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Chen T, Ly H, Stairs DB, Jackson CR, Chen G. Histological features indicate the risk of progression of patients with Barrett's esophagus. Pathol Res Pract 2025; 266:155812. [PMID: 39793338 DOI: 10.1016/j.prp.2025.155812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 11/15/2024] [Accepted: 01/03/2025] [Indexed: 01/13/2025]
Abstract
Our understanding of predictors of progression in Barrett's esophagus (BE) remains incomplete. To address this gap, we evaluated histological features and biomarkers that could predict dysplastic/neoplastic progression in patients with BE. We conducted a retrospective study to identify eligible BE patients and classified the cases into two groups: cases with BE progression (n = 10; progressing to high-grade dysplasia or carcinoma within five years of initial diagnosis) and cases without BE progression (n = 52; without progression to high-grade dysplasia or carcinoma within five years). Morphological features were evaluated on tissue slides for the initial diagnosis of Barrett's esophagus. Biomarkers including TP53, p16, HER2, β-Catenin, c-MYC, Ki67 and SATB2,were assessed by immunohistochemistry. The results of this study revealed that histologic features, including glandular irregularity and Paneth cell metaplasia (PCM), exhibited significant predictive potential for the progression of Barrett's esophagus to high-grade dysplasia or carcinoma within five years. Additionally, the immunohistochemical biomarkers assessed in our study were not associated with progression in Barrett's esophagus. These findings indicate the potential role of morphological features in assessing the risk of progression for patients with BE at the initial diagnosis. By integrating these insights into clinical practice, we may be able to optimize surveillance strategies for patients with this condition, ultimately improving patient outcomes.
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Affiliation(s)
- Tiane Chen
- Department of Pathology and Laboratory Medicine, Penn State Health Hershey Medical Center, Penn State College of Medicine, Hershey, PA 17033, United States
| | - Hong Ly
- Department of Pathology and Laboratory Medicine, Penn State Health Hershey Medical Center, Penn State College of Medicine, Hershey, PA 17033, United States
| | - Douglas B Stairs
- Department of Pathology and Laboratory Medicine, Penn State Health Hershey Medical Center, Penn State College of Medicine, Hershey, PA 17033, United States
| | - Christopher R Jackson
- Department of Pathology and Laboratory Medicine, Penn State Health Hershey Medical Center, Penn State College of Medicine, Hershey, PA 17033, United States
| | - Guoli Chen
- Department of Pathology and Laboratory Medicine, Penn State Health Hershey Medical Center, Penn State College of Medicine, Hershey, PA 17033, United States.
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Tobi M, Khoury N, Al-Subee O, Sethi S, Talwar H, Kam M, Hatfield J, Levi E, Hallman J, Moyer MP, Kresty L, Lawson MJ, McVicker B. Predicting Regression of Barrett's Esophagus-Can All the King's Men Put It Together Again? Biomolecules 2024; 14:1182. [PMID: 39334948 PMCID: PMC11430295 DOI: 10.3390/biom14091182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 09/06/2024] [Indexed: 09/30/2024] Open
Abstract
The primary pre-neoplastic lesion of the lower esophagus in the vicinity of the gastroesophageal junction (GEJ) is any Barrett's esophageal lesions (BE), and esophageal neoplasia has increased in the US population with predispositions (Caucasian males, truncal obesity, age, and GERD). The responses to BE are endoscopic and screening cytologic programs with endoscopic ablation of various forms. The former have not been proven to be cost-effective and there are mixed results for eradication. A fresh approach is sorely needed. We prospectively followed 2229 mostly male veterans at high risk for colorectal cancer in a 27-year longitudinal long-term study, collecting data on colorectal neoplasia development and other preneoplastic lesions, including BE and spontaneous regression (SR). Another cross-sectional BE study at a similar time period investigated antigenic changes at the GEJ in both BE glandular and squamous mucosa immunohistochemistry and the role of inflammation. Ten of the prospective cohort (21.7%) experienced SR out of a total of forty-six BE patients. Significant differences between SR and stable BE were younger age (p < 0.007); lower platelet levels (p < 0.02); rectal p87 elevation in SR (p < 0.049); a reduced innate immune system (InImS) FEREFF ratio (ferritin: p87 colonic washings) (p < 0.04). Ancillary testing showed a broad range of neoplasia biomarkers. InImS markers may be susceptible to intervention using commonplace and safe medical interventions and encourage SR.
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Affiliation(s)
- Martin Tobi
- Departments of Medicine, Research and Development, John D. Dingell VAMC, 3636 John R. St., Detroit, MI 48201, USA
| | - Nabiha Khoury
- Departments of Medicine, Research and Development, John D. Dingell VAMC, 3636 John R. St., Detroit, MI 48201, USA
- Department of Medicine, Wayne State University, 42 W. Warren Ave., Detroit, MI 48201, USA
| | - Omar Al-Subee
- Departments of Medicine, Research and Development, John D. Dingell VAMC, 3636 John R. St., Detroit, MI 48201, USA
| | - Seema Sethi
- Departments of Medicine, Research and Development, John D. Dingell VAMC, 3636 John R. St., Detroit, MI 48201, USA
| | - Harvinder Talwar
- Department of Medicine, Wayne State University, 42 W. Warren Ave., Detroit, MI 48201, USA
| | - Michael Kam
- Departments of Medicine, Research and Development, John D. Dingell VAMC, 3636 John R. St., Detroit, MI 48201, USA
| | - James Hatfield
- Departments of Medicine, Research and Development, John D. Dingell VAMC, 3636 John R. St., Detroit, MI 48201, USA
| | - Edi Levi
- Departments of Medicine, Research and Development, John D. Dingell VAMC, 3636 John R. St., Detroit, MI 48201, USA
| | - Jason Hallman
- Departments of Medicine, Research and Development, John D. Dingell VAMC, 3636 John R. St., Detroit, MI 48201, USA
| | - Mary Pat Moyer
- INCELL Corporation LLC, 12734 Cimarron Path, San Antonio, TX 78249, USA
| | - Laura Kresty
- Department of Thoracic Surgery, University of Michigan, 500 S. State Street, Ann Arbor, MI 48109, USA
| | - Michael J. Lawson
- Department of Internal Medicine, University of California at Sacramento, Davis, CA 95616, USA
| | - Benita McVicker
- VA Medical Center, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68005, USA
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Ma R, Li Q, Yu G, Wang J, Li Y, Xu X, Zhu Y, Dong M, Gao Y, Li L, Li Z. A multi-omics study to investigate the progression of the Correa pathway in gastric mucosa in the context of cirrhosis. Gut Pathog 2023; 15:45. [PMID: 37752551 PMCID: PMC10521386 DOI: 10.1186/s13099-023-00571-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 09/14/2023] [Indexed: 09/28/2023] Open
Abstract
BACKGROUND Patients with liver cirrhosis (LC) are prone to gastric mucosa damage. We investigated the alterations of gastric mucosa in LC patients and their possible mechanisms through multi-omics. RESULTS We observed significant gastric mucosa microbial dysbiosis in LC subjects. Gastric mucosal microbiomes of LC patients contained a higher relative abundance of Streptococcus, Neisseria, Prevotella, Veillonella, and Porphyromonas, as well as a decreased abundance in Helicobacter and Achromobacter, than control subjects. The LC patients had higher levels of bile acids (BAs) and long-chain acylcarnitines (long-chain ACs) in serum. The gastric mucosal microbiomes were associated with serum levels of BAs and long-chain ACs. Transcriptome analyses of gastric mucosa revealed an upregulation of endothelial cell specific molecule 1, serpin family E member 1, mucin 2, caudal type homeobox 2, retinol binding protein 2, and defensin alpha 5 in LC group. Besides, the bile secretion signaling pathway was significantly upregulated in the LC group. CONCLUSIONS The alterations in the gastric mucosal microbiome and transcriptome of LC patients were identified. The impaired energy metabolism in gastric mucosal cells and bile acids might aggravate the inflammation of gastric mucosa and even exacerbate the Correa's cascade process. The gastric mucosal cells might reduce bile acid toxicity by bile acid efflux and detoxification. TRIAL REGISTRATION ChiCTR2100051070.
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Affiliation(s)
- Ruiguang Ma
- Department of Gastroenterology, Qilu Hospital of Shandong University, No. 107, Wenhuaxi Road, Jinan, 250012, China
| | - Qian Li
- Department of Gastroenterology, Qilu Hospital of Shandong University, No. 107, Wenhuaxi Road, Jinan, 250012, China
| | - Guoxian Yu
- School of Software, Shandong University, Jinan, China
| | - Jun Wang
- SDU-NTU Joint Centre for AI Research, Shandong University, Jinan, China
| | - Yueyue Li
- Department of Gastroenterology, Qilu Hospital of Shandong University, No. 107, Wenhuaxi Road, Jinan, 250012, China
| | - Xinyan Xu
- Department of Gastroenterology, Qilu Hospital of Shandong University, No. 107, Wenhuaxi Road, Jinan, 250012, China
| | - Yiqing Zhu
- Department of Gastroenterology, Qilu Hospital of Shandong University, No. 107, Wenhuaxi Road, Jinan, 250012, China
| | - Min Dong
- Department of Gastroenterology, Qilu Hospital of Shandong University, No. 107, Wenhuaxi Road, Jinan, 250012, China
| | - Yanjing Gao
- Department of Gastroenterology, Qilu Hospital of Shandong University, No. 107, Wenhuaxi Road, Jinan, 250012, China
| | - Lixiang Li
- Department of Gastroenterology, Qilu Hospital of Shandong University, No. 107, Wenhuaxi Road, Jinan, 250012, China.
| | - Zhen Li
- Department of Gastroenterology, Qilu Hospital of Shandong University, No. 107, Wenhuaxi Road, Jinan, 250012, China.
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Richter F, Röder C, Möller T, Egberts JH, Becker T, Sebens S. Detection of Circulating and Disseminated Tumor Cells and Their Prognostic Value under the Influence of Neoadjuvant Therapy in Esophageal Cancer Patients. Cancers (Basel) 2022; 14:cancers14051279. [PMID: 35267585 PMCID: PMC8909540 DOI: 10.3390/cancers14051279] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 02/25/2022] [Accepted: 02/26/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Esophageal cancer (EC) has a poor prognosis and a high mortality rate. This study investigated the expression of CK20 and DEFA5, markers being associated with circulating (CTC) and disseminated tumor cells (DTC), in blood and bone marrow (BM) of EC patients, and correlated positivity rates with clinical data to assess the prognostic impact. Both markers were detected in blood and BM of EC patients and the control cohort so that a cut-off value was determined to define marker positivity for correlation with clinical parameters. CK20 and DEFA5 positivity in liquid biopsies of EC patients did not correlate with overall survival (OS). However, CK20 positivity in BM and DEFA5 negativity in blood were associated with reduced OS in patients without neoadjuvant therapy. In patients with neoadjuvant therapy, DEFA5 positivity in BM was associated with improved OS, pointing to the potential of DEFA5 as a prognostic biomarker in liquid biopsies of EC patients. Abstract Detection of circulating (CTC) or disseminated tumor cells (DTC) are correlated with negative prognosis in esophageal cancer (EC) patients. In this study, DTC- and CTC-associated markers CK20 and DEFA5 were determined by RT-PCR in EC patients and correlated with clinical parameters to determine their prognostic impact. The blood and bone marrow (BM) of 216 EC patients after tumor resection with or without neoadjuvant therapy and as control blood samples from 38 healthy donors and BM from 24 patients with non-malignant diseases were analyzed. Both markers were detected in blood and BM of EC patients and the control cohort. A cut-off value was determined to define marker positivity for correlation with clinical data. CK20 expression was detected in 47/206 blood samples and in 49/147 BM samples of EC patients. DEFA5 positivity was determined in 96/206 blood samples and 98/147 BM samples, not correlating with overall survival (OS). However, CK20 positivity in BM and DEFA5 negativity in blood were associated with reduced OS in EC patients without neoadjuvant therapy, while in patients with neoadjuvant therapy DEFA5 positivity in BM was associated with improved OS. Overall, our study suggests DEFA5 as a prognostic biomarker in liquid biopsies of EC patients which requires further validation.
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Affiliation(s)
- Florian Richter
- Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, 24105 Kiel, Germany; (F.R.); (T.M.); (T.B.)
| | - Christian Röder
- Institute for Experimental Cancer Research, Kiel University (CAU) and University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, 24105 Kiel, Germany;
| | - Thorben Möller
- Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, 24105 Kiel, Germany; (F.R.); (T.M.); (T.B.)
| | | | - Thomas Becker
- Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, 24105 Kiel, Germany; (F.R.); (T.M.); (T.B.)
| | - Susanne Sebens
- Institute for Experimental Cancer Research, Kiel University (CAU) and University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, 24105 Kiel, Germany;
- Correspondence: ; Tel.: +49-431-500-30501
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Qiao Q, Bai R, Song W, Gao H, Zhang M, Lu J, Hong M, Zhang X, Sun P, Zhang Q, Zhao P. Human α-defensin 5 suppressed colon cancer growth by targeting PI3K pathway. Exp Cell Res 2021; 407:112809. [PMID: 34487729 DOI: 10.1016/j.yexcr.2021.112809] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 08/23/2021] [Accepted: 09/01/2021] [Indexed: 01/06/2023]
Abstract
Defensins are highly conserved antimicrobial peptides, which ubiquitously expressed in different species. In addition to the functions in host defense, their aberrant expression have also been documented in cancerous tissue including breast cancer, lung caner and renal carcinoma etc. Whereas, roles of Defensin Alpha 5 (DEFA5) in colon cancer has not been explored. Bioinformatic analysis was used to study the expression of DEFA5 and its correlation with clinical outcomes; Western blot, qPCR, Co-immunoprecipitation, xenograft models were used to the study the molecular mechanism. Decreased expression of DEFA5 at protein level was observed in colon tissues. Colon cancer cell lines proliferation and colony formation capacity were significantly suppressed by DEFA5 overexpression. Moreover, in vivo tumor growth in nude mice was also suppressed by DEFA5 overexpression, suggesting a tumor suppressor role of DEFA5 in colon cancer. Mechanistically, DEFA5 directly binds to the subunits of PI3K complex, thus attenuates the downstream signaling transduction, leads to delayed cell growth and metastasis. Collectively, we concluded that DEFA5 showed an inhibitory effect in colon cancer cell growth and may serve as a potential tumor suppressor in colon cancer.
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Affiliation(s)
- Qiao Qiao
- Department of Obstetrics and Gynecology, Affiliated Hospital of Inner Mongolia Medical University, No.1, Tongdao North Street, Huimin District, Hohhot, 010050, PR China.
| | - Ruixia Bai
- Department of Clinical Laboratory, Inner Mongolia People's Hospital, Zhaowuda Road, Hohhot, 010018, PR China.
| | - Wanying Song
- Laboratory of Microbiology and Immunology, School of Basic Medical Science, Inner Mongolia Medical University, Xinhua Street, Hohhot, 010059, PR China.
| | - Haining Gao
- Laboratory of Microbiology and Immunology, School of Basic Medical Science, Inner Mongolia Medical University, Xinhua Street, Hohhot, 010059, PR China.
| | - Minyu Zhang
- Laboratory of Microbiology and Immunology, School of Basic Medical Science, Inner Mongolia Medical University, Xinhua Street, Hohhot, 010059, PR China.
| | - Jingkun Lu
- Laboratory of Microbiology and Immunology, School of Basic Medical Science, Inner Mongolia Medical University, Xinhua Street, Hohhot, 010059, PR China.
| | - Mei Hong
- Laboratory of Microbiology and Immunology, School of Basic Medical Science, Inner Mongolia Medical University, Xinhua Street, Hohhot, 010059, PR China.
| | - Xuan Zhang
- Laboratory of Microbiology and Immunology, School of Basic Medical Science, Inner Mongolia Medical University, Xinhua Street, Hohhot, 010059, PR China.
| | - Peng Sun
- Laboratory of Microbiology and Immunology, School of Basic Medical Science, Inner Mongolia Medical University, Xinhua Street, Hohhot, 010059, PR China.
| | - Qian Zhang
- Pediatric Intensive Care Unit, Affiliated Hospital of Inner Mongolia Medical University, 1#, Xinhua Street, Hohhot, 010050, PR China.
| | - Pengwei Zhao
- Laboratory of Microbiology and Immunology, School of Basic Medical Science, Inner Mongolia Medical University, Xinhua Street, Hohhot, 010059, PR China.
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Zeng D, Hu Z, Yi Y, Valeria B, Shan G, Chen Z, Zhan C, Lin M, Lin Z, Wang Q. Differences in genetics and microenvironment of lung adenocarcinoma patients with or without TP53 mutation. BMC Pulm Med 2021; 21:316. [PMID: 34635074 PMCID: PMC8507221 DOI: 10.1186/s12890-021-01671-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 09/13/2021] [Indexed: 02/07/2023] Open
Abstract
Background Differences in genetics and microenvironment of LUAD patients with or without TP53 mutation were analyzed to illustrate the role of TP53 mutation within the carcinogenesis of LUAD, which will provide new concepts for the treatment of LUAD. Methods
In this study, we used genetics and clinical info from the TCGA database, including somatic mutations data, RNA-seq, miRNA-seq, and clinical data. More than one bioinformatics tools were used to analyze the unique genomic pattern of TP53-related LUAD. Results According to TP53 gene mutation status, we divided the LUAD patients into two groups, including 265 in the mutant group (MU) and 295 in the wild-type group (WT). 787 significant somatic mutations were detected between the groups, including mutations in titin (TTN), type 2 ryanodine receptor (RYR2) and CUB and Sushi multiple domains 3(CSMD3), which were up-regulated in the MU. However, no significant survival difference was observed. At the RNA level, we obtained 923 significantly differentially expressed genes; in the MU, α-defensin 5(DEFA5), pregnancy-specific glycoprotein 5(PSG5) and neuropeptide Y(NPY) were the most up-regulated genes, glucose-6-phosphatase (G6PC), alpha-fetoprotein (AFP) and carry gametocidal (GC) were the most down-regulated genes. GSVA analysis revealed 30 significant pathways. Compared with the WT, the expression of 12 pathways in the mutant group was up-regulated, most of which pointed to cell division. There were significant differences in tumor immune infiltrating cells, such as Macrophages M1, T cells CD4 memory activated, Mast cells resting, and Dendritic cells resting. In terms of immune genes, a total of 35 immune-related genes were screened, of which VGF (VGF nerve growth factor inducible) and PGC (peroxisome proliferator-activated receptor gamma coactivator) were the most significant up-regulated and down-regulated genes, respectively. Research on the expression pattern of immunomodulators found that 9 immune checkpoint molecules and 6 immune costimulatory molecules were considerably wholly different between the two groups. Conclusions Taking the mutant group as a reference, LUAD patients in the mutant group had significant differences in somatic mutations, mRNA-seq, miRNA-seq, immune infiltration, and immunomodulators, indicating that TP53 mutation plays a crucial role in the occurrence and development of LUAD. Supplementary Information The online version contains supplementary material available at 10.1186/s12890-021-01671-8.
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Affiliation(s)
- Dejun Zeng
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Zhengyang Hu
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Yanjun Yi
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Besskaya Valeria
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Guangyao Shan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Zhencong Chen
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Cheng Zhan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Miao Lin
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
| | - Zongwu Lin
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
| | - Qun Wang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
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D'Souza SM, Houston K, Keenan L, Yoo BS, Parekh PJ, Johnson DA. Role of microbial dysbiosis in the pathogenesis of esophageal mucosal disease: A paradigm shift from acid to bacteria? World J Gastroenterol 2021; 27:2054-2072. [PMID: 34025064 PMCID: PMC8117736 DOI: 10.3748/wjg.v27.i18.2054] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/06/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Genomic sequencing, bioinformatics, and initial speciation (e.g., relative abundance) of the commensal microbiome have revolutionized the way we think about the "human" body in health and disease. The interactions between the gut bacteria and the immune system of the host play a key role in the pathogenesis of gastrointestinal diseases, including those impacting the esophagus. Although relatively stable, there are a number of factors that may disrupt the delicate balance between the luminal esophageal microbiome (EM) and the host. These changes are thought to be a product of age, diet, antibiotic and other medication use, oral hygiene, smoking, and/or expression of antibiotic products (bacteriocins) by other flora. These effects may lead to persistent dysbiosis which in turn increases the risk of local inflammation, systemic inflammation, and ultimately disease progression. Research has suggested that the etiology of gastroesophageal reflux disease-related esophagitis includes a cytokine-mediated inflammatory component and is, therefore, not merely the result of esophageal mucosal exposure to corrosives (i.e., acid). Emerging evidence also suggests that the EM plays a major role in the pathogenesis of disease by inciting an immunogenic response which ultimately propagates the inflammatory cascade. Here, we discuss the potential role for manipulating the EM as a therapeutic option for treating the root cause of various esophageal disease rather than just providing symptomatic relief (i.e., acid suppression).
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Affiliation(s)
- Steve M D'Souza
- Department of Internal Medicine, Division of Gastroenterology, Eastern Virginia Medical School, Norfolk, VA 23502, United States
| | - Kevin Houston
- Department of Internal Medicine, Division of Gastroenterology, Eastern Virginia Medical School, Norfolk, VA 23502, United States
| | - Lauren Keenan
- Department of Internal Medicine, Division of Gastroenterology, Eastern Virginia Medical School, Norfolk, VA 23502, United States
| | - Byung Soo Yoo
- Department of Internal Medicine, Division of Gastroenterology, Eastern Virginia Medical School, Norfolk, VA 23502, United States
| | - Parth J Parekh
- Department of Internal Medicine, Division of Gastroenterology, Eastern Virginia Medical School, Norfolk, VA 23502, United States
| | - David A Johnson
- Department of Internal Medicine, Division of Gastroenterology, Eastern Virginia Medical School, Norfolk, VA 23502, United States
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Wu Z, Ding Z, Cheng B, Cui Z. The inhibitory effect of human DEFA5 in growth of gastric cancer by targeting BMI1. Cancer Sci 2021; 112:1075-1083. [PMID: 33503272 PMCID: PMC7935777 DOI: 10.1111/cas.14827] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 01/18/2021] [Accepted: 01/25/2021] [Indexed: 12/24/2022] Open
Abstract
Defensins, a class of small cysteine‐rich cationic polypeptides across cellular life, are identified as antimicrobial compounds that display direct antimicrobial and immune signaling activities that are involved in the host defense. In addition to their roles in the innate immune system, accumulating studies have reported that some members of defensins are expressed and involved in some cancer cells, such as colon cancer, colorectal cancer, lung cancer and renal cell carcinomas. However, the roles of α‐Defensin 5 (DEFA5) in tumorigenesis and development remain unknown. In the present study, bioinformatics analysis and quantitative PCR results showed that the expression level of DEFA5 was dramatically downregulated in human gastric cancer. Overexpression of human DEFA5 in gastric cancer cell lines SGC7901 and BGC823 effectively diminished cell proliferation and reduced the colony forming ability. Moreover, DEFA5 overexpression induced cell cycle arrest by significantly increasing the number of G1‐phase cells. Consistently, in vivo tumor formation experiments in nude mice showed the suppression of the tumor growth by DEFA5 overexpression, suggesting an inhibitory effect of DEFA5 in gastric cancer. Mechanistically, DEFA5 directly binds to BMI1, which subsequently decreased its binding at the CDKN2a locus and upregulated the expression of 2 cyclin‐dependent kinase inhibitors, p16 and p19. Taken together, we concluded that DEFA5 showed an inhibitory effect in gastric cancer cell growth and may serve as a potential tumor suppressor in gastric cancer.
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Affiliation(s)
- Zhongwei Wu
- Department of Emergency Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhaohui Ding
- Department of Gastrointestinal surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Bo Cheng
- Department of Emergency Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zongchao Cui
- Department of Emergency Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Nam H, Jeong HJ, Jo Y, Lee JY, Ha DH, Kim JH, Chung JH, Cho YS, Cho DW, Lee SJ, Jang J. Multi-layered Free-form 3D Cell-printed Tubular Construct with Decellularized Inner and Outer Esophageal Tissue-derived Bioinks. Sci Rep 2020; 10:7255. [PMID: 32350326 PMCID: PMC7190629 DOI: 10.1038/s41598-020-64049-6] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Accepted: 04/06/2020] [Indexed: 02/07/2023] Open
Abstract
The incidences of various esophageal diseases (e.g., congenital esophageal stenosis, tracheoesophageal fistula, esophageal atresia, esophageal cancer) are increasing, but esophageal tissue is difficult to be recovered because of its weak regenerative capability. There are no commercialized off-the-shelf alternatives to current esophageal reconstruction and regeneration methods. Surgeons usually use ectopic conduit tissues including stomach and intestine, presumably inducing donor site morbidity and severe complications. To date, polymer-based esophageal substitutes have been studied as an alternative. However, the fabrication techniques are nearly limited to creating only cylindrical outer shapes with the help of additional apparatus (e.g., mandrels for electrospinning) and are unable to recapitulate multi-layered characteristic or complex-shaped inner architectures. 3D bioprinting is known as a suitable method to fabricate complex free-form tubular structures with desired pore characteristic. In this study, we developed a extrusion-based 3D printing technique to control the size and the shape of the pore in a single extrusion process, so that the fabricated structure has a higher flexibility than that fabricated in the conventional process. Based on this suggested technique, we developed a bioprinted 3D esophageal structure with multi-layered features and converged with biochemical microenvironmental cues of esophageal tissue by using decellularizedbioinks from mucosal and muscular layers of native esophageal tissues. The two types of esophageal tissue derived-decellularized extracellular matrix bioinks can mimic the inherent components and composition of original tissues with layer specificity. This structure can be applied to full-thickness circumferential esophageal defects and esophageal regeneration.
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Affiliation(s)
- Hyoryung Nam
- Department of Creative IT Engineering, Pohang University of Science and Technology, San 31, Pohang, Gyeongbuk, Republic of Korea
| | - Hun-Jin Jeong
- Department of Mechanical Engineering, Wonkwang University, Iksan-daero, Iksan, Jeollabuk-do, Republic of Korea
| | - Yeonggwon Jo
- School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, San 31, Pohang, Gyeongbuk, Republic of Korea
| | - Jae Yeon Lee
- Department of Mechanical Engineering, Pohang University of Science and Technology, San 31, Pohang, Gyeongbuk, Republic of Korea
| | - Dong-Heon Ha
- Department of Mechanical Engineering, Pohang University of Science and Technology, San 31, Pohang, Gyeongbuk, Republic of Korea
| | - Ji Hyun Kim
- Department of Surgery, Collage of Medicine, The Catholic University of Korea, Banpo-daero, Seoul, Republic of Korea
| | - Jae Hee Chung
- Department of Surgery, Collage of Medicine, The Catholic University of Korea, Banpo-daero, Seoul, Republic of Korea
| | - Young-Sam Cho
- Department of Mechanical Engineering, Wonkwang University, Iksan-daero, Iksan, Jeollabuk-do, Republic of Korea
- Department of Mechanical and Design Engineering, Wonkwang University, Iksan-daero, Iksan, Jeollabuk-do, Republic of Korea
| | - Dong-Woo Cho
- Department of Mechanical Engineering, Pohang University of Science and Technology, San 31, Pohang, Gyeongbuk, Republic of Korea
| | - Seung-Jae Lee
- Department of Mechanical Engineering, Wonkwang University, Iksan-daero, Iksan, Jeollabuk-do, Republic of Korea.
- Department of Mechanical and Design Engineering, Wonkwang University, Iksan-daero, Iksan, Jeollabuk-do, Republic of Korea.
| | - Jinah Jang
- Department of Creative IT Engineering, Pohang University of Science and Technology, San 31, Pohang, Gyeongbuk, Republic of Korea.
- School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, San 31, Pohang, Gyeongbuk, Republic of Korea.
- Department of Mechanical Engineering, Pohang University of Science and Technology, San 31, Pohang, Gyeongbuk, Republic of Korea.
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Singh R, Balasubramanian I, Zhang L, Gao N. Metaplastic Paneth Cells in Extra-Intestinal Mucosal Niche Indicate a Link to Microbiome and Inflammation. Front Physiol 2020; 11:280. [PMID: 32296343 PMCID: PMC7138011 DOI: 10.3389/fphys.2020.00280] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 03/12/2020] [Indexed: 12/12/2022] Open
Abstract
Paneth cells are residents of the intestinal epithelium. Abnormal appearance of Paneth cells has been widely documented in non-intestinal tissues within the digestive tract and even observed in non-gastrointestinal organs. Although metaplastic Paneth cells are part of the overarching pathology of intestinal metaplasia (IM), only a fraction of intestinal metaplastic lesions contain Paneth cells. We survey literature documenting metaplastic Paneth cells to gain insights into mechanism underlying their etiologic development as well as their potential relevance to human health. A synthesized view from this study suggests that the emergence of metaplastic Paneth cells at extra-intestinal mucosal sites likely represents a protective, anti-bacterial, and inflammatory response evoked by an altered microbial activity.
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Affiliation(s)
- Rajbir Singh
- Department of Biological Sciences, Rutgers University, Newark, NJ, United States
| | | | - Lanjing Zhang
- Department of Biological Sciences, Rutgers University, Newark, NJ, United States.,Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, United States.,Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States.,Department of Pathology, Princeton Medical Center, Plainsboro, NJ, United States
| | - Nan Gao
- Department of Biological Sciences, Rutgers University, Newark, NJ, United States.,Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States
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11
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Jeong D, Kim H, Kim D, Ban S, Oh S, Ji S, Kang D, Lee H, Ahn TS, Kim HJ, Bae SB, Lee MS, Kim CJ, Kwon HY, Baek MJ. Defensin alpha 6 (DEFA6) is a prognostic marker in colorectal cancer. Cancer Biomark 2019; 24:485-495. [PMID: 30932884 DOI: 10.3233/cbm-182221] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Defensin alpha 6 (DEFA6) is a member of the alpha defensin family of microbicidal and cytotoxic peptides that defend against bacteria and viruses. Here, we provide a novel function of DEFA6 in tumorigenesis of colorectal cancer (CRC) in vitro and in vivo. Specifically, DEFA6 is highly expressed in both CRC cancer cell lines as well as patient-derived samples at the level of RNA and protein. By shRNA-mediated loss of function of DEFA6, we found that proliferation, migration, invasion, colony forming ability of CRC cell lines were impaired in the absence of DEFA6 in vitro. Furthermore, DEFA6-deficient cancer cells exhibited significantly reduced growth rates compared to control cells in vivo. More importantly, by analyzing 352 patient-derived samples, we revealed that DEFA6 is associated with overall survival rate of CRC patients and thus an independent prognostic marker for CRC. These results suggest that DEFA6 plays an essential oncogenic role in CRC and serves a good therapeutic target for the disease.
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Affiliation(s)
- Dongjun Jeong
- Department of Pathology, College of Medicine, Soonchunhyang University, Chungcheongnam-do, 330-722, Korea.,Soonchunhyang Medical Science Research Institute, College of Medicine, Soonchunhyang University, Chungcheongnam-do, 330-722, Korea
| | - Hyeongjoo Kim
- Soonchunhyang Medical Science Research Institute, College of Medicine, Soonchunhyang University, Chungcheongnam-do, 330-722, Korea
| | - Doyeon Kim
- Soonchunhyang Medical Science Research Institute, College of Medicine, Soonchunhyang University, Chungcheongnam-do, 330-722, Korea
| | - Seona Ban
- Soonchunhyang Medical Science Research Institute, College of Medicine, Soonchunhyang University, Chungcheongnam-do, 330-722, Korea
| | - Seunghyun Oh
- Soonchunhyang Medical Science Research Institute, College of Medicine, Soonchunhyang University, Chungcheongnam-do, 330-722, Korea
| | - Sanghee Ji
- Soonchunhyang Medical Science Research Institute, College of Medicine, Soonchunhyang University, Chungcheongnam-do, 330-722, Korea
| | - DongHyun Kang
- Department of Surgery, College of Medicine, Soonchunhyang University, Chungcheongnam-do, 330-723, Korea
| | - Hyunyong Lee
- Department of Surgery, College of Medicine, Soonchunhyang University, Chungcheongnam-do, 330-723, Korea
| | - Tae Sung Ahn
- Department of Surgery, College of Medicine, Soonchunhyang University, Chungcheongnam-do, 330-723, Korea
| | - Han Jo Kim
- Department of Oncology, College of Medicine, Soonchunhyang University, Chungcheongnam-do, 330-722, Korea
| | - Sang Byung Bae
- Department of Oncology, College of Medicine, Soonchunhyang University, Chungcheongnam-do, 330-722, Korea
| | - Moon Soo Lee
- Department of Surgery, College of Medicine, Soonchunhyang University, Chungcheongnam-do, 330-723, Korea
| | - Chang-Jin Kim
- Department of Pathology, College of Medicine, Soonchunhyang University, Chungcheongnam-do, 330-722, Korea
| | - Hyog Young Kwon
- Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Chungcheongnam-do, 31151, Korea
| | - Moo-Jun Baek
- Department of Surgery, College of Medicine, Soonchunhyang University, Chungcheongnam-do, 330-723, Korea
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12
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Studies on the Interaction of Tumor-Derived HD5 Alpha Defensins with Adenoviruses and Implications for Oncolytic Adenovirus Therapy. J Virol 2017; 91:JVI.02030-16. [PMID: 28077642 DOI: 10.1128/jvi.02030-16] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 12/20/2016] [Indexed: 12/19/2022] Open
Abstract
Defensins are small antimicrobial peptides capable of neutralizing human adenovirus (HAdV) in vitro by binding capsid proteins and blocking endosomal escape of virus. In humans, the alpha defensin HD5 is produced by specialized epithelial cells of the gastrointestinal and genito-urinary tracts. Here, we demonstrate, using patient biopsy specimens, that HD5 is also expressed as an active, secreted peptide by epithelial ovarian and lung cancer cells in situ This finding prompted us to study the role of HD5 in infection and spread of replication-competent, oncolytic HAdV type 3 (HAdV3). HAdV3 produces large amounts of penton-dodecahedra (PtDd), virus-like particles, during replication. We have previously shown that PtDd are involved in opening epithelial junctions, thus facilitating lateral spread of de novo-produced virions. Here, we describe a second function of PtDd, namely, the blocking of HD5. A central tool to prove that viral PtDd neutralize HD5 and support spread of progeny virus was an HAdV3 mutant virus in which formation of PtDd was disabled (mut-Ad3GFP, where GFP is green fluorescent protein). We demonstrated that viral spread of mut-Ad3GFP was blocked by synthetic HD5 whereas that of the wild-type (wt) form (wt-Ad3GFP) was only minimally impacted. In human colon cancer Caco-2 cells, induction of cellular HD5 expression by fibroblast growth factor 9 (FGF9) significantly inhibited viral spread and progeny virus production of mut-Ad3GFP but not of wt-Ad3GFP. Finally, the ectopic expression of HD5 in tumor cells diminished the in vivo oncolytic activity of mut-Ad3GFP but not of wt-Ad3GFP. These data suggest a new mechanism of HAdV3 to overcome innate antiviral host responses. Our study has implications for oncolytic adenovirus therapy.IMPORTANCE Previously, it has been reported that human defensin HD5 inactivates specific human adenoviruses by binding to capsid proteins and blocking endosomal escape of virus. The central new findings described in our manuscript are the following: (i) the discovery of a new mechanism used by human adenovirus serotype 3 to overcome innate antiviral host responses that is based on the capacity of HAdV3 to produce subviral penton-dodecahedral particles that act as decoys for HD5, thus preventing the inactivation of virus progeny produced upon replication; (ii) the demonstration that ectopic HD5 expression in cancer cells decreases the oncolytic efficacy of a serotype 5-based adenovirus vector; and (iii) the demonstration that epithelial ovarian and lung cancers express HD5. The study improves our understanding of how adenoviruses establish infection in epithelial tissues and has implications for cancer therapy with oncolytic adenoviruses.
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13
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Chen W, Frankel WL, Cronley KM, Yu L, Zhou X, Yearsley MM. Significance of paneth cell metaplasia in Barrett esophagus: a morphologic and clinicopathologic study. Am J Clin Pathol 2015; 143:665-71. [PMID: 25873500 DOI: 10.1309/ajcpvujmcvbc9pkm] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
OBJECTIVES The metaplastic intestinal epithelium in Barrett esophagus (BE) occasionally contains Paneth cells; however, little is known regarding the prevalence and significance of Paneth cell metaplasia (PCM) in BE. METHODS We evaluated 757 esophageal biopsy specimens with intestinal metaplasia (IM) for PCM. Outcome analysis was performed in 299 cases with complete clinical data using multinomial logistic regression. RESULTS Thirty-one percent (234/757) of the IM cases showed PCM. Paneth cells are decreased when BE epithelium becomes increasingly dysplastic. Long-segment BE shows significantly more PCM than short-segment BE. On follow-up biopsies, patients without PCM (NPCM) are three times more likely to regress than patients with PCM, regardless of dysplasia, BE segment length, age, or sex. However, there is no significant difference in terms of progression to dysplasia/adenocarcinoma between the PCM and NPCM groups. CONCLUSIONS The presence of PCM is associated with less disease regression and is not associated with more disease progression.
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Affiliation(s)
- Wei Chen
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus
| | - Wendy L. Frankel
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus
| | - Kevin M. Cronley
- Department of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus
| | - Lianbo Yu
- Center for Biostatistics, The Ohio State University Wexner Medical Center, Columbus
| | - Xiaoping Zhou
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus
| | - Martha M. Yearsley
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus
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14
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Wang W, Yang SF, Ren LH, Zhang XX, Yu SL. Effect of bifidobacterium on defensin-5 expression in intestinal injury of preweaning rats. World J Gastroenterol 2015; 21:2638-2644. [PMID: 25759531 PMCID: PMC4351213 DOI: 10.3748/wjg.v21.i9.2638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2014] [Accepted: 12/08/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the protective effect of bifidobacterium in endotoxin-induced intestinal injury in preweaning rats.
METHODS: Preweaning rats were randomly divided into three groups (n = 40 for each): a control group (group C), a model group (group E) and a treatment group (group T). Both groups E and T were intraperitoneally injected with lipopolysaccharide (LPS) at a dose of 5 mg/kg (5 mg/L in normal saline), and group T was intragastrically administrated with bifidobacterium suspension (2.0 × 109 CFU/mL, 0.5 mL each time, twice a day, until the end of the experiment) 7 d before LPS administration. Group C was intraperitoneally injected with normal saline. After intraperitoneal injection and intragastric administration, the rats were placed back to the initial cage to receive breast feeding. The rats were killed at 2, 6, 12, 24 or 72 h, respectively, after endotoxin or physiological saline injection to collect serum and ileal tissue samples. Myeloperoxidase (MPO) contents in serum and ileum were detected at different times, and expression of ileal defensin-5 mRNA was evaluated by reverse transcription-polymerase chain reaction.
RESULTS: Serum and ileal MPO contents in group E were significantly higher than those in group C (serum contents: 107.50 ± 17.70 vs 157.14 ± 24.67, P < 0.05; ileal contents: 1.03 ± 0.21 vs 1.57 ± 0.33, P < 0.05), which peaked at 12 h and 6 h, respectively. MPO contents in group T were significantly lower than those in group E (serum contents: 114.38 ± 24.56 vs 145.25 ± 23.62, P < 0.05; ileal contents: 1.25 ± 0.24 vs 1.57 ± 0.33, P < 0.05). The expression of defensin-5 mRNA in group E was significantly higher than that in group C (0.953 ± 0.238 vs 0.631 ± 0.146, P < 0.05), which peaked at 2 h, and then decreased gradually. The expression of defensin-5 mRNA in group T was significantly lower than that in group E (0.487 ± 0.149 vs 0.758 ± 0.160, P < 0.05) apparently in 24 h. The expression of defensin-5 mRNA at 2 h in group T was significantly higher than that in group C (0.824 ± 0.158 vs 0.631 ± 0.146, P < 0.05).
CONCLUSION: MPO and defensin-5 mRNA increase in preweaning rats with LPS-induced intestinal injury. Bifidobacterium protects the gut by inhibiting MPO activity, not by increasing defensin-5 secretion.
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15
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E-cadherin expression in Barrett’s esophagus and esophageal carcinoma. Esophagus 2014. [DOI: 10.1007/s10388-014-0424-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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