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Yazlık MO, Özkan H, Vural SA, Kaya U, Müştak İB, Mutluer Altınbaş İ, Tunç AS, Özöner Ö, Altınbaş YF, Alpler K, Vural MR. Pyometra alters uterine aquaporins related with lipopolysaccharide concentrations and antioxidant enzyme activities in bitches. Anim Reprod Sci 2024; 271:107621. [PMID: 39471705 DOI: 10.1016/j.anireprosci.2024.107621] [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: 07/27/2024] [Revised: 09/24/2024] [Accepted: 10/20/2024] [Indexed: 11/01/2024]
Abstract
Pyometra is a common life-threatening inflammatory disease with a complex etiopathogenesis that develops during the diestrus stage and can be observed in elderly intact bitches. The present study evaluated five aquaporin (AQP1, AQP2, AQP3, AQP5, and AQP9) transcript abundances and immunolocalization in the uterine tissue, and investigated their relationship with uterine tissue and blood lipopolysaccharide (LPS) concentration, superoxide dismutase (SOD) and glutathione peroxidase (GPX) activity, and nitric oxide (NO) production in dogs suffering from pyometra. The study sampled 36 client-owned intact bitches from different breeds, of which 24 cases were diagnosed with pyometra. Twelve of these bitches in the diestrus stage that presented for elective ovariohysterectomy were used as the control group. Blood samples were collected into tubes without anticoagulant for serum progesterone, LPS concentration, and antioxidant activities at the time of diagnosis. Bacteriological and tissue samples from the uteri were collected after the ovariohysterectomy. The tissue samples were used to determine antioxidant activity, and hormone and toxin concentrations. Transcript abundance of uterine AQPs were determined by qPCR, and their presence and localization were determined by by immunohistochemistry. For all pyometra samples, the bacteria isolated from the uterine swabs were Escherichia coli. Compared to the control group, AQP1, AQP2, and AQP5 were downregulated more than 2-fold, whereas AQP9 was upregulated nearly 3-fold and AQP3 was upregulated more than 4-fold in the pyometra affected uteri (P<0.05). Uterine AQP1 was moderately negatively correlated with serum LPS concentration (r=-0.568, P<0.01) and tissue NO production (r=-0.407, P<0.05). AQP5 was positively correlated with serum SOD activity (r=0.485, P<0.05) and negatively correlated with serum LPS concentration (r=-0.512, P<0.05). AQP9 was negatively correlated with tissue SOD and serum GPx activity. This is the first study to identify AQP9 transcript abundance and immunolocalization in canine uterine tissue. Uterine AQP1, AQP2, AQP3, AQP5, and AQP9 transcript abundances were altered in spontaneously developed canine pyometra while AQP transcript abundance was negatively related to serum toxin concentration, NO production, and antioxidant enzyme activity. Further studies should be conducted to determine the role of altered abundances of AQPs transcripts in pyometra pathogenesis.
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Affiliation(s)
- Murat Onur Yazlık
- Ankara University, Faculty of Veterinary Medicine, Department of Obstetrics and Gynecology, Ankara 06110, Turkiye.
| | - Hüseyin Özkan
- Hatay Mustafa Kemal University, Faculty of Veterinary Medicine, Department of Genetics, Hatay 31060, Turkiye.
| | - Sevil Atalay Vural
- Ankara University, Faculty of Veterinary Medicine, Department of Pathology, Ankara 06110, Turkiye.
| | - Ufuk Kaya
- Hatay Mustafa Kemal University, Faculty of Veterinary Medicine, Department of Biostatistics, Hatay 31060, Turkiye.
| | - İnci Başak Müştak
- Ankara University Faculty of Veterinary Medicine Department of Microbiology, Ankara 06110, Turkiye.
| | - İpek Mutluer Altınbaş
- Ankara University, Faculty of Veterinary Medicine, Department of Obstetrics and Gynecology, Ankara 06110, Turkiye; Ankara University Graduate School of Health Sciences, Ankara 06110, Turkiye.
| | - Arda Selin Tunç
- Ankara University, Faculty of Veterinary Medicine, Department of Pathology, Ankara 06110, Turkiye.
| | - Özgür Özöner
- Siirt University, Faculty of Veterinary Medicine, Department of Pathology, Siirt 56100, Turkiye.
| | - Yunus Furkan Altınbaş
- Ankara University, Faculty of Veterinary Medicine, Department of Obstetrics and Gynecology, Ankara 06110, Turkiye; Ankara University Graduate School of Health Sciences, Ankara 06110, Turkiye.
| | - Kamil Alpler
- Ankara University, Faculty of Veterinary Medicine, Department of Pathology, Ankara 06110, Turkiye; Ankara University Graduate School of Health Sciences, Ankara 06110, Turkiye.
| | - Mehmet Rıfat Vural
- Ankara University, Faculty of Veterinary Medicine, Department of Obstetrics and Gynecology, Ankara 06110, Turkiye.
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Vastrad B, Vastrad C. Screening and identification of key biomarkers associated with endometriosis using bioinformatics and next-generation sequencing data analysis. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2024; 25:116. [DOI: 10.1186/s43042-024-00572-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 08/23/2024] [Indexed: 01/04/2025] Open
Abstract
Abstract
Background
Endometriosis is a common cause of endometrial-type mucosa outside the uterine cavity with symptoms such as painful periods, chronic pelvic pain, pain with intercourse and infertility. However, the early diagnosis of endometriosis is still restricted. The purpose of this investigation is to identify and validate the key biomarkers of endometriosis.
Methods
Next-generation sequencing dataset GSE243039 was obtained from the Gene Expression Omnibus database, and differentially expressed genes (DEGs) between endometriosis and normal control samples were identified. After screening of DEGs, gene ontology (GO) and REACTOME pathway enrichment analyses were performed. Furthermore, a protein–protein interaction (PPI) network was constructed and modules were analyzed using the Human Integrated Protein–Protein Interaction rEference database and Cytoscape software, and hub genes were identified. Subsequently, a network between miRNAs and hub genes, and network between TFs and hub genes were constructed using the miRNet and NetworkAnalyst tool, and possible key miRNAs and TFs were predicted. Finally, receiver operating characteristic curve analysis was used to validate the hub genes.
Results
A total of 958 DEGs, including 479 upregulated genes and 479 downregulated genes, were screened between endometriosis and normal control samples. GO and REACTOME pathway enrichment analyses of the 958 DEGs showed that they were mainly involved in multicellular organismal process, developmental process, signaling by GPCR and muscle contraction. Further analysis of the PPI network and modules identified 10 hub genes, including vcam1, snca, prkcb, adrb2, foxq1, mdfi, actbl2, prkd1, dapk1 and actc1. Possible target miRNAs, including hsa-mir-3143 and hsa-mir-2110, and target TFs, including tcf3 (transcription factor 3) and clock (clock circadian regulator), were predicted by constructing a miRNA-hub gene regulatory network and TF-hub gene regulatory network.
Conclusions
This investigation used bioinformatics techniques to explore the potential and novel biomarkers. These biomarkers might provide new ideas and methods for the early diagnosis, treatment and monitoring of endometriosis.
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Muro P, Zhang L, Li S, Zhao Z, Jin T, Mao F, Mao Z. The emerging role of oxidative stress in inflammatory bowel disease. Front Endocrinol (Lausanne) 2024; 15:1390351. [PMID: 39076514 PMCID: PMC11284038 DOI: 10.3389/fendo.2024.1390351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 06/19/2024] [Indexed: 07/31/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic immune-mediated condition that affects the digestive system and includes Crohn's disease (CD) and ulcerative colitis (UC). Although the exact etiology of IBD remains uncertain, dysfunctional immunoregulation of the gut is believed to be the main culprit. Amongst the immunoregulatory factors, reactive oxygen species (ROS) and reactive nitrogen species (RNS), components of the oxidative stress event, are produced at abnormally high levels in IBD. Their destructive effects may contribute to the disease's initiation and propagation, as they damage the gut lining and activate inflammatory signaling pathways, further exacerbating the inflammation. Oxidative stress markers, such as malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and serum-free thiols (R-SH), can be measured in the blood and stool of patients with IBD. These markers are elevated in patients with IBD, and their levels correlate with the severity of the disease. Thus, oxidative stress markers can be used not only in IBD diagnosis but also in monitoring the response to treatment. It can also be targeted in IBD treatment through the use of antioxidants, including vitamin C, vitamin E, glutathione, and N-acetylcysteine. In this review, we summarize the role of oxidative stress in the pathophysiology of IBD, its diagnostic targets, and the potential application of antioxidant therapies to manage and treat IBD.
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Affiliation(s)
- Peter Muro
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Li Zhang
- Nanjing Lishui People’s Hospital, Zhongda Hospital, Southeast University, Nanjing, China
| | - Shuxuan Li
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Zihan Zhao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Tao Jin
- Department of Gastrointestinal and Endoscopy, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Fei Mao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Zhenwei Mao
- The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang City, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, China
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Jelinsky S, Lee I, Monetti M, Breitkopf S, Martz F, Kongala R, Culver J, Vo V, Xue L, Gieseck R, Dickinson C, Kasaian M, Lord JD. Proteomic Differences in Colonic Epithelial Cells in Ulcerative Colitis Have an Epigenetic Basis. GASTRO HEP ADVANCES 2024; 3:830-841. [PMID: 39280905 PMCID: PMC11401595 DOI: 10.1016/j.gastha.2024.04.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 04/30/2024] [Indexed: 09/18/2024]
Abstract
Background and Aims The colonic epithelium serves as both a barrier to lumenal contents and a gatekeeper of inflammatory responses. In ulcerative colitis (UC), epithelial dysfunction is a core feature, but little is known about the cellular changes that may underlie disease pathology. We therefore evaluated how the chromatin epigenetics and proteome of epithelial cells differs between health and UC. Methods We sorted live CD326+ epithelial cells from colon biopsies of healthy control (HC) screening colonoscopy recipients and from inflamed or uninflamed colon segments of UC patients on no biologic nor immunomodulator therapy (n = 5-7 subjects per group). Cell lysates were analyzed by proteomic evaluation and nuclei were analyzed for open chromatin with assay for transposase-accessible chromatin using sequencing. Results Proteins most highly elevated in inflamed UC biopsies relative to HC were those encoded by the HLA-DRA (P = 3.1 × 10-33) and CD74 (P = 1.6 × 10-27), genes associated with antigen presentation, and the antimicrobial dual oxidase 2 (DUOX2) (P = 3.2 × 10-28) and lipocalin-2 (P = 2.2 × 10-26) genes. Conversely, the water channel aquaporin 8 was strikingly less common with inflammation (P = 1.9 × 10-18). Assay for transposase-accessible chromatin using sequencing revealed more open chromatin around the aquaporin 8 gene in HCs (P = 2.0 × 10-2) and more around the DUOX2/DUOXA2 locus in inflamed UC colon (P = 5.7 × 10-4), suggesting an epigenetic basis for differential protein expression by epithelial cells in health and disease. Conclusion Numerous differences exist between the proteome and chromatin of colonic epithelial cells in UC patients and HCs, some of which correlate to suggest specific epigenetic mechanisms regulating the epithelial proteome.
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Affiliation(s)
- Scott Jelinsky
- Department of Inflammation and Immunology, Pfizer, Cambridge, Massachusetts
| | - Isac Lee
- Department of Inflammation and Immunology, Pfizer, Cambridge, Massachusetts
| | - Mara Monetti
- Internal Medicine Research Unit, Pfizer, Cambridge, Massachusetts
| | | | - Flora Martz
- Translational Research Program, Benaroya Research Institute, Seattle, Washington
| | - Ramya Kongala
- Translational Research Program, Benaroya Research Institute, Seattle, Washington
| | - Jeffrey Culver
- Internal Medicine Research Unit, Pfizer, Cambridge, Massachusetts
| | - Vanessa Vo
- Internal Medicine Research Unit, Pfizer, Cambridge, Massachusetts
| | - Liang Xue
- Machine Learning and Computational Sciences, Early Clinical Development, Pfizer, Cambridge, Massachusetts
| | - Richard Gieseck
- Department of Inflammation and Immunology, Pfizer, Cambridge, Massachusetts
| | - Caitlyn Dickinson
- Department of Inflammation and Immunology, Pfizer, Cambridge, Massachusetts
| | - Marion Kasaian
- Department of Inflammation and Immunology, Pfizer, Cambridge, Massachusetts
| | - James D Lord
- Translational Research Program, Benaroya Research Institute, Seattle, Washington
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Islam MR, Akash S, Jony MH, Alam MN, Nowrin FT, Rahman MM, Rauf A, Thiruvengadam M. Exploring the potential function of trace elements in human health: a therapeutic perspective. Mol Cell Biochem 2023; 478:2141-2171. [PMID: 36637616 DOI: 10.1007/s11010-022-04638-3] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 12/08/2022] [Indexed: 01/14/2023]
Abstract
A trace element, known as a minor element, is a chemical element whose concentration is very low. They are divided into essential and non-essential classes. Numerous physiological and metabolic processes in both plants and animals require essential trace elements. These essential trace elements are so directly related to the metabolic and physiologic processes of the organism that either their excess or deficiency can result in severe bodily malfunction or, in the worst situations, death. Elements can be found in nature in various forms and are essential for the body to carry out its varied functions. Trace elements are crucial for biological, chemical, and molecular cell activity. Nutritional deficits can lead to weakened immunity, increased susceptibility to oral and systemic infections, delayed physical and mental development, and lower productivity. Trace element enzymes are involved in many biological and chemical processes. These compounds act as co-factors for a number of enzymes and serve as centers for stabilizing the structures of proteins and enzymes, allowing them to mediate crucial biological processes. Some trace elements control vital biological processes by attaching to molecules on the cell membrane's receptor site or altering the structure of the membrane to prevent specific molecules from entering the cell. Some trace elements are engaged in redox reactions. Trace elements have two purposes. They are required for the regular stability of cellular structures, but when lacking, they might activate alternate routes and induce disorders. Therefore, thoroughly understanding these trace elements is essential for maintaining optimal health and preventing disease.
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Affiliation(s)
- Md Rezaul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, 1207, Dhaka, Bangladesh
| | - Shopnil Akash
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, 1207, Dhaka, Bangladesh
| | - Maruf Hossain Jony
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, 1207, Dhaka, Bangladesh
| | - Md Noor Alam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, 1207, Dhaka, Bangladesh
| | - Feana Tasmim Nowrin
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, 1207, Dhaka, Bangladesh
| | - Md Mominur Rahman
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, 1207, Dhaka, Bangladesh
| | - Abdur Rauf
- Department of Chemistry, University of Swabi, Anbar, Khyber Pakhtunkhwa, Pakistan.
| | - Muthu Thiruvengadam
- Department of Applied Bioscience, College of Life and Environmental Sciences, Konkuk University, Seoul, 05029, South Korea.
- Department of Microbiology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Science, Chennai, 600077, Tamil Nadu, India.
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Wu J, Xing L, Zheng Y, Yu Y, Wu R, Liu X, Li L, Huang Y. Disease-specific protein corona formed in pathological intestine enhances the oral absorption of nanoparticles. Acta Pharm Sin B 2023; 13:3876-3891. [PMID: 37719377 PMCID: PMC10501873 DOI: 10.1016/j.apsb.2023.02.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 01/25/2023] [Accepted: 02/06/2023] [Indexed: 03/06/2023] Open
Abstract
Protein corona (PC) has been identified to impede the transportation of intravenously injected nanoparticles (NPs) from blood circulation to their targeted sites. However, how intestinal PC (IPC) affects the delivery of orally administered NPs are still needed to be elucidated. Here, we found that IPC exerted "positive effect" or "negative effect" depending on different pathological conditions in the gastrointestinal tract. We prepared polystyrene nanoparticles (PS) adsorbed with different IPC derived from the intestinal tract of healthy, diabetic, and colitis rats (H-IPC@PS, D-IPC@PS, C-IPC@PS). Proteomics analysis revealed that, compared with healthy IPC, the two disease-specific IPC consisted of a higher proportion of proteins that were closely correlated with transepithelial transport across the intestine. Consequently, both D-IPC@PS and C-IPC@PS mainly exploited the recycling endosome and ER-Golgi mediated secretory routes for intracellular trafficking, which increased the transcytosis from the epithelium. Together, disease-specific IPC endowed NPs with higher intestinal absorption. D-IPC@PS posed "positive effect" on intestinal absorption into blood circulation for diabetic therapy. Conversely, C-IPC@PS had "negative effect" on colitis treatment because of unfavorable absorption in the intestine before arriving colon. These results imply that different or even opposite strategies to modulate the disease-specific IPC need to be adopted for oral nanomedicine in the treatment of variable diseases.
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Affiliation(s)
- Jiawei Wu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Liyun Xing
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Yaxian Zheng
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Yinglan Yu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Ruinan Wu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Xi Liu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Lian Li
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Yuan Huang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
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Chaudière J. Biological and Catalytic Properties of Selenoproteins. Int J Mol Sci 2023; 24:10109. [PMID: 37373256 DOI: 10.3390/ijms241210109] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/06/2023] [Accepted: 06/08/2023] [Indexed: 06/29/2023] Open
Abstract
Selenocysteine is a catalytic residue at the active site of all selenoenzymes in bacteria and mammals, and it is incorporated into the polypeptide backbone by a co-translational process that relies on the recoding of a UGA termination codon into a serine/selenocysteine codon. The best-characterized selenoproteins from mammalian species and bacteria are discussed with emphasis on their biological function and catalytic mechanisms. A total of 25 genes coding for selenoproteins have been identified in the genome of mammals. Unlike the selenoenzymes of anaerobic bacteria, most mammalian selenoenzymes work as antioxidants and as redox regulators of cell metabolism and functions. Selenoprotein P contains several selenocysteine residues and serves as a selenocysteine reservoir for other selenoproteins in mammals. Although extensively studied, glutathione peroxidases are incompletely understood in terms of local and time-dependent distribution, and regulatory functions. Selenoenzymes take advantage of the nucleophilic reactivity of the selenolate form of selenocysteine. It is used with peroxides and their by-products such as disulfides and sulfoxides, but also with iodine in iodinated phenolic substrates. This results in the formation of Se-X bonds (X = O, S, N, or I) from which a selenenylsulfide intermediate is invariably produced. The initial selenolate group is then recycled by thiol addition. In bacterial glycine reductase and D-proline reductase, an unusual catalytic rupture of selenium-carbon bonds is observed. The exchange of selenium for sulfur in selenoproteins, and information obtained from model reactions, suggest that a generic advantage of selenium compared with sulfur relies on faster kinetics and better reversibility of its oxidation reactions.
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Affiliation(s)
- Jean Chaudière
- CBMN (CNRS, UMR 5248), University of Bordeaux, 33600 Pessac, France
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Peng F, Xu Q, Jing X, Chi X, Zhang Z, Meng X, Liu X, Yan J, Liu X, Shao S. GPX2 promotes EMT and metastasis in non-small cell lung cancer by activating PI3K/AKT/mTOR/Snail signaling axis. FASEB Bioadv 2023; 5:233-250. [PMID: 37287867 PMCID: PMC10242197 DOI: 10.1096/fba.2022-00045] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 02/01/2023] [Accepted: 03/03/2023] [Indexed: 10/15/2023] Open
Abstract
Lung cancer, with non-small cell lung cancer (NSCLC) being the main subtype, is the leading cause of cancer death worldwide, which is mainly due to the cancer metastasis. Glutathione peroxidase 2 (GPX2), an antioxidant enzyme, is involved in tumor progression and metastasis. Nevertheless, the role of GPX2 in NSCLC metastasis has not been clarified. In this study, we found that GPX2 expression was elevated in NSCLC tissues and high GPX2 expression was correlated with poor prognosis in patients with NSCLC. In addtion, GPX2 expression was related to the patient's clinicopathological features, including lymph node metastasis, tumor size, and TNM stage. Overexpression of GPX2 promoted epithelial-mesenchymal transition (EMT), migration, and invasion of NSCLC cells in vitro. Knockdown of GPX2 showed the opposite effects in vitro and inhibited the metastasis of NSCLC cells in nude mice. Furthermore, GPX2 reduced reactive oxygen species (ROS) accumulation and activated the PI3K/AKT/mTOR/Snail signaling axis. Therefore, our results indicate that GPX2 promotes EMT and metastasis of NSCLC cells by activating the PI3K/AKT/mTOR/Snail signaling axis via the removal of ROS. GPX2 may be an effective diagnostic and prognostic biomarker for NSCLC.
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Affiliation(s)
- Fang Peng
- Liaoning Key Laboratory of ProteomicsDalian Medical UniversityDalianChina
- Department of PathologySecond Affiliated Hospital of Dalian Medical UniversityDalianChina
| | - Qiushi Xu
- Department of NeurosurgeryDalian Municipal Central HospitalDalianChina
| | - Xiaomeng Jing
- Department of PathologySecond Affiliated Hospital of Dalian Medical UniversityDalianChina
| | - Xinming Chi
- Liaoning Key Laboratory of ProteomicsDalian Medical UniversityDalianChina
| | - Zheming Zhang
- Liaoning Key Laboratory of ProteomicsDalian Medical UniversityDalianChina
| | - Xiangpeng Meng
- Liaoning Key Laboratory of ProteomicsDalian Medical UniversityDalianChina
| | - Xinyuan Liu
- Liaoning Key Laboratory of ProteomicsDalian Medical UniversityDalianChina
| | - Jiao Yan
- Liaoning Key Laboratory of ProteomicsDalian Medical UniversityDalianChina
| | - Xuefeng Liu
- Institute of Cancer Stem CellDalian Medical UniversityDalianChina
| | - Shujuan Shao
- Liaoning Key Laboratory of ProteomicsDalian Medical UniversityDalianChina
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Jarmakiewicz-Czaja S, Ferenc K, Filip R. Antioxidants as Protection against Reactive Oxidative Stress in Inflammatory Bowel Disease. Metabolites 2023; 13:metabo13040573. [PMID: 37110231 PMCID: PMC10146410 DOI: 10.3390/metabo13040573] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 04/13/2023] [Accepted: 04/16/2023] [Indexed: 04/29/2023] Open
Abstract
Inflammatory bowel disease (IBD) belongs to a group of chronic diseases characterised by periods of exacerbation and remission. Despite many studies and observations, its aetiopathogenesis is still not fully understood. The interactions of genetic, immunological, microbiological, and environmental factors can induce disease development and progression, but there is still a lack of information on these mechanisms. One of the components that can increase the risk of occurrence of IBD, as well as disease progression, is oxidative stress. Oxidative stress occurs when there is an imbalance between reactive oxygen species (ROS) and antioxidants. The endogenous and exogenous components that make up the body's antioxidant defence can significantly affect IBD prophylaxis and reduce the risk of exacerbation by neutralising and removing ROS, as well as influencing the inflammatory state.
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Affiliation(s)
| | - Katarzyna Ferenc
- Institute of Medicine, Medical College of Rzeszow University, 35-959 Rzeszow, Poland
| | - Rafał Filip
- Institute of Medicine, Medical College of Rzeszow University, 35-959 Rzeszow, Poland
- Department of Gastroenterology with IBD Unit, Clinical Hospital No. 2, 35-301 Rzeszow, Poland
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Ji Y, Yang Y, Sun S, Dai Z, Ren F, Wu Z. Insights into diet-associated oxidative pathomechanisms in inflammatory bowel disease and protective effects of functional amino acids. Nutr Rev 2022; 81:95-113. [PMID: 35703919 DOI: 10.1093/nutrit/nuac039] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
There has been a substantial rise in the incidence and prevalence of clinical patients presenting with inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis. Accumulating evidence has corroborated the view that dietary factors (particularly diets with high levels of saturated fat or sugar) are involved in the development and progression of IBD, which is predominately associated with changes in the composition of the gut microbiota and an increase in the generation of reactive oxygen species. Notably, the ecological imbalance of the gut microbiome exacerbates oxidative stress and inflammatory responses, leading to perturbations of the intestinal redox balance and immunity, as well as mucosal integrity. Recent findings have revealed that functional amino acids, including L-glutamine, glycine, L-arginine, L-histidine, L-tryptophan, and hydroxyproline, are effectively implicated in the maintenance of intestinal redox and immune homeostasis. These amino acids and their metabolites have oxygen free-radical scavenging and inflammation-relieving properties, and they participate in modulation of the microbial community and the metabolites in the gut. The principal focus of this article is a review of recent advances in the oxidative pathomechanisms of IBD development and progression in relation to dietary factors, with a particular emphasis on the redox and signal transduction mechanisms of host cells in response to unbalanced diets and enterobacteria. In addition, an update on current understanding of the protective effects of functional amino acids against IBD, together with the underlying mechanisms for this protection, have been provided.
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Affiliation(s)
- Yun Ji
- are with the State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, China Agricultural University, Beijing, China.,are with the Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing, China
| | - Ying Yang
- are with the State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, China Agricultural University, Beijing, China
| | - Shiqiang Sun
- are with the State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, China Agricultural University, Beijing, China
| | - Zhaolai Dai
- are with the State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, China Agricultural University, Beijing, ChinaChina
| | - Fazheng Ren
- are with the Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing, China
| | - Zhenlong Wu
- are with the State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, China Agricultural University, Beijing, China.,are with the Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing, China
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11
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Huang J, Zhang J, Wang F, Zhang B, Tang X. Revealing immune infiltrate characteristics and potential diagnostic value of immune-related genes in ulcerative colitis: An integrative genomic analysis. Front Public Health 2022; 10:1003002. [PMID: 36388363 PMCID: PMC9660254 DOI: 10.3389/fpubh.2022.1003002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 10/17/2022] [Indexed: 01/27/2023] Open
Abstract
Objectives Ulcerative colitis (UC) is an autoimmune disease of the colon. The aim of this study was to explore the characteristics of immune infiltrates in UC patients and identify immune-related diagnostic biomarkers for UC. Methods Three gene expression profiles were acquired from the GEO database, followed by identification of differentially expressed genes (DEGs) by Linear Modeling of Microarray Data. Enrichment analysis of Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Disease Ontology (DO) were performed to analyze the biological functions of DEGs. Subsequently, the single sample gene set enrichment analysis (ssGSEA) was performed to identify immune infiltration characteristics of UC. Correlations between diagnostic genes and immune infiltration were explored to identify markers with the greatest diagnostic potential, and a UC diagnostic model was subsequently constructed. Finally, the prediction performance of the model was quantified by nomogram, non-correlated nomogram, and ROC curve. Results A total of 3111 DEGs (1,608 up-regulated and 1,503 down-regulated genes) were identified. DEGs were significantly involved in the immune system and UC-related pathways. Immune infiltration profiles of colonic tissue were significantly different between healthy individuals and UC patients. High proportions of resting of aDCs, B cells, CD8+ T cells, DCs, iDCs, Macrophages, Neutrophils, pDCs, T helper cells, Tfh, Th1 cells, Th2 cells, TIL and Treg were found in UC samples. A 5-gene based diagnostic prediction model was constructed and the results of nomogram, non-correlated nomogram and ROC curve suggested the powerful diagnostic value of the model. Conclusions This study identified the immune infiltrate characteristics and 5 immune-related genes for UC. The model based on the immune-related genes facilitates the early diagnosis of UC and provides a basis for the evaluation of the prognosis of UC.
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Affiliation(s)
- Jinke Huang
- Department of Gastroenterology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Jiaqi Zhang
- Department of Gastroenterology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China,Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Fengyun Wang
- Department of Gastroenterology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China,Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Beihua Zhang
- Department of Gastroenterology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China,Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Xudong Tang
- Department of Gastroenterology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China,Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China,*Correspondence: Xudong Tang
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12
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Ishii T, Warabi E, Mann GE. Mechanisms underlying Nrf2 nuclear translocation by non-lethal levels of hydrogen peroxide: p38 MAPK-dependent neutral sphingomyelinase2 membrane trafficking and ceramide/PKCζ/CK2 signaling. Free Radic Biol Med 2022; 191:191-202. [PMID: 36064071 DOI: 10.1016/j.freeradbiomed.2022.08.036] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 08/22/2022] [Accepted: 08/29/2022] [Indexed: 12/14/2022]
Abstract
Hydrogen peroxide is an aerobic metabolite playing a central role in redox signaling and oxidative stress. H2O2 could activate redox sensitive transcription factors, such as Nrf2, AP-1 and NF-κB by different manners. In some cells, treatment with non-lethal levels of H2O2 induces rapid activation of Nrf2, which upregulates expression of a set of genes involved in glutathione (GSH) synthesis and defenses against oxidative damage. It depends on two steps, the rapid translational activation of Nrf2 and facilitation of Nrf2 nuclear translocation. We review the molecular mechanisms by which H2O2 induces nuclear translocation of Nrf2 in cultured cells by highlighting the role of neutral sphingomyelinase 2 (nSMase2), a GSH sensor. H2O2 enters cells through aquaporin channels in the plasma membrane and is rapidly reduced to H2O by GSH peroxidases to consume cellular GSH, resulting in nSMase2 activation to generate ceramide. H2O2 also activates p38 MAP kinase, which enhances transfer of nSMase2 from perinuclear regions to plasma membrane lipid rafts to accelerate ceramide generation. Low levels of ceramide activate PKCζ, which then activates casein kinase 2 (CK2). These protein kinases are able to phosphorylate Nrf2 to stabilize and activate it. Notably, Nrf2 also binds to caveolin-1 (Cav1), which protects Nrf2 from Keap1-mediated degradation and limits Nrf2 nuclear translocation. We propose that Cav1serves as a signaling hub for the control of H2O2-mediated phosphorylation of Nrf2 by kinases, which results in release of Nrf2 from Cav1 to facilitate nuclear translocation. In summary, H2O2 induces GSH depletion which is recovered by Nrf2 activation dependent on p38/nSMase2/ceramide signaling.
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Affiliation(s)
- Tetsuro Ishii
- School of Medicine, University of Tsukuba, Tsukuba, Ibaraki, 305-8577, Japan.
| | - Eiji Warabi
- School of Medicine, University of Tsukuba, Tsukuba, Ibaraki, 305-8577, Japan.
| | - Giovanni E Mann
- King's British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Sciences & Medicine, King's College London, 150 Stamford Street, London, SE1 9NH, UK.
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13
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Wang D, Zhang Y, Chen Q, Kuang Y, Fan J, Xu X, Zhu H, Gao Q, Cheng S, Cong X, Liu Y. Selenium-enriched Cardamine violifolia improves growth performance with potential regulation of intestinal health and antioxidant function in weaned pigs. Front Vet Sci 2022; 9:964766. [PMID: 36032298 PMCID: PMC9403540 DOI: 10.3389/fvets.2022.964766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 07/22/2022] [Indexed: 11/23/2022] Open
Abstract
This study was conducted to evaluate the effects of different Selenium (Se) sources on growth performance, intestinal function and antioxidant status of weaned piglets. A total of 300 weaned pigs were randomly allocated to 5 treatment groups with 5 replicates of 12 pigs/pen. The control group was corn-soybean basal diet without any additional Se supplement. The experimental diets were supplemented with 0.3 mg/kg of Se from sodium selenite (SS), Se-enriched yeast (SEY), Se-enriched Cardamine violifolia (SEC) and 0.3+0.3 mg/kg of Se from SEY and SEC, respectively. The trial lasted for 4 weeks. The results showed that diets supplementation with SEY, SEC or SEY+SEC could improve average daily gain and reduce feed/gain ratio during the entire study. Compared with the control group, SEC or SEY+SEC improved intestinal morphology, indicated by greater villus height and villus height/ crypt depth ratio. In addition, SEC or SEY+SEC also increased maltase and lactase activities as well as tight junction protein expression. Different Se sources decreased malondialdehyde (MDA) concentration and improved superoxide dismutase (SOD) activity in serum. In the jejunum, SEY or SEC reduced MDA concentration and increased total antioxidant capacity (T-AOC) compared with the control group. Moreover, SEY+SEC increased the antioxidant parameters including SOD and T-AOC in the jejunum. Dietary SEY or SEC supplementation significantly increased the mRNA expression of selenoproteins including thioredoxin reductase 1 (TXNRD1), selenoprotein I (SELENOI), selenoprotein S (SELENOS), and selenoprotein P (SELENOP) in the jejunum. In conclusion, organic Se sources, especially Cardamine violifolia, improve growth performance, potentially by regulating intestinal function, antioxidant capacity and selenoprotein expression in piglets.
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Affiliation(s)
- Dan Wang
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, China
| | - Yue Zhang
- Enshi Se-Run Material Engineering Technology Co., Ltd., Enshi, China
| | - Qinliang Chen
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, China
| | - Yanling Kuang
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, China
| | - Jiajun Fan
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, China
| | - Xiao Xu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, China
| | - Huiling Zhu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, China
| | - Qingyu Gao
- Enshi Se-Run Material Engineering Technology Co., Ltd., Enshi, China
| | - Shuiyuan Cheng
- National R&D Center for Se-rich Agricultural Products Processing, School of Modern Industry for Selenium Science and Engineering, Wuhan Polytechnic University, Wuhan, China
| | - Xin Cong
- Enshi Se-Run Material Engineering Technology Co., Ltd., Enshi, China
- *Correspondence: Yulan Liu
| | - Yulan Liu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, China
- Xin Cong
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14
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Dutta A, Das M. Deciphering the Role of Aquaporins in Metabolic Diseases: A Mini Review. Am J Med Sci 2022; 364:148-162. [DOI: 10.1016/j.amjms.2021.10.029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 06/16/2021] [Accepted: 10/21/2021] [Indexed: 12/23/2022]
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15
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Jadaun PK, Chatterjee S. COVID-19 and dys-regulation of pulmonary endothelium: implications for vascular remodeling. Cytokine Growth Factor Rev 2021; 63:69-77. [PMID: 34728151 PMCID: PMC9611904 DOI: 10.1016/j.cytogfr.2021.10.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 10/05/2021] [Accepted: 10/13/2021] [Indexed: 01/08/2023]
Abstract
Coronavirus disease-2019 (COVID-19),
the disease caused by severe acute respiratory syndrome-coronavirus-2,
has claimed more than 4.4 million lives worldwide (as of 20 August 2021).
Severe cases of the disease often result in respiratory distress due to
cytokine storm, and mechanical ventilation is required. Although, the
lungs are the primary organs affected by the disease, more evidence on
damage to the heart, kidney, and liver is emerging. A common link in
these connections is the cardiovascular network. Inner lining of the
blood vessels, called endothelium, is formed by a single layer of
endothelial cells. Several clinical manifestations involving the
endothelium have been reported, such as its activation via
immunomodulation, endotheliitis, thrombosis, vasoconstriction, and
distinct intussusceptive angiogenesis (IA), a unique and rapid process of
blood-vessel formation by splitting a vessel into two lumens. In fact,
the virus directly infects the endothelium via TMPRSS2 spike glycoprotein
priming to facilitate ACE-2-mediated viral entry. Recent studies have
indicated a significant increase in remodeling of the pulmonary vascular
bed via intussusception in patients with COVID-19. However, the lack of
circulatory biomarkers for IA limits its detection in COVID-19
pathogenesis. In this review, we describe the implications of
angiogenesis in COVID-19, unique features of the pulmonary vascular bed
and its remodeling, and a rapid and non-invasive assessment of IA to
overcome the technical limitations in patients with
COVID-19.
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Affiliation(s)
- Pavitra K Jadaun
- Hepatology, Department for BioMedical Research, University of Bern, Bern, Switzerland
| | - Suvro Chatterjee
- Department of Biotechnology, University of Burdwan, Golap Bag Campus, Burdwan, India.
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da Silva IV, Soveral G. Aquaporins in Immune Cells and Inflammation: New Targets for Drug Development. Int J Mol Sci 2021; 22:ijms22041845. [PMID: 33673336 PMCID: PMC7917738 DOI: 10.3390/ijms22041845] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/06/2021] [Accepted: 02/09/2021] [Indexed: 12/25/2022] Open
Abstract
The mammalian immune system senses foreign antigens by mechanisms that involve the interplay of various kinds of immune cells, culminating in inflammation resolution and tissue clearance. The ability of the immune cells to communicate (via chemokines) and to shift shape for migration, phagocytosis or antigen uptake is mainly supported by critical proteins such as aquaporins (AQPs) that regulate water fluid homeostasis and volume changes. AQPs are protein channels that facilitate water and small uncharged molecules’ (such as glycerol or hydrogen peroxide) diffusion through membranes. A number of AQP isoforms were found upregulated in inflammatory conditions and are considered essential for the migration and survival of immune cells. The present review updates information on AQPs’ involvement in immunity and inflammatory processes, highlighting their role as crucial players and promising targets for drug discovery.
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Affiliation(s)
- Inês V. da Silva
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal;
- Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal
| | - Graça Soveral
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal;
- Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal
- Correspondence: ; Tel.: +351-217946461
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Irrazabal T, Thakur BK, Croitoru K, Martin A. Preventing Colitis-Associated Colon Cancer With Antioxidants: A Systematic Review. Cell Mol Gastroenterol Hepatol 2021; 11:1177-1197. [PMID: 33418102 PMCID: PMC7907812 DOI: 10.1016/j.jcmgh.2020.12.013] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 12/30/2020] [Accepted: 12/30/2020] [Indexed: 12/14/2022]
Abstract
Inflammatory bowel disease (IBD) patients have an increased risk of developing colitis-associated colon cancer (CAC); however, the basis for inflammation-induced genetic damage requisite for neoplasia is unclear. Several studies have shown that IBD patients have signs of increased oxidative damage, which could be a result of genetic and environmental factors such as an excess in oxidant molecules released during chronic inflammation, mitochondrial dysfunction, a failure in antioxidant capacity, or oxidant promoting diets. It has been suggested that chronic oxidative environment in the intestine leads to the DNA lesions that precipitate colon carcinogenesis in IBD patients. Indeed, several preclinical and clinical studies show that different endogenous and exogenous antioxidant molecules are effective at reducing oxidation in the intestine. However, most clinical studies have focused on the short-term effects of antioxidants in IBD patients but not in CAC. This review article examines the role of oxidative DNA damage as a possible precipitating event in CAC in the context of chronic intestinal inflammation and the potential role of exogenous antioxidants to prevent these cancers.
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Affiliation(s)
| | - Bhupesh K Thakur
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Kenneth Croitoru
- Department of Medicine, Division of Gastroenterology, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Alberto Martin
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
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18
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Buday K, Conrad M. Emerging roles for non-selenium containing ER-resident glutathione peroxidases in cell signaling and disease. Biol Chem 2020; 402:271-287. [PMID: 33055310 DOI: 10.1515/hsz-2020-0286] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 10/08/2020] [Indexed: 12/16/2022]
Abstract
Maintenance of cellular redox control is pivotal for normal cellular functions and cell fate decisions including cell death. Among the key cellular redox systems in mammals, the glutathione peroxidase (GPX) family of proteins is the largest conferring multifaceted functions and affecting virtually all cellular processes. The endoplasmic reticulum (ER)-resident GPXs, designated as GPX7 and GPX8, are the most recently added members of this family of enzymes. Recent studies have provided exciting insights how both enzymes support critical processes of the ER including oxidative protein folding, maintenance of ER redox control by eliminating H2O2, and preventing palmitic acid-induced lipotoxicity. Consequently, numerous pathological conditions, such as neurodegeneration, cancer and metabolic diseases have been linked with altered GPX7 and GPX8 expression. Studies in mice have demonstrated that loss of GPX7 leads to increased differentiation of preadipocytes, increased tumorigenesis and shortened lifespan. By contrast, GPX8 deficiency in mice results in enhanced caspase-4/11 activation and increased endotoxic shock in colitis model. With the increasing recognition that both types of enzymes are dysregulated in various tumor entities in man, we deem a review of the emerging roles played by GPX7 and GPX8 in health and disease development timely and appropriate.
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Affiliation(s)
- Katalin Buday
- Institute of Metabolism and Cell Death, Helmholtz Zentrum München, Ingolstädter Landstr. 1, D-85764Neuherberg, Germany
| | - Marcus Conrad
- Institute of Metabolism and Cell Death, Helmholtz Zentrum München, Ingolstädter Landstr. 1, D-85764Neuherberg, Germany.,National Research Medical University, Laboratory of Experimental Oncology, Ostrovityanova 1, 117997Moscow, Russia
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19
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Krzystek-Korpacka M, Kempiński R, Bromke MA, Neubauer K. Oxidative Stress Markers in Inflammatory Bowel Diseases: Systematic Review. Diagnostics (Basel) 2020; 10:E601. [PMID: 32824619 PMCID: PMC7459713 DOI: 10.3390/diagnostics10080601] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Revised: 08/08/2020] [Accepted: 08/12/2020] [Indexed: 02/06/2023] Open
Abstract
Precise diagnostic biomarker in inflammatory bowel diseases (IBD) is still missing. We conducted a comprehensive overview of oxidative stress markers (OSMs) as potential diagnostic, differential, progression, and prognostic markers in IBD. A Pubmed, Web of Knowledge, and Scopus search of original articles on OSMs in IBD, published between January 2000 and April 2020, was conducted. Out of 874 articles, 79 eligible studies were identified and used to prepare the interpretative synthesis. Antioxidants followed by lipid peroxidation markers were the most popular and markers of oxidative DNA damage the least popular. There was a disparity in the number of retrieved papers evaluating biomarkers in the adult and pediatric population (n = 6). Of the reviewed OSMs, a promising performance has been reported for serum total antioxidant status as a mucosal healing marker, mucosal 8-OHdG as a progression marker, and for multi-analyte panels of lipid peroxidation products assessed non-invasively in breath as diagnostic and differential markers in the pediatric population. Bilirubin, in turn, was the only validated marker. There is a desperate need for non-invasive biomarkers in IBD which, however, will not be met in the near future by oxidative stress markers as they are promising but mostly at the early research phase of discovery.
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Affiliation(s)
| | - Radosław Kempiński
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland;
| | - Mariusz A. Bromke
- Department of Medical Biochemistry, Wroclaw Medical University, Chałubińskiego 10, 50-368 Wroclaw, Poland;
| | - Katarzyna Neubauer
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland;
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20
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Escudero-Hernández C, Münch A, Østvik AE, Granlund AVB, Koch S. The Water Channel Aquaporin 8 is a Critical Regulator of Intestinal Fluid Homeostasis in Collagenous Colitis. J Crohns Colitis 2020; 14:962-973. [PMID: 32016376 PMCID: PMC7393183 DOI: 10.1093/ecco-jcc/jjaa020] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Diarrhoea is a common, debilitating symptom of gastrointestinal disorders. Pathomechanisms probably involve defects in trans-epithelial water transport, but the role of aquaporin [AQP] family water channels in diarrhoea-predominant diseases is unknown. We investigated the involvement of AQPs in the pathobiology of collagenous colitis [CC], which features chronic, watery diarrhoea despite overtly normal intestinal epithelial cells [IECs]. METHODS We assessed the expression of all AQP family members in mucosal samples of CC patients before and during treatment with the corticosteroid drug budesonide, steroid-refractory CC patients and healthy controls. Samples were analysed by genome-wide mRNA sequencing [RNA-seq] and quantitative real-time PCR [qPCR]. In some patients, we performed tissue microdissection followed by RNA-seq to explore the IEC-specific CC transcriptome. We determined changes in the protein levels of the lead candidates in IEC by confocal microscopy. Finally, we investigated the regulation of AQP expression by corticosteroids in model cell lines. RESULTS Using qPCR and RNA-seq, we identified loss of AQP8 expression as a hallmark of active CC, which was reverted by budesonide treatment in steroid-responsive but not refractory patients. Consistently, decreased AQP8 mRNA and protein levels were observed in IECs of patients with active CC, and steroid drugs increased AQP8 expression in model IECs. Moreover, low APQ8 expression was strongly associated with higher stool frequency in CC patients. CONCLUSION Down-regulation of epithelial AQP8 may impair water resorption in active CC, resulting in watery diarrhoea. Our results suggest that AQP8 is a potential drug target for the treatment of diarrhoeal disorders.
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Affiliation(s)
| | - Andreas Münch
- Department of Biomedical and Clinical Sciences [BKV), Linköping University, Linköping, Sweden,Division of Gastroenterology and Hepatology, Department of Biomedical and Clinical Sciences [BKV), Faculty of Health Science, Linköpings University, Linköping, Sweden,Corresponding authors: Andreas Münch, MD PhD, Division of Gastroenterology and Hepatology, Department of Biomedical and Clinical Sciences [BKV), Faculty of Health Sciences, Linköping University, Linköping, 58185, Sweden. Tel: +46 100130000; ; Stefan Koch, PhD, BKV/MII—Plan 13, s-581 83 Linköping, Sweden. Tel: +46 13 282969;
| | - Ann-Elisabet Østvik
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway,Department of Gastroenterology and Hepatology, St Olav’s University Hospital, Trondheim, Norway,Clinic of Medicine, St Olav’s University Hospital, Trondheim, Norway
| | - Atle van Beelen Granlund
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway,Clinic of Medicine, St Olav’s University Hospital, Trondheim, Norway,Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Stefan Koch
- Department of Biomedical and Clinical Sciences [BKV), Linköping University, Linköping, Sweden,Wallenberg Centre for Molecular Medicine (WCMM), Linköping University, Linköping, Sweden,Corresponding authors: Andreas Münch, MD PhD, Division of Gastroenterology and Hepatology, Department of Biomedical and Clinical Sciences [BKV), Faculty of Health Sciences, Linköping University, Linköping, 58185, Sweden. Tel: +46 100130000; ; Stefan Koch, PhD, BKV/MII—Plan 13, s-581 83 Linköping, Sweden. Tel: +46 13 282969;
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Osorio D, Pinzón A, Martín-Jiménez C, Barreto GE, González J. Multiple Pathways Involved in Palmitic Acid-Induced Toxicity: A System Biology Approach. Front Neurosci 2020; 13:1410. [PMID: 32076395 PMCID: PMC7006434 DOI: 10.3389/fnins.2019.01410] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 12/12/2019] [Indexed: 01/26/2023] Open
Abstract
Inflammation is a complex biological response to injuries, metabolic disorders or infections. In the brain, astrocytes play an important role in the inflammatory processes during neurodegenerative diseases. Recent studies have shown that the increase of free saturated fatty acids such as palmitic acid produces a metabolic inflammatory response in astrocytes generally associated with damaging mechanisms such as oxidative stress, endoplasmic reticulum stress, and autophagic defects. In this aspect, the synthetic neurosteroid tibolone has shown to exert protective functions against inflammation in neuronal experimental models without the tumorigenic effects exerted by sexual hormones such as estradiol and progesterone. However, there is little information regarding the specific mechanisms of tibolone in astrocytes during inflammatory insults. In the present study, we performed a genome-scale metabolic reconstruction of astrocytes that was used to study astrocytic response during an inflammatory insult by palmitate through Flux Balance Analysis methods and data mining. In this aspect, we assessed the metabolic fluxes of human astrocytes under three different scenarios: healthy (normal conditions), induced inflammation by palmitate, and tibolone treatment under palmitate inflammation. Our results suggest that tibolone reduces the L-glutamate-mediated neurotoxicity in astrocytes through the modulation of several metabolic pathways involved in glutamate uptake. We also identified a set of reactions associated with the protective effects of tibolone, including the upregulation of taurine metabolism, gluconeogenesis, cPPAR and the modulation of calcium signaling pathways. In conclusion, the different scenarios studied in our model allowed us to identify several metabolic fluxes perturbed under an inflammatory response and the protective mechanisms exerted by tibolone.
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Affiliation(s)
- Daniel Osorio
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, United States
| | - Andrés Pinzón
- Laboratorio de Bioinformática y Biología de Sistemas, Universidad Nacional de Colombia, Bogotá, Colombia
| | - Cynthia Martín-Jiménez
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - George E. Barreto
- Department of Biological Sciences, University of Limerick, Limerick, Ireland
- Health Research Institute, University of Limerick, Limerick, Ireland
| | - Janneth González
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia
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22
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Red lentil supplementation reduces the severity of dextran sodium sulfate-induced colitis in C57BL/6 male mice. J Funct Foods 2020. [DOI: 10.1016/j.jff.2019.103625] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
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23
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Yan L, Liang M, Hou X, Zhang Y, Zhang H, Guo Z, Jinyu J, Feng Z, Mei Z. The role of microRNA-16 in the pathogenesis of autoimmune diseases: A comprehensive review. Biomed Pharmacother 2019; 112:108583. [DOI: 10.1016/j.biopha.2019.01.044] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 01/06/2019] [Accepted: 01/15/2019] [Indexed: 12/20/2022] Open
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Kim JE, Yun WB, Lee ML, Choi JY, Park JJ, Kim HR, Song BR, Hong JT, Song HK, Hwang DY. Synergic Laxative Effects of an Herbal Mixture of Liriope platyphylla, Glycyrrhiza uralensis, and Cinnamomum cassia in Loperamide-Induced Constipation of Sprague Dawley Rats. J Med Food 2019; 22:294-304. [PMID: 30724689 DOI: 10.1089/jmf.2018.4234] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Constipation is an acute or chronic illness attributed to various causes, ranging from lifestyle habits to side effects of a disease. To improve the laxative effects of some traditional medicines, herbal mixtures of Liriope platyphylla, Glycyrrhiza uralensis, and Cinnamomum cassia (LGC) were evaluated for their mechanism of action and therapeutic effects in loperamide (Lop)-induced constipated Sprague Dawley rats by examining alterations in excretion parameters, histological structure, mucin secretion, and related protein levels. Food intake and water consumption were constant for all animals. We observed that the Lop+LGC-treated group had significantly greater excretion of stool and urine than was observed in the Lop+Vehicle-treated group. Administration of LGC in the constipation model restored the intestinal transit ratio to normal levels, and increased the number of goblet cells, mucosal layer, and muscle thickness. Mucin secretion was greater in the Lop+LGC-treated group than in the Lop+Vehicle-treated group, and the expression of MUC2 and AQP8 genes were also increased. In addition, reverse transcription polymerase chain reaction and Western blot revealed an increase in the muscarinic acetylcholine receptors (mAChRs) in the Lop+LGC-treated group compared to the Lop+Vehicle-treated group. Furthermore, compared with the Lop+Vehicle-treated group, treatment with LGC reduced the phosphorylation of PKC and PI3K, and expression of Gα protein, but increased levels of IP3. Our results suggest that the traditional herbal mixture of LGC induces a potent laxative effect in Lop-induced constipation through mucosal tissue changes and mucin production. We also demonstrated that the laxative effect of LGC is closely related to the expression of mAChR and its downstream signals, suggesting the possibility of developing a constipation-laxative agent using LGC.
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Affiliation(s)
- Ji Eun Kim
- 1 Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Woo Bin Yun
- 1 Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Mi Lim Lee
- 1 Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Jun Young Choi
- 1 Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Jin Ju Park
- 1 Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Hye Ryeong Kim
- 1 Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Bo Ram Song
- 1 Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Jin Tae Hong
- 2 College of Pharmacy, Chungbuk National University, Chungju, Korea
| | - Hyun Keun Song
- 3 Biomedical Science Institute, Changwon National University, Changwon-si, Gyeongsangnam-do, Korea
| | - Dae Youn Hwang
- 1 Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
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Kunisawa K, Shimizu T, Kushima I, Aleksic B, Mori D, Osanai Y, Kobayashi K, Taylor AM, Bhat MA, Hayashi A, Baba H, Ozaki N, Ikenaka K. Dysregulation of schizophrenia-related aquaporin 3 through disruption of paranode influences neuronal viability. J Neurochem 2018; 147:395-408. [PMID: 30025158 PMCID: PMC6205917 DOI: 10.1111/jnc.14553] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Revised: 06/28/2018] [Accepted: 07/16/2018] [Indexed: 12/23/2022]
Abstract
Myelinated axons segregate the axonal membrane into four defined regions: the node of Ranvier, paranode, juxtaparanode, and internode. The paranodal junction consists of specific component proteins, such as neurofascin155 (NF155) on the glial side, and Caspr and Contactin on the axonal side. Although paranodal junctions are thought to play crucial roles in rapid saltatory conduction and nodal assembly, the role of their interaction with neurons is not fully understood. In a previous study, conditional NF155 knockout in oligodendrocytes led to disorganization of the paranodal junctions. To examine if disruption of paranodal junctions affects neuronal gene expression, we prepared total RNA from the retina of NF155 conditional knockout, and performed expression analysis. We found that the expression level of 433 genes changed in response to paranodal junction ablation. Interestingly, expression of aquaporin 3 (AQP3) was significantly reduced in NF155 conditional knockout mice, but not in cerebroside sulfotransferase knockout (CST-KO) mice, whose paranodes are not originally formed during development. Copy number variations have an important role in the etiology of schizophrenia (SCZ). We observed rare duplications of AQP3 in SCZ patients, suggesting a correlation between abnormal AQP3 expression and SCZ. To determine if AQP3 over-expression in NF155 conditional knockout mice influences neuronal function, we performed adeno-associated virus (AAV)-mediated over-expression of AQP3 in the motor cortex of mice and found a significant increase in caspase 3-dependent neuronal apoptosis in AQP3-transduced cells. This study may provide new insights into therapeutic approaches for SCZ by regulating AQP3 expression, which is associated with paranodal disruption.
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Affiliation(s)
- Kazuo Kunisawa
- Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki 444-8787, Japan
- SOKENDAI (The Graduate University for Advanced Studies), Okazaki 444-8787, Japan
| | - Takeshi Shimizu
- Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki 444-8787, Japan
- SOKENDAI (The Graduate University for Advanced Studies), Okazaki 444-8787, Japan
| | - Itaru Kushima
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Branko Aleksic
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Daisuke Mori
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
- Brain and Mind Research Center, Nagoya University, Nagoya 466-8550, Japan
| | - Yasuyuki Osanai
- Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki 444-8787, Japan
- SOKENDAI (The Graduate University for Advanced Studies), Okazaki 444-8787, Japan
| | - Kenta Kobayashi
- Section of Viral Vector Development, National Institute for Physiological Sciences, Okazaki 444-8585, Japan
- SOKENDAI (The Graduate University for Advanced Studies), Okazaki 444-8787, Japan
| | - Anna M. Taylor
- Department of Cellular and Integrative Physiology, School of Medicine, University of Texas Health Science Center, San Antonio 78229-3900, USA
| | - Manzoor A. Bhat
- Department of Cellular and Integrative Physiology, School of Medicine, University of Texas Health Science Center, San Antonio 78229-3900, USA
| | - Akiko Hayashi
- Department of Molecular Neurobiology, Tokyo University of Pharmacy and Life Sciences, Hachioji 192-0392, Japan
| | - Hiroko Baba
- Department of Molecular Neurobiology, Tokyo University of Pharmacy and Life Sciences, Hachioji 192-0392, Japan
| | - Norio Ozaki
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Kazuhiro Ikenaka
- Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki 444-8787, Japan
- SOKENDAI (The Graduate University for Advanced Studies), Okazaki 444-8787, Japan
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Peters KM, Carlson BA, Gladyshev VN, Tsuji PA. Selenoproteins in colon cancer. Free Radic Biol Med 2018; 127:14-25. [PMID: 29793041 PMCID: PMC6168369 DOI: 10.1016/j.freeradbiomed.2018.05.075] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 05/18/2018] [Accepted: 05/20/2018] [Indexed: 02/07/2023]
Abstract
Selenocysteine-containing proteins (selenoproteins) have been implicated in the regulation of various cell signaling pathways, many of which are linked to colorectal malignancies. In this in-depth excurse into the selenoprotein literature, we review possible roles for human selenoproteins in colorectal cancer, focusing on the typical hallmarks of cancer cells and their tumor-enabling characteristics. Human genome studies of single nucleotide polymorphisms in various genes coding for selenoproteins have revealed potential involvement of glutathione peroxidases, thioredoxin reductases, and other proteins. Cell culture studies with targeted down-regulation of selenoproteins and studies utilizing knockout/transgenic animal models have helped elucidate the potential roles of individual selenoproteins in this malignancy. Those selenoproteins, for which strong links to development or progression of colorectal cancer have been described, may be potential future targets for clinical interventions.
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Affiliation(s)
- Kristin M Peters
- Dept. of Biological Sciences, Towson University, 8000 York Rd, Towson, MD 21252, United States.
| | - Bradley A Carlson
- National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, United States.
| | - Vadim N Gladyshev
- Dept. of Medicine, Brigham & Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, United States.
| | - Petra A Tsuji
- Dept. of Biological Sciences, Towson University, 8000 York Rd, Towson, MD 21252, United States.
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27
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Gîlcă-Blanariu GE, Diaconescu S, Ciocoiu M, Ștefănescu G. New Insights into the Role of Trace Elements in IBD. BIOMED RESEARCH INTERNATIONAL 2018; 2018:1813047. [PMID: 30258848 PMCID: PMC6146599 DOI: 10.1155/2018/1813047] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 06/11/2018] [Accepted: 08/11/2018] [Indexed: 02/07/2023]
Abstract
Micronutrient deficiencies are common in inflammatory bowel disease and have clinical impact, being both a sign of complicated disease and a cause of morbidity. The involved systemic inflammatory response is responsible for altering the concentration of a wide range of trace elements in the serum, including zinc and selenium. This review summarizes recent advances and evidence-based knowledge regarding the impact of selenium and zinc on oxidative stress and microbiota changes in IBD patients. Getting new insight into the impact of malnutrition, particularly on the micronutrients' impact on the development, composition, and metabolism of microbiota, as well as the influence of oxidative stress and the mucosal immune response, could help in implementing new management strategies for IBD patients, with focus on a more integrated approach.
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Affiliation(s)
| | - Smaranda Diaconescu
- Department of Pediatrics, Titu Maiorescu University, Faculty of Medicine, Bucharest, Romania
| | - Manuela Ciocoiu
- Department of Pathophysiology, Grigore T Popa University of Medicine and Pharmacy, Iași, Romania
| | - Gabriela Ștefănescu
- Department of Gastroenterology, Grigore T Popa University of Medicine and Pharmacy, Iași, Romania
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Catalán N, Villasante A, Wacyk J, Ramírez C, Romero J. Fermented Soybean Meal Increases Lactic Acid Bacteria in Gut Microbiota of Atlantic Salmon (Salmo salar). Probiotics Antimicrob Proteins 2018; 10:566-576. [PMID: 29274013 DOI: 10.1007/s12602-017-9366-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The main goal of the present study was to address the effect of feeding fermented soybean meal-based diet to Atlantic salmon on gut microbiota. Further, expression of genes of interest, including cathelicidin antimicrobial peptide (cath), mucin 2 (muc2), aquaporin (aqp8ab), and proliferating cell nuclear antigen (pcna), in proximal intestine of fish fed either experimental diet was analyzed. Three experimental diets, including a control fishmeal (30% FM), soybean meal (30% SBM), or fermented soybean meal diet (30% FSBM) were randomly assigned to triplicate tanks during a 50-day trial. The PCR-TTGE showed microbiota composition was influenced by experimental diets. Bands corresponding to genus Lactobacillus and Pediococcus were characteristic in fish fed the FSBM-based diet. On the other hand, bands corresponding to Isoptericola, Cellulomonas, and Clostridium sensu stricto were only observed in fish FM-based diet, while Acinetobacter and Altererythrobacter were detected in fish fed SBM-based diet. The expression of muc2 and aqp8ab were significantly greater in fish fed the FSBM-based diet compared with the control group. Our results suggest feeding FSBM to Atlantic salmon may (1) boost health and growth physiology in fish by promoting intestinal lactic acid bacteria growth, having a prebiotic-like effect, (2) promote proximal intestine health by increasing mucin production, and (3) boost intestinal trans-cellular uptake of water. Further research to better understands the effects of bioactive compounds derived from the fermentation process of plant feedstuff on gut microbiota and the effects on health and growth in fish is required.
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Affiliation(s)
- Natalia Catalán
- Laboratorio de Biotecnología, Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile
| | - Alejandro Villasante
- Laboratorio de Biotecnología, Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile
| | - Jurij Wacyk
- Departamento de Producción Animal, Facultad de Ciencias Agronómicas, Universidad de Chile, Santiago, Chile
| | - Carolina Ramírez
- Laboratorio de Biotecnología, Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile
| | - Jaime Romero
- Laboratorio de Biotecnología, Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile.
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29
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Nettleford SK, Prabhu KS. Selenium and Selenoproteins in Gut Inflammation-A Review. Antioxidants (Basel) 2018; 7:antiox7030036. [PMID: 29494512 PMCID: PMC5874522 DOI: 10.3390/antiox7030036] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 02/17/2018] [Accepted: 02/24/2018] [Indexed: 12/21/2022] Open
Abstract
Inflammatory bowel disease (IBD), characterized by severe flares and remissions, is a debilitating condition. While the etiology is unknown, many immune cells, such as macrophages, T cells and innate lymphoid cells, are implicated in the pathogenesis of the disease. Previous studies have shown the ability of micronutrient selenium (Se) and selenoproteins to impact inflammatory signaling pathways implicated in the pathogenesis of the disease. In particular, two transcription factors, nuclear factor-κB (NF-κB), and peroxisome proliferator activated receptor (PPAR)γ, which are involved in the activation of immune cells, and are also implicated in various stages of inflammation and resolution, respectively, are impacted by Se status. Available therapies for IBD produce detrimental side effects, resulting in the need for alternative therapies. Here, we review the current understanding of the role of NF-κB and PPARγ in the activation of immune cells during IBD, and how Se and selenoproteins modulate effective resolution of inflammation to be considered as a promising alternative to treat IBD.
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Affiliation(s)
- Shaneice K Nettleford
- Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, USA.
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA.
| | - K Sandeep Prabhu
- Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, USA.
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA.
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30
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Meli R, Pirozzi C, Pelagalli A. New Perspectives on the Potential Role of Aquaporins (AQPs) in the Physiology of Inflammation. Front Physiol 2018; 9:101. [PMID: 29503618 PMCID: PMC5820367 DOI: 10.3389/fphys.2018.00101] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 01/31/2018] [Indexed: 12/19/2022] Open
Abstract
Aquaporins (AQPs) are emerging, in the last few decades, as critical proteins regulating water fluid homeostasis in cells involved in inflammation. AQPs represent a family of ubiquitous membrane channels that regulate osmotically water flux in various tissues and sometimes the transport of small solutes, including glycerol. Extensive data indicate that AQPs, working as water channel proteins, regulate not only cell migration, but also common events essential for inflammatory response. The involvement of AQPs in several inflammatory processes, as demonstrated by their dysregulation both in human and animal diseases, identifies their new role in protection and response to different noxious stimuli, including bacterial infection. This contribution could represent a new key to clarify the dilemma of host-pathogen communications, and opens up new scenarios regarding the investigation of the modulation of specific AQPs, as target for new pharmacological therapies. This review provides updated information on the underlying mechanisms of AQPs in the regulation of inflammatory responses in mammals and discusses the broad spectrum of options that can be tailored for different diseases and their pharmacological treatment.
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Affiliation(s)
- Rosaria Meli
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Claudio Pirozzi
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Alessandra Pelagalli
- Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy.,Institute of Biostructure and Bioimaging, National Research Council (CNR), Naples, Italy
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31
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Hayashi R, Hayashi S, Sakai M, Arai K, Chikuda M, Machida S. Gender differences in mRNA expression of aquaporin 8 and glutathione peroxidase in cataractous lens following intake of an antioxidant supplement. Exp Eye Res 2018; 168:28-32. [PMID: 29317238 DOI: 10.1016/j.exer.2018.01.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2017] [Revised: 12/18/2017] [Accepted: 01/03/2018] [Indexed: 12/28/2022]
Abstract
Antioxidants can decrease oxidative damage and prevent age-related ocular disease. Our previous investigation on human aqueous humor following intake of a lutein-containing antioxidant supplement reported an increase in the scavenging activity of superoxide in both genders and an increase in the amount of hydrogen peroxide (H2O2) in females. Aquaporin 8 (AQP8) is a diffusion facilitator of H2O2 and glutathione peroxidase (Gpx) is a H2O2 scavenging enzyme. The correlation between AQP8 and Gpx may be the key to determining how oxidative stress in the aqueous humor affects the lens after intake of antioxidant supplements. In this study, 24 patients with the same grade of binocular cataract were included. Anterior capsule samples, including lens epithelial cells (LECs), were collected during cataract surgery before (as pre-intake samples) and after 6 weeks of oral intake of Ocuvite Lutein ® (as post-intake samples). The mRNA expression of APQ8 and Gpx was measured using real-time polymerase chain reaction. Among males, AQP8 expression decreased significantly after the supplementation (P = .03), while there was no statistical change among females. AQP8 expression was significantly correlated to that of Gpx in post-intake samples among females (R = 0.69, P = .02), while no correlation was evident among males. The results suggest antioxidant supplementation may work by different mechanisms on LECs between genders. After supplementation, a decrease in AQP8 in LECs may inhibit the influx of H2O2 from the aqueous humor in males. In females however, the correlation between AQP8 and Gpx in LECs may indicate an increase in Gpx activity following the influx of H2O2 from the aqueous humor and further scavenging of H2O2.
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Affiliation(s)
- Rijo Hayashi
- Department of Ophthalmology, Koshigaya Hospital, Dokkyo Medical University, Koshigaya, Saitama, Japan.
| | - Shimmin Hayashi
- Department of Ophthalmology, Koshigaya Hospital, Dokkyo Medical University, Koshigaya, Saitama, Japan; Lively Eye Clinic, Soka, Saitama, Japan.
| | - Miki Sakai
- Department of Ophthalmology, Koshigaya Hospital, Dokkyo Medical University, Koshigaya, Saitama, Japan.
| | - Kiyomi Arai
- Department of Ophthalmology, Koshigaya Hospital, Dokkyo Medical University, Koshigaya, Saitama, Japan.
| | - Makoto Chikuda
- Department of Ophthalmology, Koshigaya Hospital, Dokkyo Medical University, Koshigaya, Saitama, Japan.
| | - Shigeki Machida
- Department of Ophthalmology, Koshigaya Hospital, Dokkyo Medical University, Koshigaya, Saitama, Japan.
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32
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Yue X. Epithelial Deletion of Sulf2 Exacerbates Bleomycin-Induced Lung Injury, Inflammation, and Mortality. Am J Respir Cell Mol Biol 2017; 57:560-569. [PMID: 28657777 DOI: 10.1165/rcmb.2016-0367oc] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Epithelial injury has been proposed to be the initiating factor in the pathogenesis of idiopathic pulmonary fibrosis (IPF). We have shown previously that heparan sulfate 6-O-endosulfatase (Sulf) 2 is overexpressed in the hyperplastic type II alveolar epithelial cells (AECs) in the IPF lungs. By removing 6-O-sulfates from specific heparan sulfate intrachain sites, Sulf2 modulates the functions of many growth factors and cytokines. In this study, we hypothesized that Sulf2 plays a regulatory role in alveolar epithelial injury and repair, using the murine bleomycin model. Consistent with our findings in human IPF lungs, bleomycin treatment in mice resulted in up-regulation of Sulf2 mRNA in whole-lung extracts and overexpression of Sulf2 protein in type II AECs on lung tissue sections. Sulf2 protein was detectable in bronchoalveolar lavage fluid at baseline, and its level was significantly increased after bleomycin exposure. To study the role of Sulf2 in alveolar injury and repair in vivo, we generated a doxycycline-inducible epithelial-specific Sulf2 conditional knockout (Sulf2 CKO) mouse line. After bleomycin exposure, Sulf2 CKO mice exhibited enhanced neutrophil infiltration in the lung, with elevated levels of total protein, lactate dehydrogenase, and cytokines (granulocyte colony-stimulating factor and interferon-γ-inducible protein 10) in bronchoalveolar lavage fluid compared with wild-type littermates. We further showed that both the p53-p21 DNA damage response and the transforming growth factor-β1 signaling pathway were up-regulated in Sulf2 CKO mice compared with wild-type. Finally, Sulf2 CKO mice suffered increased mortality after bleomycin exposure. In conclusion, Sulf2 expression in type II AECs plays a protective role in epithelial injury, inflammation and mortality.
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Affiliation(s)
- Xinping Yue
- Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, Louisiana
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33
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Hayashi R, Hayashi S, Fukuda K, Sakai M, Machida S. Immunolocation of Aquaporin 8 in Human Cataractous Lenticular Epithelial Cells. Biomed Hub 2017; 2:1-5. [PMID: 31988920 PMCID: PMC6945952 DOI: 10.1159/000480290] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 08/14/2017] [Indexed: 12/11/2022] Open
Abstract
Purpose/Aim Aquaporin 8 (AQP8) is a diffusion facilitator of hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) through cell membranes. The purpose of this study was to confirm and localize AQP8 in human lenticular epithelial cells (LECs). Materials and Methods Lenticular anterior capsule samples, including LECs, were collected during cataract surgery of cataract patients after informed consent. The localization of AQP8 was detected by immunohistochemical staining using an antibody to AQP8. Real-time polymerase chain reaction (RT-PCR) was also used to determine the AQP8 mRNA expression levels. The PCR products were analyzed by gel electrophoresis following analyses of band density. Results Immunohistochemical staining showed AQP8 was distributed throughout the whole area of the anterior capsulotomy. AQP8 labeling was observed surrounding and within the cytoplasm of LECs. RT-PCR and gel electrophoresis also revealed the presence of AQP8 mRNA in the lenticular anterior capsule. The results of immunohistochemical staining were comparable to those of RT-PCR and gel electrophoresis. Conclusions The results of this study indicate the distribution of AQP8 in human LECs. This is the first investigation confirming the presence of AQP8 in human LECs.
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Affiliation(s)
- Rijo Hayashi
- Department of Ophthalmology, Koshigaya Hospital, Dokkyo Medical University, Koshigaya, Japan
| | - Shimmin Hayashi
- Department of Ophthalmology, Koshigaya Hospital, Dokkyo Medical University, Lively Eye Clinic, Koshigaya, Japan
| | - Kazunori Fukuda
- Koshigaya Hospital Joint Research Center, Dokkyo Medical University, Koshigaya, Japan
| | - Miki Sakai
- Department of Ophthalmology, Koshigaya Hospital, Dokkyo Medical University, Koshigaya, Japan
| | - Shigeki Machida
- Department of Ophthalmology, Koshigaya Hospital, Dokkyo Medical University, Koshigaya, Japan
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34
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Tian T, Wang Z, Zhang J. Pathomechanisms of Oxidative Stress in Inflammatory Bowel Disease and Potential Antioxidant Therapies. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:4535194. [PMID: 28744337 PMCID: PMC5506473 DOI: 10.1155/2017/4535194] [Citation(s) in RCA: 411] [Impact Index Per Article: 51.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 05/22/2017] [Accepted: 05/31/2017] [Indexed: 12/22/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic gastrointestinal disease whose incidence has risen worldwide in recent years. Accumulating evidence shows that oxidative stress plays an essential role in the pathogenesis and progression of IBD. This review highlights the generation of reactive oxygen species (ROS) and antioxidant defense mechanisms in the gastrointestinal (GI) tract, the involvement of oxidative stress signaling in the initiation and progression of IBD and its relationships with genetic susceptibility and the mucosal immune response. In addition, potential therapeutic strategies for IBD that target oxidative stress signaling are reviewed and discussed. Though substantial progress has been made in understanding the role of oxidative stress in IBD in humans and experimental animals, the underlying mechanisms are still not well defined. Thus, further studies are needed to validate how oxidative stress signaling is involved in and contributes to the development of IBD.
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Affiliation(s)
- Tian Tian
- College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China
| | - Ziling Wang
- College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China
| | - Jinhua Zhang
- College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China
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35
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Jones RM, Neish AS. Redox signaling mediated by the gut microbiota. Free Radic Biol Med 2017; 105:41-47. [PMID: 27989756 DOI: 10.1016/j.freeradbiomed.2016.10.495] [Citation(s) in RCA: 125] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 10/17/2016] [Accepted: 10/21/2016] [Indexed: 12/27/2022]
Abstract
The microbiota that inhabits the mammalian intestine can influence a range of physiological functions, including the modulation of immune responses, enhancement epithelial barrier function, and the stimulation of cell proliferation. While the mechanisms by which commensal prokaryotes stimulate immune signaling networks are well-characterized, less is known about the mechanistic control over homeostatic pathways within tissues. Recent reports by our research group have demonstrated that contact between the gut epithelia and some groups of enteric commensal bacteria prompts the rapid generation of reactive oxygen species (ROS) within host cells. Whereas the bacterial-induced production of ROS in phagocytes in response to ligand binding to Formyl Peptide Receptors (FPRs) and ensuing activation of NADPH oxidase 2 (Nox2) is a well-defined mechanism, ROS generated by other cell types such as intestinal epithelia in response to microbial signals via FPRs and the NADPH oxidase 1 (Nox1) is less appreciated. Importantly, enzymatically generated ROS have been shown to function as second messengers in many signal transduction pathways via the transient oxidative activity on sensor proteins bearing oxidant-sensitive thiol groups. Examples of redox sensitive proteins include tyrosine phosphatases that serve as regulators of MAPK pathways, focal adhesion kinase, as well as components involved NF-kB activation. Here, we review the leading edge discoveries gleaned from investigations that focus on microbial-induced generation of ROS and their functional effects on host physiology. These studies identify the functional molecular elements and mechanistic events that mediate the established effects of the normal microbiota on intestinal physiology.
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Affiliation(s)
- Rheinallt M Jones
- Department of Pediatrics, Emory University School of Medicine, Whitehead Biomedical Research Building, 615 Michaels St, Room 105-L, Atlanta, GA 30322, United States
| | - Andrew S Neish
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Whitehead Biomedical Research Building, 615 Michaels St, Room 105-L, Atlanta, GA 30322, United States.
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Pérez S, Taléns-Visconti R, Rius-Pérez S, Finamor I, Sastre J. Redox signaling in the gastrointestinal tract. Free Radic Biol Med 2017; 104:75-103. [PMID: 28062361 DOI: 10.1016/j.freeradbiomed.2016.12.048] [Citation(s) in RCA: 181] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Revised: 12/20/2016] [Accepted: 12/31/2016] [Indexed: 12/16/2022]
Abstract
Redox signaling regulates physiological self-renewal, proliferation, migration and differentiation in gastrointestinal epithelium by modulating Wnt/β-catenin and Notch signaling pathways mainly through NADPH oxidases (NOXs). In the intestine, intracellular and extracellular thiol redox status modulates the proliferative potential of epithelial cells. Furthermore, commensal bacteria contribute to intestine epithelial homeostasis through NOX1- and dual oxidase 2-derived reactive oxygen species (ROS). The loss of redox homeostasis is involved in the pathogenesis and development of a wide diversity of gastrointestinal disorders, such as Barrett's esophagus, esophageal adenocarcinoma, peptic ulcer, gastric cancer, ischemic intestinal injury, celiac disease, inflammatory bowel disease and colorectal cancer. The overproduction of superoxide anion together with inactivation of superoxide dismutase are involved in the pathogenesis of Barrett's esophagus and its transformation to adenocarcinoma. In Helicobacter pylori-induced peptic ulcer, oxidative stress derived from the leukocyte infiltrate and NOX1 aggravates mucosal damage, especially in HspB+ strains that downregulate Nrf2. In celiac disease, oxidative stress mediates most of the cytotoxic effects induced by gluten peptides and increases transglutaminase levels, whereas nitrosative stress contributes to the impairment of tight junctions. Progression of inflammatory bowel disease relies on the balance between pro-inflammatory redox-sensitive pathways, such as NLRP3 inflammasome and NF-κB, and the adaptive up-regulation of Mn superoxide dismutase and glutathione peroxidase 2. In colorectal cancer, redox signaling exhibits two Janus faces: On the one hand, NOX1 up-regulation and derived hydrogen peroxide enhance Wnt/β-catenin and Notch proliferating pathways; on the other hand, ROS may disrupt tumor progression through different pro-apoptotic mechanisms. In conclusion, redox signaling plays a critical role in the physiology and pathophysiology of gastrointestinal tract.
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Affiliation(s)
- Salvador Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain
| | - Raquel Taléns-Visconti
- Department of Pharmacy and Pharmaceutical Technology and Parasitology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain
| | - Sergio Rius-Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain
| | - Isabela Finamor
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain
| | - Juan Sastre
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain.
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Kim JE, Go J, Sung JE, Lee HA, Yun WB, Hong JT, Hwang DY. Uridine stimulate laxative effect in the loperamide-induced constipation of SD rats through regulation of the mAChRs signaling pathway and mucin secretion. BMC Gastroenterol 2017; 17:21. [PMID: 28122499 PMCID: PMC5267432 DOI: 10.1186/s12876-017-0576-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Accepted: 01/18/2017] [Indexed: 12/12/2022] Open
Abstract
Background Uridine (Urd), which has been reported as a major component of RNA, plays an important role in various biological process including neuroprotection, biochemical modulation and glycolysis, although its role in constipation has yet to be established. Therefore, in this study, we investigated the laxative effects of Urd on chronic constipation. Methods The constipation phenotypes and their related mechanisms were investigated in the transverse colons of SD rats with loperamide (Lop)-induced constipation after treatment with 100 mg/kg of Urd. Results The number, weight and water contents of stools were significantly higher in the Lop + Urd treated group than the Lop + Vehicle treated group, while food intake and water consumption of the same group were maintained at a constant level. The thickness of the mucosa layer, muscle and flat luminal surface, as well as the number of goblet cells, paneth cells and lipid droplets were enhanced in the Lop + Urd treated group. Furthermore, the expression of the muscarinic acetylcholine receptors M2 and M3 (mAChR M2 and M3) at the transcriptional and translational level was recovered in the Lop + Urd treated group, while some markers such as Gα and inositol triphosphate (IP3) in their downstream signaling pathway were completely recovered by Urd treatment. Moreover, the ability for mucin secretion and the expression of membrane water channel (aquaporine 8, AQP8) were increased significantly in the Lop + Urd treated group compared with Lop + Vehicle treated group. Finally, the activity of Urd was confirmed in primary smooth muscle of rat intestine cells (pRISMC) based on Gα expression and IP3 concentration. Conclusions The results of the present study provide the first strong evidence that Urd can be considered an important candidate for improving chronic constipation induced by Lop treatment in animal models.
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Affiliation(s)
- Ji Eun Kim
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, 50 Cheonghak-ri, Samnangjin-eup Miryang-si, Gyeongsangnam-do, 627-706, Korea
| | - Jun Go
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, 50 Cheonghak-ri, Samnangjin-eup Miryang-si, Gyeongsangnam-do, 627-706, Korea
| | - Ji Eun Sung
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, 50 Cheonghak-ri, Samnangjin-eup Miryang-si, Gyeongsangnam-do, 627-706, Korea
| | - Hyun Ah Lee
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, 50 Cheonghak-ri, Samnangjin-eup Miryang-si, Gyeongsangnam-do, 627-706, Korea
| | - Woo Bin Yun
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, 50 Cheonghak-ri, Samnangjin-eup Miryang-si, Gyeongsangnam-do, 627-706, Korea
| | - Jin Tae Hong
- College of Pharmacy, Chungbuk National University, Chungju, 361-763, Korea
| | - Dae Youn Hwang
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, 50 Cheonghak-ri, Samnangjin-eup Miryang-si, Gyeongsangnam-do, 627-706, Korea.
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Jin X, Chen D, Zheng RH, Zhang H, Chen YP, Xiang Z. miRNA-133a-UCP2 pathway regulates inflammatory bowel disease progress by influencing inflammation, oxidative stress and energy metabolism. World J Gastroenterol 2017; 23:76-86. [PMID: 28104982 PMCID: PMC5221288 DOI: 10.3748/wjg.v23.i1.76] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 10/09/2016] [Accepted: 11/16/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the role of the miR-133a-UCP2 pathway in the pathogenesis of inflammatory bowel disease (IBD) and to explore the potential downstream mechanisms with respect to inflammation, oxidative stress and energy metabolism.
METHODS C57BL/6 mice were fed dextran sulfate sodium (DSS) liquid for 7 consecutive days, followed by the administration of saline to the DSS group, UCP2 siRNA to the UCP2 group and a miR-133a mimic to the miR-133a group on days 8 and 11. Body weight, stool consistency and rectal bleeding were recorded daily, and these composed the disease activity index (DAI) score for the assessment of disease severity. After cervical dislocation was performed on day 14, the length of the colon in each mouse was measured, and colonic tissue was collected for further study, which included the following: haematoxylin and eosin staining, UCP2 and miR-133a detection by immunohistochemical staining, western blot and quantitative real-time PCR, measurement of apoptosis by TUNEL assay, and the assessment of inflammation (TNF-α, IL-1β, IL-6 and MCP1), oxidative stress (H2O2 and MDA) and metabolic parameters (ATP) by ELISA and colorimetric methods.
RESULTS An animal model of IBD was successfully established, as shown by an increased DAI score, shortened colon length and specific pathologic changes, along with significantly increased UCP2 and decreased miR-133a levels. Compared with the DSS group, the severity of IBD was alleviated in the UCP2 and the miR-133a groups after successful UCP2 knockdown and miR-133a overexpression. The extent of apoptosis, as well as the levels of TNF-α, IL-1β, MDA and ATP, were significantly increased in both the UCP2 and miR-133a groups compared with the DSS group.
CONCLUSION The miR-133a-UCP2 pathway participates in IBD by altering downstream inflammation, oxidative stress and markers of energy metabolism, which provides novel clues and potential therapeutic targets for IBD.
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Colonic and Hepatic Modulation by Lipoic Acid and/or N-Acetylcysteine Supplementation in Mild Ulcerative Colitis Induced by Dextran Sodium Sulfate in Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:4047362. [PMID: 27957238 PMCID: PMC5124475 DOI: 10.1155/2016/4047362] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 10/03/2016] [Accepted: 10/10/2016] [Indexed: 02/07/2023]
Abstract
Lipoic acid (LA) and N-acetylcysteine (NAC) are antioxidant and anti-inflammatory agents that have not yet been tested on mild ulcerative colitis (UC). This study aims to evaluate the action of LA and/or NAC, on oxidative stress and inflammation markers in colonic and hepatic rat tissues with mild UC, induced by dextran sodium sulfate (DSS) (2% w/v). LA and/or NAC (100 mg·kg·day-1, each) were given, once a day, in the diet, in a pretreatment phase (7 days) and during UC induction (5 days). Colitis induction was confirmed by histological and biochemical analyses (high performance liquid chromatography, spectrophotometry, and Multiplex®). A redox imbalance occurred before an immunological disruption in the colon. NAC led to a decrease in hydrogen peroxide (H2O2), malondialdehyde (MDA) levels, and myeloperoxidase activity. In the liver, DSS did not cause damage but treatments with both antioxidants were potentially harmful, with LA increasing MDA and LA + NAC increasing H2O2, tumor necrosis factor alpha, interferon gamma, and transaminases. In summary, NAC exhibited the highest colonic antioxidant and anti-inflammatory activity, while LA + NAC caused hepatic damage.
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Selenoproteins and oxidative stress-induced inflammatory tumorigenesis in the gut. Cell Mol Life Sci 2016; 74:607-616. [PMID: 27563706 DOI: 10.1007/s00018-016-2339-2] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 08/02/2016] [Accepted: 08/09/2016] [Indexed: 12/11/2022]
Abstract
Selenium is an essential micronutrient that is incorporated into at least 25 selenoproteins encoded by the human genome, many of which serve antioxidant functions. Because patients with inflammatory bowel disease (IBD) demonstrate nutritional deficiencies and are at increased risk for colon cancer due to heightened inflammation and oxidative stress, selenoprotein dysfunction may contribute to disease progression. Over the years, numerous studies have analyzed the effects of selenoprotein loss and shown that they are important mediators of intestinal inflammation and carcinogenesis. In particular, recent work has focused on the role of selenoprotein P (SEPP1), a major selenium transport protein which also has endogenous antioxidant function. These experiments determined SEPP1 loss altered immune and epithelial cellular function in a murine model of colitis-associated carcinoma. Here, we discuss the current knowledge of SEPP1 and selenoprotein function in the setting of IBD, colitis, and inflammatory tumorigenesis.
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Abstract
Voltage-gated ion channels are key regulators of cell excitability. There is significant evidence that these channels are subject to modulation by redox status of the cells. Here we review the post-translational modifications of ion channels that occur in colonic inflammation. The redox mechanisms involve tyrosine nitration, covalent modification of cysteine residues and sulfhydration by hydrogen sulfide in experimental colitis. In the setting of colonic inflammation, modifications of cysteine and tyrosine are likely to occur at several sites within the same channel complex. In this review we describe alterations in channel function due to specific modifications of tyrosine and cysteine residues by reactive nitrogen, oxygen and hydrogen-sulfide resulting in altered motility.
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Affiliation(s)
- Hamid I Akbarali
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, 1112 East Clay Street, McGuire Hall Rm# 317, Richmond, VA 23298, USA Country.
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Kudva AK, Shay AE, Prabhu KS. Selenium and inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 2015; 309:G71-7. [PMID: 26045617 PMCID: PMC4504954 DOI: 10.1152/ajpgi.00379.2014] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 05/31/2015] [Indexed: 01/31/2023]
Abstract
Dietary intake of the micronutrient selenium is essential for normal immune functions. Selenium is cotranslationally incorporated as the 21st amino acid, selenocysteine, into selenoproteins that function to modulate pathways involved in inflammation. Epidemiological studies have suggested an inverse association between selenium levels and inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis that can potentially progress to colon cancer. However, the underlying mechanisms are not well understood. Here we summarize the current literature on the pathophysiology of IBD, which is multifactorial in origin with unknown etiology. We have focused on a few selenoproteins that mediate gastrointestinal inflammation and activate the host immune response, wherein macrophages play a pivotal role. Changes in cellular oxidative state coupled with altered expression of selenoproteins in macrophages drive the switch from a proinflammatory phenotype to an anti-inflammatory phenotype to efficiently resolve inflammation in the gut and restore epithelial barrier integrity. Such a phenotypic plasticity is accompanied by changes in cytokines, chemokines, and bioactive metabolites, including eicosanoids that not only mitigate inflammation but also partake in restoring gut homeostasis through diverse pathways involving differential regulation of transcription factors such as nuclear factor-κB and peroxisome proliferator-activated receptor-γ. The role of the intestinal microbiome in modulating inflammation and aiding in selenium-dependent resolution of gut injury is highlighted to provide novel insights into the beneficial effects of selenium in IBD.
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Affiliation(s)
- Avinash K. Kudva
- Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania
| | - Ashley E. Shay
- Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania
| | - K. Sandeep Prabhu
- Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania
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Li FX, Huang LZ, Dong C, Wang JP, Wu HJ, Shuang SM. Down-regulation of aquaporin3 expression by lipopolysaccharide via p38/c-Jun N-terminal kinase signalling pathway in HT-29 human colon epithelial cells. World J Gastroenterol 2015; 21:4547-4554. [PMID: 25914463 PMCID: PMC4402301 DOI: 10.3748/wjg.v21.i15.4547] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2014] [Revised: 12/07/2014] [Accepted: 01/08/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the influence of lipopolysaccharide (LPS) through the p38/c-Jun N-terminal kinase (JNK) signalling pathway on aquaporin 3 (AQP3) expression in HT-29 human colon epithelial cells.
METHODS: HT-29 cells were treated with LPS, and then the membrane localisation of AQP3 was examined by immunofluorescence staining. The mRNA and protein expression of AQP3 with LPS exposure was measured by real-time reverse transcription-PCR and Western blot, respectively. Activation of p38 and JNK was evaluated by detection of phosphorylation of p38 and JNK using Western blot assay. AQP3 protein expression was determined by Western blot in cells after treatment with SB203580, a selective p38 MAPK inhibitor, or SP600125, a selective JNK inhibitor.
RESULTS: In HT-29 cells, the transcription and protein expression of AQP3 were decreased by LPS in a dose- and time-dependent manner, the expression of AQP3 was significantly decreased with the increased concentration of LPS, and at a dose of 100 μg/mL LPS, AQP3 mRNA and protein levels were decreased by a maximum (P < 0.05) of 1.51-fold and 1.49-fold, respectively. When cells were treated with 100 μg/mL LPS for 0, 3, 6, 12, and 24 h, the AQP3 mRNA level was significantly decreased at an early time point of 3 h, and reached about 10% of the control level at 24 h post-treatment (P < 0.05). Down-regulation of AQP3 expression was significantly inhibited by the p38 inhibitor (SB203580) and JNK inhibitor (SP600125).
CONCLUSION: p38 and JNK may be promising targets for the preservation of AQP3 expression and may be beneficial to the clinical management of diarrhoea.
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Ricanek P, Lunde LK, Frye SA, Støen M, Nygård S, Morth JP, Rydning A, Vatn MH, Amiry-Moghaddam M, Tønjum T. Reduced expression of aquaporins in human intestinal mucosa in early stage inflammatory bowel disease. Clin Exp Gastroenterol 2015; 8:49-67. [PMID: 25624769 PMCID: PMC4296881 DOI: 10.2147/ceg.s70119] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Objectives The aim of this study was to investigate the relationship between aquaporin (AQP) water channel expression and the pathological features of early untreated inflammatory bowel disease (IBD) in humans. Methods Patients suspected to have IBD on the basis of predefined symptoms, including abdominal pain, diarrhea, and/or blood in stool for more than 10 days, were examined at the local hospital. Colonoscopy with biopsies was performed and blood samples were taken. Patients who did not meet the diagnostic criteria for IBD and who displayed no evidence of infection or other pathology in the gut were included as symptomatic non-IBD controls. AQP1, 3, 4, 5, 7, 8, and 9 messenger RNA (mRNA) levels were quantified in biopsies from the distal ileum and colon by quantitative real-time polymerase chain reaction. Protein expression of selected AQPs was assessed by confocal microscopy. Through multiple alignments of the deduced amino acid sequences, the putative three-dimensional structures of AQP1, 3, 7, and 8 were modeled. Results AQP1, 3, 7, and 8 mRNAs were detected in all parts of the intestinal mucosa. Notably, AQP1 and AQP3 mRNA levels were reduced in the ileum of patients with Crohn’s disease, and AQP7 and AQP8 mRNA levels were reduced in the ileum and the colon of patients with ulcerative colitis. Immunofluorescence confocal microscopy showed localization of AQP3, 7, and 8 at the mucosal epithelium, whereas the expression of AQP1 was mainly confined to the endothelial cells and erythrocytes. The reduction in the level of AQP3, 7, and 8 mRNA was confirmed by immunofluorescence, which also indicated a reduction of apical immunolabeling for AQP8 in the colonic surface epithelium and crypts of the IBD samples. This could indicate loss of epithelial polarity in IBD, leading to disrupted barrier function. Conclusion AQPs 1 and 8 and the aquaglyceroporins AQPs 3 and 7 are the AQPs predominantly expressed in the lower intestinal tract of humans. Their expression is significantly reduced in patients with IBD, and they are differentially expressed in specific bowel segments in patients with Crohn’s disease and ulcerative colitis. The data present a link between gut inflammation and water/solute homeostasis, suggesting that AQPs may play a significant role in IBD pathophysiology.
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Affiliation(s)
- Petr Ricanek
- Department of Microbiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway ; Department of Gastroenterology, Akershus University Hospital, Lørenskog and Campus Ahus, Institute of Clinical Medicine, University of Oslo, Lørenskog, Norway
| | - Lisa K Lunde
- Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Norway
| | - Stephan A Frye
- Department of Microbiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Mari Støen
- Department of Microbiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Ståle Nygård
- Bioinformatics Core Facility, Institute for Medical Informatics, Oslo University Hospital and University of Oslo, Norway
| | - Jens P Morth
- Centre for Molecular Medicine, Nordic EMBL Partnership, University of Oslo, Norway ; Institute for Experimental Research, Oslo University Hospital (Ullevaal), Oslo, Norway
| | - Andreas Rydning
- Department of Gastroenterology, Akershus University Hospital, Lørenskog and Campus Ahus, Institute of Clinical Medicine, University of Oslo, Lørenskog, Norway
| | - Morten H Vatn
- EpiGen Institute, Campus Ahus, Institute of Clinical Medicine, University of Oslo, Lørenskog, Norway ; Section of Gastroenterology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | | | - Tone Tønjum
- Department of Microbiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway ; Department of Microbiology, University of Oslo, Oslo, Norway
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Welch MG, Margolis KG, Li Z, Gershon MD. Oxytocin regulates gastrointestinal motility, inflammation, macromolecular permeability, and mucosal maintenance in mice. Am J Physiol Gastrointest Liver Physiol 2014; 307:G848-62. [PMID: 25147234 PMCID: PMC4200316 DOI: 10.1152/ajpgi.00176.2014] [Citation(s) in RCA: 102] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Accepted: 08/18/2014] [Indexed: 01/31/2023]
Abstract
Enteric neurons express oxytocin (OT); moreover, enteric neurons and enterocytes express developmentally regulated OT receptors (OTRs). Although OT (with secretin) opposes intestinal inflammation, physiological roles played by enteric OT/OTR signaling have not previously been determined. We tested hypotheses that OT/OTR signaling contributes to enteric nervous system (ENS)-related gastrointestinal (GI) physiology. GI functions and OT effects were compared in OTR-knockout (OTRKO) and wild-type (WT) mice. Stool mass and water content were greater in OTRKO mice than in WT. GI transit time in OTRKO animals was faster than in WT; OT inhibited in vitro generation of ENS-dependent colonic migrating motor complexes in WT but not in OTRKO mice. Myenteric neurons were hyperplastic in OTRKO animals, and mucosal exposure to cholera toxin (CTX) in vitro activated Fos in more myenteric neurons in OTRKO than WT than in WT mice; OT inhibited the CTX response in WT but not in OTRKO mice. Villi and crypts were shorter in OTRKO than in WT mice, and transit-amplifying cell proliferation in OTRKO crypts was deficient. Macromolecular intestinal permeability in OTRKO was greater than WT mice, and experimental colitis was more severe in OTRKO mice; moreover, OT protected WT animals from colitis. Observations suggest that OT/OTR signaling acts as a brake on intestinal motility, decreases mucosal activation of enteric neurons, and promotes enteric neuronal development and/or survival. It also regulates proliferation of crypt cells and mucosal permeability; moreover OT/OTR signaling is protective against inflammation. Oxytocinergic signaling thus appears to play an important role in multiple GI functions that are subject to neuronal regulation.
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Affiliation(s)
- Martha G Welch
- Department of Psychiatry, Pediatrics, and Pathology and Cell Biology, Columbia University, College of Physicians and Surgeons, New York, New York
| | - Kara G Margolis
- Department of Psychiatry, Pediatrics, and Pathology and Cell Biology, Columbia University, College of Physicians and Surgeons, New York, New York
| | - Zhishan Li
- Department of Psychiatry, Pediatrics, and Pathology and Cell Biology, Columbia University, College of Physicians and Surgeons, New York, New York
| | - Michael D Gershon
- Department of Psychiatry, Pediatrics, and Pathology and Cell Biology, Columbia University, College of Physicians and Surgeons, New York, New York
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Sakai H, Sato K, Kai Y, Shoji T, Hasegawa S, Nishizaki M, Sagara A, Yamashita A, Narita M. Distribution of aquaporin genes and selection of individual reference genes for quantitative real-time RT-PCR analysis in multiple tissues of the mouse. Can J Physiol Pharmacol 2014; 92:789-96. [PMID: 25188728 DOI: 10.1139/cjpp-2014-0157] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Aquaporins (AQPs) are a family of water-transporting proteins that are selectively expressed in epithelial, endothelial, and many other cell types of various tissues, where they play important physiological functions. However, the accurate distribution of AQP gene expression has not yet been examined in various tissues of the mouse. We first evaluated the tissue distribution of AQP gene expression using tongue, nasal epithelium, bronchus, trachea, lung, esophagus, stomach, ileum, transverse colon, liver, pancreas, whole blood, thigh muscle, spinal cord, brain, thoracic aorta, heart, kidney, thymus, spleen, skin, eye, and testis of the mouse. Furthermore, for a quantitative analysis, we selected appropriate reference genes for normalized qRT-PCR data in various tissues. The stability of the reference genes was assessed using NormFinder. The stably expressed genes identified in the present study were 18s rRNA. When 18s rRNA was used, as the best reference gene in the present study, the genes for AQPs 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, and 12 were notably expressed in the eye, lung, testis, eye, spinal cord, trachea, kidney, testis, testis, testis, testis, and pancreas. These results, regarding the distribution of AQPs, suggest that AQPs may be involved in various physiological and pathophysiological processes.
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Affiliation(s)
- Hiroyasu Sakai
- a Division of Pharmacy Professional Development & Research, School of Pharmacy, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
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Piechota-Polanczyk A, Fichna J. Review article: the role of oxidative stress in pathogenesis and treatment of inflammatory bowel diseases. Naunyn Schmiedebergs Arch Pharmacol 2014; 387:605-20. [PMID: 24798211 PMCID: PMC4065336 DOI: 10.1007/s00210-014-0985-1] [Citation(s) in RCA: 273] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Accepted: 04/24/2014] [Indexed: 12/12/2022]
Abstract
In this review, we focus on the role of oxidative stress in the aetiology of inflammatory bowel diseases (IBD) and colitis-associated colorectal cancer and discuss free radicals and free radical-stimulated pathways as pharmacological targets for anti-IBD drugs. We also suggest novel anti-oxidative agents, which may become effective and less-toxic alternatives in IBD and colitis-associated colorectal cancer treatment. A Medline search was performed to identify relevant bibliography using search terms including: ‘free radicals,’ ‘antioxidants,’ ‘oxidative stress,’ ‘colon cancer,’ ‘ulcerative colitis,’ ‘Crohn’s disease,’ ‘inflammatory bowel disease.’ Several therapeutics commonly used in IBD treatment, among which are immunosuppressants, corticosteroids and anti-TNF-α antibodies, could also affect the IBD progression by interfering with cellular oxidative stress and cytokine production. Experimental data shows that these drugs may effectively scavenge free radicals, increase anti-oxidative capacity of cells, influence multiple signalling pathways, e.g. MAPK and NF-kB, and inhibit pro-oxidative enzyme and cytokine concentration. However, their anti-oxidative and anti-inflammatory effectiveness still needs further investigation. A highly specific antioxidative activity may be important for the clinical treatment and relapse of IBD. In the future, a combination of currently used pharmaceutics, together with natural and synthetic anti-oxidative compounds, like lipoic acid or curcumine, could be taken into account in the design of novel anti-IBD therapies.
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Cooked navy and black bean diets improve biomarkers of colon health and reduce inflammation during colitis. Br J Nutr 2014; 111:1549-63. [PMID: 24521520 DOI: 10.1017/s0007114513004352] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Common beans contain non-digestible fermentable components (SCFA precursors) and phenolic compounds (phenolic acids, flavonoids and anthocyanins) with demonstrated antioxidant and anti-inflammatory potential. The objective of the present study was to assess the in vivo effect of cooked whole-bean flours, with differing phenolic compound levels and profiles, in a mouse model of acute colitis. C57BL/6 mice were fed a 20 % navy bean or black bean flour-containing diet or an isoenergetic basal diet (BD) for 2 weeks before the induction of experimental colitis via 7 d dextran sodium sulphate (DSS, 2 % (w/v) in the drinking-water) exposure. Compared with the BD, both bean diets increased caecal SCFA and faecal phenolic compound concentrations (P< 0·05), which coincided with both beneficial and adverse effects on colonic and systemic inflammation. On the one hand, bean diets reduced mRNA expression of colonic inflammatory cytokines (IL-6, IL-9, IFN-γ and IL-17A) and increased anti-inflammatory IL-10 (P< 0·05), while systemically reduced circulating cytokines (IL-1β, TNFα, IFNγ, and IL-17A, P< 0·05) and DSS-induced oxidative stress. On the other hand, bean diets enhanced DSS-induced colonic damage as indicated by an increased histological injury score and apoptosis (cleaved caspase-3 and FasL mRNA expression) (P< 0·05). In conclusion, bean-containing diets exerted both beneficial and adverse effects during experimental colitis by reducing inflammatory biomarkers both locally and systemically while aggravating colonic mucosal damage. Further research is required to understand the mechanisms through which beans exert their effects on colonic inflammation and the impact on colitis severity in human subjects.
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Latorre E, Matheus N, Layunta E, Alcalde AI, Mesonero JE. IL-10 counteracts proinflammatory mediator evoked oxidative stress in Caco-2 cells. Mediators Inflamm 2014; 2014:982639. [PMID: 25147442 PMCID: PMC4132333 DOI: 10.1155/2014/982639] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Revised: 07/11/2014] [Accepted: 07/12/2014] [Indexed: 01/04/2023] Open
Abstract
Oxidative stress is thought to play a key role in the development of intestinal damage in intestinal inflammatory diseases. Several molecules are involved in the intestinal inflammation, either as pro- or anti-inflammatory factors; however, their effects on intestinal oxidative stress seem to be controversial. This work analyzes the contribution of pro- and anti-inflammatory molecules to the balance of oxidative damage in intestinal epithelial cells, as well as their effects on cellular antioxidant enzyme activity. With this purpose, the lipid and protein oxidation, together with the activity of catalase, superoxide dismutase, and glutathione peroxidase, were determined in the Caco-2 cells treated with serotonin, adenosine, melatonin, and TNFα, as proinflammatory factors, and IL-10, as an anti-inflammatory cytokine. The results have shown that all the proinflammatory factors assayed increased oxidative damage. In addition, these factors also inhibited the activity of antioxidant enzymes in the cells, except melatonin. In contrast, IL-10 did not alter these parameters but was able to reduce the prooxidant effects yielded by serotonin, adenosine, melatonin, or TNFα, in part by restoring the antioxidant enzymes activities. In summary, proinflammatory factors may induce oxidative damage in intestinal epithelial cells, whereas IL-10 seems to be able to restore the altered redox equilibrium in Caco-2 cells.
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Affiliation(s)
- Eva Latorre
- 1Department of Pharmacology and Physiology, Faculty of Veterinary Sciences, University of Zaragoza, Miguel Servet 177, 50013 Zaragoza, Spain
| | - Nyurky Matheus
- 1Department of Pharmacology and Physiology, Faculty of Veterinary Sciences, University of Zaragoza, Miguel Servet 177, 50013 Zaragoza, Spain
- 2Department of Basic Sciences, Faculty of Veterinary Sciences, University of Centroccidental Lisandro Alvarado, Núcleo Hector Ochoa Zuleta, Tarabana 3023, Lara, Venezuela
| | - Elena Layunta
- 1Department of Pharmacology and Physiology, Faculty of Veterinary Sciences, University of Zaragoza, Miguel Servet 177, 50013 Zaragoza, Spain
| | - Ana Isabel Alcalde
- 1Department of Pharmacology and Physiology, Faculty of Veterinary Sciences, University of Zaragoza, Miguel Servet 177, 50013 Zaragoza, Spain
| | - José Emilio Mesonero
- 1Department of Pharmacology and Physiology, Faculty of Veterinary Sciences, University of Zaragoza, Miguel Servet 177, 50013 Zaragoza, Spain
- *José Emilio Mesonero:
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Biasi F, Leonarduzzi G, Oteiza PI, Poli G. Inflammatory bowel disease: mechanisms, redox considerations, and therapeutic targets. Antioxid Redox Signal 2013; 19:1711-47. [PMID: 23305298 PMCID: PMC3809610 DOI: 10.1089/ars.2012.4530] [Citation(s) in RCA: 212] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Oxidative stress is thought to play a key role in the development of intestinal damage in inflammatory bowel disease (IBD), because of its primary involvement in intestinal cells' aberrant immune and inflammatory responses to dietary antigens and to the commensal bacteria. During the active disease phase, activated leukocytes generate not only a wide spectrum of pro-inflammatory cytokines, but also excess oxidative reactions, which markedly alter the redox equilibrium within the gut mucosa, and maintain inflammation by inducing redox-sensitive signaling pathways and transcription factors. Moreover, several inflammatory molecules generate further oxidation products, leading to a self-sustaining and auto-amplifying vicious circle, which eventually impairs the gut barrier. The current treatment of IBD consists of long-term conventional anti-inflammatory therapy and often leads to drug refractoriness or intolerance, limiting patients' quality of life. Immune modulators or anti-tumor necrosis factor α antibodies have recently been used, but all carry the risk of significant side effects and a poor treatment response. Recent developments in molecular medicine point to the possibility of treating the oxidative stress associated with IBD, by designing a proper supplementation of specific lipids to induce local production of anti-inflammatory derivatives, as well as by developing biological therapies that target selective molecules (i.e., nuclear factor-κB, NADPH oxidase, prohibitins, or inflammasomes) involved in redox signaling. The clinical significance of oxidative stress in IBD is now becoming clear, and may soon lead to important new therapeutic options to lessen intestinal damage in this disease.
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Affiliation(s)
- Fiorella Biasi
- 1 Department of Clinical and Biological Sciences, University of Turin , San Luigi Gonzaga Hospital, Orbassano, Italy
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