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Hsu CY, Jasim SA, Rasool KH, H M, Kaur J, Jabir MS, Alhajlah S, Kumar A, Jawad SF, Husseen B. Divergent functions of TLRs in gastrointestinal (GI) cancer: Overview of their diagnostic, prognostic and therapeutic value. Semin Oncol 2025; 52:152344. [PMID: 40347779 DOI: 10.1016/j.seminoncol.2025.152344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2025] [Revised: 03/10/2025] [Accepted: 03/15/2025] [Indexed: 05/14/2025]
Abstract
The relationship between the innate immune signal and the start of the adaptive immune response is the central idea of this theory. By controlling the inflammatory and tissue-repair reactions to damage, the Toll-like receptors (TLRs), as a family of PRRs, have attracted increasing attention for its function in protecting the host against infection and preserving tissue homeostasis. Microbial infection, damage, inflammation, and tissue healing have all been linked to the development of malignancies, especially gastrointestinal (GI) cancers. Recently, increased studies on TLR recognition and binding, as well as their ligands, have significantly advanced our knowledge of the various TLR signaling pathways and offered therapy options for GI malignancies. Upon activation by pathogen-associated or damage-associated molecular patterns (DAMPs and PAMPs), TLRs trigger key pathways like NF-κB, MAPK, and IRF. NF-κB activation promotes inflammation, cell survival, and proliferation, often contributing to tumor growth, metastasis, and therapy resistance. MAPK pathways similarly drive uncontrolled cell growth and invasion, while IRF pathways modulate interferon production, yielding both anti-tumor and protumor effects. The resulting chronic inflammatory environment within tumors can foster progression, yet TLR activation can also stimulate beneficial anti-tumor immune responses. However, the functions of TLR expression in GI cancers and their diagnostic and prognostic along with therapeutic value have not yet entirely been elucidated. Understanding how TLR activation contributes to anti-cancer immunity against GI malignancies may hasten immunotherapy developments and increase patient survival.
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Affiliation(s)
- Chou-Yi Hsu
- Thunderbird School of Global Management, Arizona State University Tempe Campus, Phoenix, Arizona, USA
| | - Saade Abdalkareem Jasim
- Medical Laboratory Techniques Department, Al-maarif University College, Anbar, Iraq; Biotechnology Department, College of Applied Science, Fallujah University, Fallujah, Iraq
| | - Khetam Habeeb Rasool
- Department of Biology, College of Science, University of Mustansiriyah, Mustansiriyah, Iraq
| | - Malathi H
- Department of Biotechnology and Genetics, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Jaswinder Kaur
- Chandigarh Pharmacy College, Chandigarh Group of Colleges, Mohali, Punjab, India
| | - Majid S Jabir
- Department of Applied Sciences, University of Technology, Anbar, Iraq
| | - Sharif Alhajlah
- Department of Medical Laboratories, College of Applied Medical Sciences, Shaqra University, Shaqra, Saudi Arabia.
| | - Abhinav Kumar
- Department of Nuclear and Renewable Energy, Ural Federal University Named after the First President of Russia Boris Yeltsin, Ekaterinburg, Russia; Centre for Research Impact & Outcome, Chitkara University, Rajpura, Punjab, India; Institute of Engineering and Technology, Chitkara University, Rajpura, Punjab, India
| | - Sabrean F Jawad
- Department of Pharmacy, Al-Mustaqbal University College, Hillah, Babylon, Iraq
| | - Beneen Husseen
- Medical Laboratory Technique College, the Islamic University, Najaf, Iraq; Medical Laboratory Technique College, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq; Medical Laboratory Technique College, the Islamic University of Babylon, Babylon, Iraq
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Kong W, Gao Y, Zhao S, Yang H. Cancer stem cells: advances in the glucose, lipid and amino acid metabolism. Mol Cell Biochem 2024; 479:2545-2563. [PMID: 37882986 DOI: 10.1007/s11010-023-04861-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Accepted: 09/13/2023] [Indexed: 10/27/2023]
Abstract
Cancer stem cells (CSCs) are a class of cells with self-renewal and multi-directional differentiation potential, which are present in most tumors, particularly in aggressive tumors, and perform a pivotal role in recurrence and metastasis and are expected to be one of the important targets for tumor therapy. Studies of tumor metabolism in recent years have found that the metabolic characteristics of CSCs are distinct from those of differentiated tumor cells, which are unique to CSCs and contribute to the maintenance of the stemness characteristics of CSCs. Moreover, these altered metabolic profiles can drive the transformation between CSCs and non-CSCs, implying that these metabolic alterations are important markers for CSCs to play their biological roles. The identification of metabolic changes in CSCs and their metabolic plasticity mechanisms may provide some new opportunities for tumor therapy. In this paper, we review the metabolism-related mechanisms of CSCs in order to provide a theoretical basis for their potential application in tumor therapy.
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Affiliation(s)
- Weina Kong
- Department of Obstetrics and Gynecology, Xijing Hospital, Air Forth Military Medical University, 127 Changle West Road, Xincheng District, Xi'an City, Shaanxi Province, China
| | - Yunge Gao
- Department of Obstetrics and Gynecology, Xijing Hospital, Air Forth Military Medical University, 127 Changle West Road, Xincheng District, Xi'an City, Shaanxi Province, China
| | - Shuhua Zhao
- Department of Obstetrics and Gynecology, Xijing Hospital, Air Forth Military Medical University, 127 Changle West Road, Xincheng District, Xi'an City, Shaanxi Province, China
| | - Hong Yang
- Department of Obstetrics and Gynecology, Xijing Hospital, Air Forth Military Medical University, 127 Changle West Road, Xincheng District, Xi'an City, Shaanxi Province, China.
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Ma L, Yu J, Zhang H, Zhao B, Zhang J, Yang D, Luo F, Wang B, Jin B, Liu J. Effects of Immune Cells on Intestinal Stem Cells: Prospects for Therapeutic Targets. Stem Cell Rev Rep 2022; 18:2296-2314. [DOI: 10.1007/s12015-022-10347-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/27/2022] [Indexed: 11/29/2022]
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Wnt signaling pathway in cancer immunotherapy. Cancer Lett 2022; 525:84-96. [PMID: 34740608 DOI: 10.1016/j.canlet.2021.10.034] [Citation(s) in RCA: 120] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 10/06/2021] [Accepted: 10/20/2021] [Indexed: 12/11/2022]
Abstract
Wnt/β-catenin signaling is a highly conserved pathway that regulates cell proliferation, differentiation, apoptosis, stem cell self-renewal, tissue homeostasis, and wound healing. Dysregulation of the Wnt pathway is intricately involved in almost all stages of tumorigenesis in various cancers. Through direct and/or indirect effects on effector T cells, T-regulatory cells, T-helper cells, dendritic cells, and other cytokine-expressing immune cells, abnormal activation of Wnt/β-catenin signaling benefits immune exclusion and hinders T-cell-mediated antitumor immune responses. Activation of Wnt signaling results in increased resistance to immunotherapies. In this review, we summarize the process by which Wnt signaling affects cancer and immune surveillance, and the potential for targeting the Wnt-signaling pathway via cancer immunotherapy.
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Marzano M, Fosso B, Piancone E, Defazio G, Pesole G, De Robertis M. Stem Cell Impairment at the Host-Microbiota Interface in Colorectal Cancer. Cancers (Basel) 2021; 13:996. [PMID: 33673612 PMCID: PMC7957811 DOI: 10.3390/cancers13050996] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/20/2021] [Accepted: 02/23/2021] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) initiation is believed to result from the conversion of normal intestinal stem cells (ISCs) into cancer stem cells (CSCs), also known as tumor-initiating cells (TICs). Hence, CRC evolves through the multiple acquisition of well-established genetic and epigenetic alterations with an adenoma-carcinoma sequence progression. Unlike other stem cells elsewhere in the body, ISCs cohabit with the intestinal microbiota, which consists of a diverse community of microorganisms, including bacteria, fungi, and viruses. The gut microbiota communicates closely with ISCs and mounting evidence suggests that there is significant crosstalk between host and microbiota at the ISC niche level. Metagenomic analyses have demonstrated that the host-microbiota mutually beneficial symbiosis existing under physiologic conditions is lost during a state of pathological microbial imbalance due to the alteration of microbiota composition (dysbiosis) and/or the genetic susceptibility of the host. The complex interaction between CRC and microbiota is at the forefront of the current CRC research, and there is growing attention on a possible role of the gut microbiome in the pathogenesis of CRC through ISC niche impairment. Here we primarily review the most recent findings on the molecular mechanism underlying the complex interplay between gut microbiota and ISCs, revealing a possible key role of microbiota in the aberrant reprogramming of CSCs in the initiation of CRC. We also discuss recent advances in OMICS approaches and single-cell analyses to explore the relationship between gut microbiota and ISC/CSC niche biology leading to a desirable implementation of the current precision medicine approaches.
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Affiliation(s)
- Marinella Marzano
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Consiglio Nazionale delle Ricerche, 70126 Bari, Italy; (M.M.); (B.F.); (G.P.)
| | - Bruno Fosso
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Consiglio Nazionale delle Ricerche, 70126 Bari, Italy; (M.M.); (B.F.); (G.P.)
| | - Elisabetta Piancone
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari ‘Aldo Moro’, 70126 Bari, Italy; (E.P.); (G.D.)
| | - Giuseppe Defazio
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari ‘Aldo Moro’, 70126 Bari, Italy; (E.P.); (G.D.)
| | - Graziano Pesole
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Consiglio Nazionale delle Ricerche, 70126 Bari, Italy; (M.M.); (B.F.); (G.P.)
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari ‘Aldo Moro’, 70126 Bari, Italy; (E.P.); (G.D.)
| | - Mariangela De Robertis
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari ‘Aldo Moro’, 70126 Bari, Italy; (E.P.); (G.D.)
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Yuan C, Zhang P, Jin Y, Ullah Shah A, Zhang E, Yang Q. Single-Blinded Study Highlighting the Differences between the Small Intestines of Neonatal and Weaned Piglets. Animals (Basel) 2021; 11:ani11020271. [PMID: 33494523 PMCID: PMC7910829 DOI: 10.3390/ani11020271] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 01/18/2021] [Accepted: 01/19/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary The gut mucosa of pigs, which contains intestinal epithelium and subepithelial immune cells, forms a barrier against microorganisms. Nonetheless, infectious diseases of the digestive tract remain the most frequent and recurrent conditions in the swine industry. Changes in intestinal morphology and structure primarily occur at birth and during weaning. However, the difference in the intestinal structures between neonatal and weaned piglets remains unclear. In this study, for the first time, we evaluated the differences in the small intestine between neonatal (0-day-old) and weaned piglets (21-day-old) and analyzed the morphology and immunological components of the small intestines of 0- and 21-day-old piglets, thereby providing preliminary data for future mechanistic studies. Abstract The gut is one of the body’s major immune structures, and the gut mucosa, which contains intestinal epithelium and subepithelial immune cells, is the primary site for eliciting local immune responses to foreign antigens. Intestinal immune system development in pigs is a transitional period during birth and weaning. This study compares the morphological and immunological differences in the small intestine of neonatal and weaned piglets to potentially prevent intestinal infectious diseases in neonatal piglets. Histological analyses of weaned piglet intestines showed increased crypt depth, higher IEL count, and larger ileal Peyer’s patches compared with those of neonates. Additionally, the ileal villi of weaned piglets were longer than those of neonatal piglets, and claudin-3 protein expression was significantly higher in weaned than in neonatal piglets. The numbers of CD3+ T, goblet, and secretory cells were also higher in the small intestines of weaned piglets than in those of neonates. No significant differences were observed in the secretory IgA-positive cell number in the jejunum of weaned and neonatal piglets. The mRNA expression of most pattern recognition receptors genes in the duodenum and jejunum was higher in the weaned than neonatal piglets; however, the opposite was true in the ileum. The mRNA levels of IL-1β and TNF-α in the jejunal and ileal mucosa were higher in weaned piglets than in neonatal piglets. There were significantly fewer CD3+, CD4+, and CD8+ T cells from peripheral blood-mononuclear cells in neonatal piglets. Our study provides insights regarding the different immune mechanisms within the small intestines of 0- and 21-day-old piglets. Studies on the additional developmental stages and how differences in the small intestines affect the response of pigs to pathogens remain warranted.
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Affiliation(s)
| | | | | | | | | | - Qian Yang
- Correspondence: ; Tel.: +86-025-8439-5817
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Chen Z, Jiang L. The clinical application of fruquintinib on colorectal cancer. Expert Rev Clin Pharmacol 2019; 12:713-721. [PMID: 31177854 DOI: 10.1080/17512433.2019.1630272] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Zhongguang Chen
- Department of Pharmaceutical, Central Hospital of Linyi City, Yishui, Shandong, China
| | - Lili Jiang
- Ultrasound Medical Department, Jinan Central Hospital Affiliated to Shandong University, Jinan, China
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O'Connell AE, Zhou F, Shah MS, Murphy Q, Rickner H, Kelsen J, Boyle J, Doyle JJ, Gangwani B, Thiagarajah JR, Kamin DS, Goldsmith JD, Richmond C, Breault DT, Agrawal PB. Neonatal-Onset Chronic Diarrhea Caused by Homozygous Nonsense WNT2B Mutations. Am J Hum Genet 2018; 103:131-137. [PMID: 29909964 PMCID: PMC6035368 DOI: 10.1016/j.ajhg.2018.05.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Accepted: 05/17/2018] [Indexed: 12/13/2022] Open
Abstract
Homozygous nonsense mutations in WNT2B were identified in three individuals from two unrelated families with severe, neonatal-onset osmotic diarrhea after whole-exome sequencing was performed on trios from the two families. Intestinal biopsy samples from affected individuals were used for histology and immunofluorescence and to generate enteroids ex vivo. Histopathologic evaluation demonstrated chronic inflammatory changes in the stomach, duodenum, and colon. Immunofluorescence demonstrated diminished staining for OLFM4, a marker for intestinal stem cells (ISCs). The enteroids generated from WNT2B-deficient intestinal epithelium could not be expanded and did not survive passage. Addition of CHIR-99021 (a GSK3A and GSK3B inhibitor and activator of canonical WNT/β-CATENIN signaling) could not rescue WNT2B-deficient enteroids. Addition of supplemental recombinant murine WNT2B was able to perpetuate small enteroids for multiple passages but failed to expand their number. Enteroids showed a 10-fold increase in the expression of LEF1 mRNA and a 100-fold reduction in TLR4 expression, compared with controls by quantitative RT-PCR, indicating alterations in canonical WNT and microbial pattern-recognition signaling. In summary, individuals with homozygous nonsense mutations in WNT2B demonstrate severe intestinal dysregulation associated with decreased ISC number and function, likely explaining their diarrheal phenotype. WNT2B deficiency should be considered for individuals with neonatal-onset diarrhea.
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Affiliation(s)
- Amy E O'Connell
- Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
| | - Fanny Zhou
- Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA
| | - Manasvi S Shah
- Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA
| | - Quinn Murphy
- Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA
| | - Hannah Rickner
- Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA
| | - Judith Kelsen
- Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - John Boyle
- Division of Gastroenterology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Jefferson J Doyle
- Department of Ophthalmology, Boston Children's Hospital, Boston, MA 02115, USA
| | - Bharti Gangwani
- Department of Ophthalmology, Boston Children's Hospital, Boston, MA 02115, USA
| | - Jay R Thiagarajah
- Division of Gastroenterology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
| | - Daniel S Kamin
- Division of Gastroenterology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
| | | | - Camilla Richmond
- Division of Gastroenterology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
| | - David T Breault
- Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA
| | - Pankaj B Agrawal
- Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
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Xia L, Yang Y, Wang J, Jing Y, Yang Q. Impact of TGEV infection on the pig small intestine. Virol J 2018; 15:102. [PMID: 29914507 PMCID: PMC6006930 DOI: 10.1186/s12985-018-1012-9] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 06/03/2018] [Indexed: 02/07/2023] Open
Abstract
Background Pig diarrhea causes high mortality and large economic losses in the swine industry. Transmissible gastroenteritis virus (TGEV) causes pig diarrhea, with 100% mortality in piglets less than 2 weeks old. No investigation has yet been made of the small intestine of piglets that survived infection by TGEV. Methods In this study, we evaluated the impact of TGEV infection on the small intestine of recovered pigs. Results Histological analyses showed that TGEV infection led to villi atrophy, and reduced villous height and crypt depth. The number of SIgA positive cells, CD3+T cells, and dendritic cells (DCs) in jejunum decreased after TGEV infection in vivo. In contrast, microfold cell (M cell) numbers and cell proliferation increased in infected pigs. TGEV infection also significantly enhanced the mRNA expression levels of cytokine IL-1β, IL-6, TNF-α, IL-10, and TGF-β. Additionally, lower gene copy numbers of Lactobacillus, and higher numbers of Enterobacteriaceae, were detected in mucosal scraping samples from TGEV-infected pigs. Conclusions TGEV infection damages the small intestine, impairs immune functions, and increases pathogenic bacterial loading, all of which may facilitate secondary infections by other pathogens. These findings help quantify the impact of TGEV infection and clarify the pathogenic mechanisms underlying its effects in pigs.
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Affiliation(s)
- Lu Xia
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Weigang 1, Nanjing, Jiangsu, 210095, People's Republic of China
| | - Yunhan Yang
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Weigang 1, Nanjing, Jiangsu, 210095, People's Republic of China
| | - Jialu Wang
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Weigang 1, Nanjing, Jiangsu, 210095, People's Republic of China
| | - Yuchao Jing
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Weigang 1, Nanjing, Jiangsu, 210095, People's Republic of China
| | - Qian Yang
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Weigang 1, Nanjing, Jiangsu, 210095, People's Republic of China.
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Serum Interleukin 9 Levels Predict Disease Severity and the Clinical Efficacy of Infliximab in Patients with Crohn's Disease. Inflamm Bowel Dis 2017. [PMID: 28644181 DOI: 10.1097/mib.0000000000001172] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Interleukin (IL)-9 drives gut inflammation, but its role in Crohn's disease (CD) is unclear. We aimed to analyze correlations between serum IL-9 levels and disease severity and to evaluate their predictive value in relation to the clinical efficacy of infliximab (IFX) in patients with CD. METHODS Between January 2013 and December 2015, 100 consecutive patients with active CD and 50 age- and sex-matched control individuals were recruited from a tertiary center. Their serum IL-9 levels were measured using an enzyme-linked immunosorbent assay. Correlations between the serum IL-9 levels and disease severity were examined. The serum IL-9 level was explored as a predictor of clinical remission and mucosal healing at week 30 in 50 patients for whom IFX therapy was administered. RESULTS The serum IL-9 levels were significantly higher in the patients with active CD (22.0 pg/mL) than in the control individuals (6.3 pg/mL) (P < 0.001); they differed according to disease severity (moderate-to-severe CD: 29.1 pg/mL versus mild CD: 12.9 pg/mL) (P < 0.001), and they correlated well with the clinical activity of CD. IFX lowered the serum IL-9 level in patients who achieved efficacy at week 30. The areas under the curves for the IL-9 levels at weeks 14 and 30 that could predict clinical remission and mucosal healing at week 30 were 0.803 and 0.752 and 0.746 and 0.781, respectively. CONCLUSIONS Serum IL-9 levels correlate with disease severity and the clinical efficacy of IFX in patients with CD, and IL-9 may be a promising novel biomarker for CD monitoring.
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Hou Q, Ye L, Huang L, Yu Q. The Research Progress on Intestinal Stem Cells and Its Relationship with Intestinal Microbiota. Front Immunol 2017; 8:599. [PMID: 28588586 PMCID: PMC5440531 DOI: 10.3389/fimmu.2017.00599] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Accepted: 05/08/2017] [Indexed: 12/12/2022] Open
Abstract
The intestine is home to trillions of microorganisms, and the vast diversity within this gut microbiota exists in a balanced state to protect the intestinal mucosal barrier. Research into the association of the intestinal microbiota with health and disease (including diet, nutrition, obesity, inflammatory bowel disease, and cancer) continues to expand, with the field advancing at a rapid rate. Intestinal stem cells (ISCs) are the fundamental component of the mucosal barrier; they undergo continuous proliferation to replace the epithelium, which is also intimately involved in intestinal diseases. The intestinal microbiota, such as Lactobacillus, communicates with ISCs both directly and indirectly to regulate the proliferation and differentiation of ISCs. Moreover, Salmonella infection significantly decreased the expression of intestinal stem cell markers Lgr5 and Bmi1. However, the detailed interaction of intestinal microbiota and ISCs are still unclear. This review considers the progress of research on the model and niches of ISCs, as well as the complex interplay between the gut microbiota and ISCs, which will be crucial for explaining the mechanisms of intestinal diseases related to imbalances in the intestinal microbiota and ISCs.
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Affiliation(s)
- Qihang Hou
- College of veterinary medicine, Nanjing Agricultural University, Nanjing, China
| | - Lulu Ye
- College of veterinary medicine, Nanjing Agricultural University, Nanjing, China
| | - Lulu Huang
- College of veterinary medicine, Nanjing Agricultural University, Nanjing, China
| | - Qinghua Yu
- College of veterinary medicine, Nanjing Agricultural University, Nanjing, China
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Lu R, Voigt RM, Zhang Y, Kato I, Xia Y, Forsyth CB, Keshavarzian A, Sun J. Alcohol Injury Damages Intestinal Stem Cells. Alcohol Clin Exp Res 2017; 41:727-734. [PMID: 28195397 DOI: 10.1111/acer.13351] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 02/07/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND Alcohol consumption is associated with intestinal injury including intestinal leakiness and the risk of developing progressive gastrointestinal cancer. Alcoholics have disruption of intestinal barrier dysfunction that persists weeks after stopping alcohol intake, and this occurs in spite of the fact that intestinal epithelial cells turn over every 3 to 5 days. The renewal and functional regulation of the intestinal epithelium largely relies on intestinal stem cells (ISCs). Chronic inflammation and tissue damage in the intestine can injure stem cells including accumulation of mutations that may result in ISC dysfunction and transformation. ISCs are a key element in intestinal function and pathology; however, very little is known about the effects of alcohol on ISCs. We hypothesize that dysregulation of ISCs is one mechanism by which alcohol induces long-lasting intestinal damage. METHODS In Vivo: Small intestinal samples from alcohol- and control-fed mice were assessed for ISC markers (Lgr5 and Bmi1) and the changes of the β-catenin signaling using immunofluorescent microscopy, Western blotting, and RT-PCR. Ex Vivo: Organoids were generated from small intestine tissue and subsequently exposed to alcohol and analyzed for ISC markers, β-catenin signaling. RESULTS Chronic alcohol consumption significantly decreased the expression of stem cell markers, Bmi1 in the small intestine of the alcohol-fed mice and also resulted in dysregulation of the β-catenin signaling-an essential regulator of its target gene Lgr5 and ISC function. Exposure of small intestine-derived organoids to 0.2% alcohol significantly reduced the growth of the organoids, including budding, and total surface area of the organoid cultures. Alcohol also significantly decreased the expression of Lgr5, p-β-catenin (ser552), and Bmi1 in the organoid model. CONCLUSIONS Both chronic alcohol feeding and acute exposure of alcohol resulted in ISC dysregulation which might be one mechanism for alcohol-induced long-lasting intestinal damage.
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Affiliation(s)
- Rong Lu
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Robin M Voigt
- Division of Digestive Diseases and Nutrition, Department of Medicine, Rush University Medical Center, Chicago, Illinois
| | - Yongguo Zhang
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Ikuko Kato
- Departments of Oncology and Pathology, Wayne State University School of Medicine, Detroit, Michigan
| | - Yinglin Xia
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Christopher B Forsyth
- Division of Digestive Diseases and Nutrition, Department of Medicine, Rush University Medical Center, Chicago, Illinois
| | - Ali Keshavarzian
- Division of Digestive Diseases and Nutrition, Department of Medicine, Rush University Medical Center, Chicago, Illinois
| | - Jun Sun
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
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Goudarzi M, Mak TD, Jacobs JP, Moon BH, Strawn SJ, Braun J, Brenner DJ, Fornace AJ, Li HH. An Integrated Multi-Omic Approach to Assess Radiation Injury on the Host-Microbiome Axis. Radiat Res 2016; 186:219-34. [PMID: 27512828 PMCID: PMC5304359 DOI: 10.1667/rr14306.1] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Medical responders to radiological and nuclear disasters currently lack sufficient high-throughput and minimally invasive biodosimetry tools to assess exposure and injury in the affected populations. For this reason, we have focused on developing robust radiation exposure biomarkers in easily accessible biofluids such as urine, serum and feces. While we have previously reported on urine and serum biomarkers, here we assessed perturbations in the fecal metabolome resulting from exposure to external X radiation in vivo. The gastrointestinal (GI) system is of particular importance in radiation biodosimetry due to its constant cell renewal and sensitivity to radiation-induced injury. While the clinical GI symptoms such as pain, bloating, nausea, vomiting and diarrhea are manifested after radiation exposure, no reliable bioindicator has been identified for radiation-induced gastrointestinal injuries. To this end, we focused on determining a fecal metabolomic signature in X-ray irradiated mice. There is overwhelming evidence that the gut microbiota play an essential role in gut homeostasis and overall health. Because the fecal metabolome is tightly correlated with the composition and diversity of the microorganism in the gut, we also performed fecal 16S rRNA sequencing analysis to determine the changes in the microbial composition postirradiation. We used in-house bioinformatics tools to integrate the 16S rRNA sequencing and metabolomic data, and to elucidate the gut integrated ecosystem and its deviations from a stable host-microbiome state that result from irradiation. The 16S rRNA sequencing results indicated that radiation caused remarkable alterations of the microbiome in feces at the family level. Increased abundance of common members of Lactobacillaceae and Staphylococcaceae families, and decreased abundances of Lachnospiraceae, Ruminococcaceae and Clostridiaceae families were found after 5 and 12 Gy irradiation. The metabolomic data revealed statistically significant changes in the microbial-derived products such as pipecolic acid, glutaconic acid, urobilinogen and homogentisic acid. In addition, significant changes were detected in bile acids such as taurocholic acid and 12-ketodeoxycholic acid. These changes may be associated with the observed shifts in the abundance of intestinal microbes, such as R. gnavus , which can transform bile acids.
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Affiliation(s)
- Maryam Goudarzi
- Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC
| | - Tytus D. Mak
- Mass Spectrometry Data Center, National Institute of Standards and Technology, Gaithersburg, Maryland
| | - Jonathan P. Jacobs
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Bo-Hyun Moon
- Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC
| | - Steven J. Strawn
- Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC
| | - Jonathan Braun
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - David J. Brenner
- Center for Radiological Research, Columbia University, New York, New York
| | - Albert J. Fornace
- Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
| | - Heng-Hong Li
- Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC
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14
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De Francesco F, Romano M, Zarantonello L, Ruffolo C, Neri D, Bassi N, Giordano A, Zanus G, Ferraro GA, Cillo U. The role of adipose stem cells in inflammatory bowel disease: From biology to novel therapeutic strategies. Cancer Biol Ther 2016; 17:889-98. [PMID: 27414952 DOI: 10.1080/15384047.2016.1210741] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Inflammatory bowel diseases are an increasing phenomenon in western countries and in growing populations. The physiopathology of these conditions is linked to intestinal stem cells homeostasis and regenerative potential in a chronic inflammatory microenvironment. Patients with IBD present an increased risk of developing colorectal cancer (CRC), or colitis associated cancer (CAC). Conventional treatment for IBD target the inflammatory process (and include anti-inflammatory and immunosuppressive drugs) with biological agents emerging as a therapeutic approach for non-responders to traditional therapy. Conventional treatment provides scarce results and present severe complications. The intestinal environment may host incoming stem cells, able to engraft in the epithelial damaged sites and differentiate. Therefore, stem cell therapies represent an emerging alternative in inflammatory bowel diseases, with current investigations on the use of haematopoietic and mesenchymal stem cells, in particular adipose stem cells, apparently fundamental as regenerators and as immune-modulators. Here, we discuss stem cells in intestinal homeostasis and as therapeutic agents for the treatment of inflammatory bowel diseases.
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Affiliation(s)
- Francesco De Francesco
- a Multidisciplinary Department of Medical-Surgery and Dental Specialties , School of Medicine and Surgery, Second University of Naples , Italy
| | - Maurizio Romano
- a Multidisciplinary Department of Medical-Surgery and Dental Specialties , School of Medicine and Surgery, Second University of Naples , Italy
| | - Laura Zarantonello
- b Department of Surgery , Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation, Padua University Hospital , Padua , Italy
| | - Cesare Ruffolo
- c Department of Surgery , Regional Center for hpb surgery, Regional Hospital of Treviso , TV , Italy
| | - Daniele Neri
- b Department of Surgery , Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation, Padua University Hospital , Padua , Italy
| | - Nicolò Bassi
- c Department of Surgery , Regional Center for hpb surgery, Regional Hospital of Treviso , TV , Italy
| | - Antonio Giordano
- d Department of Medicine , Surgery and Neuroscience, University of Siena , Siena , Italy.,e Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University , Philadelphia , PA , USA
| | - Giacomo Zanus
- b Department of Surgery , Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation, Padua University Hospital , Padua , Italy
| | - Giuseppe A Ferraro
- a Multidisciplinary Department of Medical-Surgery and Dental Specialties , School of Medicine and Surgery, Second University of Naples , Italy
| | - Umberto Cillo
- b Department of Surgery , Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation, Padua University Hospital , Padua , Italy
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15
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Wang H, Yang M, Lin L, Ren H, Lin C, Lin S, Shen G, Ji B, Meng C. HepG2 cells acquire stem cell-like characteristics after immune cell stimulation. Cell Oncol (Dordr) 2015; 39:35-45. [DOI: 10.1007/s13402-015-0249-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/09/2015] [Indexed: 01/06/2023] Open
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16
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Maragkoudaki M, Vaiopoulou A, Theodoropoulos GE, Legaki E, Sechi LA, Karamanolis G, Zografos G, Gazouli M. Specific detection of OCT4 isoforms in inflammatory bowel disease. Gut Pathog 2015; 7:25. [PMID: 26435752 PMCID: PMC4591585 DOI: 10.1186/s13099-015-0073-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Accepted: 09/23/2015] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Developmentally early cells are mobilized into peripheral blood in Crohn's disease (CD) patients. OCT4, is considered to be important in sustaining the pluripotency of stem cells. OCT4 splicing variants are differentially expressed in pluripotent and non-pluripotent cells. Our study aims to investigate the expression pattern of OCT4 variants and SOX-2, an essential factor implicated in self-renewal and pluripotency, in tissue and blood samples from patients with IBD. METHODS Peripheral blood and tissue samples were collected from patients with active CD and ulcerative colitis (UC), and from healthy individuals. OCT4 expression was documented by Western blot, immunohistochemistry and by reverse transcription-real-time PCR. OCT4 isoform determination was documented using specific primers. SOX-2 expression levels were also evaluated. RESULTS OCT4 protein levels were significantly higher in CD tissue samples than in CD blood samples, and in UC tissue samples. OCT4 protein was localized mainly in the cytosol. In all samples, only the OCT4 pseudogenes and the OCT4B1 variant were detected. OCT4B1 expression levels were elevated in both tissue and blood samples from CD and UC cases compared to healthy controls. In CD patients only SOX-2 mRNA levels were found slightly increased compared to healthy controls. CONCLUSION Our results suggest that OCT4 is expressed in patients with IBD. Furthermore, we found the presence of the OCT4B1 isoform in IBD in both tissue and blood samples. Our results have shown, that developmentally early cells might be mobilized into peripheral blood as result of tissue damage, indicating a possible role of these cells in repair of injured intestinal tract.
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Affiliation(s)
- Maria Maragkoudaki
- />First Department of Pediatrics, Athens University Medical School, “Aghia Sophia” Children’s Hospital, Athens, Greece
| | - Anna Vaiopoulou
- />Laboratory of Biology, Department of Basic Medical Sciences, School of Medicine, University of Athens, Michalakopoulou 176, 11527 Athens, Greece
| | - George E. Theodoropoulos
- />Colorectal and Inflammatory Bowel Diseases Unit, First Department of Propaedeutic Surgery of Athens Medical School, Athens, Greece
| | - Evangelia Legaki
- />Laboratory of Biology, Department of Basic Medical Sciences, School of Medicine, University of Athens, Michalakopoulou 176, 11527 Athens, Greece
| | - Leonardo A. Sechi
- />Sezione di Microbiologia e Virologia, Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Sassari, Italy
| | - George Karamanolis
- />Department of Surgery, “Aretaieio” University Hospital, Athens, Greece
| | - George Zografos
- />Colorectal and Inflammatory Bowel Diseases Unit, First Department of Propaedeutic Surgery of Athens Medical School, Athens, Greece
| | - Maria Gazouli
- />Laboratory of Biology, Department of Basic Medical Sciences, School of Medicine, University of Athens, Michalakopoulou 176, 11527 Athens, Greece
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17
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Flores AI, Gómez-Gómez GJ, Masedo-González &A, Martínez-Montiel MP. Stem cell therapy in inflammatory bowel disease: A promising therapeutic strategy? World J Stem Cells 2015; 7:343-351. [PMID: 25815119 PMCID: PMC4369491 DOI: 10.4252/wjsc.v7.i2.343] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 09/24/2014] [Accepted: 11/10/2014] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases are inflammatory, chronic and progressive diseases of the intestinal tract for which no curative treatment is available. Research in other fields with stem cells of different sources and with immunoregulatory cells (regulatory T-lymphocytes and dendritic T-cells) opens up new expectations for their use in these diseases. The goal for stem cell-based therapy is to provide a permanent cure. To achieve this, it will be necessary to obtain a cellular product, original or genetically modified, that has a high migration capacity and homes into the intestine, has high survival after transplantation, regulates the immune reaction while not being visible to the patient’s immune system, and repairs the injured tissue.
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18
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Dearing KR, Weiss GJ. Translating next-generation sequencing from clinical trials to clinical practice for the treatment of advanced cancers. Per Med 2015; 12:155-162. [PMID: 29754537 DOI: 10.2217/pme.14.54] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Next-generation sequencing (NGS) is being applied in oncology care to identify specific molecular aberrations of patient's tumors. The use of NGS now allows for sequencing entire human genomes within a reasonable cost and practical time frames for treatment decision making. Further delineation of epigenetics, transcriptomics, metagenomics and NGS at the level of circulating tumor DNA reveal ever increasing complexity to understand these interactions and the roles they play in cancer. With the improvement in understanding the study of proteomics, it has become clear that NGS has room for innovation to someday include sequencing of proteins. Early embarkation of NGS incorporated into clinical trials has begun. Here, we review the feasibility and practicality of translating NGS from clinical trials to clinical practice.
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Affiliation(s)
- Kristen R Dearing
- Cancer Treatment Centers of America, 14200 Celebrate Life Way, Goodyear, AZ 85338, USA
| | - Glen J Weiss
- Cancer Treatment Centers of America, 14200 Celebrate Life Way, Goodyear, AZ 85338, USA.,CRAB-Clinical Trials Consortium, 1730 Minor Ave., Seattle, WA 98101, USA
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19
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Mu J, Zhuang X, Wang Q, Jiang H, Deng ZB, Wang B, Zhang L, Kakar S, Jun Y, Miller D, Zhang HG. Interspecies communication between plant and mouse gut host cells through edible plant derived exosome-like nanoparticles. Mol Nutr Food Res 2014; 58:1561-73. [PMID: 24842810 PMCID: PMC4851829 DOI: 10.1002/mnfr.201300729] [Citation(s) in RCA: 450] [Impact Index Per Article: 40.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2013] [Revised: 03/31/2014] [Accepted: 03/31/2014] [Indexed: 12/14/2022]
Abstract
SCOPE Exosomes, small vesicles participating in intercellular communication, have been extensively studied recently; however, the role of edible plant derived exosomes in interspecies communication has not been investigated. Here, we investigate the biological effects of edible plant derived exosome-like nanoparticles (EPDENs) on mammalian cells. METHODS AND RESULTS In this study, exosome-like nanoparticles from four edible plants were isolated and characterized. We show that these EPDENs contain proteins, lipids, and microRNA. EPDENs are taken up by intestinal macrophages and stem cells. The results generated from EPDEN-transfected macrophages indicate that ginger EPDENs preferentially induce the expression of the antioxidation gene, heme oxygenase-1 and the anti-inflammatory cytokine, IL-10; whereas grapefruit, ginger, and carrot EPDENs promote activation of nuclear factor like (erythroid-derived 2). Furthermore, analysis of the intestines of canonical Wnt-reporter mice, i.e. B6.Cg-Tg(BAT-lacZ)3Picc/J mice, revealed that the numbers of β-galactosidase(+) (β-Gal) intestinal crypts are increased, suggesting that EPDEN treatment of mice leads to Wnt-mediated activation of the TCF4 transcription machinery in the crypts. CONCLUSION The data suggest a role for EPDEN-mediated interspecies communication by inducing expression of genes for anti-inflammation cytokines, antioxidation, and activation of Wnt signaling, which are crucial for maintaining intestinal homeostasis.
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Affiliation(s)
- Jingyao Mu
- Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, KY 40202
| | - Xiaoying Zhuang
- Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, KY 40202
| | - Qilong Wang
- Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, KY 40202
| | - Hong Jiang
- Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, KY 40202
| | - Zhong-Bin Deng
- Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, KY 40202
| | - Baomei Wang
- Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, KY 40202
| | - Lifeng Zhang
- Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, KY 40202
| | - Sham Kakar
- Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, KY 40202
| | - Yan Jun
- Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, KY 40202
| | - Donald Miller
- Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, KY 40202
| | - Huang-Ge Zhang
- Louisville Veterans Administration Medical Center, Louisville, KY 40206
- Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, KY 40202
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