898. [PMID: 38540888 PMCID: PMC10970063 DOI: 10.3390/foods13060898] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 03/01/2024] [Accepted: 03/12/2024] [Indexed: 01/06/2025] Open
Abstract
Inflammatory bowel disease (IBD) includes ulcerative colitis and Crohn's disease, and it is a multifactorial disease of the intestinal mucosa. Oxidative stress damage and inflammation are major risk factors for IBD. Vitamin E has powerful antioxidant and anti-inflammatory effects. Our previous work and other investigations have shown that vitamin E has a positive effect on the prevention and treatment of IBD. In this paper, the source and structure of vitamin E and the potential mechanism of vitamin E's role in IBD were summarized, and we also analyzed the status of vitamin E deficiency in patients with IBD and the effect of vitamin E supplementation on IBD. The potential mechanisms by which vitamin E plays a role in the prevention and treatment of IBD include improvement of oxidative damage, enhancement of immunity, maintenance of intestinal barrier integrity, and suppression of inflammatory cytokines, modulating the gut microbiota and other relevant factors. The review will improve our understanding of the complex mechanism by which vitamin E inhibits IBD, and it also provides references for doctors in clinical practice and researchers in this field.
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Affiliation(s)
- Qi Wu
- Hunan Key Laboratory of Grain-Oil Deep Process and Quality Control, Hunan Key Laboratory of Forestry Edible Resources Safety and Processing, Central South University of Forestry and Technology, Changsha 410004, China; (Q.W.); (H.L.); (T.X.); (Z.H.); (Z.C.)
| | - Yi Luo
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, China;
| | - Han Lu
- Hunan Key Laboratory of Grain-Oil Deep Process and Quality Control, Hunan Key Laboratory of Forestry Edible Resources Safety and Processing, Central South University of Forestry and Technology, Changsha 410004, China; (Q.W.); (H.L.); (T.X.); (Z.H.); (Z.C.)
| | - Tiantian Xie
- Hunan Key Laboratory of Grain-Oil Deep Process and Quality Control, Hunan Key Laboratory of Forestry Edible Resources Safety and Processing, Central South University of Forestry and Technology, Changsha 410004, China; (Q.W.); (H.L.); (T.X.); (Z.H.); (Z.C.)
| | - Zuomin Hu
- Hunan Key Laboratory of Grain-Oil Deep Process and Quality Control, Hunan Key Laboratory of Forestry Edible Resources Safety and Processing, Central South University of Forestry and Technology, Changsha 410004, China; (Q.W.); (H.L.); (T.X.); (Z.H.); (Z.C.)
| | - Zhongxing Chu
- Hunan Key Laboratory of Grain-Oil Deep Process and Quality Control, Hunan Key Laboratory of Forestry Edible Resources Safety and Processing, Central South University of Forestry and Technology, Changsha 410004, China; (Q.W.); (H.L.); (T.X.); (Z.H.); (Z.C.)
| | - Feijun Luo
- Hunan Key Laboratory of Grain-Oil Deep Process and Quality Control, Hunan Key Laboratory of Forestry Edible Resources Safety and Processing, Central South University of Forestry and Technology, Changsha 410004, China; (Q.W.); (H.L.); (T.X.); (Z.H.); (Z.C.)
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16
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Liu W, Zeng H. IGF2BP2 attenuates intestinal epithelial cell ferroptosis in colitis by stabilizing m 6A-modified GPX4 mRNA. Cytokine 2024; 173:156388. [PMID: 38039694 DOI: 10.1016/j.cyto.2023.156388] [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: 08/14/2023] [Revised: 09/27/2023] [Accepted: 09/30/2023] [Indexed: 12/03/2023]
Abstract
BACKGROUND Ulcerative colitis (UC) is a chronic and uncontrolled inflammatory bowel disease. N6-methyladenine (m6A) is a reversible mRNA modification method. IGF2BP2 is an RNA-binding protein regulated by m6A methylation. However, understanding of m6A-related proteins in UC is limited. This study was to analyze the function and related mechanism of IGF2BP2 in UC. METHODS The UC models were established by dextran sulfate sodium (DSS) in NCM460 cells and mice. The expression of IGF2BP2 and GPX4 in UC were detected by qPCR and western blot. The effects of IGF2BP2 on inflammation, ferroptosis and colon injury were measured by gain- and loss-of-function experiments. This study conducted a clinical evaluation of mice using the Disease Activity Index score. The molecular mechanism of IGF2BP2 in ferroptosis were analyzed by m6A RNA methylation quantification kit, RNA immunoprecipitation-qPCR analysis, and RNA stability assay. RESULTS IGF2BP2 and GPX4 were under-expressed in DSS-treated UC. IGF2BP2 enhanced the stability of GPX4 mRNA modified by m6A. IGF2BP2 overexpression repressed the ROS, MDA, and iron levels but enhanced the GSH and GPX4 levels in DSS-triggered NCM460 cells, which were partially reversed by GPX4 silencing. In UC mice, IGF2BP2 high-expression ameliorated symptoms, Disease Activity Index score, pathological changes, inflammatory reaction, and ferroptosis, which were also partly neutralized by GPX4 inhibition. CONCLUSIONS IGF2BP2 augmented the GPX4 expression by the m6A modification to weaken UC progression via suppressing ferroptosis.
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Affiliation(s)
- Wei Liu
- Department of Pediatric Gastroenterology, Children's Hospital of The First People's Hospital of Chenzhou City, Chenzhou 423000, Hunan Province, PR China
| | - Hui Zeng
- Department of Pediatric Gastroenterology, Children's Hospital of The First People's Hospital of Chenzhou City, Chenzhou 423000, Hunan Province, PR China.
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17
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Eadon MT, Rosenman MB, Zhang P, Fulton CR, Callaghan JT, Holmes AM, Levy KD, Gupta SK, Haas DM, Vuppalanchi R, Benson EA, Kreutz RP, Tillman EM, Shugg T, Pierson RC, Gufford BT, Pratt VM, Zang Y, Desta Z, Dexter PR, Skaar TC. The INGENIOUS trial: Impact of pharmacogenetic testing on adverse events in a pragmatic clinical trial. THE PHARMACOGENOMICS JOURNAL 2023; 23:169-177. [PMID: 37689822 PMCID: PMC10805517 DOI: 10.1038/s41397-023-00315-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 08/20/2023] [Accepted: 08/23/2023] [Indexed: 09/11/2023]
Abstract
Adverse drug events (ADEs) account for a significant mortality, morbidity, and cost burden. Pharmacogenetic testing has the potential to reduce ADEs and inefficacy. The objective of this INGENIOUS trial (NCT02297126) analysis was to determine whether conducting and reporting pharmacogenetic panel testing impacts ADE frequency. The trial was a pragmatic, randomized controlled clinical trial, adapted as a propensity matched analysis in individuals (N = 2612) receiving a new prescription for one or more of 26 pharmacogenetic-actionable drugs across a community safety-net and academic health system. The intervention was a pharmacogenetic testing panel for 26 drugs with dosage and selection recommendations returned to the health record. The primary outcome was occurrence of ADEs within 1 year, according to modified Common Terminology Criteria for Adverse Events (CTCAE). In the propensity-matched analysis, 16.1% of individuals experienced any ADE within 1-year. Serious ADEs (CTCAE level ≥ 3) occurred in 3.2% of individuals. When combining all 26 drugs, no significant difference was observed between the pharmacogenetic testing and control arms for any ADE (Odds ratio 0.96, 95% CI: 0.78-1.18), serious ADEs (OR: 0.91, 95% CI: 0.58-1.40), or mortality (OR: 0.60, 95% CI: 0.28-1.21). However, sub-group analyses revealed a reduction in serious ADEs and death in individuals who underwent pharmacogenotyping for aripiprazole and serotonin or serotonin-norepinephrine reuptake inhibitors (OR 0.34, 95% CI: 0.12-0.85). In conclusion, no change in overall ADEs was observed after pharmacogenetic testing. However, limitations incurred during INGENIOUS likely affected the results. Future studies may consider preemptive, rather than reactive, pharmacogenetic panel testing.
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Affiliation(s)
- Michael T Eadon
- Indiana University School of Medicine, Department of Medicine, Indianapolis, IN, USA
| | - Marc B Rosenman
- Ann & Robert H. Lurie Children's Hospital of Chicago, and Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Pengyue Zhang
- Indiana University School of Medicine, Department of Biostatistics and Heath Data Science, Indianapolis, IN, USA
| | - Cathy R Fulton
- Luddy School of Informatics, Computing, and Engineering, Indianapolis, IN, 46202, USA
| | - John T Callaghan
- Indiana University School of Medicine, Department of Medicine, Indianapolis, IN, USA
| | - Ann M Holmes
- Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, IN, 46202, USA
| | - Kenneth D Levy
- Indiana University School of Medicine, Department of Medicine, Indianapolis, IN, USA
| | - Samir K Gupta
- Indiana University School of Medicine, Department of Medicine, Indianapolis, IN, USA
| | - David M Haas
- Indiana University School of Medicine, Department of Obstetrics and Gynecology, Indianapolis, IN, USA
| | - Raj Vuppalanchi
- Indiana University School of Medicine, Department of Medicine, Indianapolis, IN, USA
| | - Eric A Benson
- Indiana University School of Medicine, Department of Medicine, Indianapolis, IN, USA
| | - Rolf P Kreutz
- Indiana University School of Medicine, Department of Medicine, Indianapolis, IN, USA
| | - Emma M Tillman
- Indiana University School of Medicine, Department of Medicine, Indianapolis, IN, USA
| | - Tyler Shugg
- Indiana University School of Medicine, Department of Medicine, Indianapolis, IN, USA
| | - Rebecca C Pierson
- Indiana University School of Medicine, Department of Medicine, Indianapolis, IN, USA
- Indiana University School of Medicine, Department of Obstetrics and Gynecology, Indianapolis, IN, USA
- Community Fertility Specialty Care, Indianapolis, IN, USA
| | - Brandon T Gufford
- Indiana University School of Medicine, Department of Medicine, Indianapolis, IN, USA
| | - Victoria M Pratt
- Indiana University School of Medicine, Department of Medical and Molecular Genetics, Indianapolis, IN, USA
| | - Yong Zang
- Indiana University School of Medicine, Department of Biostatistics and Heath Data Science, Indianapolis, IN, USA
| | - Zeruesenay Desta
- Indiana University School of Medicine, Department of Medicine, Indianapolis, IN, USA
| | - Paul R Dexter
- Indiana University School of Medicine, Department of Medicine, Indianapolis, IN, USA
| | - Todd C Skaar
- Indiana University School of Medicine, Department of Medicine, Indianapolis, IN, USA.
- Indiana University School of Medicine, Department of Medical and Molecular Genetics, Indianapolis, IN, USA.
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Marsool MDM, Vora N, Marsool ADM, Pati S, Narreddy M, Patel P, Gadam S, Prajjwal P. Ulcerative colitis: Addressing the manifestations, the role of fecal microbiota transplantation as a novel treatment option and other therapeutic updates. Dis Mon 2023; 69:101606. [PMID: 37357103 DOI: 10.1016/j.disamonth.2023.101606] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/27/2023]
Abstract
The prevalence and incidence of Ulcerative Colitis (UC), a recurrent and remitting inflammatory condition, are rising. Any part of the colon may be affected, beginning with inflammation of the mucosa in the rectum and continuing proximally continuously. Bloody diarrhea, tenesmus, fecal urgency, and stomach pain are typical presenting symptoms. Many patients present with extraintestinal manifestations (EIMs) including musculoskeletal, ocular, renal, hepatobiliary, and dermatological presentation, among others. Most cases are treated with pharmacological therapy including mesalazine and glucocorticoids. Fecal microbiota transplantation (FMT) is a novel procedure that is increasingly being used to treat UC, however, its use yet remains controversial because of uncertain efficacy. FMT can lower gut permeability and consequently disease severity by boosting short-chain fatty acids production, helping in epithelial barrier integrity preservation. Upadacitinib (JAK Kinase inhibitor) is another newer treatment option, which is an FDA-approved drug that is being used to treat UC. This review article provides a comprehensive review of the EIMs of UC, the role of FMT along with various recent clinical trials pertaining to FMT as well as other diagnostic and therapeutic updates.
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Affiliation(s)
| | - Neel Vora
- B. J. Medical College, Ahmedabad, India
| | | | - Shefali Pati
- St George's University, School of Medicine, Grenada
| | | | - Parth Patel
- Pramukhswami Medical College, Karamsad, India
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19
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Carone M, Spalinger MR, Gaultney RA, Mezzenga R, Hlavačková K, Mookhoek A, Krebs P, Rogler G, Luciani P, Aleandri S. Temperature-triggered in situ forming lipid mesophase gel for local treatment of ulcerative colitis. Nat Commun 2023; 14:3489. [PMID: 37311749 DOI: 10.1038/s41467-023-39013-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 05/25/2023] [Indexed: 06/15/2023] Open
Abstract
Ulcerative colitis is a chronic inflammatory bowel disease that strongly affects patient quality of life. Side effects of current therapies necessitate new treatment strategies that maximise the drug concentration at the site of inflammation, while minimizing systemic exposure. Capitalizing on the biocompatible and biodegradable structure of lipid mesophases, we present a temperature-triggered in situ forming lipid gel for topical treatment of colitis. We show that the gel is versatile and can host and release drugs of different polarities, including tofacitinib and tacrolimus, in a sustained manner. Further, we demonstrate its adherence to the colonic wall for at least 6 h, thus preventing leakage and improving drug bioavailability. Importantly, we find that loading known colitis treatment drugs into the temperature-triggered gel improves animal health in two mouse models of acute colitis. Overall, our temperature-triggered gel may prove beneficial in ameliorating colitis and decreasing adverse effects associated with systemic application of immunosuppressive treatments.
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Affiliation(s)
- Marianna Carone
- Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Bern, Switzerland
| | - Marianne R Spalinger
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Robert A Gaultney
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
| | - Raffaele Mezzenga
- Laboratory of Food & Soft Materials, Institute of Food, Nutrition and Health, IFNH; Department for Health Sciences and Technology, D-HEST, ETH Zurich, Zurich, Switzerland
| | - Kristýna Hlavačková
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
| | - Aart Mookhoek
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
| | - Philippe Krebs
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland.
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
| | - Paola Luciani
- Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Bern, Switzerland.
| | - Simone Aleandri
- Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Bern, Switzerland.
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20
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Nieto-Veloza A, Hong S, Reeder M, Sula MJ, D'Souza DH, Zhong Q, Dia VP. Lunasin reduces the susceptibility of IL-10 deficient mice to inflammatory bowel disease and modulates the activation of the NLRP3 inflammasome. J Nutr Biochem 2023:109383. [PMID: 37209953 DOI: 10.1016/j.jnutbio.2023.109383] [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: 11/21/2022] [Revised: 02/21/2023] [Accepted: 05/15/2023] [Indexed: 05/22/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory condition that can cause severe damage to the gastrointestinal tract leading to lower quality of life and productivity. Our goal was to investigate the protective effect of the soy peptide lunasin in an in vivo model of susceptibility to IBD and to identify the potential mechanism of action in vitro. In IL-10 deficient mice, oral administration of lunasin reduced the number and frequency of mice exhibiting macroscopic signs of susceptibility to inflammation and significantly decreased levels of the pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-18 by up to 95%, 90%, 90%, and 47%, respectively, in different sections of the small and large intestines. Dose-dependent decrease of caspase-1, IL-1β, and IL-18 in LPS-primed and ATP-activated THP-1 human macrophages demonstrated the ability of lunasin to modulate the NLRP3 inflammasome. We demonstrated that lunasin can decrease susceptibility to IBD in genetically susceptible mice by exerting anti-inflammatory properties.
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Affiliation(s)
- Andrea Nieto-Veloza
- Department of Food Science, University of Tennessee Institute of Agriculture, 2510 River Dr., Knoxville, TN, 37996, USA.
| | - Shan Hong
- Department of Food Science, University of Tennessee Institute of Agriculture, 2510 River Dr., Knoxville, TN, 37996, USA.
| | - Matthew Reeder
- Department of Food Science, University of Tennessee Institute of Agriculture, 2510 River Dr., Knoxville, TN, 37996, USA.
| | - Mee-Ja Sula
- Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, 2407 River Dr., Knoxville, TN, 37996, USA.
| | - Doris H D'Souza
- Department of Food Science, University of Tennessee Institute of Agriculture, 2510 River Dr., Knoxville, TN, 37996, USA.
| | - Qixin Zhong
- Department of Food Science, University of Tennessee Institute of Agriculture, 2510 River Dr., Knoxville, TN, 37996, USA.
| | - Vermont P Dia
- Department of Food Science, University of Tennessee Institute of Agriculture, 2510 River Dr., Knoxville, TN, 37996, USA.
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21
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Antioxidative and Protective Effect of Morchella esculenta against Dextran Sulfate Sodium-Induced Alterations in Liver. Foods 2023; 12:foods12051115. [PMID: 36900632 PMCID: PMC10000998 DOI: 10.3390/foods12051115] [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: 02/02/2023] [Revised: 03/03/2023] [Accepted: 03/05/2023] [Indexed: 03/09/2023] Open
Abstract
Morchella esculenta is an edible mushroom with special flavor and high nutritional value for humans, primarily owing to its polysaccharide constituents. M. esculenta polysaccharides (MEPs) possess remarkable pharmaceutical properties, including antioxidant, anti-inflammatory, immunomodulatory, and anti-atherogenic activities. The aim of this study was to evaluate the in vitro and in vivo antioxidant potential of MEPs. In vitro activity was determined using free radical scavenging assays, whereas in vivo activity was evaluated through dextran sodium sulfate (DSS)-induced liver injury in mice with acute colitis. MEPs effectively scavenged 1,1-diphenyl-2-picrylhydrazyl and 2,2-azinobis-6-(3-ethylbenzothiazoline sulfonic acid) free radicals in a dose-dependent manner. Additionally, DSS-induced mice showed severe liver damage, cellular infiltration, tissue necrosis, and decreased antioxidant capacity. In contrast, intragastric administration of MEPs showed hepatoprotective effects against DSS-induced liver injury. MEPs remarkably elevated the expression levels of superoxide dismutase, glutathione peroxidase, and catalase. Additionally, it decreased malondialdehyde and myeloperoxidase levels in the liver. These results indicate that the protective effects of MEP against DSS-induced hepatic injury could rely on its ability to reduce oxidative stress, suppress inflammatory responses, and improve antioxidant enzyme activity in the liver. Therefore, MEPs could be explored as potential natural antioxidant agents in medicine or as functional foods to prevent liver injury.
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22
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Cao Y, Liu H, Teng Y, Zhang S, Zhu B, Xia X. Gut microbiota mediates the anti-colitis effects of polysaccharides derived from Rhopilema esculentum Kishinouye in mice. Food Funct 2023; 14:1989-2007. [PMID: 36723100 DOI: 10.1039/d2fo02712g] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Ulcerative colitis (UC) is closely associated with the disturbance of gut microbiota. Crude polysaccharide-rich extract from Rhopilema esculentum Kishinouye has been proven to alleviate dextran sulfate sodium (DSS)-triggered colitis. However, it remains unclear whether the polysaccharides from Rhopilema esculentum (REP) in the extract play a predominant role in ameliorating colitis and whether gut microbiota mediates the beneficial effect of REP. Herein, we aimed to investigate the anti-colitis effects of REP and its mechanisms and to explore the role of REP-modulated gut microbiota in alleviating colitis in mice. Oral REP supplementation ameliorated the symptoms, inflammatory responses, colonic damage and gut microbial dysbiosis in colitic mice. REP significantly enriched SCFA-producing bacteria such as Roseburia and probiotics such as Bifidobacterium and restored the level of SCFAs especially butyric acid and propionic acid. Next, we found that transplantation of microbiota from REP-treated mice alleviated DSS-induced acute colitis, evidenced by improved gut barrier integrity and lower inflammation compared with mice receiving microbiota from control mice. Notably, dramatically enriched Bifidobacterium, Faecalibaculum and SCFA-producing bacteria including Butyricicoccus and Roseburia were found in mice receiving microbiota from the REP-treated donor mice. Lastly, the protective effect of REP supplementation on colitis was abolished in the antibiotic-treated mice. Overall, our findings suggest that REP could alleviate DSS-induced colitis in mice by regulating the imbalance of the microbiome. The polysaccharides of Rhopilema esculentum Kishinouye have the potential to be developed into promising prebiotic agents for rectifying dysbiosis of gut microbiota and preventing UC.
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Affiliation(s)
- Yu Cao
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China. .,National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning 116034, China.
| | - Huanhuan Liu
- National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning 116034, China.
| | - Yue Teng
- National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning 116034, China.
| | - Siteng Zhang
- National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning 116034, China.
| | - Beiwei Zhu
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China. .,National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning 116034, China.
| | - Xiaodong Xia
- National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning 116034, China. .,College of Food Science and Engineering, Northwest A&F University, Yangling, Shannxi 712100, China
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23
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Lan K, Yang H, Zheng J, Hu H, Zhu T, Zou X, Hu B, Liu H. Poria cocos oligosaccharides ameliorate dextran sodium sulfate-induced colitis mice by regulating gut microbiota dysbiosis. Food Funct 2023; 14:857-873. [PMID: 36537246 DOI: 10.1039/d2fo03424g] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Poria cocos, a widely accepted function food in China, has multiple pharmacological activities. This study aimed to investigate the therapeutic effect and molecular mechanism of Poria cocos oligosaccharides (PCOs) against dextran sodium sulfate (DSS)-induced mouse colitis. In this study, BALB/c mice were treated with 3% (w/v) DSS for seven days to establish a colitis model. The results showed that oral administration of PCOs (200 mg per kg per day) significantly reversed the changes in the physiological indices in colitis mice, including body weight, disease activity index scores (DAI), spleen index, and colon length. From the qRT-PCR assay, it was observed that PCOs suppressed the mRNA expression of pro-inflammatory cytokines, such as Tnf-α, Il-1β, and Il-6. In addition, PCOs protected the intestinal barrier from damage by promoting the expression of mucins and tight junction proteins at both mRNA and protein levels. Upon 16S rDNA sequencing, it was observed that PCO treatment partly reversed the changes in the gut microbiota of colitis mice by selectively regulating the abundance of specific bacteria. And Odoribacter, Muribaculum, Desulfovibrio, Oscillibacter, Escherichia-Shigella, and Turicibacter might be the critical bacteria in improving colitis via PCOs. Finally, using antibiotic mixtures to destroy the intestinal bacteria, we documented that PCO fermentation broth (PCO FB) instead of PCOs prevented the occurrence of colitis in gut microbiota-depleted mice. In conclusion, PCOs showed a protective effect on colitis by reversing gut microbiota dysbiosis. Our study sheds light on the potential application of PCOs as a prebiotic for treating colitis.
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Affiliation(s)
- Ke Lan
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, P. R. China.
| | - Huabing Yang
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, P. R. China.
| | - Junping Zheng
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, P. R. China.
| | - Haiming Hu
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, P. R. China.
| | - Tianxiang Zhu
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, P. R. China.
| | - Xiaojuan Zou
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, P. R. China.
| | - Baifei Hu
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, P. R. China.
| | - Hongtao Liu
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, P. R. China.
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24
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Kong J, Xiang Q, Shi G, Xu Z, Ma X, Wang Y, Xuan Z, Xu F. Licorice protects against ulcerative colitis via the Nrf2/PINK1-mediated mitochondrial autophagy. Immun Inflamm Dis 2023; 11:e757. [PMID: 36705402 PMCID: PMC9795328 DOI: 10.1002/iid3.757] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 12/07/2022] [Accepted: 12/11/2022] [Indexed: 12/29/2022] Open
Abstract
PURPOSE Study of the effects and mechanisms of licorice in the treatment of ulcerative colitis (UC) from the perspective of mitochondrial autophagy. METHODS BALB/C mice were induced with 3% dextran sodium sulfate to build an animal model of UC. After 7 days of modeling, different doses of licorice were administered for 7 days. Hematoxylin and eosin staining is used to detect pathological changes in the colon. Mitochondrial membrane potentials and reactive oxygen species (ROS) contents were detected by flow cytometry, and autophagy of mitochondria was observed by transmission electron microscopy. Determination of inflammatory cytokines by enzyme-linked immunosorbent assay. The oxidizing factors are detected by the kits. Western blot analysis was used to detect expressions for nuclear factor called erythropoietin (Nrf2), pten-induced protein kinase 1 (PINK1), Parkin, HO-1, P62, and LC3. RESULTS Licorice improved the pathological condition of UC mice, increasing the mitochondrial membrane potential and decreasing the ROS content. Promotes the emergence of autophagosomes and autophagosomes. The contents of interleukin (IL)-1β, IL-6, IL-17, and tumor necrosis factor-alpha were downregulated, the contents of superoxide dismutase and glutathione peroxidase were upregulated and the contents of malondialdehyde were downregulated. In addition, licorice promotes the expression of Nrf2, PINK1, Parkin, HO-1, P62, and LC3. CONCLUSION Licorice was shown to reduce levels of inflammatory factors and oxidative stress in mice with UC, possibly by promoting mitochondrial autophagy through the activation of the Nrf2/PINK1 pathway.
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Affiliation(s)
- Jinrong Kong
- School of PharmacyAnhui University of Chinese MedicineHefeiPeople's Republic of China
- Anhui Province Key Laboratory of Chinese Medicinal FormulaHefeiPeople's Republic of China
| | - Qingzhen Xiang
- School of PharmacyAnhui University of Chinese MedicineHefeiPeople's Republic of China
- Anhui Province Key Laboratory of Chinese Medicinal FormulaHefeiPeople's Republic of China
| | - Gaoxiang Shi
- School of PharmacyAnhui University of Chinese MedicineHefeiPeople's Republic of China
- Anhui Province Key Laboratory of Chinese Medicinal FormulaHefeiPeople's Republic of China
| | - Zaiping Xu
- School of PharmacyAnhui University of Chinese MedicineHefeiPeople's Republic of China
- Anhui Province Key Laboratory of Chinese Medicinal FormulaHefeiPeople's Republic of China
| | - Xiaowen Ma
- School of PharmacyAnhui University of Chinese MedicineHefeiPeople's Republic of China
- Anhui Province Key Laboratory of Chinese Medicinal FormulaHefeiPeople's Republic of China
| | - Yunlai Wang
- School of PharmacyAnhui University of Chinese MedicineHefeiPeople's Republic of China
- Anhui Province Key Laboratory of Chinese Medicinal FormulaHefeiPeople's Republic of China
| | - Zihua Xuan
- School of PharmacyAnhui University of Chinese MedicineHefeiPeople's Republic of China
- Anhui Province Key Laboratory of Chinese Medicinal FormulaHefeiPeople's Republic of China
| | - Fan Xu
- School of PharmacyAnhui University of Chinese MedicineHefeiPeople's Republic of China
- Anhui Province Key Laboratory of Chinese Medicinal FormulaHefeiPeople's Republic of China
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25
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Li Z, Zhang S, Xu L, Fang X, Wan Y, Yu D, Guo Y. A tetrapeptide from maize combined with probiotics exerted strong anti-inflammatory effects and modulated gut microbiota in DSS-induced colitis mice. Food Funct 2022; 13:12602-12618. [PMID: 36373867 DOI: 10.1039/d2fo02678c] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by recurrent gastrointestinal inflammation caused by abnormal immune response, and patients usually have intestinal flora imbalance. At present, the pathogenesis of UC is not well understood, and it appears that there is chronic activation of the immune and inflammatory cascade in genetically susceptible individuals. Some food supplements such as specific peptides and probiotics have been investigated and shown the potential for the treatment of UC. The purpose of this study is to investigate the therapeutic effect and potential mechanism of tetrapeptide from maize (TPM) and probiotic treatment on dextran sulfate sodium (DSS)-induced UC in C57BL/6J mice. Our results indicated that the therapeutic effects of TPM and probiotics are positively associated with a reduction in pro-inflammatory cytokine levels and restoration of the gut microbiota. Treatment with TPM or probiotics effectively alleviated the adverse effects of UC, including weight loss, shortened colon length, and colon and kidney tissue damage in mice. Additionally, both TPM and probiotics significantly reduced pro-inflammatory cytokine levels and oxidative stress in UC mice, and the effect was more pronounced when both were used together. Moreover, co-treatment with TPM and probiotics increased the diversity of gut microbes in UC mice, reduced the ratio of Firmicutes to Bacteroidetes (F/B) and increased the abundance of bacterial species, including Muribaculaceae, Alistipes, Ligilactobacillus and Lactobacillus, and has been shown to be beneficial for a variety of pathological conditions.
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Affiliation(s)
- Zhiguo Li
- Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun, 130012, P. R. China.
| | - Shan Zhang
- Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun, 130012, P. R. China.
| | - Li Xu
- Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun, 130012, P. R. China.
| | - Xuexun Fang
- Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun, 130012, P. R. China.
| | - Youzhong Wan
- China-Japan Union Hospital of Jilin University, Jilin University, Changchun, China 130033, P. R. China
| | - Dahai Yu
- Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun, 130012, P. R. China.
| | - Yi Guo
- Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun, 130012, P. R. China.
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26
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Drug-Related Adverse Events Necessitating Treatment Discontinuation in Pediatric Inflammatory Bowel Disease Patients. J Pediatr Gastroenterol Nutr 2022; 75:731-736. [PMID: 36171635 PMCID: PMC9645537 DOI: 10.1097/mpg.0000000000003630] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
OBJECTIVES Inflammatory bowel disease (IBD) requires long-term drug therapy in most patients, posing a risk for adverse drug events with the need for discontinuation. In this study, we investigated adverse events (AE) necessitating drug discontinuation in pediatric and adolescent IBD patients. METHODS We used data prospectively collected from IBD patients below the age of 18 enrolled in the Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS), namely demographic variables, medical characteristics, drug treatments, and related AE. We analyzed the frequency, type, and risk factors for AE necessitating drug discontinuation. RESULTS A total of 509 pediatric IBD patients fulfilled the inclusion criteria of which 262 (51.5%) were diagnosed with Crohn disease (CD), 206 (40.5%) with ulcerative colitis (UC), and 41 (8%) with IBD-unclassified (IBD-U). In total, 132 (25.9%) presented with at least 1 drug-related AE that required drug cessation. Immunomodulators [methotrexate 29/120 (24.2%), azathioprine 57/372 (15.3%)] followed by tumor necrosis factor (TNF)-alpha antagonists [adalimumab 8/72 (11.1%), infliximab 22/227 (9.7%)] accounted for the highest proportions of AE necessitating treatment discontinuation. Treatment schemes with at least 3 concomitant drugs significantly amplified the risk for development of drug-related AE [odds ratio = 2.50, 95% confidence interval (1.50-4.17)] in all pediatric IBD patients. CONCLUSIONS Drug-related AE necessitating discontinuation are common in pediatric and adolescent IBD patients. Caution needs to be taken in the case of concomitant drug use.
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Pednekar DD, Liguori MA, Marques CNH, Zhang T, Zhang N, Zhou Z, Amoako K, Gu H. From Static to Dynamic: A Review on the Role of Mucus Heterogeneity in Particle and Microbial Transport. ACS Biomater Sci Eng 2022; 8:2825-2848. [PMID: 35696291 DOI: 10.1021/acsbiomaterials.2c00182] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Mucus layers (McLs) are on the front line of the human defense system that protect us from foreign abiotic/biotic particles (e.g., airborne virus SARS-CoV-2) and lubricates our organs. Recently, the impact of McLs on human health (e.g., nutrient absorption and drug delivery) and diseases (e.g., infections and cancers) has been studied extensively, yet their mechanisms are still not fully understood due to their high variety among organs and individuals. We characterize these variances as the heterogeneity of McLs, which lies in the thickness, composition, and physiology, making the systematic research on the roles of McLs in human health and diseases very challenging. To advance mucosal organoids and develop effective drug delivery systems, a comprehensive understanding of McLs' heterogeneity and how it impacts mucus physiology is urgently needed. When the role of airway mucus in the penetration and transmission of coronavirus (CoV) is considered, this understanding may also enable a better explanation and prediction of the CoV's behavior. Hence, in this Review, we summarize the variances of McLs among organs, health conditions, and experimental settings as well as recent advances in experimental measurements, data analysis, and model development for simulations.
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Affiliation(s)
- Dipesh Dinanath Pednekar
- Department of Chemistry, Chemical and Biomedical Engineering, University of New Haven, West Haven, Connecticut 06516, United States
| | - Madison A Liguori
- Department of Chemistry, Chemical and Biomedical Engineering, University of New Haven, West Haven, Connecticut 06516, United States
| | | | - Teng Zhang
- Department of Mechanical and Aerospace Engineering, Syracuse University, Syracuse, New York 13244, United States.,BioInspired Syracuse, Syracuse University, Syracuse, New York 13244, United States
| | - Nan Zhang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China
| | - Zejian Zhou
- Department of Electrical and Computer Engineering and Computer Science, University of New Haven, West Haven, Connecticut 06516, United States
| | - Kagya Amoako
- Department of Chemistry, Chemical and Biomedical Engineering, University of New Haven, West Haven, Connecticut 06516, United States
| | - Huan Gu
- Department of Chemistry, Chemical and Biomedical Engineering, University of New Haven, West Haven, Connecticut 06516, United States
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Hydrogen peroxide responsive covalent cyclodextrin framework for targeted therapy of inflammatory bowel disease. Carbohydr Polym 2022; 285:119252. [DOI: 10.1016/j.carbpol.2022.119252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 01/14/2022] [Accepted: 02/09/2022] [Indexed: 11/20/2022]
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Xia P, Hou T, Ma M, Li S, Jin H, Luo X, Li J, Geng F, Li B. Konjac oligosaccharides attenuate DSS-induced ulcerative colitis in mice: mechanistic insights. Food Funct 2022; 13:5626-5639. [PMID: 35506498 DOI: 10.1039/d1fo04004a] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
This study aims to explore the protective effect of konjac oligosaccharides (KOS) on inflammatory bowel disease in colitis mice. During the experimental period, mice were administered 200 mg kg-1 or 600 mg kg-1 KOS, 200 mg kg-1 sulfasalazine and a combination of KOS and sulfasalazine for 14 days. The mice were then treated with drinking water containing 2.5% DSS for 9 days, while the intervention of KOS and sulfasalazine continued. At the end of the experiment, the phenotype, pathological lesion of the colon, parameters of cytokines and gut microbiota were evaluated. The results showed that mice treated with KOS exhibited alleviated pathological lesion of the colon tissue and significantly increased expression of tight junction proteins (p < 0.05). The level of inflammatory cytokines in the colon tissue of the colitis mice tended to be normal. Moreover, the analysis of the gut microbiota revealed that the structures and composition of the intestinal microorganisms were also regulated by KOS treatment. The possible internal mechanism is that KOS down-regulates the abundance of pro-inflammatory bacteria (Proteobacteria, Campilobacterota and Clostridiaceae) and up-regulates the abundance of anti-inflammatory bacteria (Bifidobacteriaceae and Akkermansiaceae). These findings provide new insights into dietary management for patients with inflammatory bowel disease.
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Affiliation(s)
- Pengkui Xia
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China. .,Key Laboratory of Environment Correlative Dietology (Huazhong Agricultural University), Ministry of Education, Wuhan 430070, China
| | - Tao Hou
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China. .,Key Laboratory of Environment Correlative Dietology (Huazhong Agricultural University), Ministry of Education, Wuhan 430070, China
| | - Muyuan Ma
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China. .,Key Laboratory of Environment Correlative Dietology (Huazhong Agricultural University), Ministry of Education, Wuhan 430070, China
| | - Sha Li
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China. .,Key Laboratory of Environment Correlative Dietology (Huazhong Agricultural University), Ministry of Education, Wuhan 430070, China
| | - Hong Jin
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China. .,Key Laboratory of Environment Correlative Dietology (Huazhong Agricultural University), Ministry of Education, Wuhan 430070, China
| | - Xuan Luo
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China. .,Key Laboratory of Environment Correlative Dietology (Huazhong Agricultural University), Ministry of Education, Wuhan 430070, China
| | - Jing Li
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China. .,Key Laboratory of Environment Correlative Dietology (Huazhong Agricultural University), Ministry of Education, Wuhan 430070, China
| | - Fang Geng
- College of Food and Biological Engineering, Chengdu University, No. 2025 Chengluo Avenue, Chengdu, 610106, China
| | - Bin Li
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China. .,Key Laboratory of Environment Correlative Dietology (Huazhong Agricultural University), Ministry of Education, Wuhan 430070, China
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Phytochemicals targeting Toll-like receptors 4 (TLR4) in inflammatory bowel disease. Chin Med 2022; 17:53. [PMID: 35484567 PMCID: PMC9047385 DOI: 10.1186/s13020-022-00611-w] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 04/14/2022] [Indexed: 12/11/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a collective term for inflammatory diseases including Crohn's disease and ulcerative colitis. Toll-like receptor 4 (TLR4) is thought to play a key role in the pathogenesis of IBD. Inhibition of TLR4 has been recognized as an effective target for the treatment of IBD. Many phytochemicals have been shown to have potential as new drugs for the treatment of IBD. This review surveyed the available literature and reports which focused on the in vivo effects of phytochemicals targeting TLR4 in different models of IBD, and clarified the significance of TLR4 as a current therapeutic target for IBD. Based on our review, we have concluded that phytochemicals targeting TLR4 are potentially effective candidates for developing new therapeutic drugs against IBD.
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Advances in the colon-targeted chitosan based drug delivery systems for the treatment of inflammatory bowel disease. Carbohydr Polym 2022; 288:119351. [DOI: 10.1016/j.carbpol.2022.119351] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/09/2022] [Accepted: 03/09/2022] [Indexed: 12/21/2022]
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Bilotta S, Arbogast J, Schart N, Frei M, Lorentz A. Resveratrol Treatment Prevents Increase of Mast Cells in Both Murine OVA Enteritis and IL-10 -/- Colitis. Int J Mol Sci 2022; 23:ijms23031213. [PMID: 35163137 PMCID: PMC8836010 DOI: 10.3390/ijms23031213] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/11/2022] [Accepted: 01/19/2022] [Indexed: 02/07/2023] Open
Abstract
Mast cells are involved in allergic and other inflammatory diseases. The polyphenol resveratrol is known for its anti-inflammatory properties and may be used as nutraceutical in mast cell associated diseases. We analyzed the effect of resveratrol on mast cells in vivo in ovalbumin-induced allergic enteritis as well as experimental colitis in IL-10−/− mice which received resveratrol via drinking water. Treatment with resveratrol prevented the increase in mast cells in both allergic enteritis and chronic colitis in duodenum as well as in colon. Further, it delayed the onset of diseases symptoms and ameliorated diseases associated parameters such as tissue damage as well as inflammatory cell infiltration in affected colon sections. In addition to the findings in vivo, resveratrol inhibited IgE-dependent degranulation and expression of pro-inflammatory cytokines such as TNF-α in IgE/DNP-activated as well as in LPS-activated bone marrow-derived mast cells. These results indicate that resveratrol may be considered as an anti-allergic and anti-inflammatory plant-derived component for the prevention or treatment of mast cell-associated disorders of the gastrointestinal tract.
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Yuan D, Li C, Huang Q, Fu X, Dong H. Current advances in the anti-inflammatory effects and mechanisms of natural polysaccharides. Crit Rev Food Sci Nutr 2022; 63:5890-5910. [PMID: 35021901 DOI: 10.1080/10408398.2022.2025535] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic, multifactorial and inflammatory disease occurring in the colon tract. Bioactive polysaccharides from natural resources have attracted extensive attention due to their safety, accessibility and good bioactivities. In recent years, a variety of natural bioactive polysaccharides have been proven to possess anti-inflammatory effects on treating acute colitis. The objective of this review was to give an up-to-date review on the anti-inflammatory effects and mechanisms of natural polysaccharides on acute colitis. The anti-inflammatory effects of natural polysaccharides on acute colitis concerning clinical symptoms amelioration, colon tissue repairment, anti-oxidative stress alleviation, anti-inflammation, immune regulation, and gut microbiota modulation were comprehensively summarized. In addition, inducible murine models for assessing the anti-inflammatory effects of natural polysaccharides on acute colitis were also concluded. This review will offer the comprehensive understanding of anti-inflammatory mechanisms of natural polysaccharides in acute colitis, and render theoretical basis for the development and application of natural polysaccharides in drug and functional food.
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Affiliation(s)
- Dan Yuan
- SCUT-Zhuhai Institute of Modern Industrial Innovation, School of Food Science and Engineering, South China University of Technology, Guangzhou, China
| | - Chao Li
- SCUT-Zhuhai Institute of Modern Industrial Innovation, School of Food Science and Engineering, South China University of Technology, Guangzhou, China
- Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety, South China University of Technology, Guangzhou, China
| | - Qiang Huang
- SCUT-Zhuhai Institute of Modern Industrial Innovation, School of Food Science and Engineering, South China University of Technology, Guangzhou, China
| | - Xiong Fu
- SCUT-Zhuhai Institute of Modern Industrial Innovation, School of Food Science and Engineering, South China University of Technology, Guangzhou, China
- Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety, South China University of Technology, Guangzhou, China
| | - Hao Dong
- College of Light Industry and Food Sciences, Zhongkai University of Agriculture and Engineering, Guangzhou, China
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Gonzalez-Pujana A, Beloqui A, Javier Aguirre J, Igartua M, Santos-Vizcaino E, Maria Hernandez R. Mesenchymal stromal cells encapsulated in licensing hydrogels exert delocalized systemic protection against ulcerative colitis via subcutaneous xenotransplantation. Eur J Pharm Biopharm 2022; 172:31-40. [DOI: 10.1016/j.ejpb.2022.01.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 01/14/2022] [Accepted: 01/18/2022] [Indexed: 12/16/2022]
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Ficus pandurata Hance Inhibits Ulcerative Colitis and Colitis-Associated Secondary Liver Damage of Mice by Enhancing Antioxidation Activity. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:2617881. [PMID: 34966476 PMCID: PMC8710911 DOI: 10.1155/2021/2617881] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 11/06/2021] [Accepted: 11/10/2021] [Indexed: 12/11/2022]
Abstract
Inflammatory bowel disease (IBD), a global disease threatening human health, is commonly accompanied by secondary liver damage (SLD) mediated by the gut-liver axis. Oxidative stress acts a critical role in the onset of IBD, during which excessive oxidation would destroy the tight junctions between intestinal cells, promote proinflammatory factors to penetrate, and thereby damage the intestinal mucosa. Ficus pandurata Hance (FPH) is widely used for daily health care in South China. Our previous study showed that FPH protected acute liver damage induced by alcohol. However, there is no study reporting FPH treating ulcerative colitis (UC). This study is designed to investigate whether FPH could inhibit UC and reveal its potential mechanism. The results showed that FPH significantly alleviated the UC disease symptoms including the body weight loss, disease activity index (DAI), stool consistency changing, rectal bleeding, and colon length loss of UC mice induced by dextran sulfate sodium (DSS) and reversed the influences of DSS on myeloperoxidase (MPO) and diamine oxidase activity (DAO). FPH suppressed UC via inhibiting the TLR4/MyD88/NF-κB pathway and strengthened the gut barrier of mice via increasing the expressions of ZO-1 and occludin and enhancing the colonic antioxidative stress property by increasing the levels of T-SOD and GSH-Px and the expressions of NRF2, HO-1, and NQO1 and reducing MDA level and Keap1, p22-phox, and NOX2 expressions. Furthermore, FPH significantly inhibited SLD related to colitis by reducing the abnormal levels of the liver index, ALT, AST, and cytokines including TNFα, LPS, LBP, sCD14, and IL-18 in the livers, as well as decreasing the protein expressions of NLRP3, TNFα, LBP, CD14, TLR4, MyD88, NF-κB, and p-NF-κB, suggesting that FPH alleviated UC-related SLD via suppressing inflammation mediated by inhibiting the TLR4/MyD88/NF-κB pathway. Our study firstly investigates the anticolitis pharmacological efficacy of FPH, suggesting that it can be enlarged to treat colitis and colitis-associated liver diseases in humans.
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Rönnblom A, Ljunggren Ö, Karlbom U. Complications and adverse effects related to surgical and medical treatment in patients with inflammatory bowel disease in a prospectively recruited population-based cohort. Scand J Gastroenterol 2021; 56:1296-1303. [PMID: 34369245 DOI: 10.1080/00365521.2021.1961309] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Medical adverse effects and surgical complications have been reported during treatment of patients with inflammatory bowel diseases (IBDs). There is however a shortage of studies describing these in the same cohort of patients. AIM To describe medical adverse effects and surgical complications in a prospectively followed population-based cohort of patients followed for at least 10 years. METHODS All newly diagnosed patients with ulcerative colitis (UC) and Crohn's disease (CD) in the county of Uppsala between 2005 and 2009 were prospectively followed. At the end of 2019, the medical notes were scrutinised and all medical adverse effects and postoperative surgical complications were registered. RESULTS A total of 330 patients with UC and 153 patients with CD in all age groups were included in the cohort. Four hundred and forty-two of these (91.5%) could be followed for 10 years or until death. One hundred and twenty-two patients (26.9%) experienced one or more adverse effects during the pharmacological treatment, and 25 of these could be classified as serious. Fifty-seven malignancies were diagnosed during the observation time. Surgery was performed in 16/330 UC and 33/153 CD patients. Frequency of early postoperative complications was 31% for UC patients and 36% for CD patients. Most complications were minor but two patients were re-operated, two needed intensive care and one patient died postoperatively. CONCLUSIONS Adverse effects related to medical therapy were experienced by approximately every fourth patient, and by every third patient that was operated.
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Affiliation(s)
- Anders Rönnblom
- Section of Gastroenterology and Hepatology, Akademiska Hospital, Magtarmmottagningen, Uppsala, Sweden
| | - Östen Ljunggren
- Department of Medical Sciences, Uppsala University, Uppsala University Hospital, Uppsala, Sweden
| | - Urban Karlbom
- Department of Surgical Sciences, Uppsala University, University Hospital, Uppsala, Sweden
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Rogler G, Singh A, Kavanaugh A, Rubin DT. Extraintestinal Manifestations of Inflammatory Bowel Disease: Current Concepts, Treatment, and Implications for Disease Management. Gastroenterology 2021; 161:1118-1132. [PMID: 34358489 PMCID: PMC8564770 DOI: 10.1053/j.gastro.2021.07.042] [Citation(s) in RCA: 424] [Impact Index Per Article: 106.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 07/28/2021] [Accepted: 07/28/2021] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel diseases (IBDs) are systemic diseases that manifest not only in the gut and gastrointestinal tract, but also in the extraintestinal organs in many patients. The quality of life for patients with IBD can be substantially affected by these extraintestinal manifestations (EIMs). It is important to have knowledge of the prevalence, pathophysiology, and clinical presentation of EIMs in order to adapt therapeutic options to cover all aspects of IBD. EIMs can occur in up to 24% of patients with IBD before the onset of intestinal symptoms, and need to be recognized to initiate appropriate diagnostic procedures. EIMs most frequently affect joints, skin, or eyes, but can also affect other organs, such as the liver, lung, and pancreas. It is a frequent misconception that a successful therapy of the intestinal inflammation will be sufficient to treat EIMs satisfactorily in most patients with IBD. In general, peripheral arthritis, oral aphthous ulcers, episcleritis, or erythema nodosum can be associated with active intestinal inflammation and can improve on standard treatment of the intestinal inflammation. However, anterior uveitis, ankylosing spondylitis, and primary sclerosing cholangitis usually occur independent of disease flares. This review provides a comprehensive overview of epidemiology, pathophysiology, clinical presentation, and treatment of EIMs in IBD.
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Affiliation(s)
- Gerhard Rogler
- Department of Gastroenterology & Hepatology, Department of Medicine, Zurich University Hospital, Zurich, Switzerland
| | - Abha Singh
- University of California, San Diego, La Jolla, CA, USA
| | | | - David T. Rubin
- University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, USA
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Machine Learning Modeling from Omics Data as Prospective Tool for Improvement of Inflammatory Bowel Disease Diagnosis and Clinical Classifications. Genes (Basel) 2021; 12:genes12091438. [PMID: 34573420 PMCID: PMC8466305 DOI: 10.3390/genes12091438] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 08/21/2021] [Accepted: 09/14/2021] [Indexed: 12/14/2022] Open
Abstract
Research of inflammatory bowel disease (IBD) has identified numerous molecular players involved in the disease development. Even so, the understanding of IBD is incomplete, while disease treatment is still far from the precision medicine. Reliable diagnostic and prognostic biomarkers in IBD are limited which may reduce efficient therapeutic outcomes. High-throughput technologies and artificial intelligence emerged as powerful tools in search of unrevealed molecular patterns that could give important insights into IBD pathogenesis and help to address unmet clinical needs. Machine learning, a subtype of artificial intelligence, uses complex mathematical algorithms to learn from existing data in order to predict future outcomes. The scientific community has been increasingly employing machine learning for the prediction of IBD outcomes from comprehensive patient data-clinical records, genomic, transcriptomic, proteomic, metagenomic, and other IBD relevant omics data. This review aims to present fundamental principles behind machine learning modeling and its current application in IBD research with the focus on studies that explored genomic and transcriptomic data. We described different strategies used for dealing with omics data and outlined the best-performing methods. Before being translated into clinical settings, the developed machine learning models should be tested in independent prospective studies as well as randomized controlled trials.
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Bupropion Ameliorates Acetic Acid-Induced Colitis in Rat: the Involvement of the TLR4/NF-kB Signaling Pathway. Inflammation 2021; 43:1999-2009. [PMID: 32594336 DOI: 10.1007/s10753-020-01273-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Inflammatory bowel disease composed of ulcerative colitis and Crohn's disease is a disorder that may involve entire gastrointestinal tract. Its pathogenesis is mainly an immune-mediated inflammation. Recently, it has been indicated that bupropion possesses anti-inflammatory properties; hence, the objective of this experiment is the investigation of the anti-inflammatory influence of bupropion on colonic lesions that emerged following the intrarectal administration of acetic acid. Thirty-six male Wistar rats were allocated randomly into six groups, including control, acetic acid, dexamethasone (2 mg/kg), and bupropion (40, 80, and 160 mg/kg). Colitis was induced by intrarectal administration of acetic acid in all study groups except control group, and animals were treated by oral administration of dexamethasone and bupropion. While macroscopic and microscopic lesions were observed after colitis induction, administration of dexamethasone and bupropion 160 mg/kg led to the remarkable improvement in lesions. In addition, the expression of TLR4 and NF-ĸB was decreased after colitis induction; however, treatment with dexamethasone (2 mg/kg) and bupropion (160 mg/kg) resulted in a significant decrease in their expression. Regarding biochemical factors, following colitis induction, TNF-α level and MPO activity were increased; nevertheless, dexamethasone (2 mg/kg) and bupropion (160 mg/kg) decreased the TNF-α and MPO activity. In conclusion, bupropion exerts anti-inflammatory influence through suppressing the TLR4 and NF-ĸB expression in the rat model of acute colitis.
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Davoudi Z, Peroutka-Bigus N, Bellaire B, Jergens A, Wannemuehler M, Wang Q. Gut Organoid as a New Platform to Study Alginate and Chitosan Mediated PLGA Nanoparticles for Drug Delivery. Mar Drugs 2021; 19:md19050282. [PMID: 34065505 PMCID: PMC8161322 DOI: 10.3390/md19050282] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/17/2021] [Accepted: 05/18/2021] [Indexed: 12/12/2022] Open
Abstract
Intestinal organoids can be used as an ex vivo epithelial model to study different drug delivery effects on epithelial cells’ luminal surface. In this study, the impact of surface charge on the delivery of 5-ASA loaded PLGA nanoparticles into the lumen of organoids was investigated. Alginate and chitosan were used to coat the nanoparticles and provide negative and positive charges on the particles, respectively. The organoid growth and viability were not affected by the presence of either alginate- or chitosan-coated nanoparticles. It was shown that nanoparticles could be transported from the serosal side of the organoids to the lumen as the dye gradually accumulated in the lumen by day 2–3 after adding the nanoparticles to the Matrigel. By day 5, the dye was eliminated from the lumen of the organoids. It was concluded that the positively charged nanoparticles were more readily transported across the epithelium into the lumen. It may be attributed to the affinity of epithelial cells to the positive charge. Thus, the organoid can be utilized as an appropriate model to mimic the functions of the intestinal epithelium and can be used as a model to evaluate the benefits of nanoparticle-based drug delivery.
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Affiliation(s)
- Zahra Davoudi
- Department of Chemical and Biological Engineering, Iowa State University, Ames, IA 50011, USA;
| | - Nathan Peroutka-Bigus
- Department of Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, IA 50011, USA; (N.P.-B.); (B.B.); (M.W.)
| | - Bryan Bellaire
- Department of Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, IA 50011, USA; (N.P.-B.); (B.B.); (M.W.)
| | - Albert Jergens
- Department of Veterinary Clinical Sciences, Iowa State University, Ames, IA 50011, USA;
| | - Michael Wannemuehler
- Department of Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, IA 50011, USA; (N.P.-B.); (B.B.); (M.W.)
| | - Qun Wang
- Department of Chemical and Biological Engineering, Iowa State University, Ames, IA 50011, USA;
- Correspondence: ; Tel.: +1-515-294-4218
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Phytochemicals Targeting JAK-STAT Pathways in Inflammatory Bowel Disease: Insights from Animal Models. Molecules 2021; 26:molecules26092824. [PMID: 34068714 PMCID: PMC8126249 DOI: 10.3390/molecules26092824] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/07/2021] [Accepted: 05/07/2021] [Indexed: 12/18/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that consists of Crohn’s disease (CD) and ulcerative colitis (UC). Cytokines are thought to be key mediators of inflammation-mediated pathological processes of IBD. These cytokines play a crucial role through the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signaling pathways. Several small molecules inhibiting JAK have been used in clinical trials, and one of them has been approved for IBD treatment. Many anti-inflammatory phytochemicals have been shown to have potential as new drugs for IBD treatment. This review describes the significance of the JAK–STAT pathway as a current therapeutic target for IBD and discusses the recent findings that phytochemicals can ameliorate disease symptoms by affecting the JAK–STAT pathway in vivo in IBD disease models. Thus, we suggest that phytochemicals modulating JAK–STAT pathways are potential candidates for developing new therapeutic drugs, alternative medicines, and nutraceutical agents for the treatment of IBD.
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An Open-Label Tolerability and Actual-Use Human Factors Study of Etrolizumab Autoinjector in Healthy Volunteers. Adv Ther 2021; 38:2406-2417. [PMID: 33778928 PMCID: PMC8107167 DOI: 10.1007/s12325-021-01651-8] [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: 12/23/2020] [Accepted: 02/03/2021] [Indexed: 11/17/2022]
Abstract
Introduction Etrolizumab is a novel, dual-action, anti-β7 integrin antibody in development for patients with moderate to severe ulcerative colitis or Crohn’s disease. Phase 3 studies use a prefilled syringe (PFS) for etrolizumab administration. In parallel, an autoinjector (AI) is being developed to increase delivery options for patients if etrolizumab is approved. Here we describe the overall development strategy and detail the first-in-human study of this AI. Methods This open-label study of healthy volunteers evaluated the tolerability and usability of the etrolizumab AI under development. The primary endpoint was the proportion of participants with greater than mild pain following injection. Adverse events (AEs) and usage errors were also assessed. Results were reported by injection site (thigh vs abdomen) and needle training (experienced vs naive). Pharmacokinetic (PK) variability between participants was an exploratory endpoint. Results Thirty participants completed the study; 97% of them did not experience any pain greater than mild, and 50% did not experience any pain at all. Three usage errors were observed, one of which resulted in delivery of a partial dose of etrolizumab. No patterns of usage errors were observed. Mild injection site reactions (ISRs) were reported; all resolved by the end of the study. Participants injecting into the abdomen reported more ISRs than those injecting into the thigh; needle training did not influence AE incidence or severity. Conclusions Results from this first-in-human study demonstrate that single injections of etrolizumab 105 mg using an AI were well tolerated in healthy volunteers, with transient, mild pain and minimal usage errors. Results from this study also informed the design of a subsequent PK comparability study evaluating exposure of etrolizumab administered by either the PFS or the AI. Overall, the availability of an AI may provide an attractive option for patients desiring a convenient, easy-to-use delivery mechanism for etrolizumab. Trial Registration NCT02629744 Electronic supplementary material The online version of this article (10.1007/s12325-021-01651-8) contains supplementary material, which is available to authorized users.
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Zhang W, Tyrrell H, Ding HT, Pulley J, Boruvka A, Erickson R, Abouhossein M, Ravanello R, Tang MT. Comparable Pharmacokinetics, Safety, and Tolerability of Etrolizumab Administered by Prefilled Syringe or Autoinjector in a Randomized Trial in Healthy Volunteers. Adv Ther 2021; 38:2418-2434. [PMID: 33778929 PMCID: PMC8107163 DOI: 10.1007/s12325-021-01661-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 02/10/2021] [Indexed: 11/24/2022]
Abstract
Introduction Etrolizumab is a novel, dual-action anti-β7 integrin antibody studied in phase 3 trials in patients with inflammatory bowel disease. An autoinjector (AI) is being developed in parallel to complement the prefilled syringe with needle safety device (PFS-NSD) for subcutaneous (SC) administration in these trials. Here we demonstrate the comparable pharmacokinetics, tolerability, and safety of both devices. Methods This randomized, open-label, two-part study in healthy participants evaluated the comparability of etrolizumab exposure between the AI and the PFS-NSD. Part 1 (pilot) involved a small number of participants, and initial results were used to finalize the design of the larger part 2 (pivotal) study. In both parts, participants were randomly assigned to receive a single SC dose of etrolizumab 105 mg by AI or PFS-NSD. Randomization was stratified by body weight. Primary pharmacokinetic outcomes were Cmax, AUClast, and AUC0–inf. Results One hundred and eighty healthy participants (part 1, n = 30; part 2, n = 150) received a single SC dose of etrolizumab by AI or PFS-NSD. Primary pharmacokinetic results from part 1 supported modification of the part 2 study design. Results from part 2 demonstrated that etrolizumab exposure was equivalent between devices, with geometric mean ratios (GMRs) between AI and PFS-NSD of 102% (90% confidence interval [CI] 94.2–111) for Cmax, 98.0% (90% CI 89.3–107) for AUClast, and 97.6% (90% CI 88.6–107) for AUC0–inf. Median tmax and mean terminal t1/2 were also similar between devices. GMRs and 90% CIs of all primary pharmacokinetic parameters were fully contained within the predefined equivalence limits (80–125%). Conclusion This pharmacokinetic study demonstrated that single SC injections of etrolizumab 105 mg using an AI or a PFS-NSD resulted in equivalent etrolizumab exposure and similar safety and tolerability in healthy participants. Taken together, these results support the use of an AI for etrolizumab administration. Trial Registration NCT02996019.
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Huang Y, Xing K, Qiu L, Wu Q, Wei H. Therapeutic implications of functional tea ingredients for ameliorating inflammatory bowel disease: a focused review. Crit Rev Food Sci Nutr 2021; 62:5307-5321. [PMID: 33635174 DOI: 10.1080/10408398.2021.1884532] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic gastro-intestinal disorders of unknown etiology. There are several drugs approved for treating IBD patients with active disease, including first-line use of aminosalicylates, and secondary choices of immunomodulators and other therapies. These medications might manage disease symptoms, but have also shown significant side-effects in IBD patients. Tea is the second largest beverage in the world and its main active ingredients including tea polyphenols, polysaccharides and tea pigments have been shown promising anti-inflammatory and antioxidant properties. In this review, we summarize the influence of different tea varieties including green tea, black tea and dark tea as potential nutritional therapy for preventing and treating IBD, and discuss the mechanisms of tea ingredients involved in the regulation of oxidative stress, inflammation, signaling pathways, and gut microbiota that could benefit for IBD disease management. Our observation directs further basic and clinical investigations on tea polyphenols and their derivatives as novel IBD therapeutic agents.
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Affiliation(s)
- Yina Huang
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, Jiangxi, China
| | - Keyu Xing
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, Jiangxi, China
| | - Liang Qiu
- Department of Medical Translational Center, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, China
| | - Qinglong Wu
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA.,Texas Children's Microbiome Center, Texas Children's Hospital, Houston, Texas, USA
| | - Hua Wei
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, Jiangxi, China
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Comparative Study of Anti-Inflammatory Effect on DSS-Induced Ulcerative Colitis Between Novel Glycyrrhiza Variety and Official Compendia. APPLIED SCIENCES-BASEL 2021. [DOI: 10.3390/app11041545] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Glycyrrhizae radix (GR), a plant commonly referred to as licorice, is used as a medicine and food worldwide. However, the utilization of GR from wild areas has caused desertification and a depletion of natural resources. Environmental restrictions and low productivity have limited plant cultivation. For this reason, an improved Glycyrrhiza variety, Wongam (WG), in cultivation and quality has been developed by Korea Rural Development Administration. To evaluate the equivalence of efficacy, several comparative studies between already-registered species and new cultivars have been conducted. This study evaluated the anti-inflammatory effect of WG extracts in a dextran sulfate sodium (DSS)-induced colitis model, in comparison to that of GR extracts. WG extract significantly improved the clinical signs of DSS-induced ulcerative colitis, including disease activity index, body weight loss, and colon length shortening, which was equivalent to the effect of GR. Furthermore, the fecal microbiota was analyzed by terminal restriction fragment length polymorphism. The composition of the fecal microbiota did not show a specific pattern based on experimental groups; however, a tendency toward an increase in the proportion of Lactobacillales was observed. These findings showed an equivalence of efficacy and the possible utilization of WG as a medicinal resource with already-registered species.
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Hossen I, Hua W, Mehmood A, Raka RN, Jingyi S, Jian-Ming J, Min X, Shakoor A, Yanping C, Wang C, Junsong X. Glochidion ellipticum Wight extracts ameliorate dextran sulfate sodium-induced colitis in mice by modulating nuclear factor kappa-light-chain-enhancer of activated B cells signalling pathway. J Pharm Pharmacol 2021; 73:410-423. [PMID: 33793884 DOI: 10.1093/jpp/rgaa044] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 11/13/2020] [Indexed: 12/22/2022]
Abstract
OBJECTIVES Glochidion ellipticum Wight is a medicinal plant, rich in polyphenols, frequently used by the indigenous communities of Bangladesh and possess with multiple health benefits. It exerts anti-inflammatory and antidiarrheal properties, but the detailed chemical constituents are yet to be elucidated. METHODS Glochidion ellipticum extracts were analyzed using ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry and then tested by both lipopolysaccharide (LPS) induced inflammation of Raw 264.7 macrophage cells and dextran sulfate sodium (DSS) induced acute colitis model. Blood serum was taken for fluorescein isothiocyanate-dextran (FITC-dextran) measurement and tissue samples were used to perform histology, RT-PCR and Western blotting. KEY FINDINGS The extracts could lower the levels of nitric oxide (NO), reactive oxygen species (ROS) and pro-inflammatory cytokines significantly in LPS induced macrophage cells. The extracts could also reduce disease activity index (DAI) score, restore antioxidants and pro-oxidants and improve macroscopic and microscopic features of colonic tissues in DSS induced mice. Expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in protein level was markedly diminished (up to 51.21% and 71.11%, respectively) in the treatment groups compared to the model group of colitic mice. CONCLUSIONS Our findings suggested that G. ellipticum extracts ameliorate DSS colitis via blocking nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway, which make them to be potential candidates for further research against inflammation and colitis.
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Affiliation(s)
- Imam Hossen
- Beijing Technology and Business University, Beijing, China.,Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing, China.,Beijing Engineering and Technology Research Center of Food Additives, Beijing, China
| | - Wu Hua
- Beijing Technology and Business University, Beijing, China.,Beijing Key Lab of Plant Resource Research and Development, Beijing, China
| | - Arshad Mehmood
- Beijing Technology and Business University, Beijing, China.,Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing, China.,Beijing Engineering and Technology Research Center of Food Additives, Beijing, China
| | - Rifat Nowshin Raka
- Beijing Technology and Business University, Beijing, China.,Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing, China.,Beijing Engineering and Technology Research Center of Food Additives, Beijing, China
| | - Song Jingyi
- Beijing Technology and Business University, Beijing, China
| | - Jin Jian-Ming
- Beijing Technology and Business University, Beijing, China.,Beijing Key Lab of Plant Resource Research and Development, Beijing, China
| | - Xu Min
- Beijing Technology and Business University, Beijing, China.,Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing, China.,Beijing Engineering and Technology Research Center of Food Additives, Beijing, China
| | - Ashbala Shakoor
- Beijing Technology and Business University, Beijing, China.,Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing, China.,Beijing Laboratory for Food Quality and Safety, Beijing, China
| | - Cao Yanping
- Beijing Technology and Business University, Beijing, China.,Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing, China
| | - Chengtao Wang
- Beijing Technology and Business University, Beijing, China.,Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing, China.,Beijing Engineering and Technology Research Center of Food Additives, Beijing, China
| | - Xiao Junsong
- Beijing Technology and Business University, Beijing, China.,Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing, China.,Beijing Engineering and Technology Research Center of Food Additives, Beijing, China
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Shin SA, Joo BJ, Lee JS, Ryu G, Han M, Kim WY, Park HH, Lee JH, Lee CS. Phytochemicals as Anti-Inflammatory Agents in Animal Models of Prevalent Inflammatory Diseases. Molecules 2020; 25:E5932. [PMID: 33333788 PMCID: PMC7765227 DOI: 10.3390/molecules25245932] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/07/2020] [Accepted: 12/11/2020] [Indexed: 02/06/2023] Open
Abstract
Phytochemicals are known to have anti-inflammatory effects in vitro and in vivo, such as in inflammatory disease model systems. Inflammation is an essential immune response to exogenous stimuli such as infection and injury. Although inflammation is a necessary host-defense mechanism, chronic inflammation is associated with the continuous local or systemic release of inflammatory mediators, non-cytokine mediators, such as ROS and NO, and inflammatory cytokines are strongly implicated in the pathogenesis of various inflammatory disorders. Phytochemicals that exhibit anti-inflammatory mechanisms that reduce sustained inflammation could be therapeutic candidates for various inflammatory diseases. These phytochemicals act by modulating several main inflammatory signaling pathways, including NF-κB, MAPKs, STAT, and Nrf-2 signaling. Here, we discuss the characteristics of phytochemicals that possess anti-inflammatory activities in various chronic inflammatory diseases and review the molecular signaling pathways altered by these anti-inflammatory phytochemicals, with a focus on transcription factor pathways. Furthermore, to evaluate the phytochemicals as drug candidates, we translate the effective doses of phytochemicals in mice or rat disease models into the human-relevant equivalent and compare the human-relevant equivalent doses of several phytochemicals with current anti-inflammatory drugs doses used in different types of chronic inflammatory diseases.
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Affiliation(s)
- Seong Ah Shin
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju-daero, Jinju, Gyeongnam 52828, Korea; (S.A.S.); (B.J.J.); (J.S.L.); (G.R.); (M.H.)
| | - Byeong Jun Joo
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju-daero, Jinju, Gyeongnam 52828, Korea; (S.A.S.); (B.J.J.); (J.S.L.); (G.R.); (M.H.)
| | - Jun Seob Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju-daero, Jinju, Gyeongnam 52828, Korea; (S.A.S.); (B.J.J.); (J.S.L.); (G.R.); (M.H.)
| | - Gyoungah Ryu
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju-daero, Jinju, Gyeongnam 52828, Korea; (S.A.S.); (B.J.J.); (J.S.L.); (G.R.); (M.H.)
| | - Minjoo Han
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju-daero, Jinju, Gyeongnam 52828, Korea; (S.A.S.); (B.J.J.); (J.S.L.); (G.R.); (M.H.)
| | - Woe Yeon Kim
- Division of Applied Life Science (BK21), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Life Sciences (RILS), Gyeongsang National University, Jinju 52828, Korea;
| | - Hyun Ho Park
- College of Pharmacy, Chung-Ang University, Seoul 06974, Korea;
| | - Jun Hyuck Lee
- Research Unit of Cryogenic Novel Material, Korea Polar Research Institute, Incheon 21990, Korea;
- Department of Polar Sciences, University of Science and Technology, Incheon 21990, Korea
| | - Chang Sup Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju-daero, Jinju, Gyeongnam 52828, Korea; (S.A.S.); (B.J.J.); (J.S.L.); (G.R.); (M.H.)
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Chemical and biological characteristics of hydrolysate of crucian carp swim bladder: Focus on preventing ulcerative colitis. J Funct Foods 2020. [DOI: 10.1016/j.jff.2020.104256] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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Mishra R, Dhawan P, Srivastava AS, Singh AB. Inflammatory bowel disease: Therapeutic limitations and prospective of the stem cell therapy. World J Stem Cells 2020; 12:1050-1066. [PMID: 33178391 PMCID: PMC7596447 DOI: 10.4252/wjsc.v12.i10.1050] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 06/02/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD), consisting primarily of ulcerative colitis and Crohn’s disease, is a group of debilitating auto-immune disorders, which also increases the risk of colitis-associated cancer. However, due to the chronic nature of the disease and inconsistent treatment outcomes of current anti-IBD drugs (e.g., approximately 30% non-responders to anti-TNFα agents), and related serious side effects, about half of all IBD patients (in millions) turn to alternative treatment options. In this regard, mucosal healing is gaining acceptance as a measure of disease activity in IBD patients as recent studies have correlated the success of mucosal healing with improved prognosis. However, despite the increasing clinical realization of the significance of the concept of mucosal healing, its regulation and means of therapeutic targeting remain largely unclear. Here, stem-cell therapy, which uses hematopoietic stem cells or mesenchymal stem cells, remains a promising option. Stem cells are the pluripotent cells with ability to differentiate into the epithelial and/or immune-modulatory cells. The over-reaching concept is that the stem cells can migrate to the damaged areas of the intestine to provide curative help in the mucosal healing process. Moreover, by differentiating into the mature intestinal epithelial cells, the stem cells also help in restoring the barrier integrity of the intestinal lining and hence prevent the immunomodulatory induction, the root cause of the IBD. In this article, we elaborate upon the current status of the clinical management of IBD and potential role of the stem cell therapy in improving IBD therapy and patient’s quality of life.
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Affiliation(s)
- Rangnath Mishra
- Global Institute of Stem Cell Therapy and Research, San Diego, CA 92122, United States
| | - Punita Dhawan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68118, United States
- Fred and Pamela Buffett Cancer Center, Omaha, NE 68118, United States
- VA Nebraska-Western Iowa Health Care System, Omaha, NE 68118, United States
| | - Anand S Srivastava
- Global Institute of Stem Cell Therapy and Research, San Diego, CA 92122, United States
| | - Amar B Singh
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68118, United States
- Fred and Pamela Buffett Cancer Center, Omaha, NE 68118, United States
- VA Nebraska-Western Iowa Health Care System, Omaha, NE 68118, United States
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50
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Plaza-Oliver M, Beloqui A, Santander-Ortega MJ, Castro-Vázquez L, Rodríguez-Robledo V, Arroyo-Jiménez MM, Préat V, Lozano MV. Ascorbyl-dipalmitate-stabilised nanoemulsions as a potential localised treatment of inflammatory bowel diseases. Int J Pharm 2020; 586:119533. [PMID: 32534160 DOI: 10.1016/j.ijpharm.2020.119533] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 06/05/2020] [Accepted: 06/06/2020] [Indexed: 12/19/2022]
Abstract
Current efforts on inflammatory bowel diseases (IBD) treatment are focused on strategies for localised drug delivery at the intestinal mucosa. Despite the potential of curcumin (CC) for IBD treatment, its low solubility and stability limit its application. Thus, the design of nanocarriers that focus CC delivery at the intestinal epithelium is an area of interest. This work proposes α-tocopherol nanoemulsions (NE) stabilised by ascorbyl-2,6-dipalmitate (ADP) as intestinal CC-carriers. The antioxidant capacity of α-tocopherol and ADP could have a synergistic effect on IBD-affected tissues, characterised by an oxidative environment. We obtained nanoemulsions (NE-ADP) with size below 200 nm, negative surface charge, stable in gastrointestinal media and no toxic in the Caco-2 cell model. Intracellular retention of NE-ADP in Caco-2 cells was observed by confocal microscopy. The extremely low Papp values obtained for CC and α-tocopherol indicated the lack of transport across the Caco-2 monolayer. Control nanoemulsion stabilised by lecithin (NE-L) was greatly transported across the Caco-2 cells monolayer, confirming the relevance of ADP on the cellular retention of NE-ADP. The therapeutic potential of NE-ADP was shown by the significant decrease of intracellular ROS levels. Altogether, these results indicate the potential of NE-ADP as a novel approach for the treatment of IBD.
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Affiliation(s)
- M Plaza-Oliver
- Cellular Neurobiology and Molecular Chemistry of the Central Nervous System Group, Faculty of Pharmacy, Spain; Regional Centre of Biomedical Research (CRIB), University of Castilla-La Mancha (UCLM), Albacete 02008, Spain
| | - A Beloqui
- Université Catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Brussels 1200, Belgium
| | - M J Santander-Ortega
- Cellular Neurobiology and Molecular Chemistry of the Central Nervous System Group, Faculty of Pharmacy, Spain; Regional Centre of Biomedical Research (CRIB), University of Castilla-La Mancha (UCLM), Albacete 02008, Spain
| | - L Castro-Vázquez
- Cellular Neurobiology and Molecular Chemistry of the Central Nervous System Group, Faculty of Pharmacy, Spain; Regional Centre of Biomedical Research (CRIB), University of Castilla-La Mancha (UCLM), Albacete 02008, Spain
| | - V Rodríguez-Robledo
- Cellular Neurobiology and Molecular Chemistry of the Central Nervous System Group, Faculty of Pharmacy, Spain; Regional Centre of Biomedical Research (CRIB), University of Castilla-La Mancha (UCLM), Albacete 02008, Spain
| | - M M Arroyo-Jiménez
- Cellular Neurobiology and Molecular Chemistry of the Central Nervous System Group, Faculty of Pharmacy, Spain; Regional Centre of Biomedical Research (CRIB), University of Castilla-La Mancha (UCLM), Albacete 02008, Spain
| | - V Préat
- Université Catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Brussels 1200, Belgium.
| | - M V Lozano
- Cellular Neurobiology and Molecular Chemistry of the Central Nervous System Group, Faculty of Pharmacy, Spain; Regional Centre of Biomedical Research (CRIB), University of Castilla-La Mancha (UCLM), Albacete 02008, Spain.
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