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Khalifa A, Alkuwayti MA, Abdallah BM, Ali EM, Ibrahim HIM. Probiotic and Rice-Derived Compound Combination Mitigates Colitis Severity. Pharmaceuticals (Basel) 2024; 17:1463. [PMID: 39598375 PMCID: PMC11597685 DOI: 10.3390/ph17111463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Revised: 10/07/2024] [Accepted: 10/30/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND This study investigated the ability of Enterococcus lactis (E. lactis) and Hasawi rice protein lysate (HPL) to suppress colitis induced by dextran sulfate sodium (DSS) in miceColitis is characterized by inflammation of the colon, and exploring potential therapeutic agents could lead to improved management strategies. METHODS Male mice were subjected to DSS treatment to induce colitis, followed by supplementation with E. lactis and/or HPL. The study assessed various parameters, including disease activity index (DAI) scores, gut permeability measured using FITC-dextran, and superoxide dismutase (SOD) activity in excised colon tissues from both treated and untreated control groups. RESULTS E. lactis supplementation significantly alleviated DSS-induced colitis, as evidenced by improved DAI scores and enhanced gut permeability. Notably, E. lactis combined with HPL (0.1 mg/108) exhibited superior tolerance to a 0.5% pancreatin solution compared to E. lactis alone. Both E. lactis and the combination treatment significantly increased SOD activity (5.6 ± 0.23 SOD U/mg protein for E. lactis and 6.7 ± 0.23 SOD U/mg protein for the combination) relative to the Azoxymethane (AOM)/DSS group, suggesting a reduction in oxidative stress. Additionally, pro-inflammatory markers were significantly reduced in the group receiving both E. lactis and HPL compared to the E. lactis-only group. Levels of proteins associated with cell death, such as PCNA, PTEN, VEGF, COX-2, and STAT-3, were significantly decreased by 14.8% to 80% following E. lactis supplementation, with the combination treatment showing the most pronounced effects. CONCLUSIONS These findings suggest E. lactis supplementation may be beneficial for colitis, with HPL potential to enhance its effectiveness.
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Affiliation(s)
- Ashraf Khalifa
- Biological Science Department, College of Science, King Faisal University, P.O. Box 400, Al-Ahsa 31982, Saudi Arabia
- Botany and Microbiology Department, Faculty of Science, Beni-Suef University, Beni-Suef 62511, Egypt
| | - Mayyadah Abdullah Alkuwayti
- Biological Science Department, College of Science, King Faisal University, P.O. Box 400, Al-Ahsa 31982, Saudi Arabia
| | - Basem M. Abdallah
- Biological Science Department, College of Science, King Faisal University, P.O. Box 400, Al-Ahsa 31982, Saudi Arabia
| | - Enas M. Ali
- Biological Science Department, College of Science, King Faisal University, P.O. Box 400, Al-Ahsa 31982, Saudi Arabia
| | - Hairul Islam M. Ibrahim
- Biological Science Department, College of Science, King Faisal University, P.O. Box 400, Al-Ahsa 31982, Saudi Arabia
- Molecular Biology Division, Pondicherry Centre for Biological Sciences and Educational Trust, Pondicherry 605004, India
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Probiotics-loaded nanoparticles attenuated colon inflammation, oxidative stress, and apoptosis in colitis. Sci Rep 2022; 12:5116. [PMID: 35332200 PMCID: PMC8948303 DOI: 10.1038/s41598-022-08915-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Accepted: 03/11/2022] [Indexed: 12/19/2022] Open
Abstract
Promising therapy is needed for treating inflammatory bowel diseases (IBD) to overcome current treatment that inefficient and associated with unnecessary health risks. Recently, the concept of incorporating natural products into nanocarriers has been intended as a promising therapy for treating IBD via modulating their stability and bioavailability. Thus, we aimed to explore the potential alleviating effects of dietary nano-supplement combined with bacillus strains (Bacillus amyloliquefaciens; BANPs) in colitis model. Rats were orally gavaged by 5% DSS and the efficacy and mechanistic actions of BANPs were evaluated by assessing the severity of clinical signs and inflammatory and apoptosis response, histopathological and immunohistochemistry examination in colonic tissues. The severity of clinical signs was successfully alleviated and fecal Lcn-2 levels, an important colitic marker, were decreased in BANPs then free BA treated groups. In contrast, inflammatory markers overexpression IL-6, IL-1β, TNFα, COX-2, and iNOS in the colitic group were reduced more prominently in BANPs treated group, unlike free BA. The amelioration of BANPs to colon injury was also correlated with oxidative stress suppression along with restoring total antioxidant capacity. Interestingly, BANPs treatment modulated apoptotic markers as proved by downregulation of cytochrome c, and caspase-3 and upregulation of Bcl-2 and Bax than free BA. The severity of the histopathological alterations in the colon was greatly reduced in BANPs than free BA groups. Remarkably, over-expression of ki67 and IL-6 in colonic tissues were suppressed in BANPs group. These findings together highlighted the beneficial efficacy of BANPs in IBD treatment which are evidenced by colonic inflammation alleviation. Taken together, these results recommend that BANPs is a promising agent that encourages its possible therapeutic role in colitis treatment.
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Martínez-Herrero S, Martínez A. Adrenomedullin: Not Just Another Gastrointestinal Peptide. Biomolecules 2022; 12:biom12020156. [PMID: 35204657 PMCID: PMC8961556 DOI: 10.3390/biom12020156] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/14/2022] [Accepted: 01/15/2022] [Indexed: 12/11/2022] Open
Abstract
Adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) are two bioactive peptides derived from the same precursor with several biological functions including vasodilation, angiogenesis, or anti-inflammation, among others. AM and PAMP are widely expressed throughout the gastrointestinal (GI) tract where they behave as GI hormones, regulating numerous physiological processes such as gastric emptying, gastric acid release, insulin secretion, bowel movements, or intestinal barrier function. Furthermore, it has been recently demonstrated that AM/PAMP have an impact on gut microbiome composition, inhibiting the growth of bacteria related with disease and increasing the number of beneficial bacteria such as Lactobacillus or Bifidobacterium. Due to their wide functions in the GI tract, AM and PAMP are involved in several digestive pathologies such as peptic ulcer, diabetes, colon cancer, or inflammatory bowel disease (IBD). AM is a key protective factor in IBD onset and development, as it regulates cytokine production in the intestinal mucosa, improves vascular and lymphatic regeneration and function and mucosal epithelial repair, and promotes a beneficial gut microbiome composition. AM and PAMP are relevant GI hormones that can be targeted to develop novel therapeutic agents for IBD, other GI disorders, or microbiome-related pathologies.
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Clostridium butyricum modulates gut microbiota and reduces colitis associated colon cancer in mice. Int Immunopharmacol 2020; 88:106862. [PMID: 32771947 DOI: 10.1016/j.intimp.2020.106862] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 07/26/2020] [Accepted: 07/28/2020] [Indexed: 12/26/2022]
Abstract
We investigate the effects of Clostridium butyricum(CB) on gut microbiota and colitis associated colon cancer(CAC) in mice.6-8 weeks old C57BL/6 mice were randomly divided into control, azoxymethane (AOM) + dextran sodium sulphate (DSS) and AOM + DSS + CB groups. Mice in the latter two groups received an intraperitoneal injection of AOM (12.5 mg/kg), followed by three cycles of DSS diluted in water (2.5% w/v). Mice in treatment group received CB (2 × 108 CFU in 200 ul normal saline) by gavage administration three times one week. Microbiota composition was assessed by 16S rRNA high-throughput sequencing. Colon samples were collected to examine severity of colitis and tumorigenesis. Cytokines including TNF-a, IL-6 and Cyclo-oxygenase-2 (COX-2) were detected by RT-qPCR. Expression of Bcl-2, Bax and the state of components of NF-κB signaling pathway were detected by western blot. The results revealed that CB regulated structure of intestinal flora and changed the microbial composition; decreased Firmicutes/ Bacteroidetes ratio in phylum level and increased the relative abundance of probiotics; decreased colitis, decreased incidence and size of colorectal cancer(CRC) and increased apoptosis of tumor cells; decreased cytokines including TNF-a and IL-6; decreased level of COX-2; decreased phosphorylation of NF-κB; decreased level of Bcl-2 and increased expression of Bax. In conclusion, CB could regulate structure and composition of gut microbiota and reduces colitis associated colon cancer in mice, the mechanism may be inhibiting NF-κB pathway and promoting apoptosis.
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Xue M, Shi L, Wang W, Chen S, Wang L. An Overview of Molecular Profiles in Ulcerative Colitis-Related Cancer. Inflamm Bowel Dis 2018; 24:1883-1894. [PMID: 29945208 DOI: 10.1093/ibd/izy221] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Indexed: 12/16/2022]
Abstract
Ulcerative colitis (UC) is an independent risk factor of colorectal cancer (CRC). Both genetic and epigentic events induce a unique molecular profile during the development from UC to UC-related CRC (UCRC). These molecular changes play varied roles in DNA repair, immune response, cell metabolism, and interaction with the microbiota during the carcinogenesis process. This review will systmatically discuss the molecular characteristics of UCRC and point out the future perspectives in this research field.
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Affiliation(s)
- Meng Xue
- Department of Gastroenterology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Institute of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang, China
| | - Liuhong Shi
- Department of Ultrasound, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Weijia Wang
- Department of Cardiology, School of Medicine, the Johns Hopkins Hospital, Baltimore, Maryland
| | - Shujie Chen
- Department of Gastroenterology, Sir Runrun Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Liangjing Wang
- Department of Gastroenterology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Institute of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang, China
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6
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Tian Y, Xu Q, Sun L, Ye Y, Ji G. Short-chain fatty acids administration is protective in colitis-associated colorectal cancer development. J Nutr Biochem 2018; 57:103-109. [PMID: 29694938 DOI: 10.1016/j.jnutbio.2018.03.007] [Citation(s) in RCA: 104] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2017] [Revised: 11/14/2017] [Accepted: 03/08/2018] [Indexed: 12/17/2022]
Abstract
Reduced short-chain fatty acids (SCFAs) have been reported in patients with ulcerative colitis, and increased intake of dietary fiber has shown to be clinically beneficial for colitis. Whether SCFAs suppress tumorigenesis in colitis-associated colorectal cancer remains unknown. The chemopreventive effect of SCFAs in colitis-associated colorectal cancer was evaluated in this study. Model of colitis-associated colorectal cancer in male BALB/c mice was induced by azoxymethane (AOM) and dextran sodium sulfate (DSS). SCFAs mix (67.5 mM acetate, 40 mM butyrate, 25.9 mM propionate) was administered in drink water during the study period. Macroscopic and histological studies were performed to examine the colorectal inflammation and tumorigenesis in AOM/DSS-induced mice treated with or without SCFA mix. The effects of SCFAs mix on colonic epithelial cellular proliferation were also assessed using Ki67 immunohistochemistry and TUNEL staining. The administration of SCFAs mix significantly reduced the tumor incidence and size in mice with AOM/DSS-induced colitis associated colorectal cancer. SCFAs mix protected from AOM/DSS-induced colorectal cancer by improving colon inflammation and disease activity index score as well as suppressing the expression of proinflammatory cytokines including IL-6, TNF-α and IL-17. A decrease in cell proliferation markers and an increase in TUNEL-positive tumor epithelial cells were also demonstrated in AOM/DSS mice treated with SCFAs mix. SCFAs mix administration prevented development of tumor and attenuated the colonic inflammation in a mouse model of colitis-associated colorectal cancer. SCFAs mix may be a potential agent in the prevention and treatment of colitis-associated colorectal cancer.
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Affiliation(s)
- Yun Tian
- Department of Oncology, Shanghai Dermatology Hospital, Tongji University, Shanghai 200443, China; Department of Oncology, the Second Affiliated Hospital of Nanjing Medical University, No. 121 Jiangjiayuan Road, Nanjing 210011, PR China; Tongji University Cancer Center, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Qing Xu
- Department of Oncology, Shanghai Dermatology Hospital, Tongji University, Shanghai 200443, China; Tongji University Cancer Center, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Liqun Sun
- Department of Intensive Care Unit, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China
| | - Ying Ye
- Emergency Center, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, PR China
| | - Guozhong Ji
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, the Second Affiliated Hospital of Nanjing Medical University, No. 121 Jiangjiayuan Road, Nanjing 210011, PR China.
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Rodríguez-Luna A, Talero E, Terencio MDC, González-Rodríguez ML, Rabasco AM, de Los Reyes C, Motilva V, Ávila-Román J. Topical Application of Glycolipids from Isochrysis galbana Prevents Epidermal Hyperplasia in Mice. Mar Drugs 2017; 16:E2. [PMID: 29295585 PMCID: PMC5793050 DOI: 10.3390/md16010002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2017] [Revised: 12/06/2017] [Accepted: 12/07/2017] [Indexed: 12/18/2022] Open
Abstract
Chronic inflammatory skin diseases such as psoriasis have a significant impact on society. Currently, the major topical treatments have many side effects, making their continued use in patients difficult. Microalgae have emerged as a source of bio-active molecules such as glycolipids with potent anti-inflammatory properties. We aimed to investigate the effects of a glycolipid (MGMG-A) and a glycolipid fraction (MGDG) obtained from the microalga Isochrysis galbana on a TPA-induced epidermal hyperplasia murine model. In a first set of experiments, we examined the preventive effects of MGMG-A and MGDG dissolved in acetone on TPA-induced hyperplasia model in mice. In a second step, we performed an in vivo permeability study by using rhodamine-containing cream, ointment, or gel to determinate the formulation that preserves the skin architecture and reaches deeper. The selected formulation was assayed to ensure the stability and enhanced permeation properties of the samples in an ex vivo experiment. Finally, MGDG-containing cream was assessed in the hyperplasia murine model. The results showed that pre-treatment with acetone-dissolved glycolipids reduced skin edema, epidermal thickness, and pro-inflammatory cytokine production (TNF-α, IL-1β, IL-6, IL-17) in epidermal tissue. The in vivo and ex vivo permeation studies showed that the cream formulation had the best permeability profile. In the same way, MGDG-cream formulation showed better permeation than acetone-dissolved preparation. MGDG-cream application attenuated TPA-induced skin edema, improved histopathological features, and showed a reduction of the inflammatory cell infiltrate. In addition, this formulation inhibited epidermal expression of COX-2 in a similar way to dexamethasone. Our results suggest that an MGDG-containing cream could be an emerging therapeutic strategy for the treatment of inflammatory skin pathologies such as psoriasis.
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Affiliation(s)
- Azahara Rodríguez-Luna
- Department of Pharmacology, Faculty of Pharmacy, Universidad de Sevilla, 41012 Sevilla, Spain.
| | - Elena Talero
- Department of Pharmacology, Faculty of Pharmacy, Universidad de Sevilla, 41012 Sevilla, Spain.
| | - María Del Carmen Terencio
- Department of Pharmacology, Faculty of Pharmacy, University of Valencia, 46010 Valencia, Spain.
- Institute of Molecular Recognition and Technological Development (IDM), 46100 Valencia, Spain.
| | | | - Antonio M Rabasco
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Universidad de Sevilla, 41012 Sevilla, Spain.
| | - Carolina de Los Reyes
- Department of Organic Chemistry, Faculty of Marine and Environmental Sciences, University of Cadiz, 11510 Puerto Real, Cádiz, Spain.
| | - Virginia Motilva
- Department of Pharmacology, Faculty of Pharmacy, Universidad de Sevilla, 41012 Sevilla, Spain.
| | - Javier Ávila-Román
- Department of Pharmacology, Faculty of Pharmacy, Universidad de Sevilla, 41012 Sevilla, Spain.
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Vendramini-Costa DB, Alcaide A, Pelizzaro-Rocha KJ, Talero E, Ávila-Román J, Garcia-Mauriño S, Pilli RA, de Carvalho JE, Motilva V. Goniothalamin prevents the development of chemically induced and spontaneous colitis in rodents and induces apoptosis in the HT-29 human colon tumor cell line. Toxicol Appl Pharmacol 2016; 300:1-12. [DOI: 10.1016/j.taap.2016.03.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 03/16/2016] [Accepted: 03/18/2016] [Indexed: 12/12/2022]
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Expression patterns of sirtuin 1-AMPK-autophagy pathway in chronic colitis and inflammation-associated colon neoplasia in IL-10-deficient mice. Int Immunopharmacol 2016; 35:248-256. [PMID: 27085036 DOI: 10.1016/j.intimp.2016.03.046] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 03/19/2016] [Accepted: 03/30/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND Interleukin-10-deficient (IL-10 (-/-)) mice spontaneously develop chronic colitis and adenocarcinoma through the dysplasia sequence. Autophagy malfunction is associated to inflammatory bowel disease (IBD) and colorectal cancer (CRC) pathogenesis. Autophagy is regulated by silent information regulator-1 (SIRT1), a NAD+-dependent histone deacetylase. Our aim was to investigate the expression changes of SIRT1-AMPK-autophagy pathway in the progression from chronic colitis to CRC. METHODS We studied C57BL/6-IL-10-deficient mice between 6 and 18weeks of age. Macroscopic and histological analysis, and characterization of inflammatory and tumor biomarkers were performed. RESULTS IL-10-deficient mice developed colitis from the age of 6weeks onward. The severity of inflammation and dysplasia, and the proliferative activity increased gradually with age. IL-10 (-/-) mice were characterized by improved levels of TNF-α and decreased expression of SIRT1. Moreover, our findings show an increase in p-AMPK expression and an activation of the autophagy in IL-10 (-/-) mice from all stages, evidenced by the accumulation of LC3-II protein, the increase in Beclin 1 expression and the reduction in Bcl-2 levels. CONCLUSIONS SIRT1-AMPK-autophagy pathway may be involved in the maintenance of chronic inflammation and dysplasia development in the IL-10-deficient mice model. Modulation of this pathway could be a novel strategy for IBD and CRC treatment.
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Talero E, García-Mauriño S, Ávila-Román J, Rodríguez-Luna A, Alcaide A, Motilva V. Bioactive Compounds Isolated from Microalgae in Chronic Inflammation and Cancer. Mar Drugs 2015; 13:6152-209. [PMID: 26437418 PMCID: PMC4626684 DOI: 10.3390/md13106152] [Citation(s) in RCA: 118] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 09/09/2015] [Accepted: 09/15/2015] [Indexed: 12/12/2022] Open
Abstract
The risk of onset of cancer is influenced by poorly controlled chronic inflammatory processes. Inflammatory diseases related to cancer development include inflammatory bowel disease, which can lead to colon cancer, or actinic keratosis, associated with chronic exposure to ultraviolet light, which can progress to squamous cell carcinoma. Chronic inflammatory states expose these patients to a number of signals with tumorigenic effects, including nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPK) activation, pro-inflammatory cytokines and prostaglandins release and ROS production. In addition, the participation of inflammasomes, autophagy and sirtuins has been demonstrated in pathological processes such as inflammation and cancer. Chemoprevention consists in the use of drugs, vitamins, or nutritional supplements to reduce the risk of developing or having a recurrence of cancer. Numerous in vitro and animal studies have established the potential colon and skin cancer chemopreventive properties of substances from marine environment, including microalgae species and their products (carotenoids, fatty acids, glycolipids, polysaccharides and proteins). This review summarizes the main mechanisms of actions of these compounds in the chemoprevention of these cancers. These actions include suppression of cell proliferation, induction of apoptosis, stimulation of antimetastatic and antiangiogenic responses and increased antioxidant and anti-inflammatory activity.
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Affiliation(s)
- Elena Talero
- Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville 41012, Spain.
| | - Sofía García-Mauriño
- Department of Plant Biology and Ecology, Faculty of Biology, University of Seville, Seville 41012, Spain.
| | - Javier Ávila-Román
- Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville 41012, Spain.
| | - Azahara Rodríguez-Luna
- Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville 41012, Spain.
| | - Antonio Alcaide
- Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville 41012, Spain.
| | - Virginia Motilva
- Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville 41012, Spain.
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Yashiro M. Molecular Alterations of Colorectal Cancer with Inflammatory Bowel Disease. Dig Dis Sci 2015; 60:2251-63. [PMID: 25840920 DOI: 10.1007/s10620-015-3646-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Accepted: 03/26/2015] [Indexed: 12/18/2022]
Abstract
Inflammatory bowel disease (IBD) is an important etiologic factor in the development of colorectal cancer (CRC). The risk of CRC begins to increase 8 or 10 years after the diagnosis of IBD. This type of cancer is called colitis-associated CRC (CA-CRC). The molecular pathogenesis of inflammatory epithelium might play a critical role in the development of CA-CRC. Genetic alterations detected in CA-CRC such as genetic mutations, microsatellite instability, and DNA hypermethylation are also recognized in sporadic CRC; however, there are differences in the timing and frequency of molecular events between CA-CRC and sporadic CRC. Interaction between gene-environmental factors, including inflammation, lifestyle, psychological stress, and prior appendectomy, might be associated with the etiopathology of IBD. The mucosal inflammatory mediators, such as oxidant stress, free radicals, and chemokines, may cause the genetic alterations. Understanding the molecular mechanisms of CA-CRC might be important to develop clinical efficacies for patients with IBD. This review discusses the molecular characteristics of CA-CRC, especially ulcerative colitis-associated CRC, including clinical features, signaling pathways, and interactions between genetic alterations and environment involved in inflammatory carcinogenesis.
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Affiliation(s)
- Masakazu Yashiro
- Department of Surgical Oncology, Oncology Institute of Geriatrics and Medical Science, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan,
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12
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Abstract
BACKGROUND Colorectal cancer is the most severe complication in inflammatory bowel disease. This study aimed to investigate the effects of the probiotic VSL#3 when administered as either preventive or concurrent treatment in the progression from chronic colitis to colon cancer. METHODS Mice were exposed to 5, 10, and 15 cycles of dextran sulfate sodium (DSS); each cycle consisted of 0.7% DSS for 1 week followed by distilled water for 10 days. VSL#3 was administered either from 2 weeks before the colitis induction or from the first day of the colitis until being killed. After each period, macroscopic and histological studies, as well as analysis of inflammatory and tumor biomarkers, were performed. RESULTS Prophylactic or concurrent VSL#3 administration attenuated the disease activity index score and colon inflammation after 5, 10, and 15 cycles of DSS, as well as reduced the histological alterations and the incidence of colonic dysplastic lesions at the 3 periods studied. None of the animals receiving VSL#3 as a concurrent treatment developed carcinoma, which is in contrast to 5% and 20% of the mice following preventive VSL#3 administration, developing carcinoma at the 10th and the 15th cycles of DSS, respectively. In addition, the probiotic reduced the proliferating cell nuclear antigen labeling index, tumor necrosis factor alpha, interleukin-1β, interleukin-6 production, cyclooxygenase-2 expression, and increased interleukin-10 levels in colon tissue at the 3 periods assayed. CONCLUSIONS VSL#3 administration reduced chronic inflammation and prevented or delayed the development of dysplasia and carcinoma in a mouse model of chronic colitis-associated cancer.
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Wang X, Zhao J, Han Z, Tang F. Protective effects of Semen Crotonis Pulveratum on trinitrobenzene sulphonic acid-induced colitis in rats and H₂O₂-induced intestinal cell apoptosis in vitro. Int J Mol Med 2015; 35:1699-707. [PMID: 25873053 DOI: 10.3892/ijmm.2015.2175] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Accepted: 03/19/2015] [Indexed: 12/07/2022] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease. Semen Crotonis Pulveratum (SCP) has been used as a traditional medicine for the treatment of UC. However, its molecular mechanisms of action have not yet been elucidated. In the present study, we aimed to investigate the preliminary mechanisms of the role of SCP on trinitrobenzene sulphonic acid (TNBS)-induced UC in rats and hydrogen peroxide (H2O2)-induced intestinal cell apoptosis in vitro. Wistar rats (n=9 per group) were randomly divided into 4 groups: the normal control group, the UC group, the UC + SCP group and the UC + sulfasalazine group as a positive control. The proportion of CD4+CD25+ T cells and CD4+CD25+Foxp3+ Tregs, and the expression levels of interleukin (IL)-6 and IL-10 in the peripheral blood, as well as the expression levels of cyclooxygenase-2 (COX-2) and intercellular adhesion molecule-1 (ICAM-1) in the colon tissues were determined by flow cytometry, ELISA and immunohistochemical staining, respectively. Rat intestinal epithelial (IEC-6) cell apoptosis induced by H2O2 was determined by TUNEL assay, flow cytometry using Annexin V/propidium iodide (PI) staining and western blot analysis of caspase-3 activation, respectively. Significantly higher proportions of circulating CD4+CD25+ T cells and CD4+CD25+Foxp3+ Tregs were present in the UC + SCP group compared with the UC group. A significantly decreased expression of IL-6 and an increased expression of IL-10 were also observed in the UC + SCP group compared with UC group. SCP significantly reduced the UC-induced increase in the expression of COX-2 and ICAM-1 in the colon tissues. SCP inhibited cell apoptosis and caspase-3 activation induced by H2O2 in the ICE-6 cells. Our data thus indicate that SCP inhibits inflammation in UC by increasing the proportion of circulating Tregs, altering cytokine production and decreasing COX-2 and ICAM-1 expression. In addition it protects against H2O2-induced intestinal cell apoptosis in vitro.
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Affiliation(s)
- Xiaohong Wang
- Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Jie Zhao
- Basic Medical College, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Zhe Han
- Basic Medical College, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Fang Tang
- Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
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Fei BY, Lv HX, Cheng YW, Yang JM. Association between the IFN-γ and IL-1 genetic polymorphisms and colorectal cancer in the Chinese Han population. J Genet 2015; 93:235-9. [PMID: 24840847 DOI: 10.1007/s12041-014-0354-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Affiliation(s)
- Bao-Ying Fei
- Department of Gastroenterology, Zhejiang Province People's Hospital, Hangzhou 310014, Zhejiang Province, People's Republic of China.
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Sánchez-Fidalgo S, Villegas I, Aparicio-Soto M, Cárdeno A, Rosillo MÁ, González-Benjumea A, Marset A, López Ó, Maya I, Fernández-Bolaños JG, Alarcón de la Lastra C. Effects of dietary virgin olive oil polyphenols: hydroxytyrosyl acetate and 3, 4-dihydroxyphenylglycol on DSS-induced acute colitis in mice. J Nutr Biochem 2015; 26:513-20. [PMID: 25736481 DOI: 10.1016/j.jnutbio.2014.12.001] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2014] [Revised: 11/26/2014] [Accepted: 12/02/2014] [Indexed: 01/16/2023]
Abstract
Hydroxytyrosol, a polyphenolic compound from extra virgin olive oil (EVOO) has exhibited an improvement in a model of DSS-induced colitis. However, other phenolic compounds present such as hydroxytyrosyl acetate (HTy-Ac) and 3,4-dihydroxyphenylglycol (DHPG) need to be explored to complete the understanding of the overall effects of EVOO on inflammatory colon mucosa. This study was designed to evaluate the effect of both HTy-Ac and DHPG dietary supplementation in the inflammatory response associated to colitis model. Six-week-old mice were randomized in four dietary groups: sham and control groups received standard diet, and other two groups were fed with HTy-Ac and DHPG, respectively, at 0.1%. After 30 days, all groups except sham received 3% DSS in drinking water for 5 days followed by a regime of 5 days of water. Acute inflammation was evaluated by Disease Activity Index (DAI), histology and myeloperoxidase (MPO) activity. Colonic expression of iNOS, COX-2, MAPKs, NF-kB and FOXP3 were determined by western blotting. Only HTy-Ac-supplemented group showed a significant DAI reduction as well as an improvement of histological damage and MPO. COX-2 and iNOS protein expression were also significantly reduced. In addition, this dietary group down-regulated JNK phosphorylation and prevented the DSS-induced nuclear translocation level of p65. However, no significant differences were observed in the FOXP3 expression. These results demonstrated, for the first time, that HTy-Ac exerts an antiinflammatory effect on acute ulcerative colitis. We concluded that HTy-Ac supplement might provide a basis for developing a new dietary strategy for the prevention of ulcerative colitis.
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Affiliation(s)
| | - Isabel Villegas
- Department of Pharmacology, Faculty of Pharmacy, University of Seville
| | | | - Ana Cárdeno
- Department of Pharmacology, Faculty of Pharmacy, University of Seville
| | | | | | - Azucena Marset
- Department of Organic Chemistry, Faculty of Pharmacy, University of Seville
| | - Óscar López
- Department of Organic Chemistry, Faculty of Pharmacy, University of Seville
| | - Inés Maya
- Department of Organic Chemistry, Faculty of Pharmacy, University of Seville
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16
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Principi M, Barone M, Pricci M, De Tullio N, Losurdo G, Ierardi E, Di Leo A. Ulcerative colitis: From inflammation to cancer. Do estrogen receptors have a role? World J Gastroenterol 2014; 20:11496-11504. [PMID: 25206257 PMCID: PMC4155343 DOI: 10.3748/wjg.v20.i33.11496] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Revised: 03/29/2014] [Accepted: 05/26/2014] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis (UC) is a condition at increased risk for colorectal carcinoma (CRC) development. Nowadays, screening and follow-up programs are routinely performed worldwide to promote the early detection of CRCs in subjects with well known risk factors (extent, duration and severity of the disorder). The diffusion of these procedures is presumably the main reason for the marked reduction of cancer incidence and mortality in the course of UC. In addition, chemoprevention has been widely investigated and developed in many medical fields, and aspirin has shown a preventive effect against CRC, while mesalazine has been strongly invoked as a potential chemopreventive agent in UC. However, available studies show some limitations due to the obvious ethical implications of drug withdrawal in UC in order to design a control group. The estrogen receptors (ER) alpha/beta balance seems to have a relevant influence on colorectal carcinogenesis and ER beta appears to parallel apoptosis, and hence an anti-carcinogenic effect. Phytoestrogens are compounds acting as ER beta agonists and have shown a promising chemopreventive effect on sporadic as well as genetically inherited CRC. There is evidence suggesting a role for ERs in UC-related carcinogenesis. In this perspective, since these substances can be considered as dietary supplements and are completely free from side effects, phytoestrogens could be an interesting option for CRC prevention, even when the disease is a consequence of long-term chronic inflammation, as in the course of UC. Further studies of their effects are warranted in both the basic research and clinical fields.
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Meeker S, Seamons A, Paik J, Treuting PM, Brabb T, Grady WM, Maggio-Price L. Increased dietary vitamin D suppresses MAPK signaling, colitis, and colon cancer. Cancer Res 2014; 74:4398-408. [PMID: 24938764 DOI: 10.1158/0008-5472.can-13-2820] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Epidemiologic studies associate low serum vitamin D levels with an increased risk of colon cancer and inflammatory diseases such as inflammatory bowel disease (IBD). 129-Smad3(tm1Par)/J (Smad3(-/-)) mice are a model of bacteria-driven colitis and colon cancer when infected with Helicobacter bilis (H. bilis). Thus, we used this mouse model to determine whether increased dietary vitamin D would reduce inflammation and colon cancer. Smad3(-/-) mice were fed purified diet with either maintenance (1 IU vitamin D/g diet; maintenance) or increased concentrations of vitamin D (5 IU vitamin D/g diet; high vitamin D). One week after diet initiation, mice were inoculated with broth or H. bilis and were necropsied at several time points postinoculation to assess inflammation, dysplasia, and neoplasia incidence. At 16 weeks postinfection, 11% of mice fed high vitamin D diet had cancer compared with 41% of mice fed maintenance diet (P = 0.0121). Evaluation at an early time point (1 week postinfection) showed that animals fed high vitamin D had decreased MAPK (p-P38 and p-JNK) activation in lamina propria leukocytes as well as decreased NFκB activation in colonic epithelial cells. Reduction in MAPK and NFκB activation correlated with decreased IBD scores (2.7 vs. 15.5; P < 0.0001) as well as decreased inflammatory cell infiltrates and reduced expression of proinflammatory cytokines in cecal tissue. These findings suggest that increased dietary vitamin D is beneficial in preventing inflammation-associated colon cancer through suppression of inflammatory responses during initiation of neoplasia or early-stage carcinogenesis.
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Affiliation(s)
- Stacey Meeker
- Department of Comparative Medicine, University of Washington, Seattle, Washington
| | - Audrey Seamons
- Department of Comparative Medicine, University of Washington, Seattle, Washington
| | - Jisun Paik
- Department of Comparative Medicine, University of Washington, Seattle, Washington
| | - Piper M Treuting
- Department of Comparative Medicine, University of Washington, Seattle, Washington
| | - Thea Brabb
- Department of Comparative Medicine, University of Washington, Seattle, Washington
| | - William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Gastroenterology, University of Washington Medical School, Seattle, Washington
| | - Lillian Maggio-Price
- Department of Comparative Medicine, University of Washington, Seattle, Washington.
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Rodrigues-Sousa T, Ladeirinha AF, Santiago AR, Carvalheiro H, Raposo B, Alarcão A, Cabrita A, Holmdahl R, Carvalho L, Souto-Carneiro MM. Deficient production of reactive oxygen species leads to severe chronic DSS-induced colitis in Ncf1/p47phox-mutant mice. PLoS One 2014; 9:e97532. [PMID: 24873968 PMCID: PMC4038546 DOI: 10.1371/journal.pone.0097532] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2014] [Accepted: 04/21/2014] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Colitis is a common clinical complication in chronic granulomatous disease (CGD), a primary immunodeficiency caused by impaired oxidative burst. Existing experimental data from NADPH-oxidase knockout mice propose contradictory roles for the involvement of reactive oxygen species in colitis chronicity and severity. Since genetically controlled mice with a point-mutation in the Ncf1 gene are susceptible to chronic inflammation and autoimmunity, we tested whether they presented increased predisposition to develop chronic colitis. METHODS Colitis was induced in Ncf1-mutant and wild-type mice by a 1st 7-days cycle of dextran sulfate sodium (DSS), intercalated by a 7-days resting period followed by a 2nd 7-days DSS-cycle. Cytokines were quantified locally in the colon inflammatory infiltrates and in the serum. Leukocyte infiltration and morphological alterations of the colon mucosa were assessed by immunohistochemistry. RESULTS Clinical scores demonstrated a more severe colitis in Ncf1-mutant mice than controls, with no recovery during the resting period and a severe chronic colitis after the 2nd cycle, confirmed by histopathology and presence of infiltrating neutrophils, macrophages, plasmocytes and lymphocytes in the colon. Severe colitis was mediated by increased local expression of cytokines (IL-6, IL-10, TNF-α, IFN-γ and IL-17A) and phosphorylation of Leucine-rich repeat kinase 2 (LRRK2). Serological cytokine titers of those inflammatory cytokines were more elevated in Ncf1-mutant than control mice, and were accompanied by systemic changes in functional subsets of monocytes, CD4+ T and B cells. CONCLUSION This suggests that an ineffective oxidative burst leads to severe chronic colitis through local accumulation of peroxynitrites, pro-inflammatory cytokines and lymphocytes and systemic immune deregulation similar to CGD.
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Affiliation(s)
- Tiago Rodrigues-Sousa
- ImmunoMetabolic Pharmacology Group, CNC- Centro de Neurociências e Biologia Celular, Universidade de Coimbra, Coimbra, Portugal
| | - Ana Filipa Ladeirinha
- Departamento de Anatomia Patológica, Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal
| | - Ana Raquel Santiago
- Instituto Biomédico de Investigação da Luz e Imagem, Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal
| | - Helena Carvalheiro
- ImmunoMetabolic Pharmacology Group, CNC- Centro de Neurociências e Biologia Celular, Universidade de Coimbra, Coimbra, Portugal
| | - Bruno Raposo
- Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden
| | - Ana Alarcão
- Departamento de Anatomia Patológica, Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal
| | - António Cabrita
- Departamento de Patologia Experimental, Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal
| | - Rikard Holmdahl
- Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden
| | - Lina Carvalho
- Departamento de Anatomia Patológica, Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal
| | - M. Margarida Souto-Carneiro
- ImmunoMetabolic Pharmacology Group, CNC- Centro de Neurociências e Biologia Celular, Universidade de Coimbra, Coimbra, Portugal
- * E-mail:
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Telmisartan attenuates colon inflammation, oxidative perturbations and apoptosis in a rat model of experimental inflammatory bowel disease. PLoS One 2014; 9:e97193. [PMID: 24831514 PMCID: PMC4022743 DOI: 10.1371/journal.pone.0097193] [Citation(s) in RCA: 109] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Accumulating evidence has indicated the implication of angiotensin II in the pathogenesis of inflammatory bowel diseases (IBD) via its proinflammatory features. Telmisartan (TLM) is an angiotensin II receptor antagonist with marked anti-inflammatory and antioxidant actions that mediated its cardio-, reno- and hepatoprotective actions. However, its impact on IBD has not been previously explored. Thus, we aimed to investigate the potential alleviating effects of TLM in tri-nitrobenezene sulphonic acid (TNBS)-induced colitis in rats. Pretreatment with TLM (10 mg/kg p.o.) attenuated the severity of colitis as evidenced by decrease of disease activity index (DAI), colon weight/length ratio, macroscopic damage, histopathological findings and leukocyte migration. TLM suppressed the inflammatory response via attenuation of tumor necrosis factor-α (TNF-α), prostaglandin E2 (PGE2) and myeloperoxidase (MPO) activity as a marker of neutrophil infiltration besides restoration of interleukin-10 (IL-10). TLM also suppressed mRNA and protein expression of nuclear factor kappa B (NF-κB) p65 and mRNA of cyclo-oxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) proinflammatory genes with concomitant upregulation of PPAR-γ. The alleviation of TLM to colon injury was also associated with inhibition of oxidative stress as evidenced by suppression of lipid peroxides and nitric oxide (NO) besides boosting glutathione (GSH), total anti-oxidant capacity (TAC) and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx). With respect to apoptosis, TLM downregulated the increased mRNA, protein expression and activity of caspase-3. It also suppressed the elevation of cytochrome c and Bax mRNA besides the upregulation of Bcl-2. Together, these findings highlight evidences for the beneficial effects of TLM in IBD which are mediated through modulation of colonic inflammation, oxidative stress and apoptosis.
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20
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Soliman NA, Keshk WA, Shoheib ZS, Ashour DS, Shamloula MM. Inflammation, Oxidative Stress and L-Fucose as Indispensable Participants in Schistosomiasis-Associated Colonic Dysplasia. Asian Pac J Cancer Prev 2014; 15:1125-31. [DOI: 10.7314/apjcp.2014.15.3.1125] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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21
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Huang Z, Li S, Song W, Li X, Li Q, Zhang Z, Han Y, Zhang X, Miao S, Du R, Wang L. Lysine-specific demethylase 1 (LSD1/KDM1A) contributes to colorectal tumorigenesis via activation of the Wnt/β-catenin pathway by down-regulating Dickkopf-1 (DKK1) [corrected]. PLoS One 2013; 8:e70077. [PMID: 23922913 PMCID: PMC3724785 DOI: 10.1371/journal.pone.0070077] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2013] [Accepted: 06/14/2013] [Indexed: 02/01/2023] Open
Abstract
We collected paired samples of tumor and adjacent normal colorectal tissues from 22 patients with colorectal carcinoma to compare the differences in the expression of lysine specific demethylase 1 (LSD1) in these two tissues. The results showed that in 19 paired samples (86.4%), LSD1 is more highly expressed in tumor tissue than in normal tissue. To explore the role of LSD1 in colorectal tumorigenesis, we used somatic cell gene targeting to generate an LSD1 knockout (KO) HCT 116 human colorectal cancer cell line as a research model. The analysis of phenotypic changes showed that LSD1 KO colorectal cancer cells are less tumorigenic, both in vivo and in vitro. The differential expression analysis of the cells by mRNA sequencing (RNA-Seq) yielded 2,663 differentially expressed genes, and 28 of these genes had highly significant differences (Q <0.01). We then selected the 4 colorectal cancer-related genes ADM, DKK1, HAS3 and SMURF2 for quantitative real-time PCR verification. The results showed that the differences in the expression of ADM, DKK1 and HAS3 were consistent with those measured using the RNA-Seq data. As DKK1 was the gene with the most significant differential expression, we analyzed the key proteins of the DKK1-related Wnt/β-catenin signaling pathway and found that, after knocking out LSD1, the amount of free β-catenin translocated to the nucleus was significantly reduced and that the transcription of the signaling pathway target gene c-Myc was down-regulated. Our studies show that LSD1 activates the Wnt/β-catenin signaling pathway by down-regulating the pathway antagonist DKK1, which may be one of the mechanisms leading to colorectal tumorigenesis.
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Affiliation(s)
- Zebin Huang
- National Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Tsinghua University, Beijing, China
| | - Shangze Li
- Department of Cellular and Developmental Biology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Wei Song
- National Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Tsinghua University, Beijing, China
| | - Xin Li
- Department of Cellular and Developmental Biology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Qinshan Li
- National Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Tsinghua University, Beijing, China
| | - Zeyan Zhang
- Department of Cellular and Developmental Biology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Yongqing Han
- National Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Tsinghua University, Beijing, China
| | - Xiaodong Zhang
- Department of Cellular and Developmental Biology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Shiying Miao
- National Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Tsinghua University, Beijing, China
| | - Runlei Du
- Department of Cellular and Developmental Biology, College of Life Sciences, Wuhan University, Wuhan, China
- * E-mail: (RD); (LW)
| | - Linfang Wang
- National Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Tsinghua University, Beijing, China
- * E-mail: (RD); (LW)
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22
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Ishii Y, Sasaki T, Serikawa M, Minami T, Okazaki A, Yukutake M, Ishigaki T, Kosaka K, Mouri T, Yoshimi S, Shimizu A, Tsuboi T, Chayama K. Elevated expression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in primary sclerosing cholangitis: ιmplications for cholangiocarcinogenesis. Int J Oncol 2013; 43:1073-9. [PMID: 23900502 DOI: 10.3892/ijo.2013.2038] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Accepted: 06/05/2013] [Indexed: 11/05/2022] Open
Abstract
Cholangiocarcinoma (CCA) occurs frequently in primary sclerosing cholangitis (PSC). Cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) induced by inflammation are believed to mediate prostaglandin E2 (PGE2) production thereby promoting carcinogenesis. Their expression in PSC-associated CCA tissues and non-neoplastic bile duct epithelial cells (BDECs) in PSC was investigated. COX-2 and mPGES-1 levels in 15 PSC patients (7 with CCA) were scored using immunohistochemical staining. The results were compared with those obtained in CCA tissues and non-neoplastic BDECs (controls) of 15 sporadic CCA patients. Non-neoplastic BDECs from large and small bile ducts were investigated separately. The mRNA expression levels of COX-2 and mPGES-1 in CCA tissues were analyzed by quantitative polymerase chain reaction. Ki-67 immunostaining was performed to evaluate cell proliferation. COX-2 was strongly expressed in PSC-associated CCA tissues and non-neoplastic BDECs in PSC. This expression was significantly upregulated in both compared with sporadic CCA tissues and non-neoplastic BDECs in sporadic CCA (both P<0.01). mPGES-1 was expressed at moderate to strong levels in PSC. Compared with controls, the expression was significantly higher in non-neoplastic small BDECs (P<0.01). COX-2 mRNA levels were significantly higher in PSC-associated tissues than in sporadic CCA tissues (P<0.01). Conversely, no differences were observed in mPGES-1 mRNA levels. Ki-67 labeling indices were higher in PSC-associated CCA tissues and non-neoplastic BDECs in PSC than in controls. In conclusion, COX-2 and mPGES-1 were highly expressed in PSC-associated CCA tissues and non-neoplastic BDECs in PSC, suggesting the involvement of COX-2 and mPGES-1 in cholangiocarcinogenesis.
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Affiliation(s)
- Yasutaka Ishii
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Minami, Hiroshima 734-8551, Japan
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23
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Dietary Crocin Inhibits Colitis and Colitis-Associated Colorectal Carcinogenesis in Male ICR Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2012; 2012:820415. [PMID: 23326291 PMCID: PMC3543809 DOI: 10.1155/2012/820415] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2012] [Revised: 12/04/2012] [Accepted: 12/06/2012] [Indexed: 01/16/2023]
Abstract
A natural carotenoid crocin is contained in saffron and gardenia flowers (crocuses and gardenias) and is used as a food colorant. This study reports the potential inhibitory effects of crocin against inflammation-associated mouse colon carcinogenesis and chemically induced colitis in male ICR mice. In the first experiment, dietary crocin significantly inhibited the development of colonic adenocarcinomas induced by azoxymethane (AOM) and dextran sodium sulfate (DSS) in mice by week 18. Crocin feeding also suppressed the proliferation and immunohistochemical expression of nuclear factor- (NF-) κB but increased the NF-E2-related factor 2 (Nrf2) expression, in adenocarcinoma cells. In the second experiment, dietary feeding with crocin for 4 weeks was able to inhibit DSS-induced colitis and decrease the mRNA expression of tumor necrosis factor α, interleukin- (IL-) 1β, IL-6, interferon γ, NF-κB, cyclooxygenase-2, and inducible nitric oxide synthase in the colorectal mucosa and increased the Nrf2 mRNA expression. Our results suggest that dietary crocin suppresses chemically induced colitis and colitis-related colon carcinogenesis in mice, at least partly by inhibiting inflammation and the mRNA expression of certain proinflammatory cytokines and inducible inflammatory enzymes. Therefore, crocin is a candidate for the prevention of colitis and inflammation-associated colon carcinogenesis.
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Cai F, Dupertuis YM, Pichard C. Role of polyunsaturated fatty acids and lipid peroxidation on colorectal cancer risk and treatments. Curr Opin Clin Nutr Metab Care 2012; 15:99-106. [PMID: 22234166 DOI: 10.1097/mco.0b013e32834feab4] [Citation(s) in RCA: 222] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW The review aims at elucidating the role of lipid peroxidation of polyunsaturated fatty acids (PUFAs) in colorectal cancer (CRC) risk and treatment. RECENT FINDINGS CRC is one of the most overriding threats to public health. Despite a broad range of treatments, up to 50% of patients will inevitably develop incurable metastatic disease. Peroxidation of PUFAs contributes to augmentation of oxidative stress and causes in consequence inflammation, which is one of the possible carcinogenic factors of CRC. End products of PUFAs might be used as biomarkers for CRC detection and surveillance for treatment. They also have cytotoxic effect in CRC cells. Experimental results suggest that ω-3 PUFAs could increase the efficacy of radiotherapy and chemotherapy of CRC. SUMMARY Lipid peroxidation, one factor of oxidative stress, might play a paramount role not only in carcinogenesis but also in potential therapeutic strategy on CRC. End products of lipid peroxidation, such as malondialdehyde, 4-hydroxy-2-nonenal, and isoprostanes, could be used as biomarkers for cancer detection, surveillance of treatment outcome and prognostic index for CRC patients. Furthermore, malondialdehyde and 4-hydroxy-2-nonenal have cytotoxic effect not only in normal cells but also in CRC cancer cells, which implies the potential role of PUFAs in CRC treatment.
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Affiliation(s)
- Fang Cai
- Nutrition Unit, Geneva University Hospital, Geneva, Switzerland
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25
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Hamed MAA, Ahmed SAA, Khaled HM. Efficiency of diagnostic biomarkers among colonic schistosomiasis Egyptian patients. Mem Inst Oswaldo Cruz 2011; 106:322-9. [PMID: 21655820 DOI: 10.1590/s0074-02762011000300011] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2010] [Accepted: 01/05/2011] [Indexed: 12/13/2022] Open
Abstract
The schistosomal parasite plays a critical role in the development of malignant lesions in different organs. The pathogenesis of cancer is currently under intense investigation to identify reliable prognostic indices for disease detection. The objective of this paper is to evaluate certain biochemical parameters as diagnostic tools to efficiently differentiate between colonic carcinoma and colonic carcinoma associated with schistosomal infection among Egyptian patients. The parameters under investigation are interleukin 2 (IL-2), tumour necrosis factor alpha (TNF-α), carcinoembryonic antigen (CEA) levels, tissue telomerase, pyruvate kinase (PK), glucose-6-phosphate dehydrogenase (G-6-PD) and lactate dehydrogenase (LDH) enzyme activities. The results revealed a significant elevation in the level of the tumour markers IL-2, TNF-α and CEA as well as the activities of LDH, telomerase and G-6-PD among non-bilharzial and bilharzial colonic cancer groups, with a more potent effect in bilharzial infection-associated colonic cancer. A significant inhibition in PK activity was recorded in the same manner as compared to normal tissues. The efficacy of this biomarker was also evaluated through detecting sensitivity, specificity, negative and positive predictive values. In conclusion, schistosomal colonic carcinoma patients displayed more drastic changes in all parameters under investigation. The combination of the selected parameters succeeded in serving as biomarkers to differentiate between the two malignant types.
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26
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Bernardi S, Zennaro C, Palmisano S, Velkoska E, Sabato N, Toffoli B, Giacomel G, Buri L, Zanconati F, Bellini G, Burrell LM, De Manzini N, Fabris B. Characterization and significance of ACE2 and Mas receptor in human colon adenocarcinoma. J Renin Angiotensin Aldosterone Syst 2011; 13:202-9. [DOI: 10.1177/1470320311426023] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Introduction: A new arm of the renin–angiotensin system (RAS) has been recently characterized; this includes angiotensin converting enzyme (ACE)2 and angiotensin (Ang)1-7, a heptapeptide acting through the Mas receptor (MasR). Recent studies show that Ang1-7 has an antiproliferative action on lung adenocarcinoma cells. The aim of this study was to characterize RAS expression in human colon adenocarcinoma and to investigate whether Ang1-7 exerts an antiproliferative effect on human colon adenocarcinoma cells. Materials and methods: Gene, protein expression and enzymatic activity of the main components of the RAS were determined on non-neoplastic colon mucosa as well as on the tumor mass and the mucosa taken 5 cm distant from it, both collected from patients with colon adenocarcinoma. Two different human colon cancer cell lines were treated with AngII and Ang1-7. Results: The novel finding of this study was that MasR was significantly upregulated in colon adenocarcinoma compared with non-neoplastic colon mucosa, which showed little or no expression of it. ACE gene expression and enzymatic activity were also increased in the tumors. However, AngII and Ang1-7 did not have any pro-/antiproliferative effects in the cell lines studied. Conclusions: The data suggest that upregulation of the MasR could be used as a diagnostic marker of colon adenocarcinoma.
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Affiliation(s)
- Stella Bernardi
- Department of Morphology and Embryology, University of Ferrara, Italy
- Baker IDI, Melbourne, Australia
| | | | - Silvia Palmisano
- Department of Surgery, University of Trieste, Cattinara Hospital, Italy
| | - Elena Velkoska
- Department of Medicine, University of Melbourne, Australia
| | - Nicoletta Sabato
- Department of Medical, Technological and Translational Sciences, University of Trieste, Italy
| | - Barbara Toffoli
- Institute for Maternal and Child Health, IRCCS Burlo Garofalo, Italy
| | - Greta Giacomel
- Department of Surgery, University of Trieste, Cattinara Hospital, Italy
| | - Luigi Buri
- Gastroenterology and Digestive Endoscopy Unit, Cattinara Hospital, Italy
| | - Fabrizio Zanconati
- Department of Pathology, University of Trieste, Cattinara Hospital, Italy
| | - Giuseppe Bellini
- Department of Medical, Technological and Translational Sciences, University of Trieste, Italy
| | | | - Nicolò De Manzini
- Department of Surgery, University of Trieste, Cattinara Hospital, Italy
| | - Bruno Fabris
- Department of Medical, Technological and Translational Sciences, University of Trieste, Italy
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27
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Oral administration of Lactobacillus plantarum K68 ameliorates DSS-induced ulcerative colitis in BALB/c mice via the anti-inflammatory and immunomodulatory activities. Int Immunopharmacol 2011; 11:2159-66. [PMID: 21996541 DOI: 10.1016/j.intimp.2011.09.013] [Citation(s) in RCA: 103] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2011] [Revised: 09/13/2011] [Accepted: 09/25/2011] [Indexed: 02/07/2023]
Abstract
Many different kinds of fermented food are consumed daily in Taiwan, such as stinky tofu, suan-tsai, and fu-tsai. We have previously reported the diversity of lactic acid bacteria (LAB) at different stages of fermentation in the production of suan-tsai and fu-tsai. In this study, the anti-inflammatory and immunomodulatory activities of Lactobacillus plantarum K68 (K68) isolated from fu-tsai were evaluated. K68 significantly inhibited the production of tumor necrosis factor-α (TNF-α) and prostaglandin E(2) (PGE(2)) in lipopolysaccharide (LPS)-induced murine macrophage RAW 264.7 cells and stimulated interferon-γ (IFN-γ) production in human peripheral blood mononuclear cells (hPBMCs). Additionally, orally administered K68 ameliorated dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in BALB/c mice. Both the disease activity index (DAI) and histological scores (HIS) showed that the severity of UC was significantly reduced by oral administration of K68. Furthermore, the production of pro inflammatory cytokines TNF-α, interleukin-1β (IL-1β), and interleukin-6 (IL-6) was significantly reduced in K68-administered group. Colonic mRNA expression levels of TNF-α, cyclooxygenase-2 (COX-2), forkhead box P3 (Foxp3), suppressors of cytokine signaling 3 (SOCS3), and toll like receptor 4 (TLR4), were also reduced in the K68-administered group. These results suggest that K68 exhibits anti-inflammatory and immunomodulatory activities that ameliorate DSS-induced experimental colitis.
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Komiyama Y, Mitsuyama K, Masuda J, Yamasaki H, Takedatsu H, Andoh A, Tsuruta O, Fukuda M, Kanauchi O. Prebiotic treatment in experimental colitis reduces the risk of colitic cancer. J Gastroenterol Hepatol 2011; 26:1298-308. [PMID: 21303406 DOI: 10.1111/j.1440-1746.2011.06690.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND AND AIM Germinated barley foodstuff (GBF) is a prebiotic product that reduces colonic mucosal inflammation and the clinical symptoms observed in ulcerative colitis (UC). The risk of contracting colorectal cancer is higher in patients with UC than in that of the general population. The aim of this study is to apply this prebiotic approach to control chronic colitis and to reduce the incidence of colitic cancer. METHODS Repeated and intermitted dextran sulfate sodium administration to male Sprague-Dawley rats was used for the chronic and subacute colitis models. GBF was added as the diet (10% w/v). The incidence of adenomatous high-grade dysplasia, and pathophysiological observations, including the proliferative cell nuclear antigen (PCNA) labeling index, and clinical score, cecal organic acid profile, and the accompanying β-glucosidase activity were determined. RESULTS In the chronic phase, the incidence of adenomatous dysplasia was only confirmed in the control group, and the GBF group had no dysplasia in the entire colon; the stratified squamous epithelium area of GBF was significantly lower than that of the controls. GBF treatment significantly lowered the cecal succinate content and significantly increased β-glucosidase activity compared to the controls. In addition, colonic mucosal inflammatory damage was comparable between the two groups, while the PCNA labeling index of the colonic mucosa in the GBF group was significantly lower than that of the control group. However, in the subacute phase, the mucosal damage score of GBF was significantly attenuated, and the PCNA labeling index of the colonic mucosa in the GBF group was significantly higher than that of the control group. CONCLUSION This preliminary study demonstrated that GBF effectively prevents colitis-related dysplasia and inflammatory change in chronic and subacute colitis models by modulating the intestinal environment as a prebiotic. This prebiotic might contribute to the prevention of mucosal damage, to show different proliferative effects on the epithelium in the regeneration and steady states.
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Affiliation(s)
- Yutaka Komiyama
- Central Laboratories for Frontier Technology, Kirin Holdings Co. Ltd., Yokohama, Japan
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Motilva V, García-Mauriño S, Talero E, Illanes M. New paradigms in chronic intestinal inflammation and colon cancer: role of melatonin. J Pineal Res 2011; 51:44-60. [PMID: 21752096 DOI: 10.1111/j.1600-079x.2011.00915.x] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
In intestinal bowel disease (IBD), immune-mediated conditions exert their effects through various cells and proinflammatory mediators. Recent data support a participation of the endoplasmic reticulum stress and mitochondrial dysfunctions in IBD. Moreover, it is evident that chronic degenerative pathologies, including IBD, share comparable disease mechanisms with alteration in the autophagy mechanisms. Chronic inflammation in IBD exposes these patients to a number of signals known to have tumorigenic effects. This circuitry of inflammation and cancer modifies apoptosis and autophagy, and promotes cellular cycle progression, invasion, and angiogenesis. Melatonin has been shown as a specific antioxidant reducing oxidative damage in both lipid and aqueous cell environments. However, several studies provide further insight into the molecular mechanisms of melatonin action in the colon. In this line, recent data suggest that melatonin modulates autophagy and sirtuin activity. An anti-autophagic property of melatonin has been demonstrated, and it could contribute to its anti-oncogenic activity. Nevertheless, there is no information about whether antitumoral effects of melatonin on colon cancer are dependent on autophagy. Sirtuins have pleiotropic effects on cancer development, being reported both as facilitator and as suppressor of colon cancer development. Sirtuins and melatonin are connected through the circadian clock machinery, and melatonin seems able to correct the alterations in sirtuin activity associated with several pathological conditions. Autophagy and sirtuin activities are linked through 5'AMP-activated protein kinase (AMPK) activation, which switches on autophagy and increases sirtuin. The effect of melatonin on AMPK and the impact of this effect on IBD and colon cancer remain an open question.
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Affiliation(s)
- Virginia Motilva
- Department of Pharmacology, University of Seville, Seville, Spain.
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Protective effect of ellagic acid, a natural polyphenolic compound, in a murine model of Crohn's disease. Biochem Pharmacol 2011; 82:737-45. [PMID: 21763290 DOI: 10.1016/j.bcp.2011.06.043] [Citation(s) in RCA: 133] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2011] [Revised: 06/29/2011] [Accepted: 06/30/2011] [Indexed: 02/07/2023]
Abstract
Current epidemiological and experimental studies support a beneficial role of dietary polyphenols in several gastrointestinal diseases, including inflammatory bowel disease. The aim of this study was to gain a better understanding of the effects of a naturally occurring polyphenol, ellagic acid, present in some fruits such as pomegranate, raspberries and nuts among others, in an experimental murine model of Crohn's disease by intra-colonic administration of TNBS in rats. Analysis of the lesions were carried out by macroscopic and histological technics. Inflammation response was assessed by histology and myeloperoxidase activity. iNOS and COX-2 are upregulated by MAPKs and NF-κB nuclear transcription factor in intestinal epithelial cells thus, we determined the expression of iNOS, COX-2 and the involvement of the p38, JNK, ERK1/2 MAPKs and NF-κB signalling in the protective effect of EA by western blotting. Oral administration of EA (10-20 mg/kg) diminished the severity and extension of the intestinal injuries induced by TNBS although there was no observed a significant dose-response. In addition, EA increased mucus production in goblet cells in colon mucosa, decreased neutrophil infiltration and pro-inflammatory proteins COX-2 and iNOS overexpression. Also EA was capable of reducing the activation of p38, JNK and ERK1/2 MAPKs, preventing the inhibitory protein IκB-degradation and inducing an inhibition of the nuclear translocation level of p65 in colonic mucosa. In conclusion, EA reduces the damage in a rat model of Crohn's disease, alleviates the oxidative events and returns pro-inflammatory proteins expression to basal levels probably through MAPKs and NF-κB signalling pathways.
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M'Koma AE, Moses HL, Adunyah SE. Inflammatory bowel disease-associated colorectal cancer: proctocolectomy and mucosectomy do not necessarily eliminate pouch-related cancer incidences. Int J Colorectal Dis 2011; 26:533-552. [PMID: 21311893 PMCID: PMC4154144 DOI: 10.1007/s00384-011-1137-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/16/2011] [Indexed: 02/07/2023]
Abstract
BACKGROUND Colorectal cancer (CRC), the most lethal long-term complication of inflammatory bowel disease (IBD), is the culmination of a complex sequence of molecular and histologic derangements of the colon epithelium that are initiated and at least partially sustained by prolonged chronic inflammation. Dysplasia, the earliest histologic manifestation of this process, plays an important role in cancer prevention by providing the first clinical alert that this sequence is under way and by serving as an endpoint in colonoscopic surveillance of patients at high risk for CRC. Restorative proctocolectomy (RPC) is indicated for patients with IBD, specifically for ulcerative colitis that is refractory to medical treatment, emergency conditions, and/or in case of neoplastic transformation. Even after RPC with mucosectomy, pouch-related carcinomas have recently been reported with increasing frequency since the first report in 1984. We review IBD-associated CRC and pouch-related neoplasia prevalence, adverse events, risk factors, and surveillances. METHODS Literature of IBD-associated CRC patients and those undergoing RPC surgeries through 2010 were prospectively reviewed. RESULTS We found 12 studies from retrospective series and 15 case reports. To date, there are 43 reported cases of pouch-related cancers. Thirty-two patients had cancer in the anal transit zone (ATZ); of these, 28 patients had mucosectomy. Eleven patients had cancer found in the pouch body. CONCLUSION RPC with mucosectomy does not necessarily eliminate risks. There is little evidence to support routine surveillance of pouch mucosa and the ATZ except for patients associated with histological type C changes, sclerosing cholangitis, and unremitting pouchitis.
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Affiliation(s)
- Amosy E M'Koma
- Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, 1005 Dr. D. B. Todd Jr. Blvd, Nashville, TN 37208-3599, USA.
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Masoodi I, Tijjani BM, Wani H, Hassan NS, Khan AB, Hussain S. Biomarkers in the management of ulcerative colitis: a brief review. GERMAN MEDICAL SCIENCE : GMS E-JOURNAL 2011; 9:Doc03. [PMID: 21394194 PMCID: PMC3046642 DOI: 10.3205/000126] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/07/2010] [Revised: 01/21/2011] [Indexed: 12/21/2022]
Abstract
Several attempts have been made in the last two decades to investigate ulcerative colitis (UC) patients during the natural course of the disease so as to identify appropriate surrogate markers of disease activity. Most patients with quiescent inflammatory bowel disease have low grade inflammation and it is possible that relapse occurs only once the inflammatory process crosses a critical intensity. Since inflammation is a continuous process, its direct assessment may provide us a quantitative pre-symptomatic measure of imminent relapse. If substantial, it may allow targeted treatment early, to avert relapse or formulate newer therapeutic strategies to maintain symptomatic remission. It is clinically very important to identify these patients at a subclinical stage, noninvasively, by various biomarkers. Biomarkers help to gain an objective measurement of disease activity as symptoms are often subjective. Biomarkers also help to avoid invasive procedures which are often a burden to the patient and the health care system. If an ideal biomarker existed for UC, it would greatly facilitate the work of the gastroenterologist treating these patients. Both “classical” and “emerging” biomarkers of relevance for UC have been studied, but the quest for an ideal biomarker still continues. In this brief review we describe various biomarkers of clinical importance.
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Affiliation(s)
- Ibrahim Masoodi
- Division of Gastroenterology, King Fahad Medical City, Riyadh, Saudi Arabia.
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Villegas I, Sánchez-Fidalgo S, de la Lastra CA. Chemopreventive effect of dietary curcumin on inflammation-induced colorectal carcinogenesis in mice. Mol Nutr Food Res 2010; 55:259-67. [PMID: 20848615 DOI: 10.1002/mnfr.201000225] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2010] [Revised: 07/16/2010] [Accepted: 07/16/2010] [Indexed: 12/21/2022]
Abstract
SCOPE Curcumin is a polyphenol with a variety of pharmacologic effects. We evaluate the effect of dietary curcumin on the severity of repeated colitis-associated colorectal cancer. METHODS AND RESULTS Six-week-old C57BL/6 mice were randomized into two dietary groups: standard diet and curcumin at 0.6% diet. The mice were exposed to 15 cycles of 0.7% dextran sodium sulphate for 1 week followed by distilled water for 10 days. After curcumin diet, the disease activity index presented a statistical reduction in the last cycles, macroscopic tumors were not seen and the microscopic study showed minor neoplasic lesions with respect to standard diet-group. β-Catenin translocation to the cytoplasm and/or nucleus was observed in the tumor tissue, but this translocation and its intensity were significantly minor in the curcumin diet-DSS animals. Cytokines as tumor necrosis factor-α and IFN-γ were significantly diminished in DSS-animals fed with curcumin. Conversely, non-modification of p53 expression was observed and cyclo-oxygenase-2 and inducible nitric oxide synthase were significantly reduced in the curcumin diet-DSS group. CONCLUSION We demonstrate the protective/preventive effect of curcumin in the progression of colorectal cancer associated to colitis, which was correlated with a lowered immunoreactivity of ß-catenin, a non-modification of p53 expression, a reduction of proinflammatory cytokine levels and a decrease of inflammatory protein overexpression.
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Affiliation(s)
- Isabel Villegas
- Department of Pharmacology, School of Pharmacy, University of Seville, Seville, Spain
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