Colonic inflammation in pediatric inflammatory bowel disease: detection with magnetic resonance enterography

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Campari, Alessandro [E. Bassini Hospital - ASST Nord Milano, Radiology Department, Milan (Italy); V. Buzzi Children' s Hospital - ASST Fatebenefratelli-Sacco, Pediatric Radiology Department, Milan (Italy); Napolitano, Marcello [V. Buzzi Children' s Hospital - ASST Fatebenefratelli-Sacco, Pediatric Radiology Department, Milan (Italy); Zuin, Giovanna [V. Buzzi Children' s Hospital - ASST Fatebenefratelli-Sacco, Pediatric Department, Milan (Italy); Maestri, Luciano [V. Buzzi Children' s Hospital - ASST Fatebenefratelli-Sacco, Pediatric Surgery Department, Milan (Italy); Di Leo, Giovanni [IRCCS Policlinico San Donato, Radiology Unit, Milan (Italy); Sardanelli, Francesco [IRCCS Policlinico San Donato, Radiology Unit, Milan (Italy); Universita degli Studi di Milano, Department of Biomedical Sciences for Health, Milan (Italy)

2017-06-15

Colonic involvement in pediatric inflammatory bowel disease is common. Magnetic resonance (MR) enterography is considered the best imaging modality for pediatric inflammatory bowel disease evaluation. It is unclear whether the lack of a dedicated large bowel preparation prevents a reliable colonic assessment. To determine the diagnostic performance of standard MR enterography in detecting and grading colonic inflammatory activity. We retrospectively evaluated children who underwent both MR enterography and ileocolonoscopy with biopsies <4 weeks apart. Two radiologists independently reviewed MR examinations and quantified inflammation in each of the five colonic segments using a standardized MR score system. Findings were compared with histological examination of the corresponding segment. Mann-Whitney, Kruskal-Wallis, Jonckheere-Terpstra and Bland-Altman statistics were used. One hundred seventy-five segments from 37 examinations were included. MR enterography diagnostic performance for inflammation was as follows: sensitivity 94% (95% confidence interval [CI]: 90-97%), specificity: 64% (95% CI: 57-71%). A significant positive correlation was found between MR score and inflammatory activity histologically graded (P<0.001, Jonckheere-Terpstra test). The interobserver agreement was good (mean difference between MR enterography scores was -0.03; limits of agreement -2.8 to 2.7). Standard MR enterography is sensitive for the detection of actively inflamed colonic segments. MR enterography might provide useful information for guiding biopsies and its role as an alternative to ileocolonoscopy in monitoring colonic disease activity in children should be further investigated. (orig.)

Colonic inflammation in pediatric inflammatory bowel disease: detection with magnetic resonance enterography

International Nuclear Information System (INIS)

Campari, Alessandro; Napolitano, Marcello; Zuin, Giovanna; Maestri, Luciano; Di Leo, Giovanni; Sardanelli, Francesco

2017-01-01

Colonic involvement in pediatric inflammatory bowel disease is common. Magnetic resonance (MR) enterography is considered the best imaging modality for pediatric inflammatory bowel disease evaluation. It is unclear whether the lack of a dedicated large bowel preparation prevents a reliable colonic assessment. To determine the diagnostic performance of standard MR enterography in detecting and grading colonic inflammatory activity. We retrospectively evaluated children who underwent both MR enterography and ileocolonoscopy with biopsies <4 weeks apart. Two radiologists independently reviewed MR examinations and quantified inflammation in each of the five colonic segments using a standardized MR score system. Findings were compared with histological examination of the corresponding segment. Mann-Whitney, Kruskal-Wallis, Jonckheere-Terpstra and Bland-Altman statistics were used. One hundred seventy-five segments from 37 examinations were included. MR enterography diagnostic performance for inflammation was as follows: sensitivity 94% (95% confidence interval [CI]: 90-97%), specificity: 64% (95% CI: 57-71%). A significant positive correlation was found between MR score and inflammatory activity histologically graded (P<0.001, Jonckheere-Terpstra test). The interobserver agreement was good (mean difference between MR enterography scores was -0.03; limits of agreement -2.8 to 2.7). Standard MR enterography is sensitive for the detection of actively inflamed colonic segments. MR enterography might provide useful information for guiding biopsies and its role as an alternative to ileocolonoscopy in monitoring colonic disease activity in children should be further investigated. (orig.)

CD73 Is Critical for the Resolution of Murine Colonic Inflammation

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Margaret S. Bynoe

2012-01-01

Full Text Available CD73 is a glycosyl-phosphatidylinositol-(GPI- linked membrane protein that catalyzes the extracellular dephosphorylation of adenosine monophosphate (AMP to adenosine. Adenosine is a negative regulator of inflammation and prevents excessive cellular damage. We investigated the role of extracellular adenosine in the intestinal mucosa during the development of Dextran-Sulfate-Sodium-(DSS-salt-induced colitis in mice that lack CD73 (CD73−/− and are unable to synthesize extracellular adenosine. We have found that, compared to wild-type (WT mice, CD73−/− mice are highly susceptible to DSS-induced colitis. CD73−/− mice exhibit pronounced weight loss, slower weight recovery, an increase in gut permeability, a decrease in expression of tight junctional adhesion molecules, as well as unresolved inflammation following the removal of DSS. Moreover, colonic epithelia in CD73−/− mice exhibited increased TLR9 expression, high levels of IL-1β and TNF-α, and constitutive activation of NF-κB. We conclude that CD73 expression in the colon is critical for regulating the magnitude and the resolution of colonic immune responses.

Cathelicidin suppresses colon cancer development by inhibition of cancer associated fibroblasts

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Cheng M

2014-12-01

Full Text Available Michelle Cheng,1,* Samantha Ho,1,* Jun Hwan Yoo,1,2,* Deanna Hoang-Yen Tran,1,* Kyriaki Bakirtzi,1 Bowei Su,1 Diana Hoang-Ngoc Tran,1 Yuzu Kubota,1 Ryan Ichikawa,1 Hon Wai Koon1 1Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; 2Digestive Disease Center, CHA University Bundang Medical Center, Seongnam, Republic of Korea *These authors share co-first authorship Background: Cathelicidin (LL-37 in humans and mCRAMP in mice represents a family of endogenous antimicrobial and anti-inflammatory peptides. Cancer-associated fibroblasts can promote the proliferation of colon cancer cells and growth of colon cancer tumors. Methods: We examined the role of cathelicidin in the development of colon cancer, using subcutaneous human HT-29 colon-cancer-cell-derived tumor model in nude mice and azoxymethane- and dextran sulfate-mediated colon cancer model in C57BL/6 mice. We also determined the indirect antitumoral mechanism of cathelicidin via the inhibition of epithelial–mesenchymal transition (EMT of colon cancer cells and fibroblast-supported colon cancer cell proliferation. Results: Intravenous administration of cathelicidin expressing adeno-associated virus significantly reduced the size of tumors, tumor-derived collagen expression, and tumor-derived fibroblast expression in HT-29-derived subcutaneous tumors in nude mice. Enema administration of the mouse cathelicidin peptide significantly reduced the size and number of colonic tumors in azoxymethane- and dextran sulfate-treated mice without inducing apoptosis in tumors and the adjacent normal colonic tissues. Cathelicidin inhibited the collagen expression and vimentin-positive fibroblast expression in colonic tumors. Cathelicidin did not directly affect HT-29 cell viability, but did significantly reduce tumor growth factor-ß1-induced EMT of colon cancer cells. Media conditioned by the

Relationship between airway colonization, inflammation and exacerbation frequency in COPD.

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Tumkaya, Munir; Atis, Sibel; Ozge, Cengiz; Delialioglu, Nuran; Polat, Gurbuz; Kanik, Arzu

2007-04-01

To evaluate bacterial colonization and the airway inflammatory response, and its relationship to the frequency of exacerbation in patients with stable chronic obstructive pulmonary disease (COPD). Quantitative bacteriologic cultures, neutrophil elastase, myeloperoxidase (MPO), tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-8 were measured in bronchoalveoler lavage (BAL) in 39 patients with stable COPD [19 with frequent exacerbation (> or = 3/year), and 20 with infrequent] and in 18 healthy controls (10 smokers and 8 non-smokers). BAL revealed the microorganisms with potential pathogenicity above the established threshold (> or = 10(3)cfu/ml) in 68.4% of patients with frequent exacerbation, 55% of infrequent exacerbation, 40% of smokers and 12.5% of non-smokers controls (P=0.05). BAL MPO, IL-8 and TNF-alpha levels were found to be significantly higher in COPD as compared to controls (P=0.001). However, only IL-8 level was significantly higher in COPD patients with frequent exacerbation as compared to infrequent (P=0.001). Airway bacterial load correlated with levels of airway inflammation markers in COPD (P<0.05). The bacterial load and airway inflammation contributes to each other in stable COPD. However, there is a link only between interleukine (IL)-8 and frequent exacerbations. Clearly, the relationship between bacterial colonization, airway inflammation and frequent exacerbations is of major importance in understanding of the COPD pathogenesis.

Ionizing radiation, inflammation, and their interactions in colon carcinogenesis in Mlh1-deficient mice.

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Morioka, Takamitsu; Miyoshi-Imamura, Tomoko; Blyth, Benjamin J; Kaminishi, Mutsumi; Kokubo, Toshiaki; Nishimura, Mayumi; Kito, Seiji; Tokairin, Yutaka; Tani, Shusuke; Murakami-Murofushi, Kimiko; Yoshimi, Naoki; Shimada, Yoshiya; Kakinuma, Shizuko

2015-03-01

Genetic, physiological and environmental factors are implicated in colorectal carcinogenesis. Mutations in the mutL homolog 1 (MLH1) gene, one of the DNA mismatch repair genes, are a main cause of hereditary colon cancer syndromes such as Lynch syndrome. Long-term chronic inflammation is also a key risk factor, responsible for colitis-associated colorectal cancer; radiation exposure is also known to increase colorectal cancer risk. Here, we studied the effects of radiation exposure on inflammation-induced colon carcinogenesis in DNA mismatch repair-proficient and repair-deficient mice. Male and female Mlh1(-/-) and Mlh1(+/+) mice were irradiated with 2 Gy X-rays when aged 2 weeks or 7 weeks and/or were treated with 1% dextran sodium sulfate (DSS) in drinking water for 7 days at 10 weeks old to induce mild inflammatory colitis. No colon tumors developed after X-rays and/or DSS treatment in Mlh1(+/+) mice. Colon tumors developed after DSS treatment alone in Mlh1(-/-) mice, and exposure to radiation prior to DSS treatment increased the number of tumors. Histologically, colon tumors in the mice resembled the subtype of well-to-moderately differentiated adenocarcinomas with tumor-infiltrating lymphocytes of human Lynch syndrome. Immunohistochemistry revealed that expression of both p53 and β-catenin and loss of p21 and adenomatosis polyposis coli proteins were observed at the later stages of carcinogenesis, suggesting a course of molecular pathogenesis distinct from typical sporadic or colitis-associated colon cancer in humans. In conclusion, radiation exposure could further increase the risk of colorectal carcinogenesis induced by inflammation under the conditions of Mlh1 deficiency. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Haemophilus influenzae from Patients with Chronic Obstructive Pulmonary Disease Exacerbation Induce More Inflammation than Colonizers

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Chin, Cecilia L.; Manzel, Lori J.; Lehman, Erin E.; Humlicek, Alicia L.; Shi, Lei; Starner, Timothy D.; Denning, Gerene M.; Murphy, Timothy F.; Sethi, Sanjay; Look, Dwight C.

2005-01-01

Rationale: Airway infection with Haemophilus influenzae causes airway inflammation, and isolation of new strains of this bacteria is associated with increased risk of exacerbations in patients with chronic obstructive pulmonary disease (COPD). Objective: To determine whether strains of H. influenzae associated with exacerbations cause more inflammation than strains that colonize the airways of patients with COPD. Methods: Exacerbation strains of H. influenzae were isolated from patients during exacerbation of clinical symptoms with subsequent development of a homologous serum antibody response and were compared with colonization strains that were not associated with symptom worsening or an antibody response. Bacterial strains were compared using an in vivo mouse model of airway infection and in vitro cell culture model of bacterial adherence and defense gene and signaling pathway activation in primary human airway epithelial cells. Results: H. influenzae associated with exacerbations caused more airway neutrophil recruitment compared with colonization strains in the mouse model of airway bacterial infection. Furthermore, exacerbation strains adhered to epithelial cells in significantly higher numbers and induced more interleukin-8 release after interaction with airway epithelial cells. This effect was likely mediated by increased activation of the nuclear factor-κB and p38 mitogen-activated protein kinase signaling pathways. Conclusions: The results indicate that H. influenzae strains isolated from patients during COPD exacerbations often induce more airway inflammation and likely have differences in virulence compared with colonizing strains. These findings support the concept that bacteria infecting the airway during COPD exacerbations mediate increased airway inflammation and contribute to decreased airway function. PMID:15805181

Carrageenan-Induced Colonic Inflammation Is Reduced in Bcl10 Null Mice and Increased in IL-10-Deficient Mice

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Sumit Bhattacharyya

2013-01-01

Full Text Available The common food additive carrageenan is a known activator of inflammation in mammalian tissues and stimulates both the canonical and noncanonical pathways of NF-κB activation. Exposure to low concentrations of carrageenan (10 μg/mL in the water supply has produced glucose intolerance, insulin resistance, and impaired insulin signaling in C57BL/6 mice. B-cell leukemia/lymphoma 10 (Bcl10 is a mediator of inflammatory signals from Toll-like receptor (TLR 4 in myeloid and epithelial cells. Since the TLR4 signaling pathway is activated in diabetes and by carrageenan, we addressed systemic and intestinal inflammatory responses following carrageenan exposure in Bcl10 wild type, heterozygous, and null mice. Fecal calprotectin and circulating keratinocyte chemokine (KC, nuclear RelA and RelB, phospho(Thr559-NF-κB-inducing kinase (NIK, and phospho(Ser36-IκBα in the colonic epithelial cells were significantly less (P<0.001 in the carrageenan-treated Bcl10 null mice than in controls. IL-10-deficient mice exposed to carrageenan in a germ-free environment showed an increase in activation of the canonical pathway of NF-κB (RelA activation, but without increase in RelB or phospho-Bcl10, and exogenous IL-10 inhibited only the canonical pathway of NF-κB activation in cultured colonic cells. These findings demonstrate a Bcl10 requirement for maximum development of carrageenan-induced inflammation and lack of complete suppression by IL-10 of carrageenan-induced inflammation.

Hypoxia inhibits colonic ion transport via activation of AMP kinase.

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Collins, Danielle

2012-02-01

BACKGROUND AND AIMS: Mucosal hypoxia is a common endpoint for many pathological processes including ischemic colitis, colonic obstruction and anastomotic failure. Previous studies suggest that hypoxia modulates colonic mucosal function through inhibition of chloride secretion. However, the molecular mechanisms underlying this observation are poorly understood. AMP-activated protein kinase (AMPK) is a metabolic energy regulator found in a wide variety of cells and has been linked to cystic fibrosis transmembrane conductance regulator (CFTR) mediated chloride secretion in several different tissues. We hypothesized that AMPK mediates many of the acute effects of hypoxia on human and rat colonic electrolyte transport. METHODS: The fluorescent chloride indicator dye N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide was used to measure changes in intracellular chloride concentrations in isolated single rat colonic crypts. Ussing chamber experiments in human colonic mucosa were conducted to evaluate net epithelial ion transport. RESULTS: This study demonstrates that acute hypoxia inhibits electrogenic chloride secretion via AMPK mediated inhibition of CFTR. Pre-treatment of tissues with the AMPK inhibitor 6-[4-(2-piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyyrazolo [1,5-a] pyrimidine (compound C) in part reversed the effects of acute hypoxia on chloride secretion. CONCLUSION: We therefore suggest that AMPK is a key component of the adaptive cellular response to mucosal hypoxia in the colon. Furthermore, AMPK may represent a potential therapeutic target in diseased states or in prevention of ischemic intestinal injury.

Interaction of Dietary Fatty Acids with Tumour Necrosis Factor Family Cytokines during Colon Inflammation and Cancer

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Straková, Nicol; Vaculová, Alena Hyršlová; Tylichová, Zuzana; Šafaříková, Barbora; Kozubík, Alois

2014-01-01

Intestinal homeostasis is precisely regulated by a number of endogenous regulatory molecules but significantly influenced by dietary compounds. Malfunction of this system may result in chronic inflammation and cancer. Dietary essential n-3 polyunsaturated fatty acids (PUFAs) and short-chain fatty acid butyrate produced from fibre display anti-inflammatory and anticancer activities. Both compounds were shown to modulate the production and activities of TNF family cytokines. Cytokines from the TNF family (TNF-α, TRAIL, and FasL) have potent inflammatory activities and can also regulate apoptosis, which plays an important role in cancer development. The results of our own research showed enhancement of apoptosis in colon cancer cells by a combination of either docosahexaenoic acid (DHA) or butyrate with TNF family cytokines, especially by promotion of the mitochondrial apoptotic pathway and modulation of NFκB activity. This review is focused mainly on the interaction of dietary PUFAs and butyrate with these cytokines during colon inflammation and cancer development. We summarised recent knowledge about the cellular and molecular mechanisms involved in such effects and outcomes for intestinal cell behaviour and pathologies. Finally, the possible application for the prevention and therapy of colon inflammation and cancer is also outlined. PMID:24876678

Chronic ethanol feeding promotes azoxymethane and dextran sulfate sodium-induced colonic tumorigenesis potentially by enhancing mucosal inflammation

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Shukla, Pradeep K.; Chaudhry, Kamaljit K.; Mir, Hina; Gangwar, Ruchika; Yadav, Nikki; Manda, Bhargavi; Meena, Avtar S.; Rao, RadhaKrishna

2016-01-01

Alcohol consumption is one of the major risk factors for colorectal cancer. However, the mechanism involved in this effect of alcohol is unknown. We evaluated the effect of chronic ethanol feeding on azoxymethane and dextran sulfate sodium (AOM/DSS)-induced carcinogenesis in mouse colon. Inflammation in colonic mucosa was assessed at a precancerous stage by evaluating mucosal infiltration of neutrophils and macrophages, and analysis of cytokine and chemokine gene expression. Chronic ethanol feeding significantly increased the number and size of polyps in colon of AOM/DSS treated mice. Confocal microscopic and immunoblot analyses showed a significant elevation of phospho-Smad, VEGF and HIF1α in the colonic mucosa. RT-PCR analysis at a precancerous stage indicated that ethanol significantly increases the expression of cytokines IL-1α, IL-6 and TNFα, and the chemokines CCL5/RANTES, CXCL9/MIG and CXCL10/IP-10 in the colonic mucosa of AOM/DSS treated mice. Confocal microscopy showed that ethanol feeding induces a dramatic elevation of myeloperoxidase, Gr1 and CD68-positive cells in the colonic mucosa of AOM/DSS-treated mice. Ethanol feeding enhanced AOM/DSS-induced suppression of tight junction protein expression and elevated cell proliferation marker, Ki-67 in the colonic epithelium. This study demonstrates that chronic ethanol feeding promotes colonic tumorigenesis potentially by enhancing inflammation and elevation of proinflammatory cytokines and chemokines

Inhibition of autophagy induced by TSA sensitizes colon cancer cell to radiation.

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He, Gang; Wang, Yan; Pang, Xueli; Zhang, Bo

2014-02-01

Radiotherapy is one of the main treatments for clinical cancer therapy. However, its application was limited due to lack of radiosensitivity in some cancers. Trichostatin A (TSA) is a classic histone deacetylases inhibitor (HDACi) that specifically inhibits the biochemical functions of HDAC and is demonstrated to be an active anticancer drug. However, whether it could sensitize colon cancer to radiation is not clear. Our results showed that TSA enhanced the radiosensitivity of colon cancer cells as determined by CCK-8 and clonogenic survival assay. Moreover, apoptotic cell death induced by radiation was enhanced by TSA treatment. Additionally, TSA also induced autophagic response in colon cancer cells, while autophagy inhibition led to cell apoptosis and enhanced the radiosensitivity of colon cancer cells. Our data suggested that inhibition of cytoprotective autophagy sensitizes cancer cell to radiation, which might be further investigated for clinical cancer radiotherapy.

Zileuton, 5-lipoxygenase inhibitor, acts as a chemopreventive agent in intestinal polyposis, by modulating polyp and systemic inflammation.

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Elias Gounaris

Full Text Available Leukotrienes and prostaglandins, products of arachidonic acid metabolism, sustain both systemic and lesion-localized inflammation. Tumor-associated Inflammation can also contribute to the pathogenesis of colon cancer. Patients with inflammatory bowel disease (IBD have increased risk of developing colon cancer. The levels of 5-lipoxygenase (5-LO, the key enzyme for leukotrienes production, are increased in colon cancer specimens and colonic dysplastic lesions. Here we report that Zileuton, a specific 5-LO inhibitor, can prevent polyp formation by efficiently reducing the tumor-associated and systemic inflammation in APCΔ468 mice.In the current study, we inhibited 5-LO by dietary administration of Zileuton in the APCΔ468 mouse model of polyposis and analyzed the effect of in vivo 5-LO inhibition on tumor-associated and systemic inflammation.Zileuton-fed mice developed fewer polyps and displayed marked reduction in systemic and polyp-associated inflammation. Pro-inflammatory cytokines and pro-inflammatory innate and adaptive immunity cells were reduced both in the lesions and systemically. As part of tumor-associated inflammation Leukotriene B4 (LTB4, product of 5-LO activity, is increased focally in human dysplastic lesions. The 5-LO enzymatic activity was reduced in the serum of Zileuton treated polyposis mice.This study demonstrates that dietary administration of 5-LO specific inhibitor in the polyposis mouse model decreases polyp burden, and suggests that Zileuton may be a potential chemo-preventive agent in patients that are high-risk of developing colon cancer.

Red meat and colon cancer : dietary haem-induced colonic cytotoxicity and epithelial hyperproliferation are inhibited by calcium

NARCIS (Netherlands)

Sesink, ALA; Termont, DSML; Kleibeuker, JH; Van der Meer, R

2001-01-01

High intake of red meat is associated with increased colon cancer risk. We have shown earlier that this may be due to the high haem content of red meat, because dietary haem increased cytolytic activity of faecal water and colonic epithelial proliferation. Dietary calcium inhibits diet-induced

MiR-34a inhibits colon cancer proliferation and metastasis by inhibiting platelet-derived growth factor receptor α.

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Li, Chunyan; Wang, Yulin; Lu, Shuming; Zhang, Zhuqing; Meng, Hua; Liang, Lina; Zhang, Yan; Song, Bo

2015-11-01

The microRNA (miRNA), miR‑34a is significant in colon cancer progression. In the present study, the role of miR‑34a in colon cancer cell proliferation and metastasis was investigated. It was found that the expression of miR‑34a in colon cancer tissues and cell lines was lower when compared with that of normal tissues and cells. Further research demonstrated that miR‑34a inhibited cell proliferation, induced G1 phase arrest, and suppressed metastasis and epithelial mesenchymal transition in colon cancer cells. Bioinformatic prediction indicated that platelet‑derived growth factor receptor α (PDGFRA) was a potential target gene of miR‑34a and a luciferase assay identified that PDGFRA was a novel direct target gene of miR‑34a. In addition, assays of western blot analyses and quantitative reverse‑transcription polymerase chain reaction confirmed that miR‑34a decreased PDGFRA mRNA expression and protein levels in colon cancer cells. Assessment of cellular function indicated that miR‑34a inhibited colon cancer progression via PDGFRA. These findings demonstrate that miR‑34a may act as a negative regulator in colon cancer by targeting PDGFRA.

GFAP and Fos immunoreactivity in lumbo-sacral spinal cord and medulla oblongata after chronic colonic inflammation in rats

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Sun, Yi-Ning; Luo, Jin-Yan; Rao, Zhi-Ren; Lan, Li; Duan, Li

2005-01-01

AIM: To investigate the response of astrocytes and neurons in rat lumbo-sacral spinal cord and medulla oblongata induced by chronic colonic inflammation, and the relationship between them. METHODS: Thirty-three male Sprague-Dawley rats were randomly divided into two groups: experimental group (n = 17), colonic inflammation was induced by intra-luminal administration of trinitrobenzenesulfonic acid (TNBS); control group (n = 16), saline was administered intra-luminally. After 3, 7, 14, and 28 d of administration, the lumbo-sacral spinal cord and medulla oblongata were removed and processed for anti-glial fibrillary acidic protein (GFAP), Fos and GFAP/Fos immunohistochemistry. RESULTS: Activated astrocytes positive for GFAP were mainly distributed in the superficial laminae (laminae I-II) of dorsal horn, intermediolateral nucleus (laminae V), posterior commissural nucleus (laminae X) and anterolateral nucleus (laminae IX). Fos-IR (Fos-immunoreactive) neurons were mainly distributed in the deeper laminae of the spinal cord (laminae III-IV, V-VI). In the medulla oblongata, both GFAP-IR astrocytes and Fos-IR neurons were mainly distributed in the medullary visceral zone (MVZ). The density of GFAP in the spinal cord of experimental rats was significantly higher after 3, 7, and 14 d of TNBS administration compared with the controls (50.4±16.8, 29.2±6.5, 24.1±5.6, P0.05). CONCLUSION: Astrocytes in spinal cord and medulla oblongata can be activated by colonic inflammation. The activated astrocytes are closely related to Fos-IR neurons. With the recovery of colonic inflammation, the activity of astrocytes in the spinal cord and medulla oblongata is reduced. PMID:16097052

Inhibition of aldose reductase prevents experimental allergic airway inflammation in mice.

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Umesh C S Yadav

2009-08-01

Full Text Available The bronchial asthma, a clinical complication of persistent inflammation of the airway and subsequent airway hyper-responsiveness, is a leading cause of morbidity and mortality in critically ill patients. Several studies have shown that oxidative stress plays a key role in initiation as well as amplification of inflammation in airways. However, still there are no good anti-oxidant strategies available for therapeutic intervention in asthma pathogenesis. Most recent studies suggest that polyol pathway enzyme, aldose reductase (AR, contributes to the pathogenesis of oxidative stress-induced inflammation by affecting the NF-kappaB-dependent expression of cytokines and chemokines and therefore inhibitors of AR could be anti-inflammatory. Since inhibitors of AR have already gone through phase-III clinical studies for diabetic complications and found to be safe, our hypothesis is that AR inhibitors could be novel therapeutic drugs for the prevention and treatment of asthma. Hence, we investigated the efficacy of AR inhibition in the prevention of allergic responses to a common natural airborne allergen, ragweed pollen that leads to airway inflammation and hyper-responsiveness in a murine model of asthma.Primary Human Small Airway Epithelial Cells (SAEC were used to investigate the in vitro effects of AR inhibition on ragweed pollen extract (RWE-induced cytotoxic and inflammatory signals. Our results indicate that inhibition of AR prevents RWE -induced apoptotic cell death as measured by annexin-v staining, increase in the activation of NF-kappaB and expression of inflammatory markers such as inducible nitric oxide synthase (iNOS, cycloxygenase (COX-2, Prostaglandin (PG E(2, IL-6 and IL-8. Further, BALB/c mice were sensitized with endotoxin-free RWE in the absence and presence of AR inhibitor and followed by evaluation of perivascular and peribronchial inflammation, mucin production, eosinophils infiltration and airway hyperresponsiveness. Our results

Colonic inflammation in mice is improved by cigarette smoke through iNKT cells recruitment.

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Muriel Montbarbon

Full Text Available Cigarette smoke (CS protects against intestinal inflammation during ulcerative colitis. Immunoregulatory mechanisms sustaining this effect remain unknown. The aim of this study was to assess the effects of CS on experimental colitis and to characterize the intestinal inflammatory response at the cellular and molecular levels. Using the InExpose® System, a smoking device accurately reproducing human smoking habit, we pre-exposed C57BL/6 mice for 2 weeks to CS, and then we induced colitis by administration of dextran sodium sulfate (DSS. This system allowed us to demonstrate that CS exposure improved colonic inflammation (significant decrease in clinical score, body weight loss and weight/length colonic ratio. This improvement was associated with a significant decrease in colonic proinflammatory Th1/Th17 cytokine expression, as compared to unexposed mice (TNF (p=0.0169, IFNγ (p<0.0001, and IL-17 (p=0.0008. Smoke exposure also induced an increased expression of IL-10 mRNA (p=0.0035 and a marked recruitment of iNKT (invariant Natural Killer T; CD45+ TCRβ+ CD1d tetramer+ cells in the colon of DSS-untreated mice. Demonstration of the role of iNKT cells in CS-dependent colitis improvement was performed using two different strains of NKT cells deficient mice. Indeed, in Jα18KO and CD1dKO animals, CS exposure failed to induce significant regulation of DSS-induced colitis both at the clinical and molecular levels. Thus, our study demonstrates that iNKT cells are pivotal actors in the CS-dependent protection of the colon. These results highlight the role of intestinal iNKT lymphocytes and their responsiveness to environmental stimuli. Targeting iNKT cells would represent a new therapeutic way for inflammatory bowel diseases.

Piriformospora indica root colonization triggers local and systemic root responses and inhibits secondary colonization of distal roots.

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Pedrotti, Lorenzo; Mueller, Martin J; Waller, Frank

2013-01-01

Piriformosporaindica is a basidiomycete fungus colonizing roots of a wide range of higher plants, including crop plants and the model plant Arabidopsis thaliana. Previous studies have shown that P. indica improves growth, and enhances systemic pathogen resistance in leaves of host plants. To investigate systemic effects within the root system, we established a hydroponic split-root cultivation system for Arabidopsis. Using quantitative real-time PCR, we show that initial P. indica colonization triggers a local, transient response of several defense-related transcripts, of which some were also induced in shoots and in distal, non-colonized roots of the same plant. Systemic effects on distal roots included the inhibition of secondary P. indica colonization. Faster and stronger induction of defense-related transcripts during secondary inoculation revealed that a P. indica pretreatment triggers root-wide priming of defense responses, which could cause the observed reduction of secondary colonization levels. Secondary P. indica colonization also induced defense responses in distant, already colonized parts of the root. Endophytic fungi therefore trigger a spatially specific response in directly colonized and in systemic root tissues of host plants.

Human Colon Tumors Express a Dominant-Negative Form of SIGIRR That Promotes Inflammation and Colitis-Associated Colon Cancer in Mice.

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Zhao, Junjie; Bulek, Katarzyna; Gulen, Muhammet F; Zepp, Jarod A; Karagkounis, Georgio; Martin, Bradley N; Zhou, Hao; Yu, Minjia; Liu, Xiuli; Huang, Emina; Fox, Paul L; Kalady, Matthew F; Markowitz, Sanford D; Li, Xiaoxia

2015-12-01

Single immunoglobulin and toll-interleukin 1 receptor (SIGIRR), a negative regulator of the Toll-like and interleukin-1 receptor (IL-1R) signaling pathways, controls intestinal inflammation and suppresses colon tumorigenesis in mice. However, the importance of SIGIRR in human colorectal cancer development has not been determined. We investigated the role of SIGIRR in development of human colorectal cancer. We performed RNA sequence analyses of pairs of colon tumor and nontumor tissues, each collected from 68 patients. Immunoblot and immunofluorescence analyses were used to determine levels of SIGIRR protein in primary human colonic epithelial cells, tumor tissues, and colon cancer cell lines. We expressed SIGIRR and mutant forms of the protein in Vaco cell lines. We created and analyzed mice that expressed full-length (control) or a mutant form of Sigirr (encoding SIGIRR(N86/102S), which is not glycosylated) specifically in the intestinal epithelium. Some mice were given azoxymethane (AOM) and dextran sulfate sodium to induce colitis-associated cancer. Intestinal tissues were collected and analyzed by immunohistochemical and gene expression profile analyses. RNA sequence analyses revealed increased expression of a SIGIRR mRNA isoform, SIGIRR(ΔE8), in colorectal cancer tissues compared to paired nontumor tissues. SIGIRR(ΔE8) is not modified by complex glycans and is therefore retained in the cytoplasm-it cannot localize to the cell membrane or reduce IL1R signaling. SIGIRR(ΔE8) interacts with and has a dominant-negative effect on SIGIRR, reducing its glycosylation, localization to the cell surface, and function. Most SIGIRR detected in human colon cancer tissues was cytoplasmic, whereas in nontumor tissues it was found at the cell membrane. Mice that expressed SIGIRR(N86/102S) developed more inflammation and formed larger tumors after administration of azoxymethane and dextran sulfate sodium than control mice; colon tissues from these mutant mice expressed

Curcumin and salsalate suppresses colonic inflammation and procarcinogenic signaling in high-fat-fed, azoxymethane-treated mice

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High-fat diets (HFDs) and excess adiposity increase proinflammatory cytokines in the colon, altering gene expression in a manner that promotes the development of colorectal cancer (CRC). Thus, compounds that reduce this biochemical inflammation are potential chemopreventive agents. Curcumin (CUR), a...

Oral imazalil exposure induces gut microbiota dysbiosis and colonic inflammation in mice.

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Jin, Cuiyuan; Zeng, Zhaoyang; Fu, Zhengwei; Jin, Yuanxiang

2016-10-01

The fungicide imazalil (IMZ) is used extensively in vegetable and fruit plantations and as a post-harvest treatment to avoid rot. Here, we revealed that ingestion of 25, 50 and 100 mg IMZ kg(-1) body weight for 28 d induced gut microbiota dysbiosis and colonic inflammation in mice. The relative abundance of Bacteroidetes, Firmicutes and Actinobacteria in the cecal contents decreased significantly after exposure to 100 mg kg(-1) IMZ for 28 d. In feces, the relative abundance in Bacteroidetes, Firmicutes and Actinobacteria decreased significantly after being exposed to 100 mg kg(-1) IMZ for 1, 14 and 7 d, respectively. High throughput sequencing of the V3-V4 region of the bacterial 16S rRNA gene revealed a significant reduction in the richness and diversity of microbiota in cecal contents and feces of IMZ-treated mice. Operational taxonomic units (OTUs) analysis identified 49.3% of OTUs changed in cecal contents, while 55.6% of OTUs changed in the feces after IMZ exposure. Overall, at the phylum level, the relative abundance of Firmicutes, Proteobacteria and Actinobacteria increased and that of Bacteroidetes decreased in IMZ-treated groups. At the genus level, the abundance of Lactobacillus and Bifidobacterium decreased while those of Deltaproteobacteria and Desulfovibrio increased in response to IMZ exposure. In addition, it was observed that IMZ exposure could induce colonic inflammation characterized by infiltration of inflammatory cells, elevated levels of lipocalin-2 (lcn-2) in the feces, and increased mRNA levels of Tnf-α, IL-1β, IL-22 and IFN-γ in the colon. Our findings strongly suggest that ingestion of IMZ has some risks to human health. Copyright © 2016 Elsevier Ltd. All rights reserved.

Low grade inflammation inhibits VEGF induced HUVECs migration in p53 dependent manner

International Nuclear Information System (INIS)

Panta, Sushil; Yamakuchi, Munekazu; Shimizu, Toshiaki; Takenouchi, Kazunori; Oyama, Yoko; Koriyama, Toyoyasu; Kojo, Tsuyoshi; Hashiguchi, Teruto

2017-01-01

In the course of studying crosstalk between inflammation and angiogenesis, high doses of pro-inflammatory factors have been reported to induce apoptosis in cells. Under normal circumstances also the pro-inflammatory cytokines are being released in low doses and are actively involved in cell signaling pathways. We studied the effects of low grade inflammation in growth factor induced angiogenesis using tumor necrosis factor alfa (TNFα) and vascular endothelial growth factor A (VEGF) respectively. We found that low dose of TNFα can inhibit VEGF induced angiogenesis in human umbilical vein endothelial cells (HUVECs). Low dose of TNFα induces mild upregulation and moreover nuclear localization of tumor suppressor protein 53 (P53) which causes decrease in inhibitor of DNA binding-1 (Id1) expression and shuttling to the cytoplasm. In absence of Id1, HUVECs fail to upregulate β 3 -integrin and cell migration is decreased. Connecting low dose of TNFα induced p53 to β 3 -integrin through Id1, we present additional link in cross talk between inflammation and angiogenesis. - Highlights: • Low grade inflammation (low dose of TNF alfa) inhibits VEGF induced endothelial cells migration. • The low grade inflammation with VEGF treatment upregulates P53 to a nonlethal level. • P53 activation inhibits Id1 shuttling to the cytoplasm in endothelial cells. • Inhibition of Id1 resulted in downregulation of β 3 -integrin which cause decrease in cell migration. • Inflammation and angiogenesis might cross-talk by P53 – Id1 – β 3 -integrin pathway in endothelial cells.

Diclofenac inhibits 27-hydroxycholesterol-induced inflammation.

Science.gov (United States)

Kim, Bo-Young; Son, Yonghae; Eo, Seong-Kug; Park, Young Chul; Kim, Koanhoi

2016-09-23

27-Hydroxycholesterol (27OHChol) is a cholesterol oxidation product that induces inflammation. In the current study we investigated the effects of diclofenac on inflammatory responses caused by 27OHChol using human monocyte/macrophage (THP-1) cells. Transcription and secretion of CCL2, CCL3, and CCL4 chemokines enhanced by 27OHChol were significantly attenuated by diclofenac in a concentration dependent manner. Migrations of monocytic cells and CCR5-positive Jurkat T cells were reduced proportionally to the concentrations of diclofenac. Superproduction of CCL2 and monocytic cell migration induced by 27OHChol plus LPS were significantly attenuated by diclofenac. Diclofenac also attenuated transcription of MMP-9 and release of its active gene product. These results indicate that diclofenac inhibits 27OHChol-induced inflammatory responses, thereby suppressing inflammation in a milieu rich in cholesterol oxidation products. Copyright © 2016 Elsevier Inc. All rights reserved.

Changes in Composition of Caecal Microbiota Associated with Increased Colon Inflammation in Interleukin-10 Gene-Deficient Mice Inoculated with Enterococcus Species

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Shalome A. Bassett

2015-03-01

Full Text Available Human inflammatory bowel disease (IBD is a chronic intestinal disease where the resident microbiota contributes to disease development, yet the specific mechanisms remain unclear. Interleukin-10 gene-deficient (Il10-/- mice develop inflammation similar to IBD, due in part to an inappropriate response to commensal bacteria. We have previously reported changes in intestinal morphology and colonic gene expression in Il10-/- mice in response to oral bacterial inoculation. In this study, we aimed to identify specific changes in the caecal microbiota associated with colonic inflammation in these mice. The microbiota was evaluated using pyrotag sequencing, denaturing gradient gel electrophoresis (DGGE and quantitative real-time PCR. Microbiota profiles were influenced by genotype of the mice and by bacterial inoculation, and a strong correlation was observed between the microbiota and colonic inflammation scores. Although un-inoculated Il10-/- and C57 mice had similar microbiota communities, bacterial inoculation resulted in different changes to the microbiota in Il10-/- and C57 mice. Inoculated Il10-/- mice had significantly less total bacteria than un-inoculated Il10-/- mice, with a strong negative correlation between total bacterial numbers, relative abundance of Escherichia/Shigella, microbiota diversity, and colonic inflammation score. Our results show a putative causative role for the microbiota in the development of IBD, with potentially key roles for Akkermansia, or for Bacteroides, Helicobacter, Parabacteroides, and Alistipes, depending on the composition of the bacterial inoculum. These data support the use of bacterially-inoculated Il10-/- mice as an appropriate model to investigate human IBD.

A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation

Science.gov (United States)

Duivenvoorden, Raphaël; Tang, Jun; Cormode, David P.; Mieszawska, Aneta J.; Izquierdo-Garcia, David; Ozcan, Canturk; Otten, Maarten J.; Zaidi, Neeha; Lobatto, Mark E.; van Rijs, Sarian M.; Priem, Bram; Kuan, Emma L.; Martel, Catherine; Hewing, Bernd; Sager, Hendrik; Nahrendorf, Matthias; Randolph, Gwendalyn J.; Stroes, Erik S. G.; Fuster, Valentin; Fisher, Edward A.; Fayad, Zahi A.; Mulder, Willem J. M.

2014-01-01

Inflammation is a key feature of atherosclerosis and a target for therapy. Statins have potent anti-inflammatory properties but these cannot be fully exploited with oral statin therapy due to low systemic bioavailability. Here we present an injectable reconstituted high-density lipoprotein (rHDL) nanoparticle carrier vehicle that delivers statins to atherosclerotic plaques. We demonstrate the anti-inflammatory effect of statin-rHDL in vitro and show that this effect is mediated through the inhibition of the mevalonate pathway. We also apply statin-rHDL nanoparticles in vivo in an apolipoprotein E-knockout mouse model of atherosclerosis and show that they accumulate in atherosclerotic lesions in which they directly affect plaque macrophages. Finally, we demonstrate that a 3-month low-dose statin-rHDL treatment regimen inhibits plaque inflammation progression, while a 1-week high-dose regimen markedly decreases inflammation in advanced atherosclerotic plaques. Statin-rHDL represents a novel potent atherosclerosis nanotherapy that directly affects plaque inflammation.

Characterization and pharmacological modulation of intestinal inflammation induced by ionizing radiation; Caracterisation et modulation pharmacologique de l'inflammation intestinale induite par les rayonnements ionisants

Energy Technology Data Exchange (ETDEWEB)

Gremy, O

2006-12-15

The use of radiation therapy to treat abdominal and pelvic malignancies inevitably involves exposure of healthy intestinal tissues which are very radiosensitive. As a result, most patients experience symptoms such as abdominal pain, nausea and diarrhea. Such symptoms are associated with acute damage to intestine mucosa including radio-induced inflammatory processes. With a rat model of colorectal fractionated radiation, we have shown a gradual development of a colonic inflammation during radiation planning, without evident tissue injury. This radio-induced inflammation is characterized not only by the sur expressions of pro-inflammatory cytokines and chemokines, a NF-kB activation, but also by a repression of anti-inflammatory cytokines and the nuclear receptors PPARa and RXRa, both involved in inflammation control. This early inflammation is associated with a discreet neutrophil recruitment and a macrophage accumulation. Macrophages are still abnormally numerous in tissue 27 weeks after the last day of irradiation. Inflammatory process is the most often related to a specific immune profile, either a type Th1 leading to a cellular immune response, or a type Th2 for humoral immunity. According to our studies, a unique abdominal radiation in the rat induces an ileum inflammation and an immune imbalance resulting in a Th2-type profile. Inhibiting this profile is important as its persistence promotes chronic inflammation, predisposition to bacterial infections and fibrosis which is the main delayed side-effect of radiotherapy. The treatment of rats with an immuno-modulator compound, the caffeic acid phenethyl ester (C.A.P.E.), have the potential to both reduce ileal mucosal inflammation and inhibit the radio-induced Th2 status. In order to search new therapeutic molecular target, we has been interested in the PPARg nuclear receptor involved in the maintenance of colon mucosal integrity. In our abdominal irradiation model, we have demonstrated that the prophylactic

A novel murine model of inflammatory bowel disease and inflammation-associated colon cancer with ulcerative colitis-like features.

Directory of Open Access Journals (Sweden)

Laura P Hale

Full Text Available Mutations that increase susceptibility to inflammatory bowel disease (IBD have been identified in a number of genes in both humans and mice, but the factors that govern how these mutations contribute to IBD pathogenesis and result in phenotypic presentation as ulcerative colitis (UC or Crohn disease (CD are not well understood. In this study, mice deficient in both TNF and IL-10 (T/I mice were found to spontaneously develop severe colitis soon after weaning, without the need for exogenous triggers. Colitis in T/I mice had clinical and histologic features similar to human UC, including a markedly increased risk of developing inflammation-associated colon cancer. Importantly, development of spontaneous colitis in these mice was prevented by antibiotic treatment. Consistent with the known role of Th17-driven inflammation in response to bacteria, T/I mice had elevated serumTh17-type cytokines when they developed spontaneous colitis and after systemic bacterial challenge via NSAID-induced degradation of the mucosal barrier. Although TNF production has been widely considered to be be pathogenic in IBD, these data indicate that the ability to produce normal levels of TNF actually protects against the spontaneous development of colitis in response to intestinal colonization by bacteria. The T/I mouse model will be useful for developing new rationally-based therapies to prevent and/or treat IBD and inflammation-associated colon cancer and may further provide important insights into the pathogenesis of UC in humans.

Pre-treatment with Bifidobacterium breve UCC2003 modulates Citrobacter rodentium-induced colonic inflammation and organ specificity.

Science.gov (United States)

Collins, James W; Akin, Ali R; Kosta, Artemis; Zhang, Ning; Tangney, Mark; Francis, Kevin P; Frankel, Gad

2012-11-01

Citrobacter rodentium, which colonizes the gut mucosa via formation of attaching and effacing (A/E) lesions, causes transmissible colonic hyperplasia. The aim of this study was to evaluate whether prophylactic treatment with Bifidobacterium breve UCC2003 can improve the outcome of C. rodentium infection. Six-week-old albino C57BL/6 mice were pre-treated for 3 days with B. breve, challenged with bioluminescent C. rodentium and administered B. breve or PBS-C for 8 days post-infection; control mice were either administered B. breve and mock-infected with PBS, or mock-treated with PBS-C and mock-infected with PBS. C. rodentium colonization was monitored by bacterial enumeration from faeces and by a combination of both 2D bioluminescence imaging (BLI) and composite 3D diffuse light imaging tomography with µCT imaging (DLIT-µCT). At day 8 post-infection, colons were removed and assessed for crypt hyperplasia, histology by light microscopy, bacterial colonization by immunofluorescence, and A/E lesion formation by electron microscopy. Prophylactic administration of B. breve did not prevent C. rodentium colonization or A/E lesion formation. However, this treatment did alter C. rodentium distribution within the large intestine and significantly reduced colonic crypt hyperplasia at the peak of bacterial infection. These results show that B. breve could not competitively exclude C. rodentium, but reduced pathogen-induced colonic inflammation.

Characterization and pharmacological modulation of intestinal inflammation induced by ionizing radiation; Caracterisation et modulation pharmacologique de l'inflammation intestinale induite par les rayonnements ionisants

Energy Technology Data Exchange (ETDEWEB)

Gremy, O

2006-12-15

The use of radiation therapy to treat abdominal and pelvic malignancies inevitably involves exposure of healthy intestinal tissues which are very radiosensitive. As a result, most patients experience symptoms such as abdominal pain, nausea and diarrhea. Such symptoms are associated with acute damage to intestine mucosa including radio-induced inflammatory processes. With a rat model of colorectal fractionated radiation, we have shown a gradual development of a colonic inflammation during radiation planning, without evident tissue injury. This radio-induced inflammation is characterized not only by the sur expressions of pro-inflammatory cytokines and chemokines, a NF-kB activation, but also by a repression of anti-inflammatory cytokines and the nuclear receptors PPARa and RXRa, both involved in inflammation control. This early inflammation is associated with a discreet neutrophil recruitment and a macrophage accumulation. Macrophages are still abnormally numerous in tissue 27 weeks after the last day of irradiation. Inflammatory process is the most often related to a specific immune profile, either a type Th1 leading to a cellular immune response, or a type Th2 for humoral immunity. According to our studies, a unique abdominal radiation in the rat induces an ileum inflammation and an immune imbalance resulting in a Th2-type profile. Inhibiting this profile is important as its persistence promotes chronic inflammation, predisposition to bacterial infections and fibrosis which is the main delayed side-effect of radiotherapy. The treatment of rats with an immuno-modulator compound, the caffeic acid phenethyl ester (C.A.P.E.), have the potential to both reduce ileal mucosal inflammation and inhibit the radio-induced Th2 status. In order to search new therapeutic molecular target, we has been interested in the PPARg nuclear receptor involved in the maintenance of colon mucosal integrity. In our abdominal irradiation model, we have demonstrated that the prophylactic

A Case of Sigmoid Colon Tuberculosis Mimicking Colon Cancer

OpenAIRE

Yu, Seong-Min; Park, Jong-Hwan; Kim, Min-Dae; Lee, Hee-Ryong; Jung, Peel; Ryu, Tae-Hyun; Choi, Seung-Ho; Lee, Il-Seon

2012-01-01

Tuberculosis of the sigmoid colon is a rare disorder. An 80-year-old man visited Bongseng Memorial Hospital for medical examination. A colonoscopy was performed, and a lesion in the sigmoid colon that was suspected to be colon cancer was found. A biopsy was performed, and tuberculous enteritis with chronic granulomatous inflammation was diagnosed. Intestinal tuberculosis is most frequent in the ileocecal area, followed by the ascending colon, transverse colon, duodenum, stomach, and sigmoid c...

Kynurenic acid inhibits intestinal hypermotility and xanthine oxidase activity during experimental colon obstruction in dogs.

Science.gov (United States)

Kaszaki, J; Palásthy, Z; Erczes, D; Rácz, A; Torday, C; Varga, G; Vécsei, L; Boros, M

2008-01-01

Kynurenic acid (KynA), an endogenous antagonist of N-methyl-d-aspartate (NMDA) glutamate receptors, protects the central nervous system in excitotoxic neurological diseases. We hypothesized that the inhibition of enteric glutamate receptors by KynA may influence dysmotility in the gastrointestinal tract. Group 1 of healthy dogs served as the sham-operated control, in group 2, the animals were treated with KynA, while in groups 3 and 4 mechanical colon obstruction was maintained for 7 h. Group 4 was treated with KynA at the onset of ileus. Hemodynamics and motility changes were monitored, and the activities of xanthine oxidoreductase (XOR) and myeloperoxidase (MPO) were determined from tissue samples. Colon obstruction induced a hyperdynamic circulatory reaction, significantly elevated the motility index and increased the mucosal leucocyte accumulation and the XOR activity. The KynA treatment augmented the tone of the colon, permanently decreased the motility index of the giant colonic contractions and reduced the increases in XOR and MPO activities. These effects were concomitant with the in vitro inhibition of XOR activity. In conclusion, KynA antagonizes the obstruction-induced motility responses and XOR activation in the colon. Inhibition of enteric NMDA receptors may provide an option to influence intestinal hypermotility and inflammatory changes.

Inhibition of fungal colonization by Pseudoalteromonas tunicata provides a competitive advantage during surface colonization.

Science.gov (United States)

Franks, A; Egan, S; Holmström, C; James, S; Lappin-Scott, H; Kjelleberg, S

2006-09-01

The marine epiphytic bacterium Pseudoalteromonas tunicata produces a range of extracellular secondary metabolites that inhibit an array of common fouling organisms, including fungi. In this study, we test the hypothesis that the ability to inhibit fungi provides P. tunicata with an advantage during colonization of a surface. Studies on a transposon-generated antifungal-deficient mutant of P. tunicata, FM3, indicated that a long-chain fatty acid-coenzyme A ligase is involved in the production of a broad-range antifungal compound by P. tunicata. Flow cell experiments demonstrated that production of an antifungal compound provided P. tunicata with a competitive advantage against a marine yeast isolate during surface colonization. This compound enabled P. tunicata to disrupt an already established fungal biofilm by decreasing the number of yeast cells attached to the surface by 66% +/- 9%. For in vivo experiments, the wild-type and FM3 strains of P. tunicata were used to inoculate the surface of the green alga Ulva australis. Double-gradient denaturing gradient gel electrophoresis analysis revealed that after 48 h, the wild-type P. tunicata had outcompeted the surface-associated fungal community, whereas the antifungal-deficient mutant had no effect on the fungal community. Our data suggest that P. tunicata is an effective competitor against fungal surface communities in the marine environment.

Telmisartan attenuates colon inflammation, oxidative perturbations and apoptosis in a rat model of experimental inflammatory bowel disease.

Directory of Open Access Journals (Sweden)

Hany H Arab

Full Text Available 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.

Characterization and pharmacological modulation of intestinal inflammation induced by ionizing radiation

International Nuclear Information System (INIS)

Gremy, O.

2006-12-01

The use of radiation therapy to treat abdominal and pelvic malignancies inevitably involves exposure of healthy intestinal tissues which are very radiosensitive. As a result, most patients experience symptoms such as abdominal pain, nausea and diarrhea. Such symptoms are associated with acute damage to intestine mucosa including radio-induced inflammatory processes. With a rat model of colorectal fractionated radiation, we have shown a gradual development of a colonic inflammation during radiation planning, without evident tissue injury. This radio-induced inflammation is characterized not only by the sur expressions of pro-inflammatory cytokines and chemokines, a NF-kB activation, but also by a repression of anti-inflammatory cytokines and the nuclear receptors PPARa and RXRa, both involved in inflammation control. This early inflammation is associated with a discreet neutrophil recruitment and a macrophage accumulation. Macrophages are still abnormally numerous in tissue 27 weeks after the last day of irradiation. Inflammatory process is the most often related to a specific immune profile, either a type Th1 leading to a cellular immune response, or a type Th2 for humoral immunity. According to our studies, a unique abdominal radiation in the rat induces an ileum inflammation and an immune imbalance resulting in a Th2-type profile. Inhibiting this profile is important as its persistence promotes chronic inflammation, predisposition to bacterial infections and fibrosis which is the main delayed side-effect of radiotherapy. The treatment of rats with an immuno-modulator compound, the caffeic acid phenethyl ester (C.A.P.E.), have the potential to both reduce ileal mucosal inflammation and inhibit the radio-induced Th2 status. In order to search new therapeutic molecular target, we has been interested in the PPARg nuclear receptor involved in the maintenance of colon mucosal integrity. In our abdominal irradiation model, we have demonstrated that the prophylactic

Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon.

Science.gov (United States)

Ward, Joseph B J; Lajczak, Natalia K; Kelly, Orlaith B; O'Dwyer, Aoife M; Giddam, Ashwini K; Ní Gabhann, Joan; Franco, Placido; Tambuwala, Murtaza M; Jefferies, Caroline A; Keely, Simon; Roda, Aldo; Keely, Stephen J

2017-06-01

Ward JB, Lajczak NK, Kelly OB, O'Dwyer AM, Giddam AK, Ní Gabhann J, Franco P, Tambuwala MM, Jefferies CA, Keely S, Roda A, Keely SJ. Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon. Am J Physiol Gastrointest Liver Physiol 312: G550-G558, 2017. First published March 30, 2017; doi:10.1152/ajpgi.00256.2016.-Inflammatory bowel diseases (IBD) comprise a group of common and debilitating chronic intestinal disorders for which currently available therapies are often unsatisfactory. The naturally occurring secondary bile acid, ursodeoxycholic acid (UDCA), has well-established anti-inflammatory and cytoprotective actions and may therefore be effective in treating IBD. We aimed to investigate regulation of colonic inflammatory responses by UDCA and to determine the potential impact of bacterial metabolism on its therapeutic actions. The anti-inflammatory efficacy of UDCA, a nonmetabolizable analog, 6α-methyl-UDCA (6-MUDCA), and its primary colonic metabolite lithocholic acid (LCA) was assessed in the murine dextran sodium sulfate (DSS) model of mucosal injury. The effects of bile acids on cytokine (TNF-α, IL-6, Il-1β, and IFN-γ) release from cultured colonic epithelial cells and mouse colonic tissue in vivo were investigated. Luminal bile acids were measured by gas chromatography-mass spectrometry. UDCA attenuated release of proinflammatory cytokines from colonic epithelial cells in vitro and was protective against the development of colonic inflammation in vivo. In contrast, although 6-MUDCA mimicked the effects of UDCA on epithelial cytokine release in vitro, it was ineffective in preventing inflammation in the DSS model. In UDCA-treated mice, LCA became the most common colonic bile acid. Finally, LCA treatment more potently inhibited epithelial cytokine release and protected against DSS-induced mucosal inflammation than did UDCA. These studies identify a new role for the primary metabolite of UDCA, LCA, in preventing colonic

Butyrate Inhibits Cancerous HCT116 Colon Cell Proliferation but to a Lesser Extent in Noncancerous NCM460 Colon Cells.

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Zeng, Huawei; Taussig, David P; Cheng, Wen-Hsing; Johnson, LuAnn K; Hakkak, Reza

2017-01-01

Butyrate, an intestinal microbiota metabolite of dietary fiber, exhibits chemoprevention effects on colon cancer development. However, the mechanistic action of butyrate remains to be determined. We hypothesize that butyrate inhibits cancerous cell proliferation but to a lesser extent in noncancerous cells through regulating apoptosis and cellular-signaling pathways. We tested this hypothesis by exposing cancerous HCT116 or non-cancerous NCM460 colon cells to physiologically relevant doses of butyrate. Cellular responses to butyrate were characterized by Western analysis, fluorescent microscopy, acetylation, and DNA fragmentation analyses. Butyrate inhibited cell proliferation, and led to an induction of apoptosis, genomic DNA fragmentation in HCT116 cells, but to a lesser extent in NCM460 cells. Although butyrate increased H3 histone deacetylation and p21 tumor suppressor expression in both cell types, p21 protein level was greater with intense expression around the nuclei in HCT116 cells when compared with that in NCM460 cells. Furthermore, butyrate treatment increased the phosphorylation of extracellular-regulated kinase 1/2 (p-ERK1/2), a survival signal, in NCM460 cells while it decreased p-ERK1/2 in HCT116 cells. Taken together, the activation of survival signaling in NCM460 cells and apoptotic potential in HCT116 cells may confer the increased sensitivity of cancerous colon cells to butyrate in comparison with noncancerous colon cells.

The podoplanin-CLEC-2 axis inhibits inflammation in sepsis.

Science.gov (United States)

Rayes, Julie; Lax, Siân; Wichaiyo, Surasak; Watson, Stephanie K; Di, Ying; Lombard, Stephanie; Grygielska, Beata; Smith, Stuart W; Skordilis, Kassiani; Watson, Steve P

2017-12-21

Platelets play a critical role in vascular inflammation through the podoplanin and collagen/fibrin receptors, C-type-lectin-like-2 (CLEC-2) and glycoprotein VI (GPVI), respectively. Both receptors regulate endothelial permeability and prevent peri-vascular bleeding in inflammation. Here we show that platelet-specific deletion of CLEC-2 but not GPVI leads to enhanced systemic inflammation and accelerated organ injury in two mouse models of sepsis-intra-peritoneal lipopolysaccharide and cecal ligation and puncture. CLEC-2 deficiency is associated with reduced numbers of podoplanin-expressing macrophages despite increased cytokine and chemokine levels in the infected peritoneum. Pharmacological inhibition of the interaction between CLEC-2 and podoplanin regulates immune cell infiltration and the inflammatory reaction during sepsis, suggesting that activation of podoplanin underlies the anti-inflammatory action of platelet CLEC-2. We suggest podoplanin-CLEC-2 as a novel anti-inflammatory axis regulating immune cell recruitment and activation in sepsis.

Estrogen inhibits chloride secretion caused by cholera and Escherichia coli enterotoxins in female rat distal colon.

OpenAIRE

Alzamora, Rodrigo; O'Mahony, Fiona; Harvey, Brian J

2011-01-01

Excessive Cl(-) secretion is the driving force for secretory diarrhea. 17β-Estradiol has been shown to inhibit Cl(-) secretion in rat distal colon through a nongenomic pathway. We examined whether 17β-estradiol inhibits Cl(-) secretion in an animal model of secretory diarrhea and the downstream effectors involved. The effect of 17β-estradiol on cholera toxin and heat-stable enterotoxin induced Cl(-) secretion in rat colonic mucosal sheets was studied by current-voltage clamping. Selective per...

The root barks of Morus alba and the flavonoid constituents inhibit airway inflammation.

Science.gov (United States)

Lim, Hun Jai; Jin, Hong-Guang; Woo, Eun-Rhan; Lee, Sang Kook; Kim, Hyun Pyo

2013-08-26

The root barks of Morus alba have been used in traditional medicine as an anti-inflammatory drug, especially for treating lung inflammatory disorders. To find new alternative agents against airway inflammation and to establish the scientific rationale of the herbal medicine in clinical use, the root barks of Morus alba and its flavonoid constituents were examined for the first time for their pharmacological activity against lung inflammation. For in vivo evaluation, an animal model of lipopolysaccharide-induced airway inflammation in mice was used. An inhibitory action against the production of proinflammatory molecules in lung epithelial cells and lung macrophages was examined. Against lipopolysaccharide-induced airway inflammation, the ethanol extract of the root barks of Morus alba clearly inhibited bronchitis-like symptoms, as determined by TNF-α production, inflammatory cells infiltration and histological observation at 200-400mg/kg/day by oral administration. In addition, Morus alba and their major flavonoid constituents including kuwanone E, kuwanone G and norartocarpanone significantly inhibited IL-6 production in lung epithelial cells (A549) and NO production in lung macrophages (MH-S). Taken together, it is concluded that Morus alba and the major prenylated flavonoid constituents have a potential for new agents to control lung inflammation including bronchitis. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Consumption of lycopene inhibits the growth and progression of colon cancer in a mouse xenograft model

Science.gov (United States)

A previous study indicated that lycopene could significantly inhibit the proliferation of human colon cancer cells in vitro. However, the in vivo anticancer effects of lycopene against colon cancer have not been demonstrated yet. Therefore, this study investigated whether consumption of lycopene cou...

Gemifloxacin, a Fluoroquinolone Antimicrobial Drug, Inhibits Migration and Invasion of Human Colon Cancer Cells

Directory of Open Access Journals (Sweden)

Jung-Yu Kan

2013-01-01

Full Text Available Gemifloxacin (GMF is an orally administered broad-spectrum fluoroquinolone antimicrobial agent used to treat acute bacterial exacerbation of pneumonia and bronchitis. Although fluoroquinolone antibiotics have also been found to have anti-inflammatory and anticancer effects, studies on the effect of GMF on treating colon cancer have been relatively rare. To the best of our knowledge, this is the first report to describe the antimetastasis activities of GMF in colon cancer and the possible mechanisms involved. Results have shown that GMF inhibits the migration and invasion of colon cancer SW620 and LoVo cells and causes epithelial mesenchymal transition (EMT. In addition, GMF suppresses the activation of NF-κB and cell migration and invasion induced by TNF-α and inhibits the TAK1/TAB2 interaction, resulting in decreased IκB phosphorylation and NF-κB nuclear translocation in SW620 cells. Furthermore, Snail, a critical transcriptional factor of EMT, was downregulated after GMF treatment. Overexpression of Snail by cDNA transfection significantly decreases the inhibitory effect of GMF on EMT and cell migration and invasion. In conclusion, GMF may be a novel anticancer agent for the treatment of metastasis in colon cancer.

miR-409-3p sensitizes colon cancer cells to oxaliplatin by inhibiting Beclin-1-mediated autophagy.

Science.gov (United States)

Tan, Shifan; Shi, Huijuan; Ba, Mingchen; Lin, Shengqv; Tang, Hongsheng; Zeng, Xiaoqi; Zhang, Xiangliang

2016-04-01

The chemoresistance of colon cancer cells limits the efficacy of chemotherapy. miR-409-3p has been shown to be downregulated in various types of cancer. In the present study, we examined the role of miR-409-3p in colon cancer as well as the effects of miR‑409-3p on the sensitivity of colon cancer cells to oxaliplatin. The expression of miR-409 was significantly downregulated in the human colon cancer cell lines compared with the normal colon epithelial cells. Importantly, the miR-409-3p expression levels were lower in human colon cancer patient samples than in normal colon tissues. Moreover, we observed a negative correlation between the miR‑409-3p levels and resistance to oxaliplatin: the oxaliplatin-resistant colon cancer cells exhibited significantly downregulated miR‑409-3p levels, but higher autophagic activity than the oxaliplatin-sensitive cells. Using bioinformatics analysis, we predicted that miR‑409-3p miRNA binds to the key autophagy gene encoding Beclin-1. Our findings indicated that the overexpression of miR‑409-3p inhibited Beclin-1 expression and autophagic activity by binding to the 3'-untranslated region of Beclin-1 mRNA. In addition, the overexpression of miR‑409-3p enhanced the chemosensitivity of the oxaliplatin-sensitive and oxaliplatin-resistant colon cancer cells. The restoration of Beclin-1 abrogated these effects of miR‑409-3p. In a xenograft model using nude mice, we examined the effects of miR‑409-3p on tumor growth during chemotherapy. miR‑409-3p overexpression sensitized the tumor to chemotherapy, while inhibiting chemotherapy-induced autophagy in a manner dependent on Beclin-1. The findings of our study suggest that miR-409-3p is capable of enhancing the chemosensitivity of colon cancer cells by inhibiting Beclin-1-mediated autophagy.

PGE2-induced colon cancer growth is mediated by mTORC1

International Nuclear Information System (INIS)

Dufour, Marc; Faes, Seraina; Dormond-Meuwly, Anne; Demartines, Nicolas; Dormond, Olivier

2014-01-01

Highlights: • PGE 2 activates mTORC1 in colon cancer cells. • Inhibition of mTORC1 blocks PGE 2 induced colon cancer cell growth. • mTORC1 is a signaling intermediary in PGE 2 induced colon cancer cell responses. - Abstract: The inflammatory prostaglandin E 2 (PGE 2 ) cytokine plays a key role in the development of colon cancer. Several studies have shown that PGE 2 directly induces the growth of colon cancer cells and furthermore promotes tumor angiogenesis by increasing the production of the vascular endothelial growth factor (VEGF). The signaling intermediaries implicated in these processes have however not been fully characterized. In this report, we show that the mechanistic target of rapamycin complex 1 (mTORC1) plays an important role in PGE 2 -induced colon cancer cell responses. Indeed, stimulation of LS174T cells with PGE 2 increased mTORC1 activity as observed by the augmentation of S6 ribosomal protein phosphorylation, a downstream effector of mTORC1. The PGE 2 EP 4 receptor was responsible for transducing the signal to mTORC1. Moreover, PGE 2 increased colon cancer cell proliferation as well as the growth of colon cancer cell colonies grown in matrigel and blocking mTORC1 by rapamycin or ATP-competitive inhibitors of mTOR abrogated these effects. Similarly, the inhibition of mTORC1 by downregulation of its component raptor using RNA interference blocked PGE 2 -induced LS174T cell growth. Finally, stimulation of LS174T cells with PGE 2 increased VEGF production which was also prevented by mTORC1 inhibition. Taken together, these results show that mTORC1 is an important signaling intermediary in PGE 2 mediated colon cancer cell growth and VEGF production. They further support a role for mTORC1 in inflammation induced tumor growth

microRNA-365, down-regulated in colon cancer, inhibits cell cycle progression and promotes apoptosis of colon cancer cells by probably targeting Cyclin D1 and Bcl-2.

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Nie, Jing; Liu, Lin; Zheng, Wei; Chen, Lin; Wu, Xin; Xu, Yingxin; Du, Xiaohui; Han, Weidong

2012-01-01

Deregulated microRNAs participate in carcinogenesis and cancer progression, but their roles in cancer development remain unclear. In this study, miR-365 expression was found to be downregulated in human colon cancer tissues as compared with that in matched non-neoplastic mucosa tissues, and its downregulation was correlated with cancer progression and poor survival in colon cancer patients. Functional studies revealed that restoration of miR-365 expression inhibited cell cycle progression, promoted 5-fluorouracil-induced apoptosis and repressed tumorigenicity in colon cancer cell lines. Furthermore, bioinformatic prediction and experimental validation were used to identify miR-365 target genes and indicated that the antitumor effects of miR-365 were probably mediated by its targeting and repression of Cyclin D1 and Bcl-2 expression, thus inhibiting cell cycle progression and promoting apoptosis. These results suggest that downregulation of miR-365 in colon cancer may have potential applications in prognosis prediction and gene therapy in colon cancer patients.

Oestrogen inhibits human colonic motility by a non-genomic cell membrane receptor-dependent mechanism.

LENUS (Irish Health Repository)

Hogan, A M

2012-02-01

BACKGROUND: Classical effects of oestrogen involve activation of target genes after binding nuclear receptors. Oestrogenic effects too rapid for DNA transcription (non-genomic) are known to occur. The effect of oestrogen on colonic motility is unknown despite the prevalence of gastrointestinal symptoms in pregnant and premenopausal women. METHODS: Histologically normal colon was obtained from proximal resection margins of colorectal carcinoma specimens. Circular smooth muscle strips were microdissected and suspended in organ baths under 1 g of tension. After equilibration, they were exposed to 17beta-oestradiol (n = 8) or bovine serum albumin (BSA)-conjugated 17beta-oestradiol (n = 8). Fulvestrant, an oestrogen receptor antagonist, was added to some baths (n = 8). Other strips were exposed to calphostin C or cycloheximide. Carbachol was added in increasing concentrations and contractile activity was recorded isometrically. RESULTS: Oestrogen inhibited colonic contractility (mean difference 19.7 per cent; n = 8, P < 0.001). In keeping with non-genomic, rapid-onset steroid action, the effect was apparent within minutes and reversible. It was observed with both 17beta-oestradiol and BSA-conjugated oestrogen, and was not altered by cycloheximide. Effects were inhibited by fulvestrant, suggesting receptor mediation. CONCLUSION: Oestrogen decreases contractility in human colonic smooth muscle by a non-genomic mechanism involving cell membrane coupling.

Activation of NF-κB: bridging the gap between inflammation and cancer in colitis-mediated colon carcinogenesis.

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Setia, Shruti; Nehru, Bimla; Sanyal, Sankar Nath

2014-02-01

Several studies have shown the anti-neoplastic effects of non-steroidal anti-inflammatory drugs (NSAIDs) on 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis, but how these drugs act in case of inflammation-augmented tumorigenesis is still not clear. The present study therefore designs an animal model of colitis-associated colon cancer where 3% Dextran sufate sodium (DSS) is used to develop ulcerative colitis and DMH treatment leads to colon carcinogenesis as early as in six weeks. Clinical symptoms for ulcerative colitis were studied using Disease Activity Index (DAI) while myeloperoxidase assay marked the neutrophil infiltration in DSS and DMH treated groups. The present results indicated the upregulation of the activity of inflammatory marker enzyme, cyclooxygenase-2 (cox-2) and pro-inflammatory cytokines such as TNF-α, IL-1β, IL-4 and IFN-γ with the treatment of DSS as well as DMH. The presence of cytokines in the inflammatory milieu might lead to the transformation of cytoplasmic inactive NF-κB (Nuclear Factor κB) to its active nuclear form, thereby leading to tumorigenesis. The administration of celecoxib along with DSS and DMH, revealed its chemopreventive efficacy in colitis as well as colon cancer. The effect of different doses of DMH on mouse colon was also investigated to obtain a minimum dose of DMH which can induce visible lesions in mice colons at a high incidence. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Methyl Protodioscin from the Roots of Asparagus cochinchinensis Attenuates Airway Inflammation by Inhibiting Cytokine Production

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Ju Hee Lee

2015-01-01

Full Text Available The present study was designed to find pharmacologically active compound against airway inflammation from the roots of Asparagus cochinchinensis. The 70% ethanol extract of the roots of A. cochinchinensis (ACE was found to inhibit IL-6 production from IL-1β-treated lung epithelial cells (A549 and the major constituent, methyl protodioscin (MP, also strongly inhibited the production of IL-6, IL-8, and tumor necrosis factor- (TNF- α from A549 cells at 10–100 μM. This downregulating effect of proinflammatory cytokine production was found to be mediated, at least in part, via inhibition of c-Jun N-terminal kinase (JNK and c-Jun activation pathway. When examined on an in vivo model of airway inflammation in mice, lipopolysaccharide- (LPS- induced acute lung injury, ACE, and MP significantly inhibited cell infiltration in the bronchoalveolar lavage fluid by the oral treatment at doses of 100–400 mg/kg and 30–60 mg/kg, respectively. MP also inhibited the production of proinflammatory cytokines such as IL-6, TNF-α, and IL-1β in lung tissue. All of these findings provide scientific evidence supporting the role of A. cochinchinensis as a herbal remedy in treating airway inflammation and also suggest a therapeutic value of MP on airway inflammatory disorders.

Diets That Promote Colon Inflammation Associate With Risk of Colorectal Carcinomas That Contain Fusobacterium nucleatum.

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Liu, Li; Tabung, Fred K; Zhang, Xuehong; Nowak, Jonathan A; Qian, Zhi Rong; Hamada, Tsuyoshi; Nevo, Daniel; Bullman, Susan; Mima, Kosuke; Kosumi, Keisuke; da Silva, Annacarolina; Song, Mingyang; Cao, Yin; Twombly, Tyler S; Shi, Yan; Liu, Hongli; Gu, Mancang; Koh, Hideo; Li, Wanwan; Du, Chunxia; Chen, Yang; Li, Chenxi; Li, Wenbin; Mehta, Raaj S; Wu, Kana; Wang, Molin; Kostic, Aleksander D; Giannakis, Marios; Garrett, Wendy S; Hutthenhower, Curtis; Chan, Andrew T; Fuchs, Charles S; Nishihara, Reiko; Ogino, Shuji; Giovannucci, Edward L

2018-04-24

Specific nutritional components are likely to induce intestinal inflammation, which is characterized by increased levels of interleukin 6 (IL6), C-reactive protein (CRP), and TNF receptor superfamily member 1B (TNFRSF1B) in the circulation and promotes colorectal carcinogenesis. The inflammatory effects of a diet can be estimated based on empirical dietary inflammatory pattern (EDIP) score, calculated based on intake of 18 foods associated with plasma levels of IL6, CRP, and TNFRSF1B. An inflammatory environment in the colon (based on increased levels of IL6, CRP, and TNFRSF1B in peripheral blood) contributes to impairment of the mucosal barrier and altered immune cell responses, affecting the composition of the intestinal microbiota. Colonization by Fusobacterium nucleatum has been associated with presence and features of colorectal adenocarcinoma. We investigated the association between diets that promote inflammation (based on EDIP score) and colorectal cancer subtypes classified by level of F nucleatum in the tumor microenvironment. We calculated EDIP scores based on answers to questionnaires collected from participants in the Nurses' Health Study (through June 1, 2012) and the Health Professionals Follow-up Study (through January 31, 2012). Participants in both cohorts reported diagnoses of rectal or colon cancer in biennial questionnaires; deaths from unreported colorectal cancer cases were identified through the National Death Index and next of kin. Colorectal tumor tissues were collected from hospitals where the patients underwent tumor resection and F nucleatum DNA was quantified by a PCR assay. We used multivariable duplication-method Cox proportional hazard regression to assess the associations of EDIP scores with risks of colorectal cancer subclassified by F nucleatum status. During 28 years of follow up of 124,433 participants, we documented 951 incident cases of colorectal carcinoma with tissue F nucleatum data. Higher EDIP scores associated with

GSK-3β Inhibition Attenuates CLP-Induced Liver Injury by Reducing Inflammation and Hepatic Cell Apoptosis

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Hui Zhang

2014-01-01

Full Text Available Liver dysfunction has been known to occur frequently in cases of sepsis. Excessive inflammation and apoptosis are pathological features of acute liver failure. Recent studies suggest that activation of glycogen synthase kinase- (GSK- 3β is involved in inflammation and apoptosis. We aimed to investigate the protective effects of GSK-3β inhibition on polymicrobial sepsis-induced liver injury and to explore the possible mechanisms. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP, and SB216763 was used to inhibit GSK-3β in C57BL/6 mice. GSK-3β was activated following CLP. Administration of SB216763 decreased mortality, ameliorated liver injury, and reduced hepatic apoptosis. The inhibition of GSK-3β also reduced leukocyte infiltration and hepatic inflammatory cytokine expression and release. Moreover, GSK-3β inhibition suppressed the transcriptional activity of nuclear factor-kappa B (NF-κB but enhanced the transcriptional activity of cAMP response element binding protein (CREB in the liver. In in vitro studies, GSK-3β inhibition reduced inflammatory cytokine production via modulation of NF-κB and CREB signaling pathways in lipopolysaccharide-stimulated macrophages. In conclusion, these findings suggest that GSK-3β blockade protects against CLP-induced liver via inhibition of inflammation by modulating NF-κB and CREB activity and suppression of hepatic apoptosis.

Manganese (II) induces chemical hypoxia by inhibiting HIF-prolyl hydroxylase: Implication in manganese-induced pulmonary inflammation

International Nuclear Information System (INIS)

Han, Jeongoh; Lee, Jong-Suk; Choi, Daekyu; Lee, Youna; Hong, Sungchae; Choi, Jungyun; Han, Songyi; Ko, Yujin; Kim, Jung-Ae; Mi Kim, Young; Jung, Yunjin

2009-01-01

Manganese (II), a transition metal, causes pulmonary inflammation upon environmental or occupational inhalation in excess. We investigated a potential molecular mechanism underlying manganese-induced pulmonary inflammation. Manganese (II) delayed HIF-1α protein disappearance, which occurred by inhibiting HIF-prolyl hydroxylase (HPH), the key enzyme for HIF-1α hydroxylation and subsequent von Hippel-Lindau(VHL)-dependent HIF-1α degradation. HPH inhibition by manganese (II) was neutralized significantly by elevated dose of iron. Consistent with this, the induction of cellular HIF-1α protein by manganese (II) was abolished by pretreatment with iron. Manganese (II) induced the HIF-1 target gene involved in pulmonary inflammation, vascular endothelial growth factor (VEGF), in lung carcinoma cell lines. The induction of VEGF was dependent on HIF-1. Manganese-induced VEGF promoted tube formation of HUVEC. Taken together, these data suggest that HIF-1 may be a potential mediator of manganese-induced pulmonary inflammation

Alkannin Inhibited Hepatic Inflammation in Diabetic Db/Db Mice

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Wenhua Xue

2018-03-01

Full Text Available Background/Aims: The current study was designed to investigate the protective role of alkannin (ALK on liver injury in diabetic C57BL/KsJ-db/db mice and explore its potential mechanisms. Methods: An oral glucose tolerance test (OGTT was performed. The levels of insulin, alanine aminotransferase (ALT, aspartate aminotransaminase (AST, total cholesterol (TC and triglyceride (TG were determined by commercial kits. The pro-inflammatory cytokines interleukin (IL-1β, IL-6 and tumour necrosis factor (TNF-α were determined by ELISA. The levels of the ROCK/NF-κB pathway were determined by Western blotting. Results: The contents of pro-inflammatory cytokines interleukin (IL-1β, IL-6 and tumour necrosis factor (TNF-α were inhibited by ALK, metformin or fasudil in diabetic db/db mice. Further, Western blotting analysis showed that the expression of Rho, ROCK1, ROCK2, p-NF-κBp65, and p-IκBα was significantly reversed by ALK treatment. In human hepatic HepG2 cells, the hepatoprotective effects of ALK were further characterized. With response to palmitic acid-challenge, increased amounts of insulin, ALT, AST, TG, and TC were observed, whereas ALK pretreatment significantly inhibited their leakage in HepG2 cells without appreciable cytotoxic effects. The inflammation condition was recovered with ALK treatment as shown by changes of IL-1β, IL-6 and TNF-α. Further, Western blotting analysis also suggested that ALK improves hepatic inflammation in a Rho-kinase pathway. Conclusion: The present study successfully investigated the role of Rho-kinase signalling in diabetic liver injury. ALK exhibited hepatoprotective effects in diabetic db/db mice, and it might act through improving hepatic inflammation through the Rho-kinase pathway.

Hypoxia Enhances Immunosuppression by Inhibiting CD4+ Effector T Cell Function and Promoting Treg Activity

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Astrid M. Westendorf

2017-03-01

Full Text Available Background/Aims: Hypoxia occurs in many pathological conditions, including inflammation and cancer. Within this context, hypoxia was shown to inhibit but also to promote T cell responses. Due to this controversial function, we aimed to explore whether an insufficient anti-tumour response during colitis-associated colon cancer could be ascribed to a hypoxic microenvironment. Methods: Colitis-associated colon cancer was induced in wildtype mice, and hypoxia as well as T cell immunity were analysed in the colonic tumour tissues. In addition, CD4+ effector T cells and regulatory T cells were cultured under normoxic and hypoxic conditions and examined regarding their phenotype and function. Results: We observed severe hypoxia in the colon of mice suffering from colitis-associated colon cancer that was accompanied by a reduced differentiation of CD4+ effector T cells and an enhanced number and suppressive activity of regulatory T cells. Complementary ex vivo and in vitro studies revealed that T cell stimulation under hypoxic conditions inhibited the differentiation, proliferation and IFN-γ production of TH1 cells and enhanced the suppressive capacity of regulatory T cells. Moreover, we identified an active role for HIF-1α in the modulation of CD4+ T cell functions under hypoxic conditions. Conclusion: Our data indicate that oxygen availability can function as a local modulator of CD4+ T cell responses and thus influences tumour immune surveillance in inflammation-associated colon cancer.

Cooked navy and black bean diets improve biomarkers of colon health and reduce inflammation during colitis.

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Zhang, Claire; Monk, Jennifer M; Lu, Jenifer T; Zarepoor, Leila; Wu, Wendy; Liu, Ronghua; Pauls, K Peter; Wood, Geoffrey A; Robinson, Lindsay; Tsao, Rong; Power, Krista A

2014-05-01

Common beans contain non-digestible fermentable components (SCFA precursors) and phenolic compounds (phenolic acids, flavonoids and anthocyanins) with demonstrated antioxidant and anti-inflammatory potential. The objective of the present study was to assess the in vivo effect of cooked whole-bean flours, with differing phenolic compound levels and profiles, in a mouse model of acute colitis. C57BL/6 mice were fed a 20 % navy bean or black bean flour-containing diet or an isoenergetic basal diet (BD) for 2 weeks before the induction of experimental colitis via 7 d dextran sodium sulphate (DSS, 2 % (w/v) in the drinking-water) exposure. Compared with the BD, both bean diets increased caecal SCFA and faecal phenolic compound concentrations (Pdiets reduced mRNA expression of colonic inflammatory cytokines (IL-6, IL-9, IFN-γ and IL-17A) and increased anti-inflammatory IL-10 (Pdiets enhanced DSS-induced colonic damage as indicated by an increased histological injury score and apoptosis (cleaved caspase-3 and FasL mRNA expression) (Pdiets exerted both beneficial and adverse effects during experimental colitis by reducing inflammatory biomarkers both locally and systemically while aggravating colonic mucosal damage. Further research is required to understand the mechanisms through which beans exert their effects on colonic inflammation and the impact on colitis severity in human subjects.

Effect of vitamin C on azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis-associated early colon cancer in mice.

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Jeon, Hee-Jin; Yeom, Yiseul; Kim, Yoo-Sun; Kim, Eunju; Shin, Jae-Ho; Seok, Pu Reum; Woo, Moon Jea; Kim, Yuri

2018-04-01

The objective of this study was to investigate the effects of vitamin C on inflammation, tumor development, and dysbiosis of intestinal microbiota in an azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced inflammation-associated early colon cancer mouse model. Male BALB/c mice were injected intraperitoneally with AOM [10 mg/kg body weight (b.w)] and given two 7-d cycles of 2% DSS drinking water with a 14 d inter-cycle interval. Vitamin C (60 mg/kg b.w. and 120 mg/kg b.w.) was supplemented by gavage for 5 weeks starting 2 d after the AOM injection. The vitamin C treatment suppressed inflammatory morbidity, as reflected by disease activity index (DAI) in recovery phase and inhibited shortening of the colon, and reduced histological damage. In addition, vitamin C supplementation suppressed mRNA levels of pro-inflammatory mediators and cytokines, including cyclooxygenase-2, microsomal prostaglandin E synthase-2, tumor necrosis factor-α, Interleukin (IL)-1β , and IL-6 , and reduced expression of the proliferation marker, proliferating cell nuclear antigen, compared to observations of AOM/DSS animals. Although the microbial composition did not differ significantly between the groups, administration of vitamin C improved the level of inflammation-related Lactococcus and JQ084893 to control levels. Vitamin C treatment provided moderate suppression of inflammation, proliferation, and certain inflammation-related dysbiosis in a murine model of colitis associated-early colon cancer. These findings support that vitamin C supplementation can benefit colonic health. Long-term clinical studies with various doses of vitamin C are warranted.

Targeted inhibition of the phosphoinositide 3-kinase impairs cell proliferation, survival, and invasion in colon cancer.

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Yang, Fei; Gao, Jun-Yi; Chen, Hua; Du, Zhen-Hua; Zhang, Xue-Qun; Gao, Wei

2017-01-01

Colon cancer is the third most common cancer in the world, and its metastasis and drug resistance are challenging for its effective treatment. The PI3K/Akt/mTOR pathway plays a crucial role in the pathogenesis of colon cancer. The aim of this study was to investigate the targeting of PI3K in colon cancer cells HT-29 and HCT-116 in vitro. In HT-29 and HCT-116 cells, BEZ235, a dual inhibitor of PI3K/mTOR, and shRNAtarget to PI3KCA were used to inhibit PI3K/Akt/mTOR pathway. The inhibition efficiency of PI3K/Akt/mTOR pathway was detected by RT-PCR and Western blot. Cell proliferation, migration, invasion, and apoptosis were evaluated by Cell Counting Kit-8, Transwell, and flow cytometry assays. The expression of apoptosis-related proteins (cleavage caspase 3, Bcl-2, Bax, and Bim) were also detected. We found that in HT-29 and HCT-116 cells, the treatment of BEZ235 (1 μM) and PI3KCA knockdown inhibited the activation of PI3K/Akt/mTOR pathway and significantly suppressed cell proliferation, migration, and invasion of HT-29 and HCT-116 cells. In addition, we confirmed that knockdown of BEZ235 and PI3KCA induced cell apoptosis through the upregulated levels of cleavage caspase 3 and Bax and downregulated expression of Bcl-2 and Bim. Our results indicated that targeted inhibition of the PI3K/Akt/mTOR pathway impaired cell proliferation, survival, and invasion in human colon cancer.

The flavonoid compound apigenin prevents colonic inflammation and motor dysfunctions associated with high fat diet-induced obesity.

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Gentile, Daniela; Fornai, Matteo; Colucci, Rocchina; Pellegrini, Carolina; Tirotta, Erika; Benvenuti, Laura; Segnani, Cristina; Ippolito, Chiara; Duranti, Emiliano; Virdis, Agostino; Carpi, Sara; Nieri, Paola; Németh, Zoltán H; Pistelli, Laura; Bernardini, Nunzia; Blandizzi, Corrado; Antonioli, Luca

2018-01-01

, counteracts enteric inflammation and normalizes colonic dysmotility associated with obesity.

Lactulose mediates suppression of dextran sodium sulfate-induced colon inflammation by increasing hydrogen production.

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Chen, Xiao; Zhai, Xiao; Shi, Jiazi; Liu, Wen Wu; Tao, Hengyi; Sun, Xuejun; Kang, Zhimin

2013-06-01

Molecular hydrogen (H2) is a potent antioxidant and able to protect organs from oxidative stress injuries. Orally administered lactulose, a potent H2 inducer, is digested by colon microflora and significantly increases H2 production, indicating its potential anti-inflammatory action. To evaluate the anti-inflammatory effects of lactulose on dextran sodium sulfate (DSS)-induced colitis in mice. Mice were randomly assigned into seven groups, receiving regular distilled water, H2-rich saline (peritoneal injection), DSS, oral lactulose (0.1, 0.15, 0.2 ml/10 g, respectively), and lactulose (0.2 ml/10 g) + oral antibiotics. The mouse model of human ulcerative colitis was established by supplying mice with water containing DSS. The H2 breath test was used to determine the exhaled H2 concentration. Body weight, colitis score, colon length, pathological features and tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), maleic dialdehyde (MDA) and marrow peroxidase (MPO) levels in colon lesions were evaluated. After 7 days, DSS-induced loss of body weight, increase of colitis score, shortening of colon length, pathological changes and elevated levels of TNF-α, IL-1β, MDA, and MPO in colon lesions, were significantly suppressed by oral lactulose administration and intraperitoneally injected H2-rich saline. Ingestion of antibiotics significantly compromised the anti-inflammatory effects of lactulose. The H2 breath test showed that lactulose administration significantly induced hydrogen production and that antibiotics administration could inhibit H2 production. Lactulose can prevent the development of DSS-induced colitis and alleviate oxidative stress in the colon, as measured by MDA and MPO, probably by increasing endogenous H2 production.

Fcγ receptor-mediated inflammation inhibits axon regeneration.

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Gang Zhang

Full Text Available Anti-glycan/ganglioside antibodies are the most common immune effectors found in patients with Guillain-Barré Syndrome, which is a peripheral autoimmune neuropathy. We previously reported that disease-relevant anti-glycan autoantibodies inhibited axon regeneration, which echo the clinical association of these antibodies and poor recovery in Guillain-Barré Syndrome. However, the specific molecular and cellular elements involved in this antibody-mediated inhibition of axon regeneration are not previously defined. This study examined the role of Fcγ receptors and macrophages in the antibody-mediated inhibition of axon regeneration. A well characterized antibody passive transfer sciatic nerve crush and transplant models were used to study the anti-ganglioside antibody-mediated inhibition of axon regeneration in wild type and various mutant and transgenic mice with altered expression of specific Fcγ receptors and macrophage/microglia populations. Outcome measures included behavior, electrophysiology, morphometry, immunocytochemistry, quantitative real-time PCR, and western blotting. We demonstrate that the presence of autoantibodies, directed against neuronal/axonal cell surface gangliosides, in the injured mammalian peripheral nerves switch the proregenerative inflammatory environment to growth inhibitory milieu by engaging specific activating Fcγ receptors on recruited monocyte-derived macrophages to cause severe inhibition of axon regeneration. Our data demonstrate that the antibody orchestrated Fcγ receptor-mediated switch in inflammation is one mechanism underlying inhibition of axon regeneration. These findings have clinical implications for nerve repair and recovery in antibody-mediated immune neuropathies. Our results add to the complexity of axon regeneration in injured peripheral and central nervous systems as adverse effects of B cells and autoantibodies on neural injury and repair are increasingly recognized.

CysLT(1)R antagonists inhibit tumor growth in a xenograft model of colon cancer.

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Savari, Sayeh; Liu, Minghui; Zhang, Yuan; Sime, Wondossen; Sjölander, Anita

2013-01-01

The expression of the inflammatory G-protein coupled receptor CysLT1R has been shown to be upregulated in colon cancer patients and associated with poor prognosis. The present study investigated the correlation between CysLT1R and colon cancer development in vivo using CysLT1R antagonists (ZM198,615 or Montelukast) and the nude mouse xenograft model. Two drug administration regimens were established. The first regimen was established to investigate the importance of CysLT1R in tumor initiation. Nude mice were inoculated with 50 µM CysLT1R antagonist-pretreated HCT-116 colon cancer cells and received continued treatment (5 mg/kg/day, intraperitoneally). The second regimen aimed to address the role of CysLT1R in tumor progression. Nude mice were inoculated with non-pretreated HCT-116 cells and did not receive CysLT1R antagonist treatment until recordable tumor appearance. Both regimens resulted in significantly reduced tumor size, attributed to changes in proliferation and apoptosis as determined by reduced Ki-67 levels and increased levels of p21(WAF/Cip1) (Pcolon cancer cell line HCT-116 and CysLT1R antagonists. In addition to significant reductions in cell proliferation, adhesion and colony formation, we observed induction of cell cycle arrest and apoptosis in a dose-dependent manner. The ability of Montelukast to inhibit growth of human colon cancer xenograft was further validated by using two additional colon cancer cell lines, SW-480 and HT-29. Our results demonstrate that CysLT1R antagonists inhibit growth of colon cancer xenografts primarily by reducing proliferation and inducing apoptosis of the tumor cells.

The kampo medicine Daikenchuto inhibits peritoneal fibrosis in mice.

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Kitamura, Mineaki; Nishino, Tomoya; Obata, Yoko; Oka, Satoru; Abe, Shinichi; Muta, Kumiko; Ozono, Yoshiyuki; Koji, Takehiko; Kohno, Shigeru

2015-01-01

Long-term peritoneal dialysis therapy causes inflammation and histological changes in the peritoneal membrane. Inflammation generally activates fibroblasts and results in fibroblast-myofibroblast differentiation. Heat-shock protein 47 (HSP 47), a collagen-specific molecular chaperone, is localized in myofibroblasts and is involved in the progression of peritoneal fibrosis. Daikenchuto (DKT), a Kampo medicine, is used to prevent postoperative colon adhesion. It inhibits inflammation and HSP 47 expression in the gastrointestinal tract. We examined the effect of DKT on chlorhexidine gluconate (CG)-induced peritoneal fibrosis in mice injected with 0.1% CG dissolved in 15% ethanol. DKT was dissolved in the drinking water. Histological changes were assessed using Masson trichrome staining. Cells expressing α-smooth muscle actin (α-SMA), HSP 47, phospho-Smad 2/3, F4/80, and monocyte chemotactic protein-1 were examined immunohistochemically. Compared with the control group, the peritoneal tissues of the CG group were markedly thickened, and the number of cells expressing α-SMA, HSP 47, phospho-Smad 2/3, F4/80, and monocyte chemotactic protein-1 was significantly increased. However, these changes were inhibited in the DKT-treated group. These results indicate that DKT can prevent peritoneal fibrosis by inhibiting inflammation and HSP 47 expression.

Pectin-based colon-specific drug delivery

OpenAIRE

Shailendra Shukla; Deepak Jain; Kavita Verma; Shiddarth Verma

2011-01-01

Colon-specific drug delivery have a great importance in the delivery of drugs for the treatment of local colonic, as well as systemic diseases like Crohn′s disease, ulcerative colitis, colorectal cancer, amoebiasis, asthma, arthritis and inflammation which can be achieved by targeted delivery of drug to colon. Specific systemic absorption in the colon gave interesting possibilities for the delivery of protein and peptides. It contains relatively less proteolytic enzyme activities in the colon...

The plant extract Isatis tinctoria L. extract (ITE) inhibits allergen-induced airway inflammation and hyperreactivity in mice.

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Brattström, A; Schapowal, A; Kamal, M A; Maillet, I; Ryffel, B; Moser, R

2010-07-01

The herbal Isatis tinctoria extract (ITE) inhibits the inducible isoform of cyclooxygenase (COX-2) as well as lipoxygenase (5-LOX) and therefore possesses anti-inflammatory properties. The extract might also be useful in allergic airway diseases which are characterized by chronic inflammation. ITE obtained from leaves by supercritical carbon dioxide extraction was investigated in ovalbumin (OVA) immunised BALB/c mice given intranasally together with antigen challenge in the murine model of allergic airway disease (asthma) with the analysis of the inflammatory and immune parameters in the lung. ITE given with the antigen challenge inhibited in a dose related manner the allergic response. ITE diminished airway hyperresponsiveness (AHR) and eosinophil recruitment into the bronchoalveolar lavage (BAL) fluid upon allergen challenge, but had no effect in the saline control mice. Eosinophil recruitment was further assessed in the lung by eosinophil peroxidase (EPO) activity at a dose of 30 microg ITE per mouse. Microscopic investigations revealed less inflammation, eosinophil recruitment and mucus hyperproduction in the lung in a dose related manner. Diminution of AHR and inflammation was associated with reduced IL-4, IL-5, and RANTES production in the BAL fluid at the 30 microg ITE dose, while OVA specific IgE and eotaxin serum levels remained unchanged. ITE, which has been reported inhibiting COX-2 and 5-LOX, reduced allergic airway inflammation and AHR by inhibiting the production of the Th2 cytokines IL-4 and IL-5, and RANTES. (c) 2009 Elsevier GmbH. All rights reserved.

Inhibition of phospholipaseD2 increases hypoxia-induced human colon cancer cell apoptosis through inactivating of the PI3K/AKT signaling pathway.

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Liu, Maoxi; Fu, Zhongxue; Wu, Xingye; Du, Kunli; Zhang, Shouru; Zeng, Li

2016-05-01

Hypoxia is a common feature of solid tumor, and is a direct stress that triggers apoptosis in many human cell types. As one of solid cancer, hypoxia exists in the whole course of colon cancer occurrence and progression. Our previous studies shown that hypoxia induce high expression of phospholipase D2 (PLD2) and survivin in colon cancer cells. However, the correlation between PLD2 and survivin in hypoxic colon cancer cells remains unknown. In this study, we observed significantly elevated PLD2 and survivin expression levels in colon cancer tissues and cells. This is a positive correlation between of them, and co-expression of PLD2 and survivin has a positive correlation with the clinicpatholic features including tumor size, TNM stage, and lymph node metastasis. We also found that hypoxia induced the activity of PLD increased significant mainly caused by PLD2 in colon cancer cells. However, inhibition the activity of PLD2 induced by hypoxia promotes the apoptosis of human colon cancer cells, as well as decreased the expression of apoptosis markers including survivin and bcl2. Moreover, the pharmacological inhibition of PI3K/AKT supported the hypothesis that promotes the apoptosis of hypoxic colon cancer cells by PLD2 activity inhibition may through inactivation of the PI3K/AKT signaling pathway. Furthermore, interference the PLD2 gene expression leaded to the apoptosis of hypoxic colon cancer cells increased and also decreased the expression level of survivin and bcl2 may through inactivation of PI3K/AKT signaling pathway. These results indicated that PLD2 play antiapoptotic role in colon cancer under hypoxic conditions, inhibition of the activity, or interference of PLD2 gene expression will benefit for the treatment of colon cancer patients.

[Inhibition of glycogen synthase kinase 3b activity regulates Toll-like receptor 4-mediated liver inflammation].

Science.gov (United States)

Ren, Feng; Zhang, Hai-yan; Piao, Zheng-fu; Zheng, Su-jun; Chen, Yu; Chen, De-xi; Duan, Zhong-ping

2012-09-01

To determine the mechanism underlying the therapeutic activities of glycogen synthase kinase 3b (GSK3b) against hepatic ischemia-reperfusion (H-IR) injury by investigating the inhibitive effects of GSK3b on inflammation mediated by Toll-like receptor 4 (TLR4). C57BL/6 male mice were subjected to 90 min of warm liver cephalad lobe ischemia, followed by reperfusion for various lengths of time. The mice were divided into three groups: the H-IR untreated model (control group), and the H-IR inflammation-induced models that received an intraperitoneal injection of purified lipopolysaccharide (LPS) endotoxin alone (inflammation group) or with pretreatment of the SB216763 GSK3b-specific inhibitor (intervention group). To create a parallel isolated cell system for detailed investigations of macrophages, marrow-derived stem cells were isolated from femurs of the H-IR control group of mice and used to derive primary macrophages. The cells were then divided into the same three groups as the whole mouse system: control, LPS-induced inflammation model, and inflammation model with SB216763 intervention. Differential expressions of inflammation-related proteins and genes were detected by Western blotting and real-time quantitative PCR, respectively. The phosphorylation levels of ERK, JNK and p38 MAPK were induced in liver at 1 h after reperfusion, but then steadily decreased and returned to baseline levels by 4 h after reperfusion. In addition, the phosphorylation levels of ERK and JNK were induced in macrophages at 15 min after LPS stimulation, while the phosphorylation level of p38 MAPK was induced at 1 h; SB216763 pretreatment suppressed the LPS-stimulated ERK, JNK and p38 phosphorylation in macrophages. In the mouse model, GSK3b activity was found to promote the gene expression of anti-inflammatory cytokine IL-10 (control: 0.21 ± 0.08, inflammation: 0.83 ± 0.21, intervention: 1.76 ± 0.67; F = 3.16, P = 0.027) but to significantly inhibit the gene expression of pro

Arctigenin, a phenylpropanoid dibenzylbutyrolactone lignan, inhibits type I-IV allergic inflammation and pro-inflammatory enzymes.

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Lee, Ji Yun; Kim, Chang Jong

2010-06-01

We previously reported that arctigenin, a phenylpropanoid dibenzylbutyrolactone lignan isolated from Forsythia koreana, exhibits anti-inflammatory, antioxidant, and analgesic effects in animal models. In addition, arctigenin inhibited eosinophil peroxidase and activated myeloperoxidase in inflamed tissues. In this study, we tested the effects of arctigenin on type I-IV allergic inflammation and pro-inflammatory enzymes in vitro and in vivo. Arctigenin significantly inhibited the heterologous passive cutaneous anaphylaxis induced by ovalbumin in mice at 15 mg/kg, p.o., and compound 48/80-induced histamine release from rat peritoneal mast cells at 10 microM. Arctigenin (15 mg/kg, p.o.) significantly inhibited reversed cutaneous anaphylaxis. Further, arctigenin (15 mg/kg, p.o.) significantly inhibited the Arthus reaction to sheep's red blood cells, decreasing the hemolysis titer, the hemagglutination titer, and the plaque-forming cell number for SRBCs. In addition, arctigenin significantly inhibited delayed type hypersensitivity at 15 mg/kg, p.o. and the formation of rosette-forming cells at 45 mg/kg, p.o. Contact dermatitis induced by picrylchloride and dinitrofluorobenzene was significantly (p arctigenin (0.3 mg/ear). Furthermore, arctigenin dose-dependently inhibited pro-inflammatory enzymes, such as cyclooxygenase-1 and 2, 5-lipoxygenase, phospholipase A2, and phosphodiesterase. Our results show that arctigenin significantly inhibited B- and T-cell mediated allergic inflammation as well as pro-inflammatory enzymes.

Oxytetracycline Inhibits Mucus Secretion and Inflammation in Human Airway Epithelial Cells.

Science.gov (United States)

Shah, Said Ahmad; Ishinaga, Hajime; Takeuchi, Kazuhiko

2017-01-01

Oxytetracycline is a broad-spectrum antibiotic, but its nonantibacterial effects in the human respiratory tract are unknown. In this study, the effects of oxytetracycline on mucus secretion and inflammation were examined by PCR and ELISA in the human airway epithelial cell line NCI-H292. Oxytetracycline (10 μg/mL) significantly inhibited TNF-α-induced MUC5AC gene expression and MUC5AC protein levels in NCI-H292 cells. It also downregulated IL-8 and IL-1β gene expression and IL-1β protein levels. Our findings demonstrated that oxytetracycline suppressed mucus production and inflammation in human respiratory epithelial cells, providing further evidence for the usefulness of oxytetracycline for human airway inflammatory diseases. © 2017 S. Karger AG, Basel.

Inhibition of chlorine-induced pulmonary inflammation and edema by mometasone and budesonide

Energy Technology Data Exchange (ETDEWEB)

Chen, Jing; Mo, Yiqun; Schlueter, Connie F.; Hoyle, Gary W., E-mail: Gary.Hoyle@louisville.edu

2013-10-15

Chlorine gas is a widely used industrial compound that is highly toxic by inhalation and is considered a chemical threat agent. Inhalation of high levels of chlorine results in acute lung injury characterized by pneumonitis, pulmonary edema, and decrements in lung function. Because inflammatory processes can promote damage in the injured lung, anti-inflammatory therapy may be of potential benefit for treating chemical-induced acute lung injury. We previously developed a chlorine inhalation model in which mice develop epithelial injury, neutrophilic inflammation, pulmonary edema, and impaired pulmonary function. This model was used to evaluate nine corticosteroids for the ability to inhibit chlorine-induced neutrophilic inflammation. Two of the most potent corticosteroids in this assay, mometasone and budesonide, were investigated further. Mometasone or budesonide administered intraperitoneally 1 h after chlorine inhalation caused a dose-dependent inhibition of neutrophil influx in lung tissue sections and in the number of neutrophils in lung lavage fluid. Budesonide, but not mometasone, reduced the levels of the neutrophil attractant CXCL1 in lavage fluid 6 h after exposure. Mometasone or budesonide also significantly inhibited pulmonary edema assessed 1 day after chlorine exposure. Chlorine inhalation resulted in airway hyperreactivity to inhaled methacholine, but neither mometasone nor budesonide significantly affected this parameter. The results suggest that mometasone and budesonide may represent potential treatments for chemical-induced lung injury. - Highlights: • Chlorine causes lung injury when inhaled and is considered a chemical threat agent. • Corticosteroids may inhibit lung injury through their anti-inflammatory actions. • Corticosteroids inhibited chlorine-induced pneumonitis and pulmonary edema. • Mometasone and budesonide are potential rescue treatments for chlorine lung injury.

Expression of ICAM-1 in colon epithelial cells

DEFF Research Database (Denmark)

Vainer, Ben; Sørensen, Susanne; Seidelin, Jakob

2003-01-01

Studies have suggested that in ulcerative colitis (UC), intercellular adhesion molecule-1 (ICAM-1) is involved in migration of leukocytes toward the colonic epithelium. A suitable in vitro model of chronic colonic inflammation does not exist, and the role of the epithelium is based on monolayers ...... of cancer cells. Conflicting results exist on epithelial ICAM-1 expression, and the aim of this study was to compare the expression in various models of colonic epithelium.......Studies have suggested that in ulcerative colitis (UC), intercellular adhesion molecule-1 (ICAM-1) is involved in migration of leukocytes toward the colonic epithelium. A suitable in vitro model of chronic colonic inflammation does not exist, and the role of the epithelium is based on monolayers...

PGE{sub 2}-induced colon cancer growth is mediated by mTORC1

Energy Technology Data Exchange (ETDEWEB)

Dufour, Marc, E-mail: Marc.dufour@chuv.ch; Faes, Seraina, E-mail: Seraina.faes@chuv.ch; Dormond-Meuwly, Anne, E-mail: Anne.meuwly-Dormond@chuv.ch; Demartines, Nicolas, E-mail: Demartines@chuv.ch; Dormond, Olivier, E-mail: Olivier.dormond@chuv.ch

2014-09-05

Highlights: • PGE{sub 2} activates mTORC1 in colon cancer cells. • Inhibition of mTORC1 blocks PGE{sub 2} induced colon cancer cell growth. • mTORC1 is a signaling intermediary in PGE{sub 2} induced colon cancer cell responses. - Abstract: The inflammatory prostaglandin E{sub 2} (PGE{sub 2}) cytokine plays a key role in the development of colon cancer. Several studies have shown that PGE{sub 2} directly induces the growth of colon cancer cells and furthermore promotes tumor angiogenesis by increasing the production of the vascular endothelial growth factor (VEGF). The signaling intermediaries implicated in these processes have however not been fully characterized. In this report, we show that the mechanistic target of rapamycin complex 1 (mTORC1) plays an important role in PGE{sub 2}-induced colon cancer cell responses. Indeed, stimulation of LS174T cells with PGE{sub 2} increased mTORC1 activity as observed by the augmentation of S6 ribosomal protein phosphorylation, a downstream effector of mTORC1. The PGE{sub 2} EP{sub 4} receptor was responsible for transducing the signal to mTORC1. Moreover, PGE{sub 2} increased colon cancer cell proliferation as well as the growth of colon cancer cell colonies grown in matrigel and blocking mTORC1 by rapamycin or ATP-competitive inhibitors of mTOR abrogated these effects. Similarly, the inhibition of mTORC1 by downregulation of its component raptor using RNA interference blocked PGE{sub 2}-induced LS174T cell growth. Finally, stimulation of LS174T cells with PGE{sub 2} increased VEGF production which was also prevented by mTORC1 inhibition. Taken together, these results show that mTORC1 is an important signaling intermediary in PGE{sub 2} mediated colon cancer cell growth and VEGF production. They further support a role for mTORC1 in inflammation induced tumor growth.

Targeting tumor multicellular aggregation through IGPR-1 inhibits colon cancer growth and improves chemotherapy.

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Woolf, N; Pearson, B E; Bondzie, P A; Meyer, R D; Lavaei, M; Belkina, A C; Chitalia, V; Rahimi, N

2017-09-18

Adhesion to extracellular matrix (ECM) is crucially important for survival of normal epithelial cells as detachment from ECM triggers specific apoptosis known as anoikis. As tumor cells lose the requirement for anchorage to ECM, they rely on cell-cell adhesion 'multicellular aggregation' for survival. Multicellular aggregation of tumor cells also significantly determines the sensitivity of tumor cells to the cytotoxic effects of chemotherapeutics. In this report, we demonstrate that expression of immunoglobulin containing and proline-rich receptor-1 (IGPR-1) is upregulated in human primary colon cancer. Our study demonstrates that IGPR-1 promotes tumor multicellular aggregation, and interfering with its adhesive function inhibits multicellular aggregation and, increases cell death. IGPR-1 supports colon carcinoma tumor xenograft growth in mouse, and inhibiting its activity by shRNA or blocking antibody inhibits tumor growth. More importantly, IGPR-1 regulates sensitivity of tumor cells to the chemotherapeutic agent, doxorubicin/adriamycin by a mechanism that involves doxorubicin-induced AKT activation and phosphorylation of IGPR-1 at Ser220. Our findings offer novel insight into IGPR-1's role in colorectal tumor growth, tumor chemosensitivity, and as a possible novel anti-cancer target.

Targeted inhibition of the phosphoinositide 3-kinase impairs cell proliferation, survival, and invasion in colon cancer

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Yang F

2017-09-01

Full Text Available Fei Yang,1,* Jun-Yi Gao,2,* Hua Chen,1 Zhen-Hua Du,1 Xue-Qun Zhang,3 Wei Gao4 1Department of Pathology, Jinan Central Hospital Affiliated to Shandong University, Jinan, 2Department of Clinical Medicine, Weifang Medical College, Weifang, 3Graduate School, Taishan Medical University, Xintai, 4Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, Jinan, People’s Republic of China *These authors contributed equally to this work Background: Colon cancer is the third most common cancer in the world, and its metastasis and drug resistance are challenging for its effective treatment. The PI3K/Akt/mTOR pathway plays a crucial role in the pathogenesis of colon cancer. The aim of this study was to investigate the targeting of PI3K in colon cancer cells HT-29 and HCT-116 in vitro. Methods: In HT-29 and HCT-116 cells, BEZ235, a dual inhibitor of PI3K/mTOR, and shRNAtarget to PI3KCA were used to inhibit PI3K/Akt/mTOR pathway. The inhibition efficiency of PI3K/Akt/mTOR pathway was detected by RT-PCR and Western blot. Cell proliferation, migration, invasion, and apoptosis were evaluated by Cell Counting Kit-8, Transwell, and flow cytometry assays. The expression of apoptosis-related proteins (cleavage caspase 3, Bcl-2, Bax, and Bim were also detected. Results: We found that in HT-29 and HCT-116 cells, the treatment of BEZ235 (1 µM and PI3KCA knockdown inhibited the activation of PI3K/Akt/mTOR pathway and significantly suppressed cell proliferation, migration, and invasion of HT-29 and HCT-116 cells. In addition, we confirmed that knockdown of BEZ235 and PI3KCA induced cell apoptosis through the upregulated levels of cleavage caspase 3 and Bax and downregulated expression of Bcl-2 and Bim. Conclusion: Our results indicated that targeted inhibition of the PI3K/Akt/mTOR pathway impaired cell proliferation, survival, and invasion in human colon cancer. Keywords: human colon cancer, PI3K/Akt/mTOR pathway, BEZ235, PI3KCA knockdown

Colonic inflammation accompanies an increase of β-catenin signaling and Lachnospiraceae/Streptococcaceae bacteria in the hind gut of high-fat diet-fed mice.

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Zeng, Huawei; Ishaq, Suzanne L; Zhao, Feng-Qi; Wright, André-Denis G

2016-09-01

Consumption of an obesigenic/high-fat diet (HFD) is associated with a high colon cancer risk and may alter the gut microbiota. To test the hypothesis that long-term high-fat (HF) feeding accelerates inflammatory process and changes gut microbiome composition, C57BL/6 mice were fed HFD (45% energy) or a low-fat (LF) diet (10% energy) for 36 weeks. At the end of the study, body weights in the HF group were 35% greater than those in the LF group. These changes were associated with dramatic increases in body fat composition, inflammatory cell infiltration, inducible nitric oxide synthase protein concentration and cell proliferation marker (Ki67) in ileum and colon. Similarly, β-catenin expression was increased in colon (but not ileum). Consistent with gut inflammation phenotype, we also found that plasma leptin, interleukin 6 and tumor necrosis factor α concentrations were also elevated in mice fed the HFD, indicative of chronic inflammation. Fecal DNA was extracted and the V1-V3 hypervariable region of the microbial 16S rRNA gene was amplified using primers suitable for 454 pyrosequencing. Compared to the LF group, the HF group had high proportions of bacteria from the family Lachnospiraceae/Streptococcaceae, which is known to be involved in the development of metabolic disorders, diabetes and colon cancer. Taken together, our data demonstrate, for the first time, that long-term HF consumption not only increases inflammatory status but also accompanies an increase of colonic β-catenin signaling and Lachnospiraceae/Streptococcaceae bacteria in the hind gut of C57BL/6 mice. Published by Elsevier Inc.

Curcumin Inhibits Gastric Inflammation Induced by Helicobacter Pylori Infection in a Mouse Model

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António M. Santos

2015-01-01

Full Text Available Helicobacter pylori (H. pylori infection triggers a sequence of gastric alterations starting with an inflammation of the gastric mucosa that, in some cases, evolves to gastric cancer. Efficient vaccination has not been achieved, thus it is essential to find alternative therapies, particularly in the nutritional field. The current study evaluated whether curcumin could attenuate inflammation of the gastric mucosa due to H. pylori infection. Twenty-eight C57BL/6 mice, were inoculated with the H. pylori SS1 strain; ten non-infected mice were used as controls. H. pylori infection in live mice was followed-up using a modified 13C-Urea Breath Test (13C-UBT and quantitative real-time polymerase chain reaction (PCR. Histologically confirmed, gastritis was observed in 42% of infected non-treated mice at both 6 and 18 weeks post-infection. These mice showed an up-regulation of the expression of inflammatory cytokines and chemokines, as well as of toll-like receptors (TLRs and MyD88, at both time points. Treatment with curcumin decreased the expression of all these mediators. No inflammation was observed by histology in this group. Curcumin treatment exerted a significant anti-inflammatory effect in H. pylori-infected mucosa, pointing to the promising role of a nutritional approach in the prevention of H. pylori induced deleterious inflammation while the eradication or prevention of colonization by effective vaccine is not available.

White and dark kidney beans reduce colonic mucosal damage and inflammation in response to dextran sodium sulfate.

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Monk, Jennifer M; Zhang, Claire P; Wu, Wenqing; Zarepoor, Leila; Lu, Jenifer T; Liu, Ronghua; Pauls, K Peter; Wood, Geoffrey A; Tsao, Rong; Robinson, Lindsay E; Power, Krista A

2015-07-01

Common beans are a rich source of nondigestible fermentable components and phenolic compounds that have anti-inflammatory effects. We assessed the gut-health-promoting potential of kidney beans in healthy mice and their ability to attenuate colonic inflammation following dextran sodium sulphate (DSS) exposure (via drinking water, 2% DSS w/v, 7 days). C57BL/6 mice were fed one of three isocaloric diets: basal diet control (BD), or BD supplemented with 20% cooked white (WK) or dark red kidney (DK) bean flour for 3 weeks. In healthy mice, anti-inflammatory microbial-derived cecal short chain fatty acid (SCFA) levels (acetate, butyrate and propionate), colon crypt height and colonic Mucin 1 (MUC1) and Resistin-like Molecule beta (Relmβ) mRNA expression all increased in WK- and DK-fed mice compared to BD, indicative of enhanced microbial activity, gut barrier integrity and antimicrobial defense response. During colitis, both bean diets reduced (a) disease severity, (b) colonic histological damage and (c) increased mRNA expression of antimicrobial and barrier integrity-promoting genes (Toll-like Receptor 4 (TLR4), MUC1-3, Relmβ and Trefoil Factor 3 (TFF3)) and reduced proinflammatory mediator expression [interleukin (IL)-1β, IL-6, interferon (IFN)γ, tumor necrosis factor (TNF)α and monocyte chemoattractant protein-1], which correlated with reduced colon tissue protein levels. Further, bean diets exerted a systemic anti-inflammatory effect during colitis by reducing serum levels of IL-17A, IFNγ, TNFα, IL-1β and IL-6. In conclusion, both WK and DK bean-supplemented diets enhanced microbial-derived SCFA metabolite production, gut barrier integrity and the microbial defensive response in the healthy colon, which supported an anti-inflammatory phenotype during colitis. Collectively, these data demonstrate a beneficial colon-function priming effect of bean consumption that mitigates colitis severity. Crown Copyright © 2015. Published by Elsevier Inc. All rights

Inhibition effect of Bifidobacterium longum, Lactobacillus acidophilus, Streptococcus thermophilus and Enterococcus faecalis and their related products on human colonic smooth muscle in vitro.

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Jing Gong

Full Text Available To investigate the effects of four strains, generally used in clinic, including Bifidobacterium longum, Lactobacillus acidophilus, Streptococcus thermophilus and Enterococcus faecalis, and their related products on human colonic smooth muscle in vitro.Human colonic circular muscle strips obtained from disease-free margins of resected segments from 25 patients with colorectal cancer were isometrically examined in a constant-temperature organ bath and exposed to different concentrations of living bacteria, sonicated cell fractions and cell-free supernatant (CFS. The area under the curve (AUC representing the contractility of smooth muscle strips was calculated.(1 The four living probiotics inhibited the contractility of human colonic muscle strips only at high concentration (1010 CFUs/mL, all P0.05.Four common probiotics related products, including the sonicated cell fractions and the CFS, obviously inhibited human colonic smooth muscles strips contraction in a dose-dependent manner. Only high concentration living probiotics (1010 CFUs/mL can inhibit the colonic smooth muscles strips contraction. The NO pathway may be partly involved in the inhibitory effect of CFS from Streptococcus thermophilus and Enterococcus faecalis.

Genistein inhibits proliferation of colon cancer cells by attenuating a negative effect of epidermal growth factor on tumor suppressor FOXO3 activity

International Nuclear Information System (INIS)

Qi, Wentao; Weber, Christopher R; Wasland, Kaarin; Savkovic, Suzana D

2011-01-01

Soy consumption is associated with a lower incidence of colon cancer which is believed to be mediated by one of its of components, genistein. Genistein may inhibit cancer progression by inducing apoptosis or inhibiting proliferation, but mechanisms are not well understood. Epidermal growth factor (EGF)-induced proliferation of colon cancer cells plays an important role in colon cancer progression and is mediated by loss of tumor suppressor FOXO3 activity. The aim of this study was to assess if genistein exerts anti-proliferative properties by attenuating the negative effect of EGF on FOXO3 activity. The effect of genistein on proliferation stimulated by EGF-mediated loss of FOXO3 was examined in human colonic cancer HT-29 cells. EGF-induced FOXO3 phosphorylation and translocation were assessed in the presence of genistein. EGF-mediated loss of FOXO3 interactions with p53 (co-immunoprecipitation) and promoter of p27kip1 (ChIP assay) were examined in presence of genistein in cells with mutated p53 (HT-29) and wild type p53 (HCT116). Silencing of p53 determined activity of FOXO3 when it is bound to p53. Genistein inhibited EGF-induced proliferation, while favoring dephosphorylation and nuclear retention of FOXO3 (active state) in colon cancer cells. Upstream of FOXO3, genistein acts via the PI3K/Akt pathway to inhibit EGF-stimulated FOXO3 phosphorylation (i.e. favors active state). Downstream, EGF-induced disassociation of FOXO3 from mutated tumor suppressor p53, but not wild type p53, is inhibited by genistein favoring FOXO3-p53(mut) interactions with the promoter of the cell cycle inhibitor p27kip1 in colon cancer cells. Thus, the FOXO3-p53(mut) complex leads to elevated p27kip1 expression and promotes cell cycle arrest. These novel anti-proliferative mechanisms of genistein suggest a possible role of combining genistein with other chemoreceptive agents for the treatment of colon cancer

Expression and inhibition of matrix metalloproteinase (MMP)-8, MMP-9 and MMP-12 in early colonic anastomotic repair

DEFF Research Database (Denmark)

Krarup, Peter-Martin; Eld, Mikkel; Heinemeier, Katja

2013-01-01

of specific MMPs responsible for the weakening of anastomoses can be used to optimise MMP inhibition therapy. We aimed to quantify transcript and protein levels of multiple MMPs in colonic anastomoses and evaluate the effect of inhibiting the MMPs that displayed the highest expression levels on anastomotic...

Ethanolic Extract of Traditional Chinese Medicine (TCM) Gamboge Inhibits Colon Cancer via the Wnt/Beta-Catenin Signaling Pathway in an Orthotopic Mouse Model.

Science.gov (United States)

Wang, Wei; Li, Youran; Chen, Yiqi; Chen, Hongjin; Zhu, Ping; Xu, Minmin; Wang, Hao; Wu, Minna; Yang, Zhijian; Hoffman, Robert M; Gu, Yunfei

2018-04-01

The aim of the present study was to investigate the efficacy of an ethanolic extract of gamboge (EEG), a traditional Chinese medicine (TCM), both in vitro on colon cancer cells and in vivo in an orthotopic mouse model of human colon cancer. The in vitro cytotoxicity of EEG on colon cancer cells was determined with the CCK8 proliferation assay and the Annexin V-PE/7-AAD apoptosis assay. Efficacy of EEG in vivo was evaluated in an orthotopic mouse model of human colon cancer implated with the green fluorescent protein-expressing human colon cancer cell line SW480-GFP. The tumor-bearing mice were treated with vehicle (0.2 ml/dose normal saline, po, daily), irinotecan (50 mg/kg/dose, ip, twice a week), 5-FU (15 mg/kg/dose, ip, every other day) as positive controls or EEG at doses of 12.5, 25 and 50 mg/kg/dose, po, daily. Real-time fluorescence imaging was performed to determine tumor inhibition in each treated group compared to the untreated controls. The protein expression of β-catenin, MMP-7, cyclin D1 and E-cadherin in the tumors was analyzed by immunohistochemistry. EEG significantly induced proliferation inhibition and apoptosis of SW480 colon cancer cells in vitro in a dose-dependent manner. Tumor growth in the colon-cancer orthotopic model was significantly inhibited by irinotecan, 5-FU and all three doses of EEG. The efficacy of EEG was comparable to irinotecan and 5-FU. Irinotecan, 5-FU and 50 mg/kg EEG significantly decreased the protein expression of β-catenin and MMP-7. Cyclin D1 expression was decreased and E-cadherin expression was increased by irinotecan, 5-FU and all three doses of EEG. The present study demonstrates anti-tumor efficacy of EEG on colon cancer both in vitro and in vivo through inducing proliferation inhibition and apoptosis of SW480 colon cancer cells and inhibiting tumor growth, respectively. EEG exerts anti-tumor activity at least partly via down-regulation of the Wnt/β-catenin signaling pathway. Copyright© 2018, International

Dietary pectin and calcium inhibit colonic proliferation in vivo by differing mechanisms.

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Umar, S; Morris, A P; Kourouma, F; Sellin, J H

2003-12-01

Diet plays an important role in promoting and/or preventing colon cancer; however, the effects of specific nutrients remain uncertain because of the difficulties in correlating epidemiological and basic observations. Transmissible murine colonic hyperplasia (TMCH) induced by Citrobacter rodentium, causes significant hyperproliferation and hyperplasia in the mouse distal colon and increases the risk of subsequent neoplasia. We have recently shown that TMCH is associated with an increased abundance of cellular beta-catenin and its nuclear translocation coupled with up-regulation of its downstream targets, c-myc and cyclin D1. In this study, we examined the effects of two putatively protective nutrients, calcium and soluble fibre pectin, on molecular events linked to proliferation in the colonic epithelium during TMCH. Dietary intervention incorporating changes in calcium [high (1.0%) and low (0.1%)] and alterations in fibre content (6% pectin and fibre-free) were compared with the standard AIN-93 diet (0.5% calcium, 5% cellulose), followed by histomorphometry and immunochemical assessment of potential oncogenes. Dietary interventions did not alter the time course of Citrobacter infection. Both 1.0% calcium and 6% pectin diet inhibited increases in proliferation and crypt length typically seen in TMCH. Neither the low calcium nor fibre-free diets had significant effect. Pectin diet blocked increases in cellular beta-catenin, cyclin D1 and c-myc levels associated with TMCH by 70%, whereas neither high nor low calcium diet had significant effect on these molecules. Diets supplemented with either calcium or pectin therefore, exert anti-proliferative effects in mouse distal colon involving different molecular pathways. TMCH is thus a diet-sensitive model for examining the effect of specific nutrients on molecular characteristics of the pre-neoplastic colonic epithelium.

Ursodeoxycholic acid inhibits the proliferation of colon cancer cells by regulating oxidative stress and cancer stem-like cell growth

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Kim, EuiJoo

2017-01-01

Introduction The regulation of reactive oxygen species (ROS) exists as a therapeutic target for cancer treatments. Previous studies have shown that ursodeoxycholic acid (UDCA) suppresses the proliferation of colon cancer cells. The aim of this study was to evaluate the effect of UDCA upon the proliferation of colon cancer cells as a direct result of the regulation of ROS. Method Colon cancer cell lines (HT29 and HCT116) were treated with UDCA. The total number of cells and the number of dead cells were determined using cell counters. A fluorescein isothiocyanate-bromodeoxyuridine flow kit was used to analyze cell cycle variations. Upon exposure to UDCA, the protein levels of p27, p21, CDK2, CDK4 and CDK6 were determined using western blotting, and qRT-PCR was used to determine levels of mRNA. We preformed dichlorofluorescindiacetate (DCF-DA) staining to detect alteration of intracellular ROS using fluorescence activated cell sorting (FACS). Colon cancer stem-like cell lines were generated by tumorsphere culture and treated with UDCA for seven days. The total number of tumorspheres was determined using microscopy. Results We found that UDCA reduced the total number of colon cancer cells, but did not increase the number of dead cells. UDCA inhibited the G1/S and G2/M transition phases in colon cancer cells. UDCA induced expression of cell cycle inhibitors such as p27 and p21. However, it was determined that UDCA suppressed levels of CDK2, CDK4, and CDK6. UDCA regulated intracellular ROS generation in colon cancer cells, and induced activation of Erk1/2. Finally, UDCA inhibited formation of colon cancer stem-like cells. Conclusion Our results indicate that UDCA suppresses proliferation through regulation of oxidative stress in colon cancer cells, as well as colon cancer stem-like cells. PMID:28708871

dNP2-ctCTLA-4 inhibits German cockroach extract-induced allergic airway inflammation and hyper-responsiveness via inhibition of Th2 responses.

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Lim, Sangho; Ho Sohn, Jung; Koo, Ja-Hyun; Park, Jung-Won; Choi, Je-Min

2017-08-04

German cockroaches are major household allergens that can trigger allergic airway inflammatory diseases with sensitive T-cell responses. Although the use of immune modulatory biologics, such as antibodies, to mediate allergic responses has recently been examined, only systemic administration is available because of the size limitations on intranasal administration. Here we utilized a cell-permeable peptide, dNP2, to deliver the cytoplasmic domain of cytotoxic T-lymphocyte antigen-4 (ctCTLA-4) through the airway epithelium to modulate Th2 responses in a German cockroach extract (GCE)-induced allergic airway inflammation model. The intranasal delivery efficiency of the dNP2-dTomato protein to the lungs was higher in GCE-induced asthmatic lung parenchymal cells compared to the sham cells. Intranasal administration of the dNP2-ctCTLA-4 protein inhibited airway hyper-responsiveness and reduced airway inflammation and remodeling, including goblet cell metaplasia and collagen deposition around the bronchi. The number of infiltrated cells, including eosinophils, and the levels of IL-4, IL-5, IL-13 and IFN-γ in the lungs were significantly reduced, presumably owing to inhibition of Th2 differentiation. However, intranasal administration of CTLA4-Ig did not inhibit airway inflammation. These results collectively suggest that dNP2-ctCTLA-4 is an efficient intranasally applicable candidate biologic for treating allergic asthma.

Motility and chemotaxis mediate the preferential colonization of gastric injury sites by Helicobacter pylori.

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Eitaro Aihara

2014-07-01

Full Text Available Helicobacter pylori (H. pylori is a pathogen contributing to peptic inflammation, ulceration, and cancer. A crucial step in the pathogenic sequence is when the bacterium first interacts with gastric tissue, an event that is poorly understood in vivo. We have shown that the luminal space adjacent to gastric epithelial damage is a microenvironment, and we hypothesized that this microenvironment might enhance H. pylori colonization. Inoculation with 106 H. pylori (wild-type Sydney Strain 1, SS1 significantly delayed healing of acetic-acid induced ulcers at Day 1, 7 and 30 post-inoculation, and wild-type SS1 preferentially colonized the ulcerated area compared to uninjured gastric tissue in the same animal at all time points. Gastric resident Lactobacillus spp. did not preferentially colonize ulcerated tissue. To determine whether bacterial motility and chemotaxis are important to ulcer healing and colonization, we analyzed isogenic H. pylori mutants defective in motility (ΔmotB or chemotaxis (ΔcheY. ΔmotB (10(6 failed to colonize ulcerated or healthy stomach tissue. ΔcheY (10(6 colonized both tissues, but without preferential colonization of ulcerated tissue. However, ΔcheY did modestly delay ulcer healing, suggesting that chemotaxis is not required for this process. We used two-photon microscopy to induce microscopic epithelial lesions in vivo, and evaluated accumulation of fluorescently labeled H. pylori at gastric damage sites in the time frame of minutes instead of days. By 5 min after inducing damage, H. pylori SS1 preferentially accumulated at the site of damage and inhibited gastric epithelial restitution. H. pylori ΔcheY modestly accumulated at the gastric surface and inhibited restitution, but did not preferentially accumulate at the injury site. H. pylori ΔmotB neither accumulated at the surface nor inhibited restitution. We conclude that bacterial chemosensing and motility rapidly promote H. pylori colonization of injury sites

Motility and Chemotaxis Mediate the Preferential Colonization of Gastric Injury Sites by Helicobacter pylori

Science.gov (United States)

Aihara, Eitaro; Closson, Chet; Matthis, Andrea L.; Schumacher, Michael A.; Engevik, Amy C.; Zavros, Yana; Ottemann, Karen M.; Montrose, Marshall H.

2014-01-01

Helicobacter pylori (H. pylori) is a pathogen contributing to peptic inflammation, ulceration, and cancer. A crucial step in the pathogenic sequence is when the bacterium first interacts with gastric tissue, an event that is poorly understood in vivo. We have shown that the luminal space adjacent to gastric epithelial damage is a microenvironment, and we hypothesized that this microenvironment might enhance H. pylori colonization. Inoculation with 106 H. pylori (wild-type Sydney Strain 1, SS1) significantly delayed healing of acetic-acid induced ulcers at Day 1, 7 and 30 post-inoculation, and wild-type SS1 preferentially colonized the ulcerated area compared to uninjured gastric tissue in the same animal at all time points. Gastric resident Lactobacillus spp. did not preferentially colonize ulcerated tissue. To determine whether bacterial motility and chemotaxis are important to ulcer healing and colonization, we analyzed isogenic H. pylori mutants defective in motility (ΔmotB) or chemotaxis (ΔcheY). ΔmotB (106) failed to colonize ulcerated or healthy stomach tissue. ΔcheY (106) colonized both tissues, but without preferential colonization of ulcerated tissue. However, ΔcheY did modestly delay ulcer healing, suggesting that chemotaxis is not required for this process. We used two-photon microscopy to induce microscopic epithelial lesions in vivo, and evaluated accumulation of fluorescently labeled H. pylori at gastric damage sites in the time frame of minutes instead of days. By 5 min after inducing damage, H. pylori SS1 preferentially accumulated at the site of damage and inhibited gastric epithelial restitution. H. pylori ΔcheY modestly accumulated at the gastric surface and inhibited restitution, but did not preferentially accumulate at the injury site. H. pylori ΔmotB neither accumulated at the surface nor inhibited restitution. We conclude that bacterial chemosensing and motility rapidly promote H. pylori colonization of injury sites, and thereby biases

Post-translational inhibition of IP-10 secretion in IEC by probiotic bacteria: impact on chronic inflammation.

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Gabriele Hoermannsperger

Full Text Available BACKGROUND: Clinical and experimental studies suggest that the probiotic mixture VSL#3 has protective activities in the context of inflammatory bowel disease (IBD. The aim of the study was to reveal bacterial strain-specific molecular mechanisms underlying the anti-inflammatory potential of VSL#3 in intestinal epithelial cells (IEC. METHODOLOGY/PRINCIPAL FINDINGS: VSL#3 inhibited TNF-induced secretion of the T-cell chemokine interferon-inducible protein (IP-10 in Mode-K cells. Lactobacillus casei (L. casei cell surface proteins were identified as active anti-inflammatory components of VSL#3. Interestingly, L. casei failed to block TNF-induced IP-10 promoter activity or IP-10 gene transcription at the mRNA expression level but completely inhibited IP-10 protein secretion as well as IP-10-mediated T-cell transmigration. Kinetic studies, pulse-chase experiments and the use of a pharmacological inhibitor for the export machinery (brefeldin A showed that L. casei did not impair initial IP-10 production but decreased intracellular IP-10 protein stability as a result of blocked IP-10 secretion. Although L. casei induced IP-10 ubiquitination, the inhibition of proteasomal or lysosomal degradation did not prevent the loss of intracellular IP-10. Most important for the mechanistic understanding, the inhibition of vesicular trafficking by 3-methyladenine (3-MA inhibited IP-10 but not IL-6 expression, mimicking the inhibitory effects of L. casei. These findings suggest that L. casei impairs vesicular pathways important for the secretion of IP-10, followed by subsequent degradation of the proinflammatory chemokine. Feeding studies in TNF(DeltaARE and IL-10(-/- mice revealed a compartimentalized protection of VSL#3 on the development of cecal but not on ileal or colonic inflammation. Consistent with reduced tissue pathology in IL-10(-/- mice, IP-10 protein expression was reduced in primary epithelial cells. CONCLUSIONS/SIGNIFICANCE: We demonstrate segment

GS143, an IκB ubiquitination inhibitor, inhibits allergic airway inflammation in mice

International Nuclear Information System (INIS)

Hirose, Koichi; Wakashin, Hidefumi; Oki, Mie; Kagami, Shin-ichiro; Suto, Akira; Ikeda, Kei; Watanabe, Norihiko; Iwamoto, Itsuo; Furuichi, Yasuhiro; Nakajima, Hiroshi

2008-01-01

Asthma is characterized by airway inflammation with intense eosinophil infiltration and mucus hyper-production, in which antigen-specific Th2 cells play critical roles. Nuclear factor-κB (NF-κB) pathway has been demonstrated to be essential for the production of Th2 cytokines and chemokines in the airways in murine asthma models. In the present study, we examined the effect of GS143, a novel small-molecule inhibitor of IκB ubiquitination, on antigen-induced airway inflammation and Th2 cytokine production in mice. Intranasal administration of GS143 prior to antigen challenge suppressed antigen-induced NF-κB activation in the lung of sensitized mice. Intranasal administration of GS143 also inhibited antigen-induced eosinophil and lymphocyte recruitment into the airways as well as the expression of Th2 cytokines and eotaxin in the airways. Moreover, GS143 inhibited antigen-induced differentiation of Th2 cells but not of Th1 cells in vitro. Taken together, these results suggest that IκB ubiquitination inhibitor may have therapeutic potential against asthma

Estrogen inhibits chloride secretion caused by cholera and Escherichia coli enterotoxins in female rat distal colon.

LENUS (Irish Health Repository)

Alzamora, Rodrigo

2011-05-08

Excessive Cl(-) secretion is the driving force for secretory diarrhea. 17β-Estradiol has been shown to inhibit Cl(-) secretion in rat distal colon through a nongenomic pathway. We examined whether 17β-estradiol inhibits Cl(-) secretion in an animal model of secretory diarrhea and the downstream effectors involved. The effect of 17β-estradiol on cholera toxin and heat-stable enterotoxin induced Cl(-) secretion in rat colonic mucosal sheets was studied by current-voltage clamping. Selective permeabilization of apical or basolateral membranes with amphotericin B or nystatin was used to isolate basolateral K(+) channel and apical Cl(-) channel activity, respectively. 17β-Estradiol dose-dependently inhibited secretory responses to both toxins with IC(50) values of approximately 1nM. This effect was female-gender specific, with no inhibition observed in male tissues. 17β-Estradiol responses were insensitive to the pure anti-estrogen ICI 182,720. 17β-Estradiol exerted its effects downstream of enterotoxin-induced production of second messengers (cAMP and cGMP) but was dependent on PKCδ activation. In nystatin-permeabilized tissues, apical Cl(-) currents were unaffected by 17β-estradiol treatment while basolateral K(+) current was profoundly inhibited by the hormone. This current was sensitive to the specific KCNQ1 channel inhibitors chromanol 293B and HMR-1556. In conclusion, 17β-estradiol inhibits enterotoxin-induced Cl(-) secretion via a PKCδ-dependent mechanism involving inhibition of basolateral KCNQ1 channels. These data elucidate mechanisms of 17β-estradiol inhibition of Cl(-) secretion induced by enterotoxins in intestinal epithelia, which may be relevant for the treatment of diarrheal diseases.

Estrogen inhibits chloride secretion caused by cholera and Escherichia coli enterotoxins in female rat distal colon.

LENUS (Irish Health Repository)

Alzamora, Rodrigo

2012-02-01

Excessive Cl(-) secretion is the driving force for secretory diarrhea. 17beta-Estradiol has been shown to inhibit Cl(-) secretion in rat distal colon through a nongenomic pathway. We examined whether 17beta-estradiol inhibits Cl(-) secretion in an animal model of secretory diarrhea and the downstream effectors involved. The effect of 17beta-estradiol on cholera toxin and heat-stable enterotoxin induced Cl(-) secretion in rat colonic mucosal sheets was studied by current-voltage clamping. Selective permeabilization of apical or basolateral membranes with amphotericin B or nystatin was used to isolate basolateral K(+) channel and apical Cl(-) channel activity, respectively. 17beta-Estradiol dose-dependently inhibited secretory responses to both toxins with IC(50) values of approximately 1nM. This effect was female-gender specific, with no inhibition observed in male tissues. 17beta-Estradiol responses were insensitive to the pure anti-estrogen ICI 182,720. 17beta-Estradiol exerted its effects downstream of enterotoxin-induced production of second messengers (cAMP and cGMP) but was dependent on PKCdelta activation. In nystatin-permeabilized tissues, apical Cl(-) currents were unaffected by 17beta-estradiol treatment while basolateral K(+) current was profoundly inhibited by the hormone. This current was sensitive to the specific KCNQ1 channel inhibitors chromanol 293B and HMR-1556. In conclusion, 17beta-estradiol inhibits enterotoxin-induced Cl(-) secretion via a PKCdelta-dependent mechanism involving inhibition of basolateral KCNQ1 channels. These data elucidate mechanisms of 17beta-estradiol inhibition of Cl(-) secretion induced by enterotoxins in intestinal epithelia, which may be relevant for the treatment of diarrheal diseases.

Clostridium difficile suppresses colonic vasoactive intestinal peptide associated with altered motility

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A. Nassif

1995-01-01

Full Text Available We investigated whether Clostridium difficile toxin alters colonic tissue levels of vasoactive intestinal peptide (VIP at the expense of changes in colonic motility in the isolated perfused rabbit left colon. Colonic inflammation was induced by the intracolonic administration of 10−8 M C. difflcile toxin. Strain gauge transducers were sewn onto the serosal surface of the colon to evaluate colonic motility. C. difflcile administration produced histologic changes consistent with epithelial damage. This was associated with an increased production of prostaglandin E2 and thromboxane B2. Tissue levels of VIP but not substance P were significantly reduced. This was associated with an increased number of contractions per minute and an average force of each colonic contraction. These results suggest that tissue levels of VIP are suppressed by C. difflcile and may participate in colonic dysmotility during active inflammation.

Synthetic triterpenoid induces 15-PGDH expression and suppresses inflammation-driven colon carcinogenesis.

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Choi, Sung Hee; Kim, Byung-Gyu; Robinson, Janet; Fink, Steve; Yan, Min; Sporn, Michael B; Markowitz, Sanford D; Letterio, John J

2014-06-01

Colitis-associated colon cancer (CAC) develops as a result of inflammation-induced epithelial transformation, which occurs in response to inflammatory cytokine-dependent downregulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and subsequent suppression of prostaglandin metabolism. Agents that both enhance 15-PGDH expression and suppress cyclooxygenase-2 (COX-2) production may more effectively prevent CAC. Synthetic triterpenoids are a class of small molecules that suppress COX-2 as well as inflammatory cytokine signaling. Here, we found that administration of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-C28-methyl ester (CDDO-Me) suppresses CAC in mice. In a spontaneous, inflammation-driven intestinal neoplasia model, deletion of Smad4 specifically in T cells led to progressive production of inflammatory cytokines, including TNF-α, IFN-γ, iNOS, IL-6, IL-1β; as well as activation of STAT1 and STAT3; along with suppression of 15-PGDH expression. Oral administration of CDDO-Me to mice with SMAD4-deficient T cells increased survival and suppressed intestinal epithelial neoplasia by decreasing production of inflammatory mediators and increasing expression of 15-PGDH. Induction of 15-PGDH by CDDO-Me was dose dependent in epithelial cells and was abrogated following treatment with TGF-β signaling inhibitors in vitro. Furthermore, CDDO-Me-dependent 15-PGDH induction was not observed in Smad3-/- mice. Similarly, CDDO-Me suppressed azoxymethane plus dextran sodium sulfate-induced carcinogenesis in wild-type animals, highlighting the potential of small molecules of the triterpenoid family as effective agents for the chemoprevention of CAC in humans.

Inhibition of autophagy exerts anti-colon cancer effects via apoptosis induced by p53 activation and ER stress

International Nuclear Information System (INIS)

Sakitani, Kosuke; Hirata, Yoshihiro; Hikiba, Yohko; Hayakawa, Yoku; Ihara, Sozaburo; Suzuki, Hirobumi; Suzuki, Nobumi; Serizawa, Takako; Kinoshita, Hiroto; Sakamoto, Kei; Nakagawa, Hayato; Tateishi, Keisuke; Maeda, Shin; Ikenoue, Tsuneo; Kawazu, Shoji; Koike, Kazuhiko

2015-01-01

Although some molecularly targeted drugs for colorectal cancer are used clinically and contribute to a better prognosis, the current median survival of advanced colorectal cancer patients is not sufficient. Autophagy, a basic cell survival mechanism mediated by recycling of cellular amino acids, plays an important role in cancer. Recently, autophagy has been highlighted as a promising new molecular target. The unfolded protein response (UPR) reportedly act in complementary fashion with autophagy in intestinal homeostasis. However, the roles of UPR in colon cancer under autophagic inhibition remain to be elucidated. We aim to clarify the inhibitory effect of autophagy on colon cancer. We crossed K19 CreERT and Atg5 flox/flox mice to generate Atg5 flox/flox /K19 CreERT mice. Atg5 flox/flox /K19 CreERT mice were first treated with azoxymethane/dextran sodium sulfate and then injected with tamoxifen to inhibit autophagy in CK19-positive epithelial cells. To examine the anti-cancer mechanisms of autophagic inhibition, we used colon cancer cell lines harboring different p53 gene statuses, as well as small interfering RNAs (siRNAs) targeting Atg5 and immunoglobulin heavy-chain binding protein (BiP), a chaperone to aid folding of unfolded proteins. Colon tumors in Atg5 flox/flox /K19 CreERT mice showed loss of autophagic activity and decreased tumor size (the total tumor diameter was 28.1 mm in the control and 20.7 mm in Atg5 flox/flox /K19 CreERT mice, p = 0.036). We found that p53 and UPR/endoplasmic reticulum (ER) stress-related proteins, such as cleaved caspase 3, and CAAT/enhancer-binding protein homologous protein, are up-regulated in colon tumors of Atg5 flox/flox /K19 CreERT mice. Although Atg5 and BiP silencing, respectively, increased apoptosis in p53 wild type cells, Atg5 silencing alone did not show the same effect on apoptosis in p53 mutant cells. However, co-transfection of Atg5 and BiP siRNAs led to increased apoptosis in p53 mutant cells. Blocking autophagy

Black seed oil ameliorates allergic airway inflammation by inhibiting T-cell proliferation in rats.

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Shahzad, Muhammad; Yang, Xudong; Raza Asim, M B; Sun, Qingzhu; Han, Yan; Zhang, Fujun; Cao, Yongxiao; Lu, Shemin

2009-02-01

The black seeds, from the Ranunculaceae family, have been traditionally used by various cultures as a natural remedy for several ailments. In this study, we examined the effect of black seed oil as an immunomodulator in a rat model of allergic airway inflammation. Rats sensitized to ovalbumin and challenged intranasally with ovalbumin to induce an allergic inflammatory response were compared to ovalbumin-sensitized, intranasally ovalbumin-exposed rats pretreated with intraperitoneally administered black seed oil and to control rats. The levels of IgE, IgG1 and ova-specific T-cell proliferation in spleen were measured by ELISA. The pro-inflammatory cytokine IL-4, IL-5, IL-6 and TGF-beta1 mRNA expression levels were measured by reverse transcription polymerase chain reaction. The intraperitoneal administration of black seed oil inhibited the Th2 type immune response in rats by preventing inflammatory cell infiltration and pathological lesions in the lungs. It significantly decreased the nitric oxide production in BALF, total serum IgE, IgG1 and OVA-specific IgG1 along with IL-4, IL-5, IL-6 and TGF-beta1 mRNA expression. Black seed oil treatment resulted in decreased T-cell response evident by lesser delayed type hypersensitivity and lower T-cell proliferation in spleen. In conclusion, black seed oil exhibited a significant reduction in all the markers of allergic inflammation mainly by inhibiting the delayed type hypersensitivity and T-cell proliferation. The data suggests that inhibition of T-cell response may be responsible for immunomodulatory effect of black seed oil in the rat model of allergic airway inflammation.

Necrotizing colitis associated with carcinoma of the colon

International Nuclear Information System (INIS)

Woo, Seong Ku; Lim, Jae Hoon; Kim, Soon Yong; Ahn, Chi Yul

1982-01-01

Necrotizing colitis associated with carcinoma of the colon, known also as obstructive colitis, is a disorder characterized by anulceration and inflammation of the colon proximal to an obstructive lesion, especially carcinoma of the rectosigmoid colon, and in rare instance, leads to acute gangrene of the colon. The authors analyzed radiologic findings in four cases of necrotizing colitis associated with carcinoma of the colon. Barium enema disclosed mucosal edema, nodular filling defects, irregularity of the colonic contour and typical thumbprinting appearance of involved colon proximal to an obstructing carcinoma of the colon. The mechanism of necrotizing colitis was briefly reviewed

Regulation of Laminin γ2 Expression by CDX2 in Colonic Epithelial Cells Is Impaired During Active Inflammation

DEFF Research Database (Denmark)

Coskun, Mehmet; Soendergaard, Christoffer; Jørgensen, Steffen

2017-01-01

and to assess the influence of inflammation. Transcriptional regulation of LAMC2 was examined by reporter gene assays, overexpression, and shRNA-mediated knock-down of CDX2. CDX2-DNA interactions were assessed by chromatin immunoprecipitation on Caco-2 cells without or with TNF-α, as well as in purified colonic......The expression of Caudal-related homeobox transcription factor 2 (CDX2) is impaired by tumor necrosis factor-α (TNF-α)-mediated activation of nuclear factor-κB (NF-κB) in ulcerative colitis (UC). Laminin subunit γ2 (LAMC2) is an epithelial basement membrane protein implicated in cell migration......, proliferation, differentiation, as well as tumor invasion and intestinal inflammation, and its expression is enhanced by TNF-α in a NF-κB-dependent regulation of the recently identified LAMC2 enhancer. The aim was to determine whether CDX2 is involved in the basal regulation of LAMC2 in epithelial cells...

Saccharomyces boulardii Protease Inhibits the Effects of Clostridium difficile Toxins A and B in Human Colonic Mucosa

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Castagliuolo, Ignazio; Riegler, Martin F.; Valenick, Leyla; LaMont, J. Thomas; Pothoulakis, Charalabos

1999-01-01

Saccharomyces boulardii is a nonpathogenic yeast used in the treatment of Clostridium difficile diarrhea and colitis. We have reported that S. boulardii inhibits C. difficile toxin A enteritis in rats by releasing a 54-kDa protease which digests the toxin A molecule and its brush border membrane (BBM) receptor (I. Castagliuolo, J. T. LaMont, S. T. Nikulasson, and C. Pothoulakis, Infect. Immun. 64:5225–5232, 1996). The aim of this study was to further evaluate the role of S. boulardii protease in preventing C. difficile toxin A enteritis in rat ileum and determine whether it protects human colonic mucosa from C. difficile toxins. A polyclonal rabbit antiserum raised against purified S. boulardii serine protease inhibited by 73% the proteolytic activity present in S. boulardii conditioned medium in vitro. The anti-protease immunoglobulin G (IgG) prevented the action of S. boulardii on toxin A-induced intestinal secretion and mucosal permeability to [3H]mannitol in rat ileal loops, while control rabbit IgG had no effect. The anti-protease IgG also prevented the effects of S. boulardii protease on digestion of toxins A and B and on binding of [3H]toxin A and [3H]toxin B to purified human colonic BBM. Purified S. boulardii protease reversed toxin A- and toxin B-induced inhibition of protein synthesis in human colonic (HT-29) cells. Furthermore, toxin A- and B-induced drops in transepithelial resistance in human colonic mucosa mounted in Ussing chambers were reversed by 60 and 68%, respectively, by preexposing the toxins to S. boulardii protease. We conclude that the protective effects of S. boulardii on C. difficile-induced inflammatory diarrhea in humans are due, at least in part, to proteolytic digestion of toxin A and B molecules by a secreted protease. PMID:9864230

Ibuprofen slows migration and inhibits bowel colonization by enteric nervous system precursors in zebrafish, chick and mouse

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Schill, Ellen Merrick; Lake, Jonathan I.; Tusheva, Olga A.; Nagy, Nandor; Bery, Saya K.; Foster, Lynne; Avetisyan, Marina; Johnson, Stephen L.; Stenson, William F.; Goldstein, Allan M.; Heuckeroth, Robert O.

2016-01-01

Hirschsprung Disease (HSCR) is a potentially deadly birth defect characterized by the absence of the enteric nervous system (ENS) in distal bowel. Although HSCR has clear genetic causes, no HSCR-associated mutation is 100% penetrant, suggesting gene-gene and gene-environment interactions determine HSCR occurrence. To test the hypothesis that certain medicines might alter HSCR risk we treated zebrafish with medications commonly used during early human pregnancy and discovered that ibuprofen caused HSCR-like absence of enteric neurons in distal bowel. Using fetal CF-1 mouse gut slice cultures, we found that ibuprofen treated enteric neural crest-derived cells (ENCDC) had reduced migration, fewer lamellipodia and lower levels of active RAC1/CDC42. Additionally, inhibiting ROCK, a RHOA effector and known RAC1 antagonist, reversed ibuprofen effects on migrating mouse ENCDC in culture. Ibuprofen also inhibited colonization of Ret+/− mouse bowel by ENCDC in vivo and dramatically reduced bowel colonization by chick ENCDC in culture. Interestingly, ibuprofen did not affect ENCDC migration until after at least three hours of exposure. Furthermore, mice deficient in Ptgs1 (COX 1) and Ptgs2 (COX 2) had normal bowel colonization by ENCDC and normal ENCDC migration in vitro suggesting COX-independent effects. Consistent with selective and strain specific effects on ENCDC, ibuprofen did not affect migration of gut mesenchymal cells, NIH3T3, or WT C57BL/6 ENCDC, and did not affect dorsal root ganglion cell precursor migration in zebrafish. Thus, ibuprofen inhibits ENCDC migration in vitro and bowel colonization by ENCDC in vivo in zebrafish, mouse and chick, but there are cell type and strain specific responses. These data raise concern that ibuprofen may increase Hirschsprung disease risk in some genetically susceptible children. PMID:26586201

Elaeocarpusin Inhibits Mast Cell-Mediated Allergic Inflammation

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Min-Jong Kim

2018-06-01

Full Text Available Mast cells are major effector cells for allergic responses that act by releasing inflammatory mediators, such as histamine and pro-inflammatory cytokines. Accordingly, different strategies have been pursued to develop anti-allergic and anti-inflammatory candidates by regulating the function of mast cells. The purpose of this study was to determine the effectiveness of elaeocarpusin (EL on mast cell-mediated allergic inflammation. We isolated EL from Elaeocarpus sylvestris L. (Elaeocarpaceae, which is known to possess anti-inflammatory properties. For this study, various sources of mast cells and mouse anaphylaxis models were used. EL suppressed the induction of markers for mast cell degranulation, such as histamine and β-hexosaminidase, by reducing intracellular calcium levels. Expression of pro-inflammatory cytokines, such as tumor necrosis factor-α and IL-4, was significantly decreased in activated mast cells by EL. This inhibitory effect was related to inhibition of the phosphorylation of Fyn, Lyn, Syk, and Akt, and the nuclear translocation of nuclear factor-κB. To confirm the effect of EL in vivo, immunoglobulin E-mediated passive cutaneous anaphylaxis (PCA and ovalbumin-induced active systemic anaphylaxis (ASA models were induced. EL reduced the PCA reaction in a dose dependent manner. In addition, EL attenuated ASA reactions such as hypothemia, histamine release, and IgE production. Our results suggest that EL is a potential therapeutic candidate for allergic inflammatory diseases that acts via the inhibition of mast cell degranulation and expression of proinflammatory cytokines.

Deletion of glutathione peroxidase-2 inhibits azoxymethane-induced colon cancer development.

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Mike F Müller

Full Text Available The selenoprotein glutathione peroxidase-2 (GPx2 appears to have a dual role in carcinogenesis. While it protected mice from colon cancer in a model of inflammation-triggered carcinogenesis (azoxymethane and dextran sodium sulfate treatment, it promoted growth of xenografted tumor cells. Therefore, we analyzed the effect of GPx2 in a mouse model mimicking sporadic colorectal cancer (azoxymethane-treatment only. GPx2-knockout (KO and wild-type (WT mice were adjusted to an either marginally deficient (-Se, adequate (+Se, or supranutritional (++Se selenium status and were treated six times with azoxymethane (AOM to induce tumor development. In the -Se and ++Se groups, the number of tumors was significantly lower in GPx2-KO than in respective WT mice. On the +Se diet, the number of dysplastic crypts was reduced in GPx2-KO mice. This may be explained by more basal and AOM-induced apoptotic cell death in GPx2-KO mice that eliminates damaged or pre-malignant epithelial cells. In WT dysplastic crypts GPx2 was up-regulated in comparison to normal crypts which might be an attempt to suppress apoptosis. In contrast, in the +Se groups tumor numbers were similar in both genotypes but tumor size was larger in GPx2-KO mice. The latter was associated with an inflammatory and tumor-promoting environment as obvious from infiltrated inflammatory cells in the intestinal mucosa of GPx2-KO mice even without any treatment and characterized as low-grade inflammation. In WT mice the number of tumors tended to be lowest in +Se compared to -Se and ++Se feeding indicating that selenium might delay tumorigenesis only in the adequate status. In conclusion, the role of GPx2 and presumably also of selenium depends on the cancer stage and obviously on the involvement of inflammation.

Calcimimetic R568 inhibits tetrodotoxin-sensitive colonic electrolyte secretion and reduces c-fos expression in myenteric neurons.

Science.gov (United States)

Sun, Xiangrong; Tang, Lieqi; Winesett, Steven; Chang, Wenhan; Cheng, Sam Xianjun

2018-02-01

Calcium-sensing receptor (CaSR) is expressed on neurons of both submucosal and myenteric plexuses of the enteric nervous system (ENS) and the CaSR agonist R568 inhibited Cl - secretion in intestine. The purpose of this study was to localize the primary site of action of R568 in the ENS and to explore how CaSR regulates secretion through the ENS. Two preparations of rat proximal and distal colon were used. The full-thickness preparation contained both the submucosal and myenteric plexuses, whereas for the "stripped" preparation the myenteric plexus with the muscle layers was removed. Both preparations were mounted onto Ussing chambers and Cl - secretory responses were compared by measuring changes in short circuit current (I sc ). Two tissue-specific CaSR knockouts (i.e., neuron-specific vs. enterocyte-specific) were generated to compare the effect of R568 on expression of c-fos protein in myenteric neurons by immunocytochemistry. In full-thickness colons, tetrodotoxin (TTX) inhibited I sc , both in proximal and distal colons. A nearly identical inhibition was produced by R568. However, in stripped preparations, while the effect of TTX on I sc largely remained, the effect of R568 was nearly completely eliminated. In keeping with this, R568 reduced c-fos protein expression only in myenteric neurons of wild type mice and mutant mice that contained CaSR in neurons (i.e., villin Cre/Casr flox/flox mice), but not in myenteric neurons of nestin Cre/Casr flox/flox mice in which neuronal cell CaSR was eliminated. These results indicate that R568 exerts its anti-secretory effects predominantly via CaSR-mediated inhibition of neuronal activity in the myenteric plexus. Published by Elsevier Inc.

Beneficial Effects of Anti-Interleukin-6 Antibodies on Impaired Gastrointestinal Motility, Inflammation and Increased Colonic Permeability in a Murine Model of Sepsis Are Most Pronounced When Administered in a Preventive Setup.

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Sara Nullens

Full Text Available During sepsis, gastrointestinal ileus, mucosal barrier dysfunction and bacterial translocation are accepted to be important triggers that can maintain or exacerbate the septic state. In the caecal ligation and puncture animal model of sepsis, we demonstrated that systemic and colonic interleukin-6 levels are significantly increased coinciding with an impaired colonic barrier function. We therefore aimed to study the effect of therapeutic or curative administration of anti-IL6 antibodies on overall GI motility, colonic permeability and translocation of intestinal bacteria in blood and mesenteric lymph nodes in the mouse caecal ligation and puncture model.OF-1 mice were randomized to either the preventive or curative protocol, in which they received 1 mg/kg of antibodies to interleukin-6, or its IgG isotype control solution. They subsequently underwent either the caecal ligation and puncture procedure, or sham-surgery. GI motility was assessed 48 h following the procedure, as well as colonic permeability, serum and colon cytokines, colonic tight junction proteins at the mRNA level; cultures of blood and mesenteric lymph nodes were performed.Preventive administration of anti-interleukin-6 antibodies successfully counteracted the gastrointestinal motility disturbances and impaired colonic barrier function that could be observed in vehicle-treated septic animals. Serum and colonic levels of proinflammatory cytokines were significantly lower when animals were preventively treated with anti-interleukin-6 antibodies. A repetitive injection 24 h later resulted in the most pronounced effects. Curative treatment significantly lowered systemic and colonic inflammation markers while the effects on transit and permeability were unfortunately no longer significant.Caecal ligation and puncture resulted in septic ileus with an increased colonic permeability. Antibodies to interleukin-6 were able to ameliorate gastro-intestinal motility, suppress inflammation and

Lack of STAT6 Attenuates Inflammation and Drives Protection against Early Steps of Colitis-Associated Colon Cancer.

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Leon-Cabrera, Sonia A; Molina-Guzman, Emmanuel; Delgado-Ramirez, Yael G; Vázquez-Sandoval, Armando; Ledesma-Soto, Yadira; Pérez-Plasencia, Carlos G; Chirino, Yolanda I; Delgado-Buenrostro, Norma L; Rodríguez-Sosa, Miriam; Vaca-Paniagua, Felipe; Ávila-Moreno, Federico; Gutierrez-Cirlos, Emma B; Arias-Romero, Luis E; Terrazas, Luis I

2017-05-01

Colitis-associated colon cancer (CAC) is one of the most common malignant neoplasms and a leading cause of death. The immunologic factors associated with CAC development are not completely understood. Signal transducer and activator of transcription 6 (STAT6) is part of an important signaling pathway for modulating intestinal immune function and homeostasis. However, the role of STAT6 in colon cancer progression is unclear. Following CAC induction in wild-type (WT) and STAT6-deficient mice (STAT6 -/- ), we found that 70% of STAT6 -/- mice were tumor-free after 8 weeks, whereas 100% of WT mice developed tumors. STAT6 -/- mice displayed fewer and smaller colorectal tumors than WT mice; this reduced tumorigenicity was associated with decreased proliferation and increased apoptosis in the colonic mucosa in the early steps of tumor progression. STAT6 -/- mice also exhibited reduced inflammation, diminished concentrations COX2 and nuclear β-catenin protein in the colon, and decreased mRNA expression of IL17A and TNFα, but increased IL10 expression when compared with WT mice. Impaired mucosal expression of CCL9, CCL25, and CXCR2 was also observed. In addition, the number of circulating CD11b + Ly6C hi CCR2 + monocytes and CD11b + Ly6C low Ly6G + granulocytes was both decreased in a STAT6-dependent manner. Finally, WT mice receiving a STAT6 inhibitor in vivo confirmed a significant reduction in tumor load as well as less intense signs of CAC. Our results demonstrate that STAT6 is critical in the early steps of CAC development for modulating inflammatory responses and controlling cell recruitment and proliferation. Thus, STAT6 may represent a promising target for CAC treatment. Cancer Immunol Res; 5(5); 385-96. ©2017 AACR . ©2017 American Association for Cancer Research.

Inhibition of NF-κB Expression and Allergen-induced Airway Inflammation in a Mouse Allergic Asthma Model by Andrographolide

OpenAIRE

Li, Jing; Luo, Li; Wang, Xiaoyun; Liao, Bin; Li, Guoping

2009-01-01

Andrographolide from traditional Chinese herbal medicines previously showed it possesses a strong anti-inflammatory activity. In present study, we investigated whether Andrographolide could inhibit allergen-induced airway inflammation and airways hyper-responsiveness and explored the mechanism of Andrographolide on allergen-induced airway inflammation and airways hyper-responsiveness. After sensitized and challenged by ovalbumin, the BALB/c mice were administered intraperitoneally with Androg...

Effects of dark chocolate on azoxymethane-induced colonic aberrant crypt foci.

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Hong, Mee Young; Nulton, Emily; Shelechi, Mahshid; Hernández, Lisa M; Nemoseck, Tricia

2013-01-01

Epidemiologic evidence supports that diets rich in polyphenols promote health and may delay the onset of colon cancer. Cocoa and chocolate products have some of the highest polyphenolic concentrations compared to other polyphenolic food sources. This study tested the hypothesis that a diet including dark chocolate can protect against colon cancer by inhibiting aberrant crypt foci (ACF) formation, downregulating gene expression of inflammatory mediators, and favorably altering cell kinetics. We also investigated whether bloomed dark chocolate retains the antioxidant capacity and protects against colon cancer. Forty-eight rats received either a diet containing control (no chocolate), regular dark chocolate, or bloomed dark chocolate and were injected subcutaneously with saline or azoxymethane. Relative to control, both regular and bloomed dark chocolate diets lowered the total number of ACF (P = 0.022). Chocolate diet-fed animals downregulated transcription levels of COX-2 (P = 0.035) and RelA (P = 0.045). Both chocolate diets lowered the proliferation index (P = 0.001). These results suggest that a diet including dark chocolate can reduce cell proliferation and some gene expression involving inflammation, which may explain the lower number of early preneoplastic lesions. These results provide new insight on polyphenol-rich chocolate foods and colon cancer prevention.

HDAC2 is required by the physiological concentration of glucocorticoid to inhibit inflammation in cardiac fibroblasts.

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Zhang, Haining; He, Yanhua; Zhang, Guiping; Li, Xiaobin; Yan, Suikai; Hou, Ning; Xiao, Qing; Huang, Yue; Luo, Miaoshan; Zhang, Genshui; Yi, Quan; Chen, Minsheng; Luo, Jiandong

2017-09-01

We previously suggested that endogenous glucocorticoids (GCs) may inhibit myocardial inflammation induced by lipopolysaccharide (LPS) in vivo. However, the possible cellular and molecular mechanisms were poorly understood. In this study, we investigated the role of physiological concentration of GCs in inflammation induced by LPS in cardiac fibroblasts and explored the possible mechanisms. The results showed that hydrocortisone at the dose of 127 ng/mL (equivalent to endogenous basal level of GCs) inhibited LPS (100 ng/mL)-induced productions of TNF-α and IL-1β in cardiac fibroblasts. Xanthine oxidase/xanthine (XO/X) system impaired the anti-inflammatory action of GCs through downregulating HDAC2 activity and expression. Knockdown of HDAC2 restrained the anti-inflammatory effects of physiological level of hydrocortisone, and blunted the ability of XO/X system to downregulate the inhibitory action of physiological level of hydrocortisone on cytokines. These results suggested that HDAC2 was required by the physiological concentration of GC to inhibit inflammatory response. The dysfunction of HDAC2 induced by oxidative stress might be account for GC resistance and chronic inflammatory disorders during the cardiac diseases.

Expression of ICAM-1 in colon epithelial cells

DEFF Research Database (Denmark)

Vainer, Ben; Sørensen, Susanne; Seidelin, Jakob

2003-01-01

BACKGROUND: Studies have suggested that in ulcerative colitis (UC), intercellular adhesion molecule-1 (ICAM-1) is involved in migration of leukocytes toward the colonic epithelium. A suitable in vitro model of chronic colonic inflammation does not exist, and the role of the epithelium is based on...

N-end rule pathway inhibition assists colon tumor regression via necroptosis

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Pritha Agarwalla

2016-01-01

Full Text Available Recent study has shown that N-end rule pathway, an ubiquitin dependent proteolytic system, counteracts cell death by degrading many antisurvival protein fragments like BCLxL, BRCA1, RIPK1, etc. Inhibition of the N-end rule pathway can lead to metabolic stabilization of proapoptotic protein fragments like RIPK1, thereby sensitizing cells to programmed cell death. Receptor interacting serine-threonine protein kinase-1 (RIPK1 is one of the upstream regulators of programmed necrosis known as necroptosis. Necroptosis is particularly gaining attention of cancer biologists as it provides an alternate therapeutic modality to kill cancer cells, which often evolve multiple strategies to circumvent growth inhibition by apoptosis. Utilizing the over expression of biotin receptor in cancer cells, herein, we report that coadministration of synthetic hetero-bivalent N-end rule inhibitor RFC11 and anticancer drug shikonin solubilized in a stable biotin receptor-targeted liposome exhibited significant synergistic antitumor effect in both subcutaneous and orthotopic mouse colon tumor model through induction of necroptosis with distinctive upregulation of RIPK1. Besides developing a newly targeted formulation for necroptosis induction, this report is the first in vivo evidence demonstrating that potent inhibition of N-end rule pathway can enhance therapeutic efficacy of conventional chemotherapeutics.

Hydroxylase inhibition attenuates colonic epithelial secretory function and ameliorates experimental diarrhea.

LENUS (Irish Health Repository)

Ward, Joseph B J

2012-02-01

Hydroxylases are oxygen-sensing enzymes that regulate cellular responses to hypoxia. Transepithelial Cl(-) secretion, the driving force for fluid secretion, is dependent on O(2) availability for generation of cellular energy. Here, we investigated the role of hydroxylases in regulating epithelial secretion and the potential for targeting these enzymes in treatment of diarrheal disorders. Ion transport was measured as short-circuit current changes across voltage-clamped monolayers of T(84) cells and mouse colon. The antidiarrheal efficacy of dimethyloxallyl glycine (DMOG) was tested in a mouse model of allergic disease. Hydroxylase inhibition with DMOG attenuated Ca(2+)- and cAMP-dependent secretory responses in voltage-clamped T(84) cells to 20.2 +\\/- 2.6 and 38.8 +\\/- 6.7% (n=16; P<\\/=0.001) of those in control cells, respectively. Antisecretory actions of DMOG were time and concentration dependent, being maximal after 18 h of DMOG (1 mM) treatment. DMOG specifically inhibited Na(+)\\/K(+)-ATPase pump activity without altering its expression or membrane localization. In mice, DMOG inhibited agonist-induced secretory responses ex vivo and prevented allergic diarrhea in vivo. In conclusion, hydroxylases are important regulators of epithelial Cl(-) and fluid secretion and present a promising target for development of new drugs to treat transport disorders.

Hydroxylase inhibition attenuates colonic epithelial secretory function and ameliorates experimental diarrhea.

LENUS (Irish Health Repository)

Ward, Joseph B J

2011-02-01

Hydroxylases are oxygen-sensing enzymes that regulate cellular responses to hypoxia. Transepithelial Cl(-) secretion, the driving force for fluid secretion, is dependent on O(2) availability for generation of cellular energy. Here, we investigated the role of hydroxylases in regulating epithelial secretion and the potential for targeting these enzymes in treatment of diarrheal disorders. Ion transport was measured as short-circuit current changes across voltage-clamped monolayers of T(84) cells and mouse colon. The antidiarrheal efficacy of dimethyloxallyl glycine (DMOG) was tested in a mouse model of allergic disease. Hydroxylase inhibition with DMOG attenuated Ca(2+)- and cAMP-dependent secretory responses in voltage-clamped T(84) cells to 20.2 ± 2.6 and 38.8 ± 6.7% (n=16; P≤0.001) of those in control cells, respectively. Antisecretory actions of DMOG were time and concentration dependent, being maximal after 18 h of DMOG (1 mM) treatment. DMOG specifically inhibited Na(+)\\/K(+)-ATPase pump activity without altering its expression or membrane localization. In mice, DMOG inhibited agonist-induced secretory responses ex vivo and prevented allergic diarrhea in vivo. In conclusion, hydroxylases are important regulators of epithelial Cl(-) and fluid secretion and present a promising target for development of new drugs to treat transport disorders.

Butyrate attenuates lipopolysaccharide-induced inflammation in intestinal cells and Crohn's mucosa through modulation of antioxidant defense machinery.

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Ilaria Russo

Full Text Available Oxidative stress plays an important role in the pathogenesis of inflammatory bowel disease (IBD, including Crohn's disease (CrD. High levels of Reactive Oxygen Species (ROS induce the activation of the redox-sensitive nuclear transcription factor kappa-B (NF-κB, which in turn triggers the inflammatory mediators. Butyrate decreases pro-inflammatory cytokine expression by the lamina propria mononuclear cells in CrD patients via inhibition of NF-κB activation, but how it reduces inflammation is still unclear. We suggest that butyrate controls ROS mediated NF-κB activation and thus mucosal inflammation in intestinal epithelial cells and in CrD colonic mucosa by triggering intracellular antioxidant defense systems. Intestinal epithelial Caco-2 cells and colonic mucosa from 14 patients with CrD and 12 controls were challenged with or without lipopolysaccaride from Escherichia coli (EC-LPS in presence or absence of butyrate for 4 and 24 h. The effects of butyrate on oxidative stress, p42/44 MAP kinase phosphorylation, p65-NF-κB activation and mucosal inflammation were investigated by real time PCR, western blot and confocal microscopy. Our results suggest that EC-LPS challenge induces a decrease in Gluthation-S-Transferase-alpha (GSTA1/A2 mRNA levels, protein expression and catalytic activity; enhanced levels of ROS induced by EC-LPS challenge mediates p65-NF-κB activation and inflammatory response in Caco-2 cells and in CrD colonic mucosa. Furthermore butyrate treatment was seen to restore GSTA1/A2 mRNA levels, protein expression and catalytic activity and to control NF-κB activation, COX-2, ICAM-1 and the release of pro-inflammatory cytokine. In conclusion, butyrate rescues the redox machinery and controls the intracellular ROS balance thus switching off EC-LPS induced inflammatory response in intestinal epithelial cells and in CrD colonic mucosa.

Role of neutral ceramidase in colon cancer.

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García-Barros, Mónica; Coant, Nicolas; Kawamori, Toshihiko; Wada, Masayuki; Snider, Ashley J; Truman, Jean-Philip; Wu, Bill X; Furuya, Hideki; Clarke, Christopher J; Bialkowska, Agnieszka B; Ghaleb, Amr; Yang, Vincent W; Obeid, Lina M; Hannun, Yusuf A

2016-12-01

Alterations in sphingolipid metabolism, especially ceramide and sphingosine 1-phosphate, have been linked to colon cancer, suggesting that enzymes of sphingolipid metabolism may emerge as novel regulators and targets in colon cancer. Neutral ceramidase (nCDase), a key enzyme in sphingolipid metabolism that hydrolyzes ceramide into sphingosine, is highly expressed in the intestine; however, its role in colon cancer has not been defined. Here we show that molecular and pharmacological inhibition of nCDase in colon cancer cells increases ceramide, and this is accompanied by decreased cell survival and increased apoptosis and autophagy, with minimal effects on noncancerous cells. Inhibition of nCDase resulted in loss of β-catenin and inhibition of ERK, components of pathways relevant for colon cancer development. Furthermore, inhibition of nCDase in a xenograft model delayed tumor growth and increased ceramide while decreasing proliferation. It is noteworthy that mice lacking nCDase treated with azoxymethane were protected from tumor formation. Taken together, these studies show that nCDase is pivotal for regulating initiation and development of colon cancer, and these data suggest that this enzyme is a suitable and novel target for colon cancer therapy.-García-Barros, M., Coant, N., Kawamori, T., Wada, M., Snider, A. J., Truman, J.-P., Wu, B. X., Furuya, H., Clarke, C. J., Bialkowska, A. B., Ghaleb, A., Yang, V. W., Obeid, L. M., Hannun, Y. A. Role of neutral ceramidase in colon cancer. © FASEB.

An apple oligogalactan prevents against inflammation and carcinogenesis by targeting LPS/TLR4/NF-κB pathway in a mouse model of colitis-associated colon cancer.

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Liu, Li; Li, Yu H; Niu, Yin B; Sun, Yang; Guo, Zhen J; Li, Qian; Li, Chen; Feng, Juan; Cao, Shou S; Mei, Qi B

2010-10-01

Evidence strongly supported a link between inflammation and cancer. Patients with colitis have high risk for development of colon cancer. Nuclear factor-kappa B (NF-κB), partially induced by lipopolysaccharide (LPS) binding to Toll-like receptor (TLR) 4, is a vital molecule in supervising the transformation of colitis to colon cancer. It could be a good strategy to prevent colitis carcinogenesis for targeting LPS/TLR4/NF-κB pathway. In the present study, we obtained an oligogalactan composed of five galacturonic acids from apple pectin and evaluated its protective efficacy on intestinal toxicities and carcinogenesis in a mouse model of colitis-associated colon cancer induced by 1,2-dimethylhydrazine and dextran sodium sulfate (DSS). The apple oligogalactan (AOG) was highly effective against intestinal toxicities and carcinogenesis and decreased the elevated levels of TLR4 and tumor necrosis factor-α (TNF-α) induced by inflammation in vivo in this model system. In vitro studies, AOG alone only slightly increased the levels of protein expression and messenger RNA of TLR4, phosphorylation of IκBα and production of TNF-α in HT-29 cells. However, AOG significantly decreased the elevation of all the biomarkers induced by LPS when it was combined with LPS. The effect of AOG may be related to membrane internalization and redistribution of TLR4 from cell membrane to cytoplasm. AOG is active against inflammation and carcinogenesis through targeting LPS/TLR4/NF-κB pathway. Both AOG and LPS are agonists of TLR4 for sharing the same ligand but AOG has a much lower intrinsic activity than that of LPS. AOG may be useful for treatment of colitis and prevention of carcinogenesis in the clinics.

Lactobacillus rhamnosus induced epithelial cell apoptosis, ameliorates inflammation and prevents colon cancer development in an animal model.

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Gamallat, Yaser; Meyiah, Abdo; Kuugbee, Eugene D; Hago, Ahmed Musa; Chiwala, Gift; Awadasseid, Annoor; Bamba, Djibril; Zhang, Xin; Shang, Xueqi; Luo, Fuwen; Xin, Yi

2016-10-01

Probiotics have been suggested as prophylactic measure in colon carcinogenesis. This study aimed at determining the potential prophylactic activity of Lactobacillus rhamnosus GG CGMCC 1.2134 (LGG) strain on colorectal carcinogenesis via measuring its effect on Nuclear factor kappa B (NFκB) inflammatory pathway and apoptosis. 64 Sprague Dawley rats were grouped into four as follows; Group 1 (Healthy control), Group 2 (LGG), Group 3 (cancer control Dimethyl hydrazine (DMH)) and Group 4 (LGG+DMH). LGG was administered orally to LGG and LGG+DMH groups. Colon carcinogenesis was chemically induced in LGG+DMH and DMH groups by weekly injection of 40mg/kg DMH. Animals were sacrificed after 25 weeks of experiment and tumor characteristics assessed. The change in expression of NFκB-p65, COX-2, TNFα, Bcl-2, Bax, iNOS, VEGFα, β-catenin, Casp3 and p53 were evaluated by western blotting and qRT-PCR. LGG treatment significantly reduced tumor incidence, multiplicity and volume in LGG+DMH treatment group compared to DMH cancer control group. Also, LGG treatment reduced the expression of β-catenin and the inflammatory proteins NFκB-p65, COX-2 and TNFα; the anti-apoptotic protein Bcl-2, but increased the expression of the pro-apoptotic proteins Bax, casp3 and p53 compared with DMH group. LGG have a potential protection effect against colon carcinogenesis; inducing apoptosis and ameliorating inflammation, and may hold a promise as bio-therapeutic dietary agent. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Arctigenin ameliorates inflammation in vitro and in vivo by inhibiting the PI3K/AKT pathway and polarizing M1 macrophages to M2-like macrophages.

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Hyam, Supriya R; Lee, In-Ah; Gu, Wan; Kim, Kyung-Ah; Jeong, Jin-Ju; Jang, Se-Eun; Han, Myung Joo; Kim, Dong-Hyun

2013-05-15

Seeds of Arctium lappa, containing arctigenin and its glycoside arctiin as main constituents, have been used as a diuretic, anti-inflammatory and detoxifying agent in Chinese traditional medicine. In our preliminary study, arctigenin inhibited IKKβ and NF-κB activation in peptidoglycan (PGN)- or lipopolysaccharide (LPS)-induced peritoneal macrophages. To understand the anti-inflammatory effect of arctigenin, we investigated its anti-inflammatory effect in LPS-stimulated peritoneal macrophages and on LPS-induced systemic inflammation as well as 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice. Arctigenin inhibited LPS-increased IL-1β, IL-6 and TNF-α expression in LPS-stimulated peritoneal macrophages, but increased LPS-reduced IL-10 and CD204 expression. Arctigenin inhibited LPS-induced PI3K, AKT and IKKβ phosphorylation, but did not suppress LPS-induced IRAK-1 phosphorylation. However, arctigenin did not inhibit NF-κB activation in LPS-stimulated PI3K siRNA-treated peritoneal macrophages. Arctigenin suppressed the binding of p-PI3K antibody and the nucleus translocation of NF-κB p65 in LPS-stimulated peritoneal macrophages. Arctigenin suppressed blood IL-1β and TNF-α level in mice systemically inflamed by intraperitoneal injection of LPS. Arctigenin also inhibited colon shortening, macroscopic scores and myeloperoxidase activity in TNBS-induced colitic mice. Arctigenin inhibited TNBS-induced IL-1β, TNF-α and IL-6 expression, as well as PI3K, AKT and IKKβ phosphorylation and NF-κB activation in mice, but increased IL-10 and CD204 expression. However, it did not affect IRAK-1 phosphorylation. Based on these findings, arctigenin may ameliorate inflammatory diseases, such as colitis, by inhibiting PI3K and polarizing M1 macrophages to M2-like macrophages. Copyright © 2013 Elsevier B.V. All rights reserved.

Urotensin-II receptor is over-expressed in colon cancer cell lines and in colon carcinoma in humans.

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Federico, Alessandro; Zappavigna, Silvia; Romano, Marco; Grieco, Paolo; Luce, Amalia; Marra, Monica; Gravina, Antonietta Gerarda; Stiuso, Paola; D'Armiento, Francesco Paolo; Vitale, Giovanni; Tuccillo, Concetta; Novellino, Ettore; Loguercio, Carmela; Caraglia, Michele

2014-01-01

Urotensin (U)-II receptor (UTR) has been previously reported to be over-expressed in a number of tumours. Whether UTR-related pathway plays a role in colon carcinogenesis is unknown. We evaluated UTR protein and mRNA expression in human epithelial colon cancer cell lines and in normal colon tissue, adenomatous polyps and colon cancer. U-II protein expression was assessed in cancer cell lines. Moreover, we evaluated the effects of U-II(4-11) (an UTR agonist), antagonists and knockdown of UTR protein expression through a specific shRNA, on proliferation, invasion and motility of human colon cancer cells. Cancer cell lines expressed U-II protein and UTR protein and mRNA. By immunohistochemistry, UTR was expressed in 5-30% of epithelial cells in 45 normal controls, in 30-48% in 21 adenomatous polyps and in 65-90% in 48 colon adenocarcinomas. UTR mRNA expression was increased by threefold in adenomatous polyps and eightfold in colon cancer, compared with normal colon. U-II(4-11) induced a 20-40% increase in cell growth while the blockade of the receptor with specific antagonists caused growth inhibition of 20-40%. Moreover, the knock down of UTR with a shRNA or the inhibition of UTR with the antagonist urantide induced an approximately 50% inhibition of both motility and invasion. UTR appears to be involved in the regulation of colon cancer cell invasion and motility. These data suggest that UTR-related pathway may play a role in colon carcinogenesis and that UTR may function as a target for therapeutic intervention in colon cancer. © 2013 Stichting European Society for Clinical Investigation Journal Foundation.

NOD2 Down-Regulates Colonic Inflammation by IRF4-Mediated Inhibition of K63-Linked Polyubiquitination of RICK and TRAF6

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Watanabe, Tomohiro; Asano, Naoki; Meng, Guangxun; Yamashita, Kouhei; Arai, Yasuyuki; Sakurai, Toshiharu; Kudo, Masatoshi; Fuss, Ivan J; Kitani, Atsushi; Shimosegawa, Tooru; Chiba, Tsutomu; Strober, Warren

2014-01-01

It is well established that polymorphisms of the nucleotide-binding oligomerization domain 2 (NOD2) gene, a major risk factor in Crohn's disease (CD), lead to loss of NOD2 function. However, a molecular explanation of how such loss of function leads to increased susceptibility to CD has remained unclear. In a previous study exploring this question we reported that activation of NOD2 in human dendritic cells by its ligand, muramyl dipeptide (MDP) negatively regulates Toll-like receptor (TLR)-mediated inflammatory responses. Here we show that NOD2 activation results in increased interferon regulatory factor 4 (IRF4) expression and binding to TNF receptor associated factor 6 (TRAF6) and receptor interacting serine-threonine kinase (RICK). We then show that such binding leads to IRF4-mediated inhibition of Lys63-linked polyubiquitination of TRAF6 and RICK and thus to down-regulation of NF-κB activation. Finally, we demonstrate that protection of mice from the development of experimental colitis by MDP or IRF4 administration is accompanied by similar IRF4-mediated effects on polyubiquitination of TRAF6 and RICK in colonic lamina propria mononuclear cells. These findings thus define a mechanism of NOD2-mediated regulation of innate immune responses to intestinal microflora that could explain the relation of NOD2 polymorphisms and resultant NOD2 dysfunction to CD. PMID:24670424

Neural control of colonic cell proliferation.

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Tutton, P J; Barkla, D H

1980-03-15

The mitotic rate in rat colonic crypts and in dimethylhydrazine-induced colonic carcinomas was measured using a stathmokinetic technique. In sympathectomized animals cell proliferation was retarded in the crypts but not in the tumors, whereas in animals treated with Metaraminol, a drug which releases norepinephrine from nerve terminals, crypt cell but not tumor cell proliferation was accelerated. Blockade of alpha-adrenoceptors also inhibited crypt cell proliferation. However, stimulation of beta-adrenoceptors inhibited and blockade of beta-adrenoceptors accelerated tumor cell proliferation without influencing crypt cell proliferation. Injection of either serotonin or histamine stimulated tumor but not crypt cell proliferation and blockade or serotonin receptors or histamine H2-receptors inhibited tumor cell proliferation. It is postulated that cell proliferation in the colonic crypts, like that in the jejunal crypts, is under both endocrine and autonomic neural control whereas colonic tumor cell division is subject to endocrine regulation alone.

Loss of nitric oxide-mediated inhibition of purine neurotransmitter release in the colon in the absence of interstitial cells of Cajal.

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Durnin, Leonie; Lees, Andrea; Manzoor, Sheerien; Sasse, Kent C; Sanders, Kenton M; Mutafova-Yambolieva, Violeta N

2017-11-01

Regulation of colonic motility depends on the integrity of enteric inhibitory neurotransmission mediated by nitric oxide (NO), purine neurotransmitters, and neuropeptides. Intramuscular interstitial cells of Cajal (ICC-IM) and platelet-derived growth factor receptor-α-positive (PDGFRα + ) cells are involved in generating responses to NO and purine neurotransmitters, respectively. Previous studies have suggested a decreased nitrergic and increased purinergic neurotransmission in Kit W /Kit W-v ( W/W v ) mice that display lesions in ICC-IM along the gastrointestinal tract. However, contributions of NO to these phenotypes have not been evaluated. We used small-chamber superfusion assays and HPLC to measure the spontaneous and electrical field stimulation (EFS)-evoked release of nicotinamide adenine dinucleotide (NAD + )/ADP-ribose, uridine adenosine tetraphosphate (Up4A), adenosine 5'-triphosphate (ATP), and metabolites from the tunica muscularis of human, monkey, and murine colons and circular muscle of monkey colon, and we tested drugs that modulate NO levels or blocked NO receptors. NO inhibited EFS-evoked release of purines in the colon via presynaptic neuromodulation. Colons from W/W v , Nos1 -/- , and Prkg1 -/- mice displayed augmented neural release of purines that was likely due to altered nitrergic neuromodulation. Colons from W/W v mice demonstrated decreased nitrergic and increased purinergic relaxations in response to nerve stimulation. W/W v mouse colons demonstrated reduced Nos1 expression and reduced NO release. Our results suggest that enhanced purinergic neurotransmission may compensate for the loss of nitrergic neurotransmission in muscles with partial loss of ICC. The interactions between nitrergic and purinergic neurotransmission in the colon provide novel insight into the role of neurotransmitters and effector cells in the neural regulation of gastrointestinal motility. NEW & NOTEWORTHY This is the first study investigating the role of nitric

Betulinic acid inhibits colon cancer cell and tumor growth and induces proteasome-dependent and -independent downregulation of specificity proteins (Sp transcription factors

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Pathi Satya

2011-08-01

Full Text Available Abstract Background Betulinic acid (BA inhibits growth of several cancer cell lines and tumors and the effects of BA have been attributed to its mitochondriotoxicity and inhibition of multiple pro-oncogenic factors. Previous studies show that BA induces proteasome-dependent degradation of specificity protein (Sp transcription factors Sp1, Sp3 and Sp4 in prostate cancer cells and this study focused on the mechanism of action of BA in colon cancer cells. Methods The effects of BA on colon cancer cell proliferation and apoptosis and tumor growth in vivo were determined using standardized assays. The effects of BA on Sp proteins and Sp-regulated gene products were analyzed by western blots, and real time PCR was used to determine microRNA-27a (miR-27a and ZBTB10 mRNA expression. Results BA inhibited growth and induced apoptosis in RKO and SW480 colon cancer cells and inhibited tumor growth in athymic nude mice bearing RKO cells as xenograft. BA also decreased expression of Sp1, Sp3 and Sp4 transcription factors which are overexpressed in colon cancer cells and decreased levels of several Sp-regulated genes including survivin, vascular endothelial growth factor, p65 sub-unit of NFκB, epidermal growth factor receptor, cyclin D1, and pituitary tumor transforming gene-1. The mechanism of action of BA was dependent on cell context, since BA induced proteasome-dependent and proteasome-independent downregulation of Sp1, Sp3 and Sp4 in SW480 and RKO cells, respectively. In RKO cells, the mechanism of BA-induced repression of Sp1, Sp3 and Sp4 was due to induction of reactive oxygen species (ROS, ROS-mediated repression of microRNA-27a, and induction of the Sp repressor gene ZBTB10. Conclusions These results suggest that the anticancer activity of BA in colon cancer cells is due, in part, to downregulation of Sp1, Sp3 and Sp4 transcription factors; however, the mechanism of this response is cell context-dependent.

Betulinic acid inhibits colon cancer cell and tumor growth and induces proteasome-dependent and -independent downregulation of specificity proteins (Sp) transcription factors

International Nuclear Information System (INIS)

Chintharlapalli, Sudhakar; Papineni, Sabitha; Lei, Ping; Pathi, Satya; Safe, Stephen

2011-01-01

Betulinic acid (BA) inhibits growth of several cancer cell lines and tumors and the effects of BA have been attributed to its mitochondriotoxicity and inhibition of multiple pro-oncogenic factors. Previous studies show that BA induces proteasome-dependent degradation of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 in prostate cancer cells and this study focused on the mechanism of action of BA in colon cancer cells. The effects of BA on colon cancer cell proliferation and apoptosis and tumor growth in vivo were determined using standardized assays. The effects of BA on Sp proteins and Sp-regulated gene products were analyzed by western blots, and real time PCR was used to determine microRNA-27a (miR-27a) and ZBTB10 mRNA expression. BA inhibited growth and induced apoptosis in RKO and SW480 colon cancer cells and inhibited tumor growth in athymic nude mice bearing RKO cells as xenograft. BA also decreased expression of Sp1, Sp3 and Sp4 transcription factors which are overexpressed in colon cancer cells and decreased levels of several Sp-regulated genes including survivin, vascular endothelial growth factor, p65 sub-unit of NFκB, epidermal growth factor receptor, cyclin D1, and pituitary tumor transforming gene-1. The mechanism of action of BA was dependent on cell context, since BA induced proteasome-dependent and proteasome-independent downregulation of Sp1, Sp3 and Sp4 in SW480 and RKO cells, respectively. In RKO cells, the mechanism of BA-induced repression of Sp1, Sp3 and Sp4 was due to induction of reactive oxygen species (ROS), ROS-mediated repression of microRNA-27a, and induction of the Sp repressor gene ZBTB10. These results suggest that the anticancer activity of BA in colon cancer cells is due, in part, to downregulation of Sp1, Sp3 and Sp4 transcription factors; however, the mechanism of this response is cell context-dependent

5-Geranyloxy-7-methoxycoumarin inhibits colon cancer (SW480) cells growth by inducing apoptosis.

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Patil, Jaiprakash R; Jayaprakasha, Guddadarangavvanahally K; Kim, Jinhee; Murthy, Kotamballi N Chidambara; Chetti, Mahadev B; Nam, Sang-Yong; Patil, Bhimanagouda S

2013-03-01

For the first time, three coumarins were isolated from the hexane extract of limes (Citrus aurantifolia) and purified by flash chromatography. The structures were identified by NMR (1D, 2D) and mass spectral analyses as 5-geranyloxy-7-methoxycoumarin, limettin, and isopimpinellin. These compounds inhibited human colon cancer (SW-480) cell proliferation, with 5-geranyloxy-7-methoxycoumarin showing the highest inhibition activity (67 %) at 25 µM. Suppression of SW480 cell proliferation by 5-geranyloxy-7-methoxycoumarin was associated with induction of apoptosis, as evidenced by annexin V staining and DNA fragmentation. In addition, 5-geranyloxy-7-methoxycoumarin arrested cells at the G0/G1 phase, and induction of apoptosis was demonstrated through the activation of tumour suppressor gene p53, caspase8/3, regulation of Bcl2, and inhibition of p38 MAPK phosphorylation. These findings suggest that 5-geranyloxy-7-methoxycoumarin has potential as a cancer preventive agent. Georg Thieme Verlag KG Stuttgart · New York.

Inhibition of Fungal Colonization by Pseudoalteromonas tunicata Provides a Competitive Advantage during Surface Colonization†

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Franks, A.; Egan, S.; Holmström, C.; James, S.; Lappin-Scott, H.; Kjelleberg, S.

2006-01-01

The marine epiphytic bacterium Pseudoalteromonas tunicata produces a range of extracellular secondary metabolites that inhibit an array of common fouling organisms, including fungi. In this study, we test the hypothesis that the ability to inhibit fungi provides P. tunicata with an advantage during colonization of a surface. Studies on a transposon-generated antifungal-deficient mutant of P. tunicata, FM3, indicated that a long-chain fatty acid-coenzyme A ligase is involved in the production of a broad-range antifungal compound by P. tunicata. Flow cell experiments demonstrated that production of an antifungal compound provided P. tunicata with a competitive advantage against a marine yeast isolate during surface colonization. This compound enabled P. tunicata to disrupt an already established fungal biofilm by decreasing the number of yeast cells attached to the surface by 66% ± 9%. For in vivo experiments, the wild-type and FM3 strains of P. tunicata were used to inoculate the surface of the green alga Ulva australis. Double-gradient denaturing gradient gel electrophoresis analysis revealed that after 48 h, the wild-type P. tunicata had outcompeted the surface-associated fungal community, whereas the antifungal-deficient mutant had no effect on the fungal community. Our data suggest that P. tunicata is an effective competitor against fungal surface communities in the marine environment. PMID:16957232

[Role of oral cavity colonization resistance in dental caries development].

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Petrushanko, T A; Chereda, V V; Loban', G A

2013-01-01

Colonization resistance is one of local immunity mechanisms determined by a combination of factors that inhibit the adhesion and growth of mucous membrane bacteria. We examined patients with different levels of caries intensity assessing oral mucosa colonization resistance by our own method. Caries development resulted in changes of colonization resistance with the increased rate of inhibition of the oral mucosa colonization resistance barrier.

γ-Aminobutyric acid inhibits the proliferation and increases oxaliplatin sensitivity in human colon cancer cells.

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Song, Lihua; Du, Aiying; Xiong, Ying; Jiang, Jing; Zhang, Yao; Tian, Zhaofeng; Yan, Hongli

2016-11-01

γ-Aminobutyric acid (GABA) is a natural non-protein amino acid, which broadly exists in many plant parts and is widely used as an ingredient in the food industry. In mammals, it is widely distributed in central nervous system and non-neural tissues. In addition to a primary inhibitory neurotransmitter in the central nervous system, endogenous GABA content has been found to be elevated in neoplastic tissues in colon cancer. However, the effect of extraneous GABA on colon cancer has rarely been reported. In this study, we found the inhibitory effects of GABA on the proliferation of colon cancer cells (CCCs). The amino acid also suppressed metastasis of SW480 and SW620 cells. To further study the correlated mechanism, we analyzed the changes in cell cycle distribution and found that GABA suppressed cell cycle progression through G2/M or G1/S phase. Furthermore, RNA sequencing analysis revealed GABA-induced changes in the mRNA expression of 30 genes, including EGR1, MAPK4, NR4A1, Fos, and FosB, in all the three types of CCC. Importantly, GABA enhanced the anti-tumor efficacy of oxaliplatin (OXA) in subcutaneous xenograft tumor model in nude mice. The data suggest that GABA inhibits colon cancer cell proliferation perhaps by attenuating EGR1-NR4A1 axis, EGR1-Fos axis, and by disrupting MEK-EGR1 signaling pathway. This work reveals the pharmacological value of GABA derived from food and suggests that exogenous GABA might play an auxiliary role in polychemotherapy of colon cancer.

Chikusetsu saponin IVa ameliorates high fat diet-induced inflammation in adipose tissue of mice through inhibition of NLRP3 inflammasome activation and NF-κB signaling.

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Yuan, Chengfu; Liu, Chaoqi; Wang, Ting; He, Yumin; Zhou, Zhiyong; Dun, Yaoyan; Zhao, Haixia; Ren, Dongming; Wang, Junjie; Zhang, Changcheng; Yuan, Ding

2017-05-09

Chronic metabolic inflammation in adipose tissue plays an important role in the development of obesity-associated diseases. Our previous study indicated that total saponins of Panax japonicus (SPJ) rhizoma and Chikusetsu saponin V, one main component of SPJ, could exert the anti-oxidative and anti-inflammatory effects. The present study aimed to investigate the in vivo and Ex vivo anti-inflammatory activities of another main component of SPJ, namely Chikusetsu saponin IVa (CS). CS could significantly inhibited HFD-induced lipid homeostasis, and inhibited inflammation in adipose tissue, as reflected by the decreased mRNA expression levels of inflammation-related genes and secretion of the chemokines/cytokines, inhibited the accumulation of adipose tissue macrophages (ATMs) and shifted their polarization from M1 to M2, suppressed HFD-induced expression of NLRP3 inflammasome component genes and decreased IL-1β and Caspase-1 production in mice. Moreover, CS treatment also inhibited the activation of NLRP3 inflammasome in bone marrow-derived macrophages (BMDMs). Meanwhile, CS treatment inhibited an NLRP3-induced ASC pyroptosome formation and lipopolysaccharide (LPS)-induced pyroptosis. Furthermore, CS treatment suppressed HFD-induced NF-κB signaling in vivo and LPS-induced NF-κB activation as reflected by the fact that their phosphorylated forms and the ratios of pNF-κB/NF-κB, pIKK/IKK, and pIκB/IκB were all decreased in EAT from HFD-fed mice treated with CS as compared with those of HFD mice. Taking together, this study has revealed that CS effectively inhibits HFD-induced inflammation in adipose tissue of mice through inhibiting both NLRP3 inflammasome activation and NF-κB signaling. Thus, CS can serve as a potential therapeutic drug in the prevention and treatment of inflammation-associated diseases.

Histamine H2 Receptor-Mediated Suppression of Intestinal Inflammation by Probiotic Lactobacillus reuteri.

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Gao, Chunxu; Major, Angela; Rendon, David; Lugo, Monica; Jackson, Vanessa; Shi, Zhongcheng; Mori-Akiyama, Yuko; Versalovic, James

2015-12-15

Probiotics and commensal intestinal microbes suppress mammalian cytokine production and intestinal inflammation in various experimental model systems. Limited information exists regarding potential mechanisms of probiotic-mediated immunomodulation in vivo. In this report, we demonstrate that specific probiotic strains of Lactobacillus reuteri suppress intestinal inflammation in a trinitrobenzene sulfonic acid (TNBS)-induced mouse colitis model. Only strains that possess the hdc gene cluster, including the histidine decarboxylase and histidine-histamine antiporter genes, can suppress colitis and mucosal cytokine (interleukin-6 [IL-6] and IL-1β in the colon) gene expression. Suppression of acute colitis in mice was documented by diminished weight loss, colonic injury, serum amyloid A (SAA) protein concentrations, and reduced uptake of [(18)F]fluorodeoxyglucose ([(18)F]FDG) in the colon by positron emission tomography (PET). The ability of probiotic L. reuteri to suppress colitis depends on the presence of a bacterial histidine decarboxylase gene(s) in the intestinal microbiome, consumption of a histidine-containing diet, and signaling via the histamine H2 receptor (H2R). Collectively, luminal conversion of l-histidine to histamine by hdc(+) L. reuteri activates H2R, and H2R signaling results in suppression of acute inflammation within the mouse colon. Probiotics are microorganisms that when administered in adequate amounts confer beneficial effects on the host. Supplementation with probiotic strains was shown to suppress intestinal inflammation in patients with inflammatory bowel disease and in rodent colitis models. However, the mechanisms of probiosis are not clear. Our current studies suggest that supplementation with hdc(+) L. reuteri, which can convert l-histidine to histamine in the gut, resulted in suppression of colonic inflammation. These findings link luminal conversion of dietary components (amino acid metabolism) by gut microbes and probiotic

Vaccination against IL-33 Inhibits Airway Hyperresponsiveness and Inflammation in a House Dust Mite Model of Asthma.

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Ying Lei

Full Text Available In several clinical and experimental studies IL-33 and its receptor have been found to play important roles in the development of asthma and allergic airway inflammation. We evaluated the effects of vaccination against IL-33 in a mouse model of airway inflammation induced by house dust mite (HDM allergen. Balb/c mice received the IL-33 vaccine subcutaneously, followed by intranasal administration of HDM for up to six weeks. Vaccination against IL-33 induced high titers of specific anti-IL-33 IgG antibodies that inhibited HDM-induced airway hyperresponsiveness (AHR in the conducting airways and tissue damping. The vaccination also attenuated the HDM-induced elevation in the numbers of eosinophils in bronchoalveolar lavage fluid (BALF and suppressed the accumulation of inflammatory cells in the airways. Furthermore, the levels of IL-17A, IL-25, IL-33 and TSLP in lung tissue homogenates were reduced by vaccination against IL-33. These observations demonstrate that vaccination against IL-33 inhibits HDM-induced development of AHR, airway inflammation and production of inflammatory cytokines. The results also indicate an important role of IL-33 in the regulation of AHR of the distal lung compartments. Thus, administration of such a vaccine is potentially an effective therapeutic tool for treating allergic asthma.

β-Catenin promotes colitis and colon cancer through imprinting of proinflammatory properties in T cells.

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Keerthivasan, Shilpa; Aghajani, Katayoun; Dose, Marei; Molinero, Luciana; Khan, Mohammad W; Venkateswaran, Vysak; Weber, Christopher; Emmanuel, Akinola Olumide; Sun, Tianjao; Bentrem, David J; Mulcahy, Mary; Keshavarzian, Ali; Ramos, Elena M; Blatner, Nichole; Khazaie, Khashayarsha; Gounari, Fotini

2014-02-26

The density and type of lymphocytes that infiltrate colon tumors are predictive of the clinical outcome of colon cancer. High densities of T helper 17 (T(H)17) cells and inflammation predict poor outcome, whereas infiltration by T regulatory cells (Tregs) that naturally suppress inflammation is associated with longer patient survival. However, the role of Tregs in cancer remains controversial. We recently reported that Tregs in colon cancer patients can become proinflammatory and tumor-promoting. These properties were directly linked with their expression of RORγt (retinoic acid-related orphan receptor-γt), the signature transcription factor of T(H)17 cells. We report that Wnt/β-catenin signaling in T cells promotes expression of RORγt. Expression of β-catenin was elevated in T cells, including Tregs, of patients with colon cancer. Genetically engineered activation of β-catenin in mouse T cells resulted in enhanced chromatin accessibility in the proximity of T cell factor-1 (Tcf-1) binding sites genome-wide, induced expression of T(H)17 signature genes including RORγt, and promoted T(H)17-mediated inflammation. Strikingly, the mice had inflammation of small intestine and colon and developed lesions indistinguishable from colitis-induced cancer. Activation of β-catenin only in Tregs was sufficient to produce inflammation and initiate cancer. On the basis of these findings, we conclude that activation of Wnt/β-catenin signaling in effector T cells and/or Tregs is causatively linked with the imprinting of proinflammatory properties and the promotion of colon cancer.

Berberine Reduces cAMP-Induced Chloride Secretion in T84 Human Colonic Carcinoma Cells through Inhibition of Basolateral KCNQ1 Channels.

LENUS (Irish Health Repository)

Alzamora, Rodrigo

2011-01-01

Berberine is a plant alkaloid with multiple pharmacological actions, including antidiarrhoeal activity and has been shown to inhibit Cl(-) secretion in distal colon. The aims of this study were to determine the molecular signaling mechanisms of action of berberine on Cl(-) secretion and the ion transporter targets. Monolayers of T84 human colonic carcinoma cells grown in permeable supports were placed in Ussing chambers and short-circuit current measured in response to secretagogues and berberine. Whole-cell current recordings were performed in T84 cells using the patch-clamp technique. Berberine decreased forskolin-induced short-circuit current in a concentration-dependent manner (IC(50) 80 ± 8 μM). In apically permeabilized monolayers and whole-cell current recordings, berberine inhibited a cAMP-dependent and chromanol 293B-sensitive basolateral membrane K(+) current by 88%, suggesting inhibition of KCNQ1 K(+) channels. Berberine did not affect either apical Cl(-) conductance or basolateral Na(+)-K(+)-ATPase activity. Berberine stimulated p38 MAPK, PKCα and PKA, but had no effect on p42\\/p44 MAPK and PKCδ. However, berberine pre-treatment prevented stimulation of p42\\/p44 MAPK by epidermal growth factor. The inhibitory effect of berberine on Cl(-) secretion was partially blocked by HBDDE (∼65%), an inhibitor of PKCα and to a smaller extent by inhibition of p38 MAPK with SB202190 (∼15%). Berberine treatment induced an increase in association between PKCα and PKA with KCNQ1 and produced phosphorylation of the channel. We conclude that berberine exerts its inhibitory effect on colonic Cl(-) secretion through inhibition of basolateral KCNQ1 channels responsible for K(+) recycling via a PKCα-dependent pathway.

Berberine Reduces cAMP-Induced Chloride Secretion in T84 Human Colonic Carcinoma Cells through Inhibition of Basolateral KCNQ1 Channels.

LENUS (Irish Health Repository)

Alzamora, Rodrigo

2012-02-01

Berberine is a plant alkaloid with multiple pharmacological actions, including antidiarrhoeal activity and has been shown to inhibit Cl(-) secretion in distal colon. The aims of this study were to determine the molecular signaling mechanisms of action of berberine on Cl(-) secretion and the ion transporter targets. Monolayers of T84 human colonic carcinoma cells grown in permeable supports were placed in Ussing chambers and short-circuit current measured in response to secretagogues and berberine. Whole-cell current recordings were performed in T84 cells using the patch-clamp technique. Berberine decreased forskolin-induced short-circuit current in a concentration-dependent manner (IC(50) 80 +\\/- 8 muM). In apically permeabilized monolayers and whole-cell current recordings, berberine inhibited a cAMP-dependent and chromanol 293B-sensitive basolateral membrane K(+) current by 88%, suggesting inhibition of KCNQ1 K(+) channels. Berberine did not affect either apical Cl(-) conductance or basolateral Na(+)-K(+)-ATPase activity. Berberine stimulated p38 MAPK, PKCalpha and PKA, but had no effect on p42\\/p44 MAPK and PKCdelta. However, berberine pre-treatment prevented stimulation of p42\\/p44 MAPK by epidermal growth factor. The inhibitory effect of berberine on Cl(-) secretion was partially blocked by HBDDE ( approximately 65%), an inhibitor of PKCalpha and to a smaller extent by inhibition of p38 MAPK with SB202190 ( approximately 15%). Berberine treatment induced an increase in association between PKCalpha and PKA with KCNQ1 and produced phosphorylation of the channel. We conclude that berberine exerts its inhibitory effect on colonic Cl(-) secretion through inhibition of basolateral KCNQ1 channels responsible for K(+) recycling via a PKCalpha-dependent pathway.

Inhibition of colon carcinogenesis by a standardized Cannabis sativa extract with high content of cannabidiol.

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Romano, Barbara; Borrelli, Francesca; Pagano, Ester; Cascio, Maria Grazia; Pertwee, Roger G; Izzo, Angelo A

2014-04-15

Colon cancer is a major public health problem. Cannabis-based medicines are useful adjunctive treatments in cancer patients. Here, we have investigated the effect of a standardized Cannabis sativa extract with high content of cannabidiol (CBD), here named CBD BDS, i.e. CBD botanical drug substance, on colorectal cancer cell proliferation and in experimental models of colon cancer in vivo. Proliferation was evaluated in colorectal carcinoma (DLD-1 and HCT116) as well as in healthy colonic cells using the MTT assay. CBD BDS binding was evaluated by its ability to displace [(3)H]CP55940 from human cannabinoid CB1 and CB2 receptors. In vivo, the effect of CBD BDS was examined on the preneoplastic lesions (aberrant crypt foci), polyps and tumours induced by the carcinogenic agent azoxymethane (AOM) as well as in a xenograft model of colon cancer in mice. CBD BDS and CBD reduced cell proliferation in tumoral, but not in healthy, cells. The effect of CBD BDS was counteracted by selective CB1 and CB2 receptor antagonists. Pure CBD reduced cell proliferation in a CB1-sensitive antagonist manner only. In binding assays, CBD BDS showed greater affinity than pure CBD for both CB1 and CB2 receptors, with pure CBD having very little affinity. In vivo, CBD BDS reduced AOM-induced preneoplastic lesions and polyps as well as tumour growth in the xenograft model of colon cancer. CBD BDS attenuates colon carcinogenesis and inhibits colorectal cancer cell proliferation via CB1 and CB2 receptor activation. The results may have some clinical relevance for the use of Cannabis-based medicines in cancer patients. Copyright © 2013 Elsevier GmbH. All rights reserved.

Combination of capecitabine and ludartin inhibits colon cancer ...

African Journals Online (AJOL)

Methods: Mice model of colon cancer was used in this study. Quantitative ... mRNA. Micro-vessel density was assessed using immunohistochemical analysis. ... increase in white blood cell (WBC) count, and increased median survival time of colon cancer mice from ..... tumor cells is associated with the development of.

Lipopolysaccharide inhibits colonic biotin uptake via interference with membrane expression of its transporter: a role for a casein kinase 2-mediated pathway.

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Lakhan, Ram; Said, Hamid M

2017-04-01

Biotin (vitamin B7), an essential micronutrient for normal cellular functions, is obtained from both dietary sources as well as gut microbiota. Absorption of biotin in both the small and large intestine is via a carrier-mediated process that involves the sodium-dependent multivitamin transporter (SMVT). Although different physiological and molecular aspects of intestinal biotin uptake have been delineated, nothing is known about the effect of LPS on the process. We addressed this issue using in vitro (human colonic epithelial NCM460 cells) and in vivo (mice) models of LPS exposure. Treating NCM460 cells with LPS was found to lead to a significant inhibition in carrier-mediated biotin uptake. Similarly, administration of LPS to mice led to a significant inhibition in biotin uptake by native colonic tissue. Although no changes in total cellular SMVT protein and mRNA levels were observed, LPS caused a decrease in the fraction of SMVT expressed at the cell surface. A role for casein kinase 2 (CK2) (whose activity was also inhibited by LPS) in mediating the endotoxin effects on biotin uptake and on membrane expression of SMVT was suggested by findings that specific inhibitors of CK2, as well as mutating the putative CK2 phosphorylation site (Thr 78 Ala) in the SMVT protein, led to inhibition in biotin uptake and membrane expression of SMVT. This study shows for the first time that LPS inhibits colonic biotin uptake via decreasing membrane expression of its transporter and that these effects likely involve a CK2-mediated pathway.

Methylselenol, a selenium metabolite, modulates p53 pathway and inhibits the growth of colon cancer xenografts in Balb/c mice.

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Zeng, Huawei; Cheng, Wen-Hsing; Johnson, Luann K

2013-05-01

It is has been hypothesized that methylselenol is a critical selenium metabolite for anticancer activity in vivo. In this study, we used a protein array which contained 112 different antibodies known to be involved in the p53 pathway to investigate the molecular targets of methylselenol in human HCT116 colon cancer cells. The array analysis indicated that methylselenol exposure changed the expression of 11 protein targets related to the regulation of cell cycle and apoptosis. Subsequently, we confirmed these proteins with the Western blotting approach, and found that methylselenol increased the expression of GADD 153 and p21 but reduced the level of c-Myc, E2F1 and Phos p38 MAP kinase. Similar to our previous report on human HCT116 colon cancer cells, methylselenol also inhibited cell growth and led to an increase in G1 and G2 fractions with a concomitant drop in S-phase in mouse colon cancer MC26 cells. When the MC26 cells were transplanted to their immune-competent Balb/c mice, methylselenol-treated MC26 cells had significantly less tumor growth potential than that of untreated MC26 cells. Taken together, our data suggest that methylselenol modulates the expression of key genes related to cell cycle and apoptosis and inhibits colon cancer cell proliferation and tumor growth. Copyright © 2013. Published by Elsevier Inc.

Inhibition of PKR protects against H2O2-induced injury on neonatal cardiac myocytes by attenuating apoptosis and inflammation.

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Wang, Yongyi; Men, Min; Xie, Bo; Shan, Jianggui; Wang, Chengxi; Liu, Jidong; Zheng, Hui; Yang, Wengang; Xue, Song; Guo, Changfa

2016-12-08

Reactive oxygenation species (ROS) generated from reperfusion results in cardiac injury through apoptosis and inflammation, while PKR has the ability to promote apoptosis and inflammation. The aim of the study was to investigate whether PKR is involved in hydrogen peroxide (H 2 O 2 ) induced neonatal cardiac myocytes (NCM) injury. In our study, NCM, when exposed to H 2 O 2 , resulted in persistent activation of PKR due to NCM endogenous RNA. Inhibition of PKR by 2-aminopurine (2-AP) or siRNA protected against H 2 O 2 induced apoptosis and injury. To elucidate the mechanism, we revealed that inhibition of PKR alleviated H 2 O 2 induced apoptosis companied by decreased caspase3/7 activity, BAX and caspase-3 expression. We also revealed that inhibition of PKR suppressed H 2 O 2 induced NFκB pathway and NLRP3 activation. Finally, we found ADAR1 mRNA and protein expression were both induced after H 2 O 2 treatment through STAT-2 dependent pathway. By gain and loss of ADAR1 expression, we confirmed ADAR1 modulated PKR activity. Therefore, we concluded inhibition of PKR protected against H 2 O 2 -induced injury by attenuating apoptosis and inflammation. A self-preservation mechanism existed in NCM that ADAR1 expression is induced by H 2 O 2 to limit PKR activation simultaneously. These findings identify a novel role for PKR/ADAR1 in myocardial reperfusion injury.

[6]-Gingerol induces caspase-dependent apoptosis and prevents PMA-induced proliferation in colon cancer cells by inhibiting MAPK/AP-1 signaling.

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E K Radhakrishnan

Full Text Available We report mechanism-based evidence for the anticancer and chemopreventive efficacy of [6]-gingerol, the major active principle of the medicinal plant, Ginger (Zingiber officinale, in colon cancer cells. The compound was evaluated in two human colon cancer cell lines for its cytotoxic effect and the most sensitive cell line, SW-480, was selected for the mechanistic evaluation of its anticancer and chemopreventive efficacy. The non-toxic nature of [6]-gingerol was confirmed by viability assays on rapidly dividing normal mouse colon cells. [6]-gingerol inhibited cell proliferation and induced apoptosis as evidenced by externalization of phosphatidyl serine in SW-480, while the normal colon cells were unaffected. Sensitivity to [6]-gingerol in SW-480 cells was associated with activation of caspases 8, 9, 3 &7 and cleavage of PARP, which attests induction of apoptotic cell death. Mechanistically, [6]-gingerol down-regulated Phorbol Myristate Acetate (PMA induced phosphorylation of ERK1/2 and JNK MAP kinases and activation of AP-1 transcription factor, but had only little effects on phosphorylation of p38 MAP kinase and activation of NF-kappa B. Additionally, it complemented the inhibitors of either ERK1/2 or JNK MAP kinase in bringing down the PMA-induced cell proliferation in SW-480 cells. We report the inhibition of ERK1/2/JNK/AP-1 pathway as a possible mechanism behind the anticancer as well as chemopreventive efficacy of [6]-gingerol against colon cancer.

Could Aspirin and Diets High in Fiber Act Synergistically to Reduce the Risk of Colon Cancer in Humans?

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Pan Pan

2018-01-01

Full Text Available Early inhibition of inflammation suppresses the carcinogenic process. Aspirin is the most commonly used non-steroid anti-inflammatory drugs (NSAIDs, and it irreversibly inhibits cyclooxygenase-1 and -2 (COX1, COX2. Multiple randomized clinical trials have demonstrated that aspirin offers substantial protection from colon cancer mortality. The lower aspirin doses causing only minimal gastrointestinal disturbance, ideal for long-term use, can achieve only partial and transitory inhibition of COX2. Aspirin’s principal metabolite, salicylic acid, is also found in fruits and vegetables that inhibit COX2. Other phytochemicals such as curcumin, resveratrol, and anthocyanins also inhibit COX2. Such dietary components are good candidates for combination with aspirin because they have little or no toxicity. However, obstacles to using phytochemicals for chemoprevention, including bioavailability and translational potential, must be resolved. The bell/U-shaped dose–response curves seen with vitamin D and resveratrol might apply to other phytochemicals, shedding doubt on ‘more is better’. Solutions include: (1 using special delivery systems (e.g., nanoparticles to retain phytochemicals; (2 developing robust pharmacodynamic biomarkers to determine efficacy in humans; and (3 selecting pharmacokinetic doses relevant to humans when performing preclinical experiments. The combination of aspirin and phytochemicals is an attractive low-cost and low-toxicity approach to colon cancer prevention that warrants testing, particularly in high-risk individuals.

Efficient Inhibition of wear debris-induced inflammation by locally delivered siRNA

International Nuclear Information System (INIS)

Peng Xiaochun; Tao Kun; Cheng Tao; Zhu Junfeng; Zhang Xianlong

2008-01-01

Aseptic loosening is the most common long-term complication of total joint replacement, which is associated with the generation of wear debris. The purpose of this study was to investigate the inhibitory effect of small interfering RNA (siRNA) targeting tumor necrosis factor-α (TNF-α) on wear debris-induced inflammation. A local delivery of lentivirus-mediated TNF-α siRNA into the modified murine air pouch, which was stimulated by polymethylmethacrylate (PMMA) particles, resulted in significant blockage of TNF-α both in mRNA and protein levels for up to 4 weeks. In addition, significant down-regulation of interleukin-1 (IL-1) and interleukin-6 (IL-6) was observed in TNF-α siRNA-treated pouches. The safety profile of gene therapy was proven by Bioluminescent assay and quantitative fluorescent flux. Histological analysis revealed less inflammatory responses (thinner pouch membrane and decreased cellular infiltration) in TNF-α siRNA-treated pouches. These findings suggest that local delivery of TNF-α siRNA might be an excellent therapeutic candidate to inhibit particle-induced inflammation.

Combination of capecitabine and ludartin inhibits colon cancer ...

African Journals Online (AJOL)

Purpose: To investigate the efficacy of capecitabine and ludartin in the treatment of colon cancer in mice. Methods: Mice model of colon cancer was used in this study. Quantitative real-time polymerase chain reaction (Qrt-PCR) was used to quantify the expression of vascular endothelial growth factor (VEGF) mRNA.

Inositol Hexaphosphate Inhibits Proliferation and Induces Apoptosis of Colon Cancer Cells by Suppressing the AKT/mTOR Signaling Pathway

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Małgorzata Kapral

2017-10-01

Full Text Available Abstract: AKT, a serine/threonine protein kinase and mammalian target of rapamycin (mTOR plays a critical role in the proliferation and resistance to apoptosis that are essential to the development and progression of colon cancer. Therefore, AKT/mTOR signaling pathway has been recognized as an attractive target for anticancer therapy. Inositol hexaphosphate (InsP6, a natural occurring phytochemical, has been shown to have both preventive and therapeutic effects against various cancers, however, its exact molecular mechanisms of action are not fully understood. The aim of the in vitro study was to investigate the anticancer activity of InsP6 on colon cancer with the focus on inhibiting the AKT1 kinase and p70S6K1 as mTOR effector, in relation to proliferation and apoptosis of cells. The colon cancer Caco-2 cells were cultured using standard techniques and exposed to InsP6 at different concentrations (1 mM, 2.5 mM and 5 mM. Cellular proliferative activity was monitored by 5-bromo-2′-deoxyuridine (BrdU incorporation into cellular DNA. Flow cytometric analysis was performed for cell cycle progression and apoptosis studies. Real-time RT-qPCR was used to validate mRNA levels of CDNK1A, CDNK1B, CASP3, CASP9, AKT1 and S6K1 genes. The concentration of p21 protein as well as the activities of caspase 3, AKT1 and p70S6K1 were determined by the ELISA method. The results revealed that IP6 inhibited proliferation and stimulated apoptosis of colon cancer cells. This effect was mediated by an increase in the expression of genes encoding p21, p27, caspase 3, caspase 9 as well a decrease in transcription of AKT1 and S6K1. InsP6 suppressed phosphorylation of AKT1 and p70S6K1, downstream effector of mTOR. Based on these studies it may be concluded that InsP6 can reduce proliferation and induce apoptosis through inhibition of the AKT/mTOR pathway and mTOR effector followed by modulation of the expression and activity of several key components of these pathways in

Matrine suppresses airway inflammation by downregulating SOCS3 expression via inhibition of NF-κB signaling in airway epithelial cells and asthmatic mice

Energy Technology Data Exchange (ETDEWEB)

Sun, Daqing [Department of Respiration, Xi’an Children’s Hospital, Xi’an 710003 (China); Wang, Jing [Department of Neonatology, Xi’an Children’s Hospital, Xi’an 710003 (China); Yang, Niandi [Outpatient Department, School of Aerospace Engineering, Air Force Engineering University, Xi’an 710038 (China); Ma, Haixin, E-mail: drhaixinma@163.com [Department of Quality Control, Xi’an Children’s Hospital, Xi’an 710003 (China)

2016-08-12

Matrine has been demonstrated to attenuate allergic airway inflammation. Elevated suppressor of cytokine signaling 3 (SOCS3) was correlated with the severity of asthma. The aim of this study was to investigate the effect of matrine on SOCS3 expression in airway inflammation. In this study, we found that matrine significantly inhibited OVA-induced AHR, inflammatory cell infiltration, goblet cell differentiation, and mucous production in a dose-dependent manner in mice. Matrine also abrogated the level of interleukin (IL)-4 and IL-13, but enhanced interferon (IFN)-γ expression, both in BALF and in lung homogenates. Furthermore, matrine impeded TNF-α-induced the expression of IL-6 and adhesion molecules in airway epithelial cells (BEAS-2B and MLE-12). Additionally, we found that matrine inhibited SOCS3 expression, both in asthmatic mice and TNF-α-stimulated epithelial cells via suppression of the NF-κB signaling pathway by using pcDNA3.1-SOCS3 plasmid, SOCS3 siRNA, or nuclear factor kappa-B (NF-κB) inhibitor PDTC. Conclusions: Matrine suppresses airway inflammation by downregulating SOCS3 expression via inhibition of NF-κB signaling in airway epithelial cells and asthmatic mice. - Highlights: • Matrine attenuates asthmatic symptoms and regulates Th1/Th2 balance in vivo. • Matrine suppresses inflammation responses in vitro. • Matrine decreases SOCS3 expression both in vivo and in vitro. • Matrine inhibits SOCS3 expression by suppressing NF-κB signaling.

Torilin Inhibits Inflammation by Limiting TAK1-Mediated MAP Kinase and NF-κB Activation

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Mehari Endale

2017-01-01

Full Text Available Torilin, a sesquiterpene isolated from the fruits of Torilis japonica, has shown antimicrobial, anticancer, and anti-inflammatory properties. However, data on the mechanism of torilin action against inflammation is limited. This study aimed at determining the anti-inflammatory property of torilin in LPS-induced inflammation using in vitro model of inflammation. We examined torilin’s effect on expression levels of inflammatory mediators and cytokines in LPS-stimulated RAW 264.7 macrophages. The involvement of NF-kB and AP-1, MAP kinases, and adaptor proteins were assessed. Torilin strongly inhibited LPS-induced NO release, iNOS, PGE2, COX-2, NF-α, IL-1β, IL-6, and GM-CSF gene and protein expressions. In addition, MAPKs were also suppressed by torilin pretreatment. Involvement of ERK1/2, P38MAPK, and JNK1/2 was further confirmed by PD98059, SB203580, and SP600125 mediated suppression of iNOS and COX-2 proteins. Furthermore, torilin attenuated NF-kB and AP-1 translocation, DNA binding, and reporter gene transcription. Interestingly, torilin inhibited TAK1 kinase activation with the subsequent suppression of MAPK-mediated JNK, p38, ERK1/2, and AP-1 (ATF-2 and c-jun activation and IKK-mediated I-κBα degradation, p65/p50 activation, and translocation. Together, the results revealed the suppression of NF-κB and AP-1 regulated inflammatory mediator and cytokine expressions, suggesting the test compound’s potential as a candidate anti-inflammatory agent.

E-selectin: sialyl Lewis, a dependent adhesion of colon cancer cells, is inhibited differently by antibodies against E-selectin ligands.

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Srinivas, U; Påhlsson, P; Lundblad, A

1996-09-01

Recent studies have demonstrated that selectins, a new family of cell-adhesion molecules with similar domain structures, mediate the adhesion of peripheral blood cells to interleukin-1 (IL-1)-activated endothelium. In the present study the authors evaluated the role of E-selectin-Sialyl Lewis x (SLe(x))/ Sialyl Lewis a (SLe(a)) interaction in mediating in vitro adhesion of two colon cancer cell lines, HT-29 and COLO 201, to human umbilical cord endothelial cells (HUVEC). Colon cancer cell lines had a strong expression of blood group-related carbohydrate epitopes as evaluated by fluorescence-activated cell sorter (FACS) analysis. It was established that adhesion of HT-29 and COLO 201 cells to IL-1 stimulated HUVEC was calcium dependent and could be inhibited by a monoclonal antibody directed against E-selectin. Prior incubation of cells with two different antibodies directed against SLe(x) and antibodies directed against related Lewis epitopes, Le(x) and Le(a), had no significant effect on adhesion. Three antibodies directed against SLe(a) differed in their capacity to inhibit the adhesion of HT-29 and COLO 201 cells to HUVEC. Only one antibody directed against the SLe(a) structure was effective in inhibiting adhesion of both COLO 201 and HT-29 cells. The difference could not be attributed to titre, the type or number of glycoproteins, or to a difference in the amount of SLe(a) present on individual proteins, suggesting that presence and right presentation of SLe(a) epitope might be important for adhesion of colon cancer cells. Finally, in the in vitro system used, adhesion of HT-29 and COLO 201 cells to activated HUVEC is mediated predominantly by E-selectin/SLe(a) interaction. SLe(x) and related epitopes, Le(x) and Le(a), seem to have limited relevance for colon cancer cell recognition of E-selectin.

Jussara (Euterpe edulis Mart. Supplementation during Pregnancy and Lactation Modulates the Gene and Protein Expression of Inflammation Biomarkers Induced by trans-Fatty Acids in the Colon of Offspring

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Carina Almeida Morais

2014-01-01

Full Text Available Maternal intake of trans-fatty acids (TFAs in the perinatal period triggers a proinflammatory state in offspring. Anthocyanins contained in fruit are promising modulators of inflammation. This study investigated the effect of Jussara supplementation in the maternal diet on the proinflammatory state of the colon in offspring exposed to perinatal TFAs. On the first day of pregnancy rats were divided into four groups: control diet (C, control diet with 0.5% Jussara supplementation (CJ, diet enriched with hydrogenated vegetable fat, rich in TFAs (T, or T diet supplemented with 0.5% Jussara (TJ during pregnancy and lactation. We showed that Jussara supplementation in maternal diet (CJ and TJ groups reduced carcass lipid/protein ratios, serum lipids, glucose, IL-6, TNF-α, gene expression of IL-6R, TNF-αR (P<0.05, TLR-4 (P<0.01, and increase Lactobacillus spp. (P<0.05 in the colon of offspring compared to the T group. The IL-10 (P=0.035 and IL-10/TNF-α ratio (P<0.01 was higher in the CJ group than in the T group. The 0.5% Jussara supplementation reverses the adverse effects of perinatal TFAs, improving lipid profiles, glucose levels, body composition, and gut microbiota and reducing low-grade inflammation in the colon of 21-day-old offspring, and could contribute to reducing chronic disease development.

[Effect of nonsteroidal antiinflammatory drugs on colonic lipoxygenase and cyclooxygenase activities from patients with colonic neoplasia].

Science.gov (United States)

Di Girolamo, G; Franchi, A; De Los Santos, A R; Martí, M L; Farina, M; Fernández de Gimeno, M A

2001-01-01

Lysine clonixinate (LC) is a nonsteroidal anti-inflammatory drug (NSAID) with good gastrointestinal tolerance. Treatment with LC at levels equivalent to those found in plasma following therapeutic doses resulted in significant inhibition of both cyclooxygenase 2 (COX-2) and production of 5 hydroxy-eicosatetraeonic acid (5-HETE) and slightly affected levels of cyclooxygenase 1 (COX-1) in in vitro studies carried out on human tissues. This study deals with the in vivo effect of the drug on human colon segments. Experiment 1: Five patients about to undergo hemicholectomy due to colon neoplasia were treated preoperatively with a continuous infusion of LC, to achieve a steady-state concentration between 4 and 6 mg/ml. Human colon segments from the five patients and from another five control patients receiving no treatment with [14C]-arachidonic acid were incubated. Human colon segments treated with LC showed significant inhibition of PGE2, the only prostaglandin (PG) synthesised by the tissue, as well as of 5-HETE. Experiment 2: Fifteen patients received an i.v. bolus of LC 100 mg (n1 = 5); LC 200 mg (n2 = 5) or indomethacin (INDO) 50 mg (n3 = 5). Both doses of LC showed greater inhibition of PGE2 synthesis than the INDO bolus. Both NSAIDs studied proved to have different effects on the production of 5-HETE; while treatment with LC elicited significant inhibition, levels with INDO remained unchanged. Western blotting analysis showed expression of both COX isoforms in colon segments, COX-2 levels being 20% higher. Both types of in vivo studies conducted continuous infusion and i.v. bolus, revealed that LC exerted significant inhibition of basal synthesis of PGE2 and 5-HETE.

DNA repair is indispensable for survival after acute inflammation

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Calvo, Jennifer A.; Meira, Lisiane B.; Lee, Chun-Yue I.; Moroski-Erkul, Catherine A.; Abolhassani, Nona; Taghizadeh, Koli; Eichinger, Lindsey W.; Muthupalani, Sureshkumar; Nordstrand, Line M.; Klungland, Arne; Samson, Leona D.

2012-01-01

More than 15% of cancer deaths worldwide are associated with underlying infections or inflammatory conditions, therefore understanding how inflammation contributes to cancer etiology is important for both cancer prevention and treatment. Inflamed tissues are known to harbor elevated etheno-base (ε-base) DNA lesions induced by the lipid peroxidation that is stimulated by reactive oxygen and nitrogen species (RONS) released from activated neutrophils and macrophages. Inflammation contributes to carcinogenesis in part via RONS-induced cytotoxic and mutagenic DNA lesions, including ε-base lesions. The mouse alkyl adenine DNA glycosylase (AAG, also known as MPG) recognizes such base lesions, thus protecting against inflammation-associated colon cancer. Two other DNA repair enzymes are known to repair ε-base lesions, namely ALKBH2 and ALKBH3; thus, we sought to determine whether these DNA dioxygenase enzymes could protect against chronic inflammation-mediated colon carcinogenesis. Using established chemically induced colitis and colon cancer models in mice, we show here that ALKBH2 and ALKBH3 provide cancer protection similar to that of the DNA glycosylase AAG. Moreover, Alkbh2 and Alkbh3 each display apparent epistasis with Aag. Surprisingly, deficiency in all 3 DNA repair enzymes confers a massively synergistic phenotype, such that animals lacking all 3 DNA repair enzymes cannot survive even a single bout of chemically induced colitis. PMID:22684101

Genetic disruption of tubulin acetyltransferase, αTAT1, inhibits proliferation and invasion of colon cancer cells through decreases in Wnt1/β-catenin signaling

International Nuclear Information System (INIS)

Oh, Somi; You, Eunae; Ko, Panseon; Jeong, Jangho; Keum, Seula; Rhee, Sangmyung

2017-01-01

Microtubules are required for diverse cellular processes, and abnormal regulation of microtubule dynamics is closely associated with severe diseases including malignant tumors. In this study, we report that α-tubulin N-acetyltransferase (αTAT1), a regulator of α-tubulin acetylation, is required for colon cancer proliferation and invasion via regulation of Wnt1 and its downstream genes expression. Public transcriptome analysis showed that expression of ATAT1 is specifically upregulated in colon cancer tissue. A knockout (KO) of ATAT1 in the HCT116 colon cancer cell line, using the CRISPR/Cas9 system showed profound inhibition of proliferative and invasive activities of these cancer cells. Overexpression of αTAT1 or the acetyl-mimic K40Q α-tubulin mutant in αTAT1 KO cells restored the invasiveness, indicating that microtubule acetylation induced by αTAT1 is critical for HCT116 cell invasion. Analysis of colon cancer-related gene expression in αTAT1 KO cells revealed that the loss of αTAT1 decreased the expression of WNT1. Mechanistically, abrogation of tubulin acetylation by αTAT1 knockout inhibited localization of β-catenin to the plasma membrane and nucleus, thereby resulting in the downregulation of Wnt1 and of its downstream genes including CCND1, MMP-2, and MMP-9. These results suggest that αTAT1-mediated Wnt1 expression via microtubule acetylation is important for colon cancer progression. - Highlights: • Ablation of αTAT1 inhibits HCT116 colon cancer cell invasion. • αTAT1/acetylated microtubules regulate expression of Wnt1/β-catenin target genes. • Acetylated microtubules regulate cellular localization of β-catenin. • Loss of αTAT1 prevents Wnt1 from inducing β-catenin-dependent and -independent pathways.

Tofacitinib restores the inhibition of reverse cholesterol transport induced by inflammation: understanding the lipid paradox associated with rheumatoid arthritis.

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Pérez-Baos, S; Barrasa, J I; Gratal, P; Larrañaga-Vera, A; Prieto-Potin, I; Herrero-Beaumont, G; Largo, R

2017-09-01

Patients with active rheumatoid arthritis (RA) have increased cardiovascular mortality, paradoxically associated with reduced circulating lipid levels. The JAK inhibitor tofacitinib ameliorates systemic and joint inflammation in RA with a concomitant increase in serum lipids. We analysed the effect of tofacitinib on the lipid profile of hyperlipidaemic rabbits with chronic arthritis (CA) and on the changes in reverse cholesterol transport (RCT) during chronic inflammation. CA was induced in previously immunized rabbits, fed a high-fat diet, by administering four intra-articular injections of ovalbumin. A group of rabbits received tofacitinib (10 mg·kg -1 ·day -1 ) for 2 weeks. Systemic and synovial inflammation and lipid content were evaluated. For in vitro studies, THP-1-derived macrophages were exposed to high lipid concentrations and then stimulated with IFNγ in the presence or absence of tofacitinib in order to study mediators of RCT. Tofacitinib decreased systemic and synovial inflammation and increased circulating lipid levels. Although it did not modify synovial macrophage density, it reduced the lipid content within synovial macrophages. In foam macrophages in culture, IFNγ further stimulated intracellular lipid accumulation, while the JAK/STAT inhibition provoked by tofacitinib induced lipid release by increasing the levels of cellular liver X receptor α and ATP-binding cassette transporter (ABCA1) synthesis. Active inflammation could be associated with lipid accumulation within macrophages of CA rabbits. JAK inhibition induced lipid release through RCT activation, providing a plausible explanation for the effect of tofacitinib on the lipid profile of RA patients. © 2017 The British Pharmacological Society.

Natural products to improve quality of life targeting for colon drug delivery.

Science.gov (United States)

Kim, Hyunjo

2012-03-01

The colon is largely being investigated as a site for administration of protein and peptides, which are degraded by digestive enzymes in the upper GIT. Also for local diseases of the colon such as inflammatory bowel disease, colorectal cancer and ameobiasis, drug administration to the site of action can not only reduce the dose to be administered, but also decrease the side effects. Inflammatory Bowel Disease (IBD) such as Ulcerative colitis and Crohn's disease are characterized by chronic intestinal inflammation. Intestinal bacteria initiate the activation of intestinal inflammatory processes, which are mediated by pro-inflammatory cytokines and chemokine. Increased chemokine expression has also been observed in epithelial cells, endothelial cells, and smooth muscle cells. Future trials of specific agents capable of inhibiting chemokine synthesis and secretion or blocking chemokine-chemokine receptor interaction will be important to study in patients with ulcerative colitis and Crohn's disease. Many important bioactive compounds have been discovered from natural sources using bioactivity directed fractionation and isolation (BDFl) Continuing discovery has also been facilitated by the recent development of new bioassay methods. These bioactive compounds are mostly plant secondary metabolites, and many naturally occurring pure compounds have become medicines, dietary supplements, and other useful commercial products. The present review includes various approaches investigated for colon drug delivery and their site specificity. To achieve successful colonic delivery, a drug needs to be protected from absorption and the environment of the upper gastrointestinal tract and then be abruptly released into the proximal colon, which is considered the optimum site for colon targeted delivery of drugs.

Bile acids deoxycholic acid and ursodeoxycholic acid differentially regulate human β-defensin-1 and -2 secretion by colonic epithelial cells.

Science.gov (United States)

Lajczak, Natalia K; Saint-Criq, Vinciane; O'Dwyer, Aoife M; Perino, Alessia; Adorini, Luciano; Schoonjans, Kristina; Keely, Stephen J

2017-09-01

Bile acids and epithelial-derived human β-defensins (HβDs) are known to be important factors in the regulation of colonic mucosal barrier function and inflammation. We hypothesized that bile acids regulate colonic HβD expression and aimed to test this by investigating the effects of deoxycholic acid (DCA) and ursodeoxycholic acid on the expression and release of HβD1 and HβD2 from colonic epithelial cells and mucosal tissues. DCA (10-150 µM) stimulated the release of both HβD1 and HβD2 from epithelial cell monolayers and human colonic mucosal tissue in vitro In contrast, ursodeoxycholic acid (50-200 µM) inhibited both basal and DCA-induced defensin release. Effects of DCA were mimicked by the Takeda GPCR 5 agonist, INT-777 (50 μM), but not by the farnesoid X receptor agonist, GW4064 (10 μM). INT-777 also stimulated colonic HβD1 and HβD2 release from wild-type, but not Takeda GPCR 5 -/- , mice. DCA stimulated phosphorylation of the p65 subunit of NF-κB, an effect that was attenuated by ursodeoxycholic acid, whereas an NF-κB inhibitor, BMS-345541 (25 μM), inhibited DCA-induced HβD2, but not HβD1, release. We conclude that bile acids can differentially regulate colonic epithelial HβD expression and secretion and discuss the implications of our findings for intestinal health and disease.-Lajczak, N. K., Saint-Criq, V., O'Dwyer, A. M., Perino, A., Adorini, L., Schoonjans, K., Keely, S. J. Bile acids deoxycholic acid and ursodeoxycholic acid differentially regulate human β-defensin-1 and -2 secretion by colonic epithelial cells. © FASEB.

Colon-targeted delivery of piceatannol enhances anti-colitic effects of the natural product: potential molecular mechanisms for therapeutic enhancement

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Yum S

2015-08-01

Full Text Available Soohwan Yum, Seongkeun Jeong, Sunyoung Lee, Joon Nam, Wooseong Kim, Jin-Wook Yoo, Min-Soo Kim, Bok Luel Lee, Yunjin Jung College of Pharmacy, Pusan National University, Busan, Republic of Korea Abstract: Piceatannol (PCT, an anti-colitic natural product, undergoes extensive Phase II hepatic metabolism, resulting in very low bioavailability. We investigated whether colon-targeted delivery of PCT could enhance anti-colitic effects and how therapeutic enhancement occurred at the molecular level. Molecular effects of PCT were examined in human colon carcinoma cells and inflamed colons. The anti-colitic effects of PCT in a colon-targeted capsule (colon-targeted PCT were compared with PCT in a gelatin capsule (conventional PCT in a trinitrobenzene sulfonic acid-induced rat colitis model. Colon-targeted PCT elicited greatly enhanced recovery of the colonic inflammation. In HCT116 cells, PCT inhibited nuclear factor kappaB while activating anti-colitic transcription factors, nuclear factor-erythroid 2 (NF-E2 p45-related factor 2, and hypoxia-inducible factor-1. Colon-targeted PCT, but not conventional PCT, modulated production of the target gene products of the transcription factors in the inflamed colonic tissues. Rectal administration of PCT, which simulates the therapeutic action of colon-targeted PCT, also ameliorated rat colitis and reproduced the molecular effects in the inflamed colonic tissues. Colon-targeted delivery increased therapeutic efficacy of PCT against colitis, likely resulting from multitargeted effects exerted by colon-targeted PCT. The drug delivery technique may be useful for therapeutic optimization of anti-colitic lead compounds including natural products. Keywords: piceatannol, colitis, colon-targeted delivery, multitarget, polypharmacology

Noninvasive Detection of Inflammation-Associated Colon Cancer in a Mouse Model

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Aaron C. Ericsson

2010-12-01

Full Text Available Helicobacter bilis-infected Smad3-/- mice represent an attractive model of inflammation-associated colon cancer. Most infected mice develop mucinous adenocarcinoma (MUC by 6 weeks post inoculation (PI; however, approximately one third do not progress to MUC. The ability to predict the development of MUC in mice used in therapeutic studies would confer a considerable saving of time and money. In addition, the inadvertent use of mice without MUC may confound therapeutic studies by making treatments seem falsely efficacious. We assessed both magnetic resonance imaging (MRI and fecal biomarkers in Helicobacter- and sham-inoculated mice as methods of noninvasively detecting MUC before the predicted onset of disease. Non-contrast-enhanced MRI was able to detect lesions in 58% of mice with histologically confirmed MUC; however, serial imaging sessions produced inconsistent results. MRI was also a labor- and time-intensive technique requiring anesthesia. Alternatively, inflammatory biomarkers isolated from feces at early time points were correlated to later histologic lesions. Fecal expression of interleukin 1β, macrophage inflammatory protein 1α, and regulated on activation, normal T-cell expressed, and secreted at 3 weeks PI correlated significantly with lesion severity at 9 weeks PI. For each biomarker, receiver-operator characteristic curves were also generated, and all three biomarkers performed well at 1 to 3 weeks PI, indicating that the development of MUC can be predicted based on the early expression of certain inflammatory mediators in feces.

Cyanidin-3-glucoside inhibits UVB-induced oxidative damage and inflammation by regulating MAP kinase and NF-κB signaling pathways in SKH-1 hairless mice skin

International Nuclear Information System (INIS)

Pratheeshkumar, Poyil; Son, Young-Ok; Wang, Xin; Divya, Sasidharan Padmaja; Joseph, Binoy; Hitron, John Andrew; Wang, Lei; Kim, Donghern; Yin, Yuanqin; Roy, Ram Vinod; Lu, Jian; Zhang, Zhuo; Wang, Yitao

2014-01-01

Skin cancer is one of the most commonly diagnosed cancers in the United States. Exposure to ultraviolet-B (UVB) radiation induces inflammation and photocarcinogenesis in mammalian skin. Cyanidin-3-glucoside (C3G), a member of the anthocyanin family, is present in various vegetables and fruits especially in edible berries, and displays potent antioxidant and anticarcinogenic properties. In this study, we have assessed the in vivo effects of C3G on UVB irradiation induced chronic inflammatory responses in SKH-1 hairless mice, a well-established model for UVB-induced skin carcinogenesis. Here, we show that C3G inhibited UVB-induced skin damage and inflammation in SKH-1 hairless mice. Our results indicate that C3G inhibited glutathione depletion, lipid peroxidation and myeloperoxidation in mouse skin by chronic UVB exposure. C3G significantly decreased the production of UVB-induced pro-inflammatory cytokines, such as IL-6 and TNF-α, associated with cutaneous inflammation. Likewise, UVB-induced inflammatory responses were diminished by C3G as observed by a remarkable reduction in the levels of phosphorylated MAP kinases, Erk1/2, p38, JNK1/2 and MKK4. Furthermore, C3G also decreased UVB-induced cyclooxygenase-2 (COX-2), PGE 2 and iNOS levels, which are well-known key mediators of inflammation and cancer. Treatment with C3G inhibited UVB-induced nuclear translocation of NF-κB and degradation of IκBα in mice skin. Immunofluorescence assay revealed that topical application of C3G inhibited the expression of 8-hydroxy-2′-deoxyguanosine, proliferating cell nuclear antigen, and cyclin D1 in chronic UVB exposed mouse skin. Collectively, these data indicates that C3G can provide substantial protection against the adverse effects of UVB radiation by modulating UVB-induced MAP kinase and NF-κB signaling pathways. - Highlights: • C3G inhibited UVB-induced oxidative damage and inflammation. • C3G inhibited UVB-induced COX-2, iNOS and PGE 2 production. • C3G inhibited

Cyanidin-3-glucoside inhibits UVB-induced oxidative damage and inflammation by regulating MAP kinase and NF-κB signaling pathways in SKH-1 hairless mice skin

Energy Technology Data Exchange (ETDEWEB)

Pratheeshkumar, Poyil; Son, Young-Ok; Wang, Xin; Divya, Sasidharan Padmaja [Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Joseph, Binoy [Spinal Cord and Brain Injury Research Center and Department of Physiology, University of Kentucky, Lexington, KY 40536-0509 (United States); Hitron, John Andrew; Wang, Lei [Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Kim, Donghern [Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Yin, Yuanqin [Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Cancer Institute, The First Affiliated Hospital, China Medical University, Shenyang (China); Roy, Ram Vinod [Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Lu, Jian [Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013 (China); Zhang, Zhuo [Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Wang, Yitao [State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau (China); and others

2014-10-01

Skin cancer is one of the most commonly diagnosed cancers in the United States. Exposure to ultraviolet-B (UVB) radiation induces inflammation and photocarcinogenesis in mammalian skin. Cyanidin-3-glucoside (C3G), a member of the anthocyanin family, is present in various vegetables and fruits especially in edible berries, and displays potent antioxidant and anticarcinogenic properties. In this study, we have assessed the in vivo effects of C3G on UVB irradiation induced chronic inflammatory responses in SKH-1 hairless mice, a well-established model for UVB-induced skin carcinogenesis. Here, we show that C3G inhibited UVB-induced skin damage and inflammation in SKH-1 hairless mice. Our results indicate that C3G inhibited glutathione depletion, lipid peroxidation and myeloperoxidation in mouse skin by chronic UVB exposure. C3G significantly decreased the production of UVB-induced pro-inflammatory cytokines, such as IL-6 and TNF-α, associated with cutaneous inflammation. Likewise, UVB-induced inflammatory responses were diminished by C3G as observed by a remarkable reduction in the levels of phosphorylated MAP kinases, Erk1/2, p38, JNK1/2 and MKK4. Furthermore, C3G also decreased UVB-induced cyclooxygenase-2 (COX-2), PGE{sub 2} and iNOS levels, which are well-known key mediators of inflammation and cancer. Treatment with C3G inhibited UVB-induced nuclear translocation of NF-κB and degradation of IκBα in mice skin. Immunofluorescence assay revealed that topical application of C3G inhibited the expression of 8-hydroxy-2′-deoxyguanosine, proliferating cell nuclear antigen, and cyclin D1 in chronic UVB exposed mouse skin. Collectively, these data indicates that C3G can provide substantial protection against the adverse effects of UVB radiation by modulating UVB-induced MAP kinase and NF-κB signaling pathways. - Highlights: • C3G inhibited UVB-induced oxidative damage and inflammation. • C3G inhibited UVB-induced COX-2, iNOS and PGE{sub 2} production. • C3G

The hexane fraction of Ardisia crispa Thunb. A. DC. roots inhibits inflammation-induced angiogenesis

Science.gov (United States)

2013-01-01

Background Ardisia crispa (Myrsinaceae) is used in traditional Malay medicine to treat various ailments associated with inflammation, including rheumatism. The plant’s hexane fraction was previously shown to inhibit several diseases associated with inflammation. As there is a strong correlation between inflammation and angiogenesis, we conducted the present study to investigate the anti-angiogenic effects of the plant’s roots in animal models of inflammation-induced angiogenesis. Methods We first performed phytochemical screening and high-performance liquid chromatography (HPLC) fingerprinting of the hexane fraction of Ardisia crispa roots ethanolic extract (ACRH) and its quinone-rich fraction (QRF). The anti-inflammatory properties of ACRH and QRF were tested using the Miles vascular permeability assay and the murine air pouch granuloma model following oral administration at various doses. Results Preliminary phytochemical screening of ACRH revealed the presence of flavonoids, triterpenes, and tannins. The QRF was separated from ACRH (38.38% w/w) by column chromatography, and was isolated to yield a benzoquinonoid compound. The ACRH and QRF were quantified by HPLC. The LD50 value of ACRH was 617.02 mg/kg. In the Miles vascular permeability assay, the lowest dose of ACRH (10 mg/kg) and all doses of QRF significantly reduced vascular endothelial growth factor (VEGF)-induced hyperpermeability, when compared with the vehicle control. In the murine air pouch granuloma model, ACRH and QRF both displayed significant and dose-dependent anti-inflammatory effects, without granuloma weight. ACRH and QRF significantly reduced the vascular index, but not granuloma tissue weight. Conclusions In conclusion, both ACRH and QRF showed potential anti-inflammatory properties in a model of inflammation-induced angiogenesis model, demonstrating their potential anti-angiogenic properties. PMID:23298265

Preclinical evaluation of local JAK1 and JAK2 inhibition in cutaneous inflammation.

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Fridman, Jordan S; Scherle, Peggy A; Collins, Robert; Burn, Timothy; Neilan, Claire L; Hertel, Denise; Contel, Nancy; Haley, Patrick; Thomas, Beth; Shi, Jack; Collier, Paul; Rodgers, James D; Shepard, Stacey; Metcalf, Brian; Hollis, Gregory; Newton, Robert C; Yeleswaram, Swamy; Friedman, Steven M; Vaddi, Kris

2011-09-01

JAKs are required for signaling initiated by several cytokines (e.g., IL-4, IL-12, IL-23, thymic stromal lymphopoietin (TSLP), and IFNγ) implicated in the pathogenesis of inflammatory skin diseases such as psoriasis and atopic dermatitis (AD). Direct antagonism of cytokines, such as IL-12 and IL-23 using ustekinumab, has proven effective in randomized studies in psoriasis patients. We hypothesized that local inhibition of cytokine signaling using topical administration of INCB018424, a small molecule inhibitor of JAK1 and JAK2, would provide benefit similar to systemic cytokine neutralization. In cellular assays, INCB018424 inhibits cytokine-induced JAK/signal transducers and activators of transcription (STAT) signaling and the resultant production of inflammatory proteins (e.g., IL-17, monocyte chemotactic protein-1, and IL-22) in lymphocytes and monocytes, with half-maximal inhibitory concentration values keratinocyte proliferation in a murine contact hypersensitivity model and inhibited tissue inflammation induced by either intradermal IL-23 or TSLP. Topical INCB018424 was also well tolerated in a 28-day safety study in Gottingen minipigs. These results suggest that localized JAK1/JAK2 inhibition may be therapeutic in a range of inflammatory skin disorders such as psoriasis and AD. Clinical evaluation of topical INCB018424 is ongoing.

Flavonoids casticin and chrysosplenol D from Artemisia annua L. inhibit inflammation in vitro and in vivo

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Li, Yu-Jie; Guo, Yan; Yang, Qing; Weng, Xiao-Gang; Yang, Lan; Wang, Ya-Jie; Chen, Ying; Zhang, Dong; Li, Qi; Liu, Xu-Cen; Kan, Xiao-Xi; Chen, Xi [Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700 (China); Zhu, Xiao-Xin, E-mail: zhuxx59@163.com [Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700 (China); Kmoníèková, Eva [Institute of Pharmacology and Toxicology, Faculty of Medicine in Pilsen, Charles University, Pilsen (Czech Republic); Zídek, Zdenìk [Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Vídeòská 1083, 142 20 Prague (Czech Republic)

2015-08-01

Background: The aim of our experiments was to investigate the anti-inflammatory properties of casticin and chrysosplenol D, two flavonoids present in Artemisia annua L. Methods: Topical inflammation was induced in ICR mice using croton oil. Mice were then treated with casticin or chrysosplenol D. Cutaneous histological changes and edema were assessed. ICR mice were intragastrically administrated with casticin or chrysosplenol D followed by intraperitoneal injection of lipopolysaccharide (LPS). Mouse Raw264.7 macrophage cells were incubated with casticin or chrysosplenol D. Intracellular phosphorylation was detected, and migration was assessed by trans-well assay. HT-29/NFκB-luc cells were incubated with casticin or chrysosplenol D in the presence or absence of LPS, and NF-κB activation was quantified. Results: In mice, administration of casticin (0.5, 1 and 1.5 μmol/cm{sup 2}) and chrysosplenol D (1 and 1.5 μmol/cm{sup 2}) inhibited croton oil-induced ear edema (casticin: 29.39–64.95%; chrysosplenol D: 37.76–65.89%, all P < 0.05) in a manner similar to indomethacin (0.5, 1 and 1.5 μmol/cm{sup 2}; 55.63–84.58%). Casticin (0.07, 0.13 and 0.27 mmol/kg) and chrysosplenol D (0.07, 0.14 and 0.28 mmol/kg) protected against LPS-induced systemic inflammatory response syndrome (SIRS) in mice (all P < 0.05), in a manner similar to dexamethasone (0.03 mmol/kg). Casticin and chrysosplenol D suppressed LPS-induced release of IL-1 beta, IL-6 and MCP-1, inhibited cell migration, and reduced LPS-induced IκB and c-JUN phosphorylation in Raw264.7 cells. JNK inhibitor SP600125 blocked the inhibitory effect of chrysosplenol D on cytokine release. Conclusions: The flavonoids casticin and chrysosplenol D from A. annua L. inhibited inflammation in vitro and in vivo. - Highlights: • We report a new activity of the flavonoids present in Artemisia annua L. • These flavonoids inhibit croton oil-induced ear edema in mice. • These flavonoids protect against LPS-induced SIRS in

Inhibition of glycolysis and growth of colon cancer cells by 3-(3-pyridinyl-1-(4-pyridinyl-2-propen-1-one (3PO in combination with butyrate, 2-deoxy glucose, 3-bromopyruvate or biguanides

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Lea MA

2015-09-01

Full Text Available Introduction: Glycolysis shows a positive correlation with growth of human colon cancer cells. PFKFB3 is an important enzyme regulating glycolysis in many tumor cells and presents a target for cancer chemotherapy. We studied the action of an inhibitor of PFKFB3, 3-(3-pyridinyl-1-(4-pyridinyl-2-propen-1-one (3PO, as a single agent and in combination with other molecules that affect glycolysis. Materials and methods: Effects on growth were studied in four human colon cancer cell lines. Glucose metabolism was monitored by uptake from the incubation medium and lactic acid production was judged by acidification of the medium. Induction of alkaline phosphatase served as a marker of differentiation. Results: Growth of colon cancer cells was inhibited by 3PO and butyrate but only butyrate induced activation of alkaline phosphatase. Although metformin and phenformin can increase glucose metabolism, they inhibit colon cancer cell growth and can exert additive inhibitory effects in combination with 3PO. Additive growth inhibitory effects with 3PO were also observed with two compounds that inhibit glycolysis: 2-deoxyglucose and 3-bromopyruvate. Conclusion: 3PO was an inhibitor of growth of colon cancer cells and may be a useful agent in combination with other drugs that inhibit colon cancer cell proliferation.

Salmonella enterica serovar typhimurium exploits inflammation to compete with the intestinal microbiota.

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Bärbel Stecher

2007-10-01

Full Text Available Most mucosal surfaces of the mammalian body are colonized by microbial communities ("microbiota". A high density of commensal microbiota inhabits the intestine and shields from infection ("colonization resistance". The virulence strategies allowing enteropathogenic bacteria to successfully compete with the microbiota and overcome colonization resistance are poorly understood. Here, we investigated manipulation of the intestinal microbiota by the enteropathogenic bacterium Salmonella enterica subspecies 1 serovar Typhimurium (S. Tm in a mouse colitis model: we found that inflammatory host responses induced by S. Tm changed microbiota composition and suppressed its growth. In contrast to wild-type S. Tm, an avirulent invGsseD mutant failing to trigger colitis was outcompeted by the microbiota. This competitive defect was reverted if inflammation was provided concomitantly by mixed infection with wild-type S. Tm or in mice (IL10(-/-, VILLIN-HA(CL4-CD8 with inflammatory bowel disease. Thus, inflammation is necessary and sufficient for overcoming colonization resistance. This reveals a new concept in infectious disease: in contrast to current thinking, inflammation is not always detrimental for the pathogen. Triggering the host's immune defence can shift the balance between the protective microbiota and the pathogen in favour of the pathogen.

5-HT3 and 5-HT4 antagonists inhibit peristaltic contractions in guinea-pig distal colon by mechanisms independent of endogenous 5-HT

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Tiong Cheng Sia

2013-08-01

Full Text Available Recent studies have shown that endogenous serotonin is not required for colonic peristalsis in vitro, nor gastrointestinal (GI transit in vivo. However, antagonists of 5-Hydroxytryptamine (5-HT receptors can inhibit peristalsis and GI-transit in mammals, including humans. This raises the question of how these antagonists inhibit GI-motility and transit, if depletion of endogenous 5-HT does not cause any significant inhibitory changes to either GI-motility or transit ? We investigated the mechanism by which 5-HT3 and 5-HT4 antagonists inhibit distension-evoked peristaltic contractions in guinea-pig distal colon. In control animals, repetitive peristaltic contractions of the circular muscle were evoked in response to fixed fecal pellet distension. Distension-evoked peristaltic contractions were unaffected in animals with mucosa and submucosal plexus removed, that were also treated with reserpine (to deplete neuronal 5-HT. In control animals, peristaltic contractions were blocked temporarily by ondansetron (1-10µM and SDZ-205-557 (1-10µM in many animals. Interestingly, after this temporary blockade, and whilst in the continued presence of these antagonists, peristaltic contractions recovered, with characteristics no different from controls. Surprisingly, similar effects were seen in mucosa-free preparations, which had no detectable 5-HT, as detected by mass spectrometry. In summary, distension-evoked peristaltic reflex contractions of the circular muscle layer of the guinea-pig colon can be inhibited temporarily, or permanently, in the same preparation by selective 5-HT3 and 5-HT4 antagonists, depending on the concentration of the antagonists applied. These effects also occur in preparations that lack any detectable 5-HT. We suggest caution should be exercised when interpreting the effects of 5-HT3 and 5-HT4 antagonists; and the role of endogenous 5-HT, in the generation of distension-evoked colonic peristalsis.

A PAF receptor antagonist inhibits acute airway inflammation and late-phase responses but not chronic airway inflammation and hyperresponsiveness in a primate model of asthma

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R. H. Gundel

1992-01-01

Full Text Available We have examined the effects of a PAF receptor antagonist, WEB 2170, on several indices of acute and chronic airway inflammation and associated changes in lung function in a primate model of allergic asthma. A single oral administration WEB 2170 provided dose related inhibition of the release of leukotriene C4 (LTC4 and prostaglandin D2 (PGD2 recovered and quantified in bronchoalveolar lavage (BAL fluid obtained during the acute phase response to inhaled antigen. In addition, oral WEB 2170 treatment in dual responder primates blocked the acute influx of neutrophils into the airways as well as the associated late-phase airway obstruction occurring 6 h after antigen inhalation. In contrast, a multiple dosing regime with WEB 2170 (once a day for 7 consecutive days failed to reduce the chronic airway inflammation (eosinophilic and associated airway hyperresponsiveness to inhaled methacholine that is characteristic of dual responder monkeys. Thus, we conclude that the generation of PAF following antigen inhalation contributes to the development of lipid mediators, acute airway inflammation and associated late-phase airway obstruction in dual responder primates; however, PAF does not play a significant role in the maintenance of chronic airway inflammation and associated airway hyperresponsiveness in this primate model.

The Role of Sphingosine-1-Phosphate and Ceramide-1-Phosphate in Inflammation and Cancer

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Nitai C. Hait

2017-01-01

Full Text Available Inflammation is part of our body’s response to tissue injury and pathogens. It helps to recruit various immune cells to the site of inflammation and activates the production of mediators to mobilize systemic protective processes. However, chronic inflammation can increase the risk of diseases like cancer. Apart from cytokines and chemokines, lipid mediators, particularly sphingosine-1-phosphate (S1P and ceramide-1-phosphate (C1P, contribute to inflammation and cancer. S1P is an important player in inflammation-associated colon cancer progression. On the other hand, C1P has been recognized to be involved in cancer cell growth, migration, survival, and inflammation. However, whether C1P is involved in inflammation-associated cancer is not yet established. In contrast, few studies have also suggested that S1P and C1P are involved in anti-inflammatory pathways regulated in certain cell types. Ceramide is the substrate for ceramide kinase (CERK to yield C1P, and sphingosine is phosphorylated to S1P by sphingosine kinases (SphKs. Biological functions of sphingolipid metabolites have been studied extensively. Ceramide is associated with cell growth inhibition and enhancement of apoptosis while S1P and C1P are associated with enhancement of cell growth and survival. Altogether, S1P and C1P are important regulators of ceramide level and cell fate. This review focuses on S1P and C1P involvement in inflammation and cancer with emphasis on recent progress in the field.

The effect of Saccharomyces boulardii on human colon cells and inflammation in rats with trinitrobenzene sulfonic acid-induced colitis.

Science.gov (United States)

Lee, Sang Kil; Kim, Youn Wha; Chi, Sung-Gil; Joo, Yeong-Shil; Kim, Hyo Jong

2009-02-01

Saccharomyces boulardii (S. boulardii) has beneficial effects in the treatment of intestinal inflammation; however, little is known about the mechanisms by which these effects occur. We investigated the effects of S. boulardii on the expression of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and interleukin-8 (IL-8), using human HT-29 colonocytes and a rat model of trinitrobenzene sulfonic acid (TNBS)-induced colitis. The effect of S. boulardii on gene expression was assessed by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), and Northern blot and Western blot assays. Pharmacological inhibitors for various signaling pathways were used to determine the signaling pathways implicated in the S. boulardii regulation of PPAR-gamma and IL-8. We found that S. boulardii up-regulated and down-regulated PPAR-gamma and IL-8 expression at the transcription level, both in vitro and in vivo (P Saccharomyces boulardii blocked tumor necrosis factor-alpha (TNF-alpha) regulation of PPAR-gamma and IL-8 through disruption of TNF-alpha-mediated nuclear factor kappa B (NF-kappaB) activation. Furthermore, S. boulardii suppressed colitis and expression of pro-inflammatory cytokine genes in vivo (P boulardii reduces colonic inflammation and regulates inflammatory gene expression.

Colonic motility and enema spreading

International Nuclear Information System (INIS)

Hardy, J.G.; Wood, E.; Clark, A.G.; Reynolds, J.R.; Queen's Medical Centre, Nottingham

1986-01-01

Radiolabelled enema solution was administered to eight healthy subjects, both in fasted and fed states. Enema spreading was monitored over a 4-h period using gamma scintigraphy and colonic motility was recorded simultaneously using a pressure sensitive radiotelemetry capsule. The rate and extent of enema dispersion were unaffected by eating. Spreading could be correlated with colonic motility and was inhibited by aboral propulsion of the colonic contents. (orig.)

Concomitant consumption of lycopene and fish oil inhibits tumor growth and progression in a mouse xenograft model of colon cancer

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Our previous report showed that concomitant supplementation of lycopene and eicosa-pentaenoic acid synergistically inhibited the proliferation of human colon cancer HT-29 cells in vitro. To validate our findings, the present study investigated whether consumption of lycopene and fish oil would help ...

Activating transcription factor-3 (ATF3) functions as a tumor suppressor in colon cancer and is up-regulated upon heat-shock protein 90 (Hsp90) inhibition

International Nuclear Information System (INIS)

Hackl, Christina; Stoeltzing, Oliver; Lang, Sven A; Moser, Christian; Mori, Akira; Fichtner-Feigl, Stefan; Hellerbrand, Claus; Dietmeier, Wolfgang; Schlitt, Hans J; Geissler, Edward K

2010-01-01

Activating transcription factor-3 (ATF3) is involved in the complex process of cellular stress response. However, its exact role in cancer is discussed controversially because both tumor suppressive and oncogenic effects have been described. Here we followed-up on our previous observation that inhibition of Hsp90 may increase ATF3 expression and sought to determine the role of ATF3 in colon cancer. Regulation of ATF3 was determined in cancer cells using signaling inhibitors and a heat-shock protein-90 (Hsp90) antagonist. Human HCT116 cancer cells were stably transfected with an ATF3-shRNA or a luciferase-shRNA expression plasmid and alterations in cell motility were assessed in migration assays. The impact of ATF3 down-regulation on cancer growth and metastasis were investigated in a subcutaneous tumor model, a model of hepatic tumor growth and in a model of peritoneal carcinomatosis. Human colon cancer tissues were analyzed for ATF3 expression. The results show that therapeutic Hsp90 inhibition substantially up-regulates the expression of ATF3 in various cancer cells, including colon, gastric and pancreatic cancer. This effect was evident both in vitro and in vivo. RNAi mediated knock-down of ATF3 in HCT116 colon cancer cells significantly increased cancer cell migration in vitro. Moreover, in xenogenic mouse models, ATF3 knock-down promoted subcutaneous tumor growth and hepatic metastasis, as well as peritoneal carcinomatosis. Importantly, ATF3 expression was lower in human colon cancer specimens, as compared to corresponding normal surrounding tissues, suggesting that ATF3 may represent a down-regulated tumor suppressor in colon cancer. In conclusion, ATF3 down-regulation in colon cancer promotes tumor growth and metastasis. Considering that blocking Hsp90 induces ATF3 expression, Hsp90 inhibition may represent a valid strategy to treat metastatic colon cancer by up-regulating this anti-metastatic transcription factor

Targeting S100P Inhibits Colon Cancer Growth and Metastasis by Lentivirus-Mediated RNA Interference and Proteomic Analysis

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Jiang, Lei; Lai, Yiu-Kay; Zhang, Jinfang; Wang, Hua; Lin, Marie CM; He, Ming-liang; Kung, Hsiang-fu

2011-01-01

S100P was recently found to be overexpressed in a variety of cancers and is considered a potential target for cancer therapy, but the functional role or mechanism of action of S100P in colon cancer is not fully understood. In the present study, we knocked down the gene expression of S100P in colon cancer cells using lentivirus-mediated RNA interference. This step resulted in significant inhibition of cancer cell growth, migration and invasion in vitro and tumor growth and liver metastasis in vivo. Moreover, S100P downstream target proteins were identified by proteomic analysis in colon cancer DLD-1 cells with deletion of S100P. Knockdown of S100P led to downregulation of thioredoxin 1 and β-tubulin and upregulation of Rho guanosine diphosphate (GDP) dissociation inhibitor α (RhoGDIA), all potential therapeutic targets in cancer. Taken together, these findings suggest that S100P plays an important role in colon tumorigenesis and metastasis, and the comprehensive and comparative analyses of proteins associated with S100P could contribute to understanding the downstream signal cascade of S100P, leading to tumorigenesis and metastasis. PMID:21327297

Hirsutine, an indole alkaloid of Uncaria rhynchophylla, inhibits inflammation-mediated neurotoxicity and microglial activation.

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Jung, Hwan Yong; Nam, Kyong Nyon; Woo, Byung-Choel; Kim, Kyoo-Pil; Kim, Sung-Ok; Lee, Eunjoo H

2013-01-01

Chronic microglial activation endangers neuronal survival through the release of various pro-inflammatory and neurotoxic factors. As such, negative regulators of microglial activation have been considered as potential therapeutic candidates to reduce the risk of neurodegeneration associated with inflammation. Uncaria rhynchophylla (U. rhynchophylla) is a traditional oriental herb that has been used for treatment of disorders of the cardiovascular and central nervous systems. Hirsutine (HS), one of the major indole alkaloids of U. rhynchophylla, has demonstrated neuroprotective potential. The aim of the present study was to examine the efficacy of HS in the repression of inflammation-induced neurotoxicity and microglial cell activation. In organotypic hippocampal slice cultures, HS blocked lipopolysaccharide (LPS)-related hippocampal cell death and production of nitric oxide (NO), prostaglandin (PG) E2 and interleukin-1β. HS was demonstrated to effectively inhibit LPS-induced NO release from cultured rat brain microglia. The compound reduced the LPS-stimulated production of PGE2 and intracellular reactive oxygen species. HS significantly decreased LPS-induced phosphorylation of the mitogen-activated protein kinases and Akt signaling proteins. In conclusion, HS reduces the production of various neurotoxic factors in activated microglial cells and possesses neuroprotective activity in a model of inflammation-induced neurotoxicity.

Luteolin inhibits the colon cancer HT-29 cell proliferation, migration and epithelial-mesenchymal transition: an experimental study

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Xin Meng

2017-11-01

Full Text Available Objective: To study the regulating effect of luteolin on colon cancer HT-29 cell proliferation, migration and epithelial-mesenchymal transition. Methods: Colon cancer HT-29 cells were cultured and randomly divided into two groups, control group were treated with serum-free medium without drugs and LUT group were treated with serum-free medium containing luteolin. After 24 h of treatment, cells were collected to extract RNA, and then fluorescent quantitative PCR method was used to determine the mRNA expression of proliferation genes, migration genes and epithelial-mesenchymal transition genes. Results: After 24 h of luteolin treatment, Lrig1, TSPYL5, Bim, SOX15 and DLC1 mRNA expression in LUT group were significantly higher than those in control group while RPS15a, Bad, TRPV5, TRPV6, PLD2, IBP, SphK1, FAK, Vimentin and N-cadherin mRNA expression were significantly lower than those in control group. Conclusion: Luteolin has inhibiting effect on colon cancer HT-29 cell proliferation, migration and epithelial-mesenchymal transition.

Vasohibin-1 suppresses colon cancer

OpenAIRE

Liu, Shuai; Han, Bing; Zhang, Qunyuan; Dou, Jie; Wang, Fang; Lin, Wenli; Sun, Yuping; Peng, Guangyong

2015-01-01

Vasohibin-1 (VASH1) is an endogenous angiogenesis inhibitor. However, the clinical relevance of VASH1 in colon cancer and its regulations on cancer angiogenesis and cancer cell biological characteristics are still unknown. Here we showed that stromal VASH1 levels were negatively correlated with tumor size, advanced clinical stage and distant metastases in colon cancer patients. Overexpression of VASH1 in colon cancer cells induced apoptosis and senescence, inhibiting cancer cell growth and co...

Anesthetic propofol reduces endotoxic inflammation by inhibiting reactive oxygen species-regulated Akt/IKKβ/NF-κB signaling.

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Chung-Hsi Hsing

Full Text Available BACKGROUND: Anesthetic propofol has immunomodulatory effects, particularly in the area of anti-inflammation. Bacterial endotoxin lipopolysaccharide (LPS induces inflammation through toll-like receptor (TLR 4 signaling. We investigated the molecular actions of propofol against LPS/TLR4-induced inflammatory activation in murine RAW264.7 macrophages. METHODOLOGY/PRINCIPAL FINDINGS: Non-cytotoxic levels of propofol reduced LPS-induced inducible nitric oxide synthase (iNOS and NO as determined by western blotting and the Griess reaction, respectively. Propofol also reduced the production of tumor necrosis factor-α (TNF-α, interleukin (IL-6, and IL-10 as detected by enzyme-linked immunosorbent assays. Western blot analysis showed propofol inhibited LPS-induced activation and phosphorylation of IKKβ (Ser180 and nuclear factor (NF-κB (Ser536; the subsequent nuclear translocation of NF-κB p65 was also reduced. Additionally, propofol inhibited LPS-induced Akt activation and phosphorylation (Ser473 partly by reducing reactive oxygen species (ROS generation; inter-regulation that ROS regulated Akt followed by NF-κB activation was found to be crucial for LPS-induced inflammatory responses in macrophages. An in vivo study using C57BL/6 mice also demonstrated the anti-inflammatory properties against LPS in peritoneal macrophages. CONCLUSIONS/SIGNIFICANCE: These results suggest that propofol reduces LPS-induced inflammatory responses in macrophages by inhibiting the interconnected ROS/Akt/IKKβ/NF-κB signaling pathways.

Anesthetic Propofol Reduces Endotoxic Inflammation by Inhibiting Reactive Oxygen Species-regulated Akt/IKKβ/NF-κB Signaling

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Hsing, Chung-Hsi; Lin, Ming-Chung; Choi, Pui-Ching; Huang, Wei-Ching; Kai, Jui-In; Tsai, Cheng-Chieh; Cheng, Yi-Lin; Hsieh, Chia-Yuan; Wang, Chi-Yun; Chang, Yu-Ping; Chen, Yu-Hong; Chen, Chia-Ling; Lin, Chiou-Feng

2011-01-01

Background Anesthetic propofol has immunomodulatory effects, particularly in the area of anti-inflammation. Bacterial endotoxin lipopolysaccharide (LPS) induces inflammation through toll-like receptor (TLR) 4 signaling. We investigated the molecular actions of propofol against LPS/TLR4-induced inflammatory activation in murine RAW264.7 macrophages. Methodology/Principal Findings Non-cytotoxic levels of propofol reduced LPS-induced inducible nitric oxide synthase (iNOS) and NO as determined by western blotting and the Griess reaction, respectively. Propofol also reduced the production of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-10 as detected by enzyme-linked immunosorbent assays. Western blot analysis showed propofol inhibited LPS-induced activation and phosphorylation of IKKβ (Ser180) and nuclear factor (NF)-κB (Ser536); the subsequent nuclear translocation of NF-κB p65 was also reduced. Additionally, propofol inhibited LPS-induced Akt activation and phosphorylation (Ser473) partly by reducing reactive oxygen species (ROS) generation; inter-regulation that ROS regulated Akt followed by NF-κB activation was found to be crucial for LPS-induced inflammatory responses in macrophages. An in vivo study using C57BL/6 mice also demonstrated the anti-inflammatory properties against LPS in peritoneal macrophages. Conclusions/Significance These results suggest that propofol reduces LPS-induced inflammatory responses in macrophages by inhibiting the interconnected ROS/Akt/IKKβ/NF-κB signaling pathways. PMID:21408125

Derricin and derricidin inhibit Wnt/β-catenin signaling and suppress colon cancer cell growth in vitro.

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Barbara F Fonseca

Full Text Available Overactivation of the Wnt/β-catenin pathway in adult tissues has been implicated in many diseases, such as colorectal cancer. Finding chemical substances that can prevent this phenomenon is an emerging problem. Recently, several natural compounds have been described as Wnt/β-catenin inhibitors and might be promising agents for the control of carcinogenesis. Here, we describe two natural substances, derricin and derricidin, belonging to the chalcone subclass, that show potent transcriptional inhibition of the Wnt/β-catenin pathway. Both chalcones are able to affect the cell distribution of β-catenin, and inhibit Wnt-specific reporter activity in HCT116 cells and in Xenopus embryos. Derricin and derricidin also strongly inhibited canonical Wnt activity in vitro, and rescued the Wnt-induced double axis phenotype in Xenopus embryos. As a consequence of Wnt/β-catenin inhibition, derricin and derricidin treatments reduce cell viability and lead to cell cycle arrest in colorectal cancer cell lines. Taken together, our results strongly support these chalcones as novel negative modulators of the Wnt/β-catenin pathway and colon cancer cell growth in vitro.

Oxysterol Sensing through the Receptor GPR183 Promotes the Lymphoid-Tissue-Inducing Function of Innate Lymphoid Cells and Colonic Inflammation.

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Emgård, Johanna; Kammoun, Hana; García-Cassani, Bethania; Chesné, Julie; Parigi, Sara M; Jacob, Jean-Marie; Cheng, Hung-Wei; Evren, Elza; Das, Srustidhar; Czarnewski, Paulo; Sleiers, Natalie; Melo-Gonzalez, Felipe; Kvedaraite, Egle; Svensson, Mattias; Scandella, Elke; Hepworth, Matthew R; Huber, Samuel; Ludewig, Burkhard; Peduto, Lucie; Villablanca, Eduardo J; Veiga-Fernandes, Henrique; Pereira, João P; Flavell, Richard A; Willinger, Tim

2018-01-16

Group 3 innate lymphoid cells (ILC3s) sense environmental signals and are critical for tissue integrity in the intestine. Yet, which signals are sensed and what receptors control ILC3 function remain poorly understood. Here, we show that ILC3s with a lymphoid-tissue-inducer (LTi) phenotype expressed G-protein-coupled receptor 183 (GPR183) and migrated to its oxysterol ligand 7α,25-hydroxycholesterol (7α,25-OHC). In mice lacking Gpr183 or 7α,25-OHC, ILC3s failed to localize to cryptopatches (CPs) and isolated lymphoid follicles (ILFs). Gpr183 deficiency in ILC3s caused a defect in CP and ILF formation in the colon, but not in the small intestine. Localized oxysterol production by fibroblastic stromal cells provided an essential signal for colonic lymphoid tissue development, and inflammation-induced increased oxysterol production caused colitis through GPR183-mediated cell recruitment. Our findings show that GPR183 promotes lymphoid organ development and indicate that oxysterol-GPR183-dependent positioning within tissues controls ILC3 activity and intestinal homeostasis. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Host-microbiota interaction induces bi-phasic inflammation and glucose intolerance in mice

DEFF Research Database (Denmark)

Molinaro, Antonio; Caesar, Robert; Holm, Louise Mannerås

2017-01-01

expansion and inflammation. Importantly, re-colonization of antibiotic treated mice displays only the delayed phase of glucose impairment and adiposity, suggesting that the early phase may be unique to colonization of the immature GF mice gut. CONCLUSIONS: Our results provide new insights on host...

Oral treatment with γ-aminobutyric acid improves glucose tolerance and insulin sensitivity by inhibiting inflammation in high fat diet-fed mice.

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Jide Tian

Full Text Available Adipocyte and β-cell dysfunction and macrophage-related chronic inflammation are critical for the development of obesity-related insulin resistance and type 2 diabetes mellitus (T2DM, which can be negatively regulated by Tregs. Our previous studies and those of others have shown that activation of γ-aminobutyric acid (GABA receptors inhibits inflammation in mice. However, whether GABA could modulate high fat diet (HFD-induced obesity, glucose intolerance and insulin resistance has not been explored. Here, we show that although oral treatment with GABA does not affect water and food consumption it inhibits the HFD-induced gain in body weights in C57BL/6 mice. Furthermore, oral treatment with GABA significantly reduced the concentrations of fasting blood glucose, and improved glucose tolerance and insulin sensitivity in the HFD-fed mice. More importantly, after the onset of obesity and T2DM, oral treatment with GABA inhibited the continual HFD-induced gain in body weights, reduced the concentrations of fasting blood glucose and improved glucose tolerance and insulin sensitivity in mice. In addition, oral treatment with GABA reduced the epididymal fat mass, adipocyte size, and the frequency of macrophage infiltrates in the adipose tissues of HFD-fed mice. Notably, oral treatment with GABA significantly increased the frequency of CD4(+Foxp3(+ Tregs in mice. Collectively, our data indicated that activation of peripheral GABA receptors inhibited the HFD-induced glucose intolerance, insulin resistance, and obesity by inhibiting obesity-related inflammation and up-regulating Treg responses in vivo. Given that GABA is safe for human consumption, activators of GABA receptors may be valuable for the prevention of obesity and intervention of T2DM in the clinic.

A Ketogenic Formula Prevents Tumor Progression and Cancer Cachexia by Attenuating Systemic Inflammation in Colon 26 Tumor-Bearing Mice

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Kentaro Nakamura

2018-02-01

Full Text Available Low-carbohydrate, high-fat diets (ketogenic diets might prevent tumor progression and could be used as supportive therapy; however, few studies have addressed the effect of such diets on colorectal cancer. An infant formula with a ketogenic composition (ketogenic formula; KF is used to treat patients with refractory epilepsy. We investigated the effect of KF on cancer and cancer cachexia in colon tumor-bearing mice. Mice were randomized into normal (NR, tumor-bearing (TB, and ketogenic formula (KF groups. Colon 26 cells were inoculated subcutaneously into TB and KF mice. The NR and TB groups received a standard diet, and the KF mice received KF ad libitum. KF mice preserved their body, muscle, and carcass weights. Tumor weight and plasma IL-6 levels were significantly lower in KF mice than in TB mice. In the KF group, energy intake was significantly higher than that in the other two groups. Blood ketone body concentrations in KF mice were significantly elevated, and there was a significant negative correlation between blood ketone body concentration and tumor weight. Therefore, KF may suppress the progression of cancer and the accompanying systemic inflammation without adverse effects on weight gain, or muscle mass, which might help to prevent cancer cachexia.

Microarray Analyses of Genes Differentially Expressed by Diet (Black Beans and Soy Flour) during Azoxymethane-Induced Colon Carcinogenesis in Rats.

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Rondini, Elizabeth A; Bennink, Maurice R

2012-01-01

We previously demonstrated that black bean (BB) and soy flour (SF)-based diets inhibit azoxymethane (AOM)-induced colon cancer. The objective of this study was to identify genes altered by carcinogen treatment in normal-appearing colonic mucosa and those attenuated by bean feeding. Ninety-five male F344 rats were fed control (AIN) diets upon arrival. At 4 and 5 weeks, rats were injected with AOM (15 mg/kg) or saline and one week later administered an AIN, BB-, or SF-based diet. Rats were sacrificed after 31 weeks, and microarrays were conducted on RNA isolated from the distal colonic mucosa. AOM treatment induced a number of genes involved in immunity, including several MHC II-associated antigens and innate defense genes (RatNP-3, Lyz2, Pla2g2a). BB- and SF-fed rats exhibited a higher expression of genes involved in energy metabolism and water and sodium absorption and lower expression of innate (RatNP-3, Pla2g2a, Tlr4, Dmbt1) and cell cycle-associated (Cdc2, Ccnb1, Top2a) genes. Genes involved in the extracellular matrix (Col1a1, Fn1) and innate immunity (RatNP-3, Pla2g2a) were induced by AOM in all diets, but to a lower extent in bean-fed animals. This profile suggests beans inhibit colon carcinogenesis by modulating cellular kinetics and reducing inflammation, potentially by preserving mucosal barrier function.

1,25(OH)2D3 attenuates TGF-β1/β2-induced increased migration and invasion via inhibiting epithelial–mesenchymal transition in colon cancer cells

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Chen, Shanwen; Zhu, Jing; Zuo, Shuai; Ma, Ju; Zhang, Junling; Chen, Guowei; Wang, Xin; Pan, Yisheng; Liu, Yucun; Wang, Pengyuan, E-mail: wangpengyuan2014@126.com

2015-12-04

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) has been reported to inhibit proliferation and migration of multiple types of cancer cells. However, the mechanism underlying its anti-metastasis effect is not fully illustrated. In this study, the effect of 1,25(OH)2D3 on TGF-β1/β2-induced epithelial–mesenchymal transition (EMT) is tested in colon cancer cells. The results suggest that 1,25(OH)2D3 inhibited TGF-β1/β2-induced increased invasion and migration of in SW-480 and HT-29 cells. 1,25(OH)2D3 also inhibited the cadherin switch in SW-480 and HT-29 cells. TGF-β1/β2-induced increased expression of EMT-related transcription factors was also inhibited by 1,25(OH)2D3. 1,25(OH)2D3 also inhibited the secretion of MMP-2 and MMP-9 and increased expression of F-actin induced by TGF-β1/β2 in SW-480 cells. Taken together, this study suggests that the suppression of EMT might be one of the mechanisms underlying the anti-metastasis effect of 1,25(OH)2D3 in colon cancer cells. - Highlights: • TGF-β1/β2-induced model of EMT was used in this study to test the effect of 1,25(OH)2D3 on EMT in colon cancer cells. • 1,25(OH)2D3 inhibited TGF-β1/β2-induced increased migration and invasion. • 1,25(OH)2D3 inhibited TGF-β1/β2-induced increased level of EMT-related transcription factors. • 1,25(OH)2D3 inhibited TGF-β1/β2-induced increased expression of F-actin in SW-480 cells.

Colon in acute intestinal infection.

Science.gov (United States)

Guarino, Alfredo; Buccigrossi, Vittoria; Armellino, Carla

2009-04-01

The colon is actively implicated in intestinal infections not only as a target of enteric pathogens and their products but also as a target organ for treatment. In the presence of diarrhea, both of osmotic and secretory nature, the colon reacts with homeostatic mechanisms to increase ion absorption. These mechanisms can be effectively exploited to decrease fluid discharge. A model of intestinal infections using rotavirus (RV) in colonic cells was set up and used to define a dual model of secretory and osmotic diarrhea in sequence. Using this model, antidiarrheal drugs were tested, namely zinc and the enkephalinase inhibitor racecadotril. Zinc was able to decrease the enterotoxic activity responsible for secretory diarrhea. It also inhibited the cytotoxic effect of RV. The mechanism of zinc was related at least in part to the activation of MAPK activity, but also a direct antiviral effect was observed. Racecadotril showed a potent and selective inhibition of active secretion, being particularly effective in the first phase of RV diarrhea. The use of drugs active at the colonic level, therefore, offers effective options to treat intestinal infections in childhood. In addition, the colon is the natural site of colonic microflora, a target of probiotic therapy, which is the first line of approach recommended by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition to treat infectious diarrhea.

Onbaekwon Suppresses Colon Cancer Cell Invasion by Inhibiting Expression of the CXC Chemokine Receptor 4.

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Kim, Buyun; Yoon, Jaewoo; Yoon, Seong Woo; Park, Byoungduck

2017-06-01

Cysteine X cysteine (CXC) chemokine receptor 4 (CXCR4) and C-X-C motif chemokine 12 (CXCL12) were originally identified as chemoattractants between immune cells and sites of inflammation. Since studies have validated an increased level of CXCL12 and its receptor in patients with colorectal cancers, CXCL12/CXCR4 axis has been considered as a valuable marker of cancer metastasis. Therefore, identification of CXCR4 inhibitors has great potential to abrogate tumor metastasis. Onbaekwon (OBW) is a complex herbal formula that is derived from the literature of traditional Korean medicine Dongeuibogam. In this study, we demonstrated that OBW suppressed CXCR4 expression in various cancer cell types in a concentration- and time-dependent manner. Both proteasomal and lysosomal inhibitors had no effect to prevent the OBW-induced suppression of CXCR4, suggesting that the inhibitory effect of OBW was not due to proteolytic degradation but occurred at the transcriptional level. Electrophoretic mobility shift assay further confirmed that OBW could block endogenous activation of nuclear factor kappa B, a key transcription factor that regulates the expression of CXCR4 in colon cancer cells. Consistent with the aforementioned molecular basis, OBW abolished cell invasion induced by CXCL12 in colon cancer cells. Together, our results suggest that OBW, as a novel inhibitor of CXCR4, could be a promising therapeutic agent contributing to cancer treatment.

Docosahexaenoic acid inhibits monocrotaline-induced pulmonary hypertension via attenuating endoplasmic reticulum stress and inflammation.

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Chen, Rui; Zhong, Wei; Shao, Chen; Liu, Peijing; Wang, Cuiping; Wang, Zhongqun; Jiang, Meiping; Lu, Yi; Yan, Jinchuan

2018-02-01

Endoplasmic reticulum (ER) stress and inflammation contribute to pulmonary hypertension (PH) pathogenesis. Previously, we confirmed that docosahexaenoic acid (DHA) could improve hypoxia-induced PH. However, little is known about the link between DHA and monocrotaline (MCT)-induced PH. Our aims were, therefore, to evaluate the effects and molecular mechanisms of DHA on MCT-induced PH in rats. Rat PH was induced by MCT. Rats were treated with DHA daily in the prevention group (following MCT injection) and the reversal group (after MCT injection for 2 wk) by gavage. After 4 wk, mean pulmonary arterial pressure (mPAP), right ventricular (RV) hypertrophy index, and morphological and immunohistochemical analyses were evaluated. Rat pulmonary artery smooth muscle cells (PASMCs) were used to investigate the effects of DHA on cell proliferation stimulated by platelet-derived growth factor (PDGF)-BB. DHA decreased mPAP and attenuated pulmonary vascular remodeling and RV hypertrophy, which were associated with suppressed ER stress. DHA blocked the mitogenic effect of PDGF-BB on PASMCs and arrested the cell cycle via inhibiting nuclear factor of activated T cells-1 (NFATc1) expression and activation and regulating cell cycle-related proteins. Moreover, DHA ameliorated inflammation in lung and suppressed macrophage and T lymphocyte accumulation in lung and adventitia of resistance pulmonary arteries. These findings suggest that DHA could protect against MCT-induced PH by reducing ER stress, suppressing cell proliferation and inflammation.

Intestinal microbiota shifts towards elevated commensal Escherichia coli loads abrogate colonization resistance against Campylobacter jejuni in mice.

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Lea-Maxie Haag

Full Text Available BACKGROUND: The zoonotic pathogen Campylobacter jejuni is a leading cause of bacterial foodborne enterocolitis in humans worldwide. The understanding of immunopathology underlying human campylobacteriosis is hampered by the fact that mice display strong colonization resistance against the pathogen due to their host specific gut microbiota composition. METHODOLOGY/PRINCIPAL FINDINGS: Since the microbiota composition changes significantly during intestinal inflammation we dissected factors contributing to colonization resistance against C. jejuni in murine ileitis, colitis and in infant mice. In contrast to healthy animals C. jejuni could stably colonize mice suffering from intestinal inflammation. Strikingly, in mice with Toxoplasma gondii-induced acute ileitis, C. jejuni disseminated to mesenteric lymphnodes, spleen, liver, kidney, and blood. In infant mice C. jejuni infection induced enterocolitis. Mice suffering from intestinal inflammation and C. jejuni susceptible infant mice displayed characteristical microbiota shifts dominated by increased numbers of commensal Escherichia coli. To further dissect the pivotal role of those distinct microbiota shifts in abrogating colonization resistance, we investigated C. jejuni infection in healthy adult mice in which the microbiota was artificially modified by feeding live commensal E. coli. Strikingly, in animals harboring supra-physiological intestinal E. coli loads, colonization resistance was significantly diminished and C. jejuni infection induced enterocolitis mimicking key features of human campylobacteriosis. CONCLUSION/SIGNIFICANCE: Murine colonization resistance against C. jejuni is abrogated by changes in the microbiota composition towards elevated E. coli loads during intestinal inflammation as well as in infant mice. Intestinal inflammation and microbiota shifts thus represent potential risk factors for C. jejuni infection. Corresponding interplays between C. jejuni and microbiota might

Preclinical Cancer Chemoprevention Studies Using Animal Model of Inflammation-Associated Colorectal Carcinogenesis

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Tanaka, Takuji [Cytopatholgy Division, Tohkai Cytopathology Institute, Cancer Research and Prevention (TCI-CaRP), 5-1-2 Minami-uzura, Gifu 500-8285 (Japan); Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194 (Japan)

2012-07-16

Inflammation is involved in all stages of carcinogenesis. Inflammatory bowel disease, such as ulcerative colitis and Crohn’s disease is a longstanding inflammatory disease of intestine with increased risk for colorectal cancer (CRC). Several molecular events involved in chronic inflammatory process are reported to contribute to multi-step carcinogenesis of CRC in the inflamed colon. They include over-production of free radicals, reactive oxygen and nitrogen species, up-regulation of inflammatory enzymes in arachidonic acid biosynthesis pathway, up-regulation of certain cytokines, and intestinal immune system dysfunction. In this article, firstly I briefly introduce our experimental animal models where colorectal neoplasms rapidly develop in the inflamed colorectum. Secondary, data on preclinical cancer chemoprevention studies of inflammation-associated colon carcinogenesis by morin, bezafibrate, and valproic acid, using this novel inflammation-related colorectal carcinogenesis model is described.

Inhibition of inflammation and oxidative stress by an imidazopyridine derivative X22 prevents heart injury from obesity.

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Qian, Yuanyuan; Zhang, Yali; Zhong, Peng; Peng, Kesong; Xu, Zheng; Chen, Xuemei; Lu, Kongqin; Chen, Gaozhi; Li, Xiaokun; Liang, Guang

2016-08-01

Inflammation and oxidative stress plays an important role in the development of obesity-related complications and cardiovascular disease. Benzimidazole and imidazopyridine compounds are a class of compounds with a variety of activities, including anti-inflammatory, antioxidant and anti-cancer. X22 is an imidazopyridine derivative we synthesized and evaluated previously for anti-inflammatory activity in lipopolysaccharide-stimulated macrophages. However, its ability to alleviate obesity-induced heart injury via its anti-inflammatory actions was unclear. This study was designed to evaluate the cardioprotective effects of X22 using cell culture studies and a high-fat diet rat model. We observed that palmitic acid treatment in cardiac-derived H9c2 cells induced a significant increase in reactive oxygen species, inflammation, apoptosis, fibrosis and hypertrophy. All of these changes were inhibited by treatment with X22. Furthermore, oral administration of X22 suppressed high-fat diet-induced oxidative stress, inflammation, apoptosis, hypertrophy and fibrosis in rat heart tissues and decreased serum lipid concentration. We also found that the anti-inflammatory and anti-oxidative actions of X22 were associated with Nrf2 activation and nuclear factor-kappaB (NF-κB) inhibition, respectively, both in vitro and in vivo. The results of this study indicate that X22 may be a promising cardioprotective agent and that Nrf2 and NF-κB may be important therapeutic targets for obesity-related complications. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Colonic localization of indium-111 labeled leukocytes in active Behcet's disease

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Harre, R.G.; Conrad, G.R.; Seabold, J.E.

1988-01-01

A patient with known Behcet's disease demonstrated intense colonic localization of In-111 labeled leukocytes. Gastrointestinal involvement had not been previously manifested, but extensive colonic inflammation was documented by endoscopy. This case illustrates the utility of In-111 labeled leukocyte imaging for detecting active bowel disease in a debilitated patient with documented Behcet's vasculitis

L-rhamnose as a source of colonic propionate inhibits insulin secretion but does not influence measures of appetite or food intake.

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Darzi, Julia; Frost, Gary S; Swann, Jonathan R; Costabile, Adele; Robertson, M Denise

2016-03-01

Activation of free fatty acid receptor (FFAR)2 and FFAR3 via colonic short-chain fatty acids, particularly propionate, are postulated to explain observed inverse associations between dietary fiber intake and body weight. Propionate is reported as the predominant colonic fermentation product from l-rhamnose, a natural monosaccharide that resists digestion and absorption reaching the colon intact, while effects of long-chain inulin on appetite have not been extensively investigated. In this single-blind randomized crossover study, healthy unrestrained eaters (n = 13) ingested 25.5 g/d l-rhamnose, 22.4 g/d inulin or no supplement (control) alongside a standardized breakfast and lunch, following a 6-d run-in to investigate if appetite was inhibited. Postprandial qualitative appetite, breath hydrogen, and plasma glucose, insulin, triglycerides and non-esterified fatty acids were assessed for 420 min, then an ad libitum meal was provided. Significant treatment x time effects were found for postprandial insulin (P = 0.009) and non-esterified fatty acids (P = 0.046) with a significantly lower insulin response for l-rhamnose (P = 0.023) than control. No differences between treatments were found for quantitative and qualitative appetite measures, although significant treatment x time effects for meal desire (P = 0.008) and desire to eat sweet (P = 0.036) were found. Breath hydrogen was significantly higher with inulin (P = 0.001) and l-rhamnose (P = 0.009) than control, indicating colonic fermentation. These findings suggest l-rhamnose may inhibit postprandial insulin secretion, however neither l-rhamnose or inulin influenced appetite. Copyright © 2015 Elsevier Ltd. All rights reserved.

HIF-1α inhibition reverses multidrug resistance in colon cancer cells via downregulation of MDR1/P-glycoprotein.

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Jianfang Chen

Full Text Available Multidrug resistance (MDR is one of the major reasons chemotherapy-based treatments fail. Hypoxia is generally associated with tumor chemoresistance. However, the correlation between the heterodimeric hypoxia-inducible factor-1 (HIF-1 and the multidrug resistance (MDR1 gene/transporter P-glycoprotein (P-gp remains unclear. This study aims to explore the molecular mechanisms of reversing colon cancer MDR by focusing on the target gene HIF-1α.A chemotherapeutic sensitivity assay was used to observe the efficiency of MDR reversal in LoVo multicellular spheroids (MCS. The apoptotic level induced by different drugs was examined by flow cytometry (FCM. Binding of HIF-1α to the MDR1 gene promoter was evaluated by Chromatin immunoprecipitation (ChIP. The relationship between HIF-1α/P-gp expression and sensitivity to chemotherapy was analyzed.The sensitivity of LoVo MCS to all four chemotherapy drugs was decreased to varying degrees under hypoxic conditions. After silencing the HIF-1α gene, the sensitivities of LoVo MCS to all four chemotherapy drugs were restored. The apoptotic levels that all the drugs induced were all decreased to various extents in the hypoxic group. After silencing HIF-1α, the apoptosis level induced by all four chemotherapy drugs increased. The expression of HIF-1α and P-gp was significantly enhanced in LoVo MCS after treatment with hypoxia. Inhibiting HIF-1α significantly decreased the expression of MDR1/P-gp mRNA or protein in both the LoVo monolayers and LoVo MCS. The ChIP assay showed that HIF-1α was bound to the MDR1 gene promoter. Advanced colon carcinoma patients with expression of both HIF-1α and P-gp were more resistant to chemotherapy than that with non expression.HIF-1α inhibition reverses multidrug resistance in colon cancer cells via downregulation of MDR1/P-gp. The expression of HIF-1α and MDR1/P-gp can be used as a predictive marker for chemotherapy resistance in colon cancer.

Up-regulation of CNDP2 facilitates the proliferation of colon cancer.

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Xue, Conglong; Zhang, Zhenwei; Yu, Honglan; Yu, Miao; Yuan, Kaitao; Yang, Ting; Miao, Mingyong; Shi, Hanping

2014-05-21

Cytosolic nonspecific dipetidase (CN2) belongs to the family of M20 metallopeptidases. It was stated in previous articles that higher expression levels of CN2 were observed in renal cell carcinoma and breast cancer. Our study explored the correlation between CN2 and colon carcinogenesis. We analysed the relationship between 183 patients clinicopathological characteristics and its CN2 expression. To detect the levels of CN2 in colon cancer cell lines and colon cancer tissues by western blot. To verify cell proliferation in colon cancer cells with knockdown of CNDP2 and explore the causes of these phenomena. The expression levels of CN2 in clinical colon tumors and colon cancer cell lines were significantly higher than that in normal colon mucosa and colon cell lines. The difference in CN2 levels was associated with tumor location (right- and left-sided colon cancer), but there was no significant association with age, gender, tumor size, tumor grade, tumor stage or serum carcinoembryonic antigen (CEA). Knockdown of CNDP2 inhibited cell proliferation, blocked cell cycle progression and retarded carcinogenesis in an animal model. The signaling pathway through which knockdown of CNDP2 inhibited cell proliferation and tumorigenesis involved in EGFR, cyclin B1 and cyclin E. Knockdown of CNDP2 can inhibit the proliferation of colon cancer in vitro and retarded carcinogenesis in vivo.

The significance of incidental focal colonic 18FDG uptake on PET scanning

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Bartholomeusz, Dylan; Schultz, Christopher

2009-01-01

Full text: The incidental discovery of colonic polyps, colonic malignancy, diverticulitis and inflammation during PET scanning is well described. This study is a retrospective review of the incidence and follow up of incidental focal FOG uptake in the colon detected during routine PET scanning. PET scan reports over 12 months were reviewed for the reporting of incidental colonic uptake and then clinical follow up performed in available patient records for the incidence of further colonic investigation and results. In 2008, 1985 PET scans were reported at the Royal Adelaide Hospital for the staging and detection of malignancy. Review of the results show that incidental focal colonic uptake was seen in 27 cases, (II female aged 56-83 years). Follow up colonoscopy was performed in 8 cases and in 4 cases showed tubulovillous adenomas, 7-9 mm in size, in the region of abnormal FOG uptake, I had divetticulae and another focal inflammation. Two colonoscopies revealed no abnormality (25% false negative rate). One patient with Head and Neck cancer did not have colonoscopy but the colonic lesion resolved on a post therapy PET scan. Of the 18 cases that did not have colonoscopic follow up 5 were reported on the PET scan to have diffuse probably physiological caecal activity but 13 had focal lesions in the large bowel. Although incidental colonic lesions were detected in only 1.3% of studies, of those having colonoscopy 75 % had significant findings.

The tumor necrosis factor family member TNFSF14 (LIGHT) is required for resolution of intestinal inflammation in mice.

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Krause, Petra; Zahner, Sonja P; Kim, Gisen; Shaikh, Raziyah B; Steinberg, Marcos W; Kronenberg, Mitchell

2014-06-01

The pathogenesis of inflammatory bowel disease (IBD) is associated with a dysregulated mucosal immune response. Expression of the tumor necrosis factor (TNF) superfamily member 14 (TNFSF14, also known as LIGHT [homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes]) on T cells is involved in their activation; transgenic expression of LIGHT on T cells in mice promotes inflammation in multiple organs, including intestine. We investigated the roles for LIGHT in recovery from intestinal inflammation in mice. We studied the role of LIGHT in intestinal inflammation using Tnfsf14(-/-) and wild-type mice. Colitis was induced by transfer of CD4(+)CD45RB(high) T cells into Rag1(-/-) or Tnfsf14(-/-)Rag1(-/-) mice, or by administration of dextran sulfate sodium to Tnfsf14(-/-) or wild-type C57BL/6J mice. Mice were weighed, colon tissues were collected and measured, and histology analyses were performed. We measured infiltrating cell populations and expression of cytokines, chemokines, and LIGHT. After administration of dextran sulfate sodium, Tnfsf14(-/-) mice developed more severe colitis than controls, based on their reduced survival, accelerated loss of body weight, and histologic scores. LIGHT protected mice from colitis via the lymphotoxin β receptor and was expressed mainly by myeloid cells in the colon. Colons of Tnfsf14(-/-) mice also had increased accumulation of innate immune cells and higher levels of cytokines than colons from control mice. LIGHT, therefore, appears to regulate inflammation in the colon. Tnfsf14(-/-) mice develop more severe colitis than control mice. LIGHT signals through the lymphotoxin β receptor in the colon to regulate the innate immune response and mediate recovery from intestinal inflammation. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

The colon. Clinical radiology and endoscopy

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Rosenbusch, G.; Reeders, J.W.A.J.

1993-01-01

This comprehensive reference work presents in-depth information on the diagnostic radiology and endoscopy of the colon. After a brief review of the history of colon examinations, two chapters explain the anatomy, physiology and pharmacology of the large intestine as well as the methods and techniques applied for radiological examination of the colon. The pathology and characteristical findings and the diagnostic evaluation of the various types of disease are the main subject, with the chapters discussing inflammations and tumors consuming by far most of the space, but there is also valuable information on vascular lesions, traumata, latrogenous or post-surgery lesions, among others, and on the characteristical findings in children. Numerous tables, radiographs and endoscopic images together with drawings illustrate and accompany the textbook information. (orig.). 492 figs., 95 tabs [de

Ameboma: A Colon Carcinoma-Like Lesion in a Colonoscopy Finding

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Chung-Cheng Lin

2013-10-01

Full Text Available Ameboma is a rare complication of amebic colitis presenting as a mass of granulation tissue with peripheral fibrosis and a core of inflammation related to amebic chronic infection. The initial presentations are usually obstruction and low gastrointestinal bleeding. The most common sites are the ascending colon and the cecum. It may mimic colon carcinoma, Crohn's disease, carcinoma of the colon, non-Hodgkin's lymphoma, tuberculosis, fungal infection, AIDS-associated lymphoma and Kaposi's sarcoma in colonoscopy findings. The therapeutic strategy should be combined with antibiotics for invasive dysentery and eradication of luminal cysts.

Soyasaponins can blunt inflammation by inhibiting the reactive oxygen species-mediated activation of PI3K/Akt/NF-kB pathway.

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Zha, Longying; Chen, Jiading; Sun, Suxia; Mao, Limei; Chu, Xinwei; Deng, Hong; Cai, Junwei; Li, Xuefeng; Liu, Zhenqi; Cao, Wenhong

2014-01-01

We and others have recently shown that soyasaponins abundant in soybeans can decrease inflammation by suppressing the nuclear factor kappa B (NF-kB)-mediated inflammation. However, the exact molecular mechanisms by which soyasaponins inhibit the NF-kB pathway have not been established. In this study in macrophages, soyasaponins (A1, A2 and I) inhibited the lipopolysaccharide (LPS)-induced release of inflammatory marker prostaglandin E2 (PGE2) to a similar extent as the NF-kB inhibitor (BAY117082). Soyasaponins (A1, A2 and I) also suppressed the LPS-induced expression of cyclooxygenase 2 (COX-2), another inflammatory marker, in a dose-dependent manner by inhibiting NF-kB activation. In defining the associated mechanisms, we found that soyasaponins (A1, A2 and I) blunted the LPS-induced IKKα/β phosphorylation, IkB phosphorylation and degradation, and NF-kB p65 phosphorylation and nuclear translocation. In studying the upstream targets of soyasaponins on the NF-kB pathway, we found that soyasaponins (A1, A2 and I) suppressed the LPS-induced activation of PI3K/Akt similarly as the PI3K inhibitor LY294002, which alone blocked the LPS-induced activation of NF-kB. Additionally, soyasaponins (A1, A2 and I) reduced the LPS-induced production of reactive oxygen species (ROS) to the same extent as the anti-oxidant N-acetyl-L-cysteine, which alone inhibited the LPS-induced phosphorylation of Akt, IKKα/β, IkBα, and p65, transactivity of NF-kB, PGE2 production, and malondialdehyde production. Finally, our results show that soyasaponins (A1, A2 and I) elevated SOD activity and the GSH/GSSG ratio. Together, these results show that soyasaponins (A1, A2 and I) can blunt inflammation by inhibiting the ROS-mediated activation of the PI3K/Akt/NF-kB pathway.

Importance of neural mechanisms in colonic mucosal and muscular dysfunction in adult rats following neonatal colonic irritation.

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Chaloner, A; Rao, A; Al-Chaer, E D; Greenwood-Van Meerveld, B

2010-02-01

Previous studies have shown that early life trauma induced by maternal separation or colonic irritation leads to hypersensitivity to colorectal distension in adulthood. We tested the hypothesis that repetitive colorectal distension in neonates leads to abnormalities in colonic permeability and smooth muscle function in the adult rat. In neonatal rats, repetitive colorectal distension was performed on days 8, 10, and 12. As adults, stool consistency was graded from 0 (formed stool) to 3 (liquid stool). Colonic tissue was isolated for histology and myeloperoxidase levels. The colonic mucosa was placed in modified Ussing chambers for measurements of permeability and short-circuit current responses to forskolin, electrical field stimulation, and carbachol. Segments of colonic musculature were placed in organ baths and contractile response to potassium chloride, electrical field stimulation, and carbachol were determined. In adult rats that experienced neonatal colonic irritation, no significant changes in colonic histology or myeloperoxidase activity were observed; however, stool consistency scores were increased. Mucosal permeability, measured as an increase in basal conductance, was significantly increased but no changes in short-circuit current responses were observed. In adulthood, rats that underwent colorectal distension as neonates exhibited an elevated smooth muscle contractile response to potassium chloride, but no changes in response to electrical field stimulation or carbachol. In summary, neonatal colonic irritation, shown previously to produce colonic hypersensitivity, leads to significant alterations in colonic mucosal and smooth muscle function characterized by loose stools, increased mucosal permeability, and increased smooth muscle contractility in the absence of colon inflammation in adulthood. Published by Elsevier Ltd.

15-Deoxy-Delta-12,14-Prostaglandin J2 Inhibits Lung Inflammation and Remodeling in Distinct Murine Models of Asthma

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Diego S. Coutinho

2017-06-01

Full Text Available 15-deoxy-Δ-12,14-prostaglandin J2 (15d-PGJ2 has been described as an anti-inflammatory lipid mediator in several in vitro and in vivo studies, but its effect on allergic pulmonary inflammation remains elusive. The aim of this study was to investigate the therapeutic potential of 15d-PGJ2 based on distinct murine models of allergic asthma triggered by either ovalbumin (OVA or house dust mite extract (HDM. Characteristics of lung inflammation, airway hyper-reactivity (AHR, mucus exacerbation, and lung remodeling in sensitized A/J mice treated or not with 15d-PGJ2 were assessed. 15d-PGJ2 treatments were carried out systemically or topically given via subcutaneous injection or intranasal instillation, respectively. Analyses were carried out 24 h after the last allergen provocation. Irrespective of the route of administration, 15d-PGJ2 significantly inhibited the peribronchial accumulation of eosinophils and neutrophils, subepithelial fibrosis and also mucus exacerbation caused by either OVA or HDM challenge. The protective effect of 15d-PGJ2 occurred in parallel with inhibition of allergen-induced AHR and lung tissue production of pro-inflammatory cytokines, such as interleukin (IL-5, IL-13, IL-17, and TNF-α. Finally, 15d-PGJ2 was found effective in inhibiting NF-κB phosphorylation upon HDM challenge as measured by Western blotting. In conclusion, our findings suggest that 15d-PGJ2 can reduce crucial features of asthma, including AHR, lung inflammation, and remodeling in distinct murine models of the disease. These effects are associated with a decrease in lung tissue generation of pro-inflammatory cytokines by a mechanism related to downregulation of NF-κB phosphorylation.

Bone-marrow-derived mesenchymal stem cells inhibit gastric aspiration lung injury and inflammation in rats.

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Zhou, Jing; Jiang, Liyan; Long, Xuan; Fu, Cuiping; Wang, Xiangdong; Wu, Xiaodan; Liu, Zilong; Zhu, Fen; Shi, Jindong; Li, Shanqun

2016-09-01

Gastric aspiration lung injury is one of the most common clinical events. This study investigated the effects of bone-marrow-derived mesenchymal stem cells (BMSCs) on combined acid plus small non-acidified particle (CASP)-induced aspiration lung injury. Enhanced green fluorescent protein (EGFP(+) ) or EGFP(-) BMSCs or 15d-PGJ2 were injected via the tail vein into rats immediately after CASP-induced aspiration lung injury. Pathological changes in lung tissues, blood gas analysis, the wet/dry weight ratio (W/D) of the lung, levels of total proteins and number of total cells and neutrophils in bronchoalveolar lavage fluid (BALF) were determined. The cytokine levels were measured using ELISA. Protein expression was determined by Western blot. Bone-marrow-derived mesenchymal stem cells treatment significantly reduced alveolar oedema, exudation and lung inflammation; increased the arterial partial pressure of oxygen; and decreased the W/D of the lung, the levels of total proteins and the number of total cells and neutrophils in BALF in the rats with CASP-induced lung injury. Bone-marrow-derived mesenchymal stem cells treatment decreased the levels of tumour necrosis factor-α and Cytokine-induced neutrophil chemoattractant (CINC)-1 and the expression of p-p65 and increased the levels of interleukin-10 and 15d-PGJ2 and the expression of peroxisome proliferator-activated receptor (PPAR)-γ in the lung tissue in CASP-induced rats. Tumour necrosis factor-α stimulated BMSCs to secrete 15d-PGJ2 . A tracking experiment showed that EGFP(+) BMSCs were able to migrate to local lung tissues. Treatment with 15d-PGJ2 also significantly inhibited CASP-induced lung inflammation and the production of pro-inflammatory cytokines. Our results show that BMSCs can protect lung tissues from gastric aspiration injury and inhibit lung inflammation in rats. A beneficial effect might be achieved through BMSC-derived 15d-PGJ2 activation of the PPAR-γ receptor, reducing the production of

Portulaca oleracea extract can inhibit nodule formation of colon cancer stem cells by regulating gene expression of the Notch signal transduction pathway.

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Jin, Heiying; Chen, Li; Wang, Shuiming; Chao, Deng

2017-07-01

To investigate whether Portulaca oleracea extract affects tumor formation in colon cancer stem cells and its chemotherapy sensitivity. In addition, to analyze associated genetic changes within the Notch signal transduction pathway. Serum-free cultures of colon cancer cells (HT-29) and HT-29 cancer stem cells were treated with the chemotherapeutic drug 5-fluorouracil to assess sensitivity. Injections of the stem cells were also given to BALB/c mice to confirm tumor growth and note its characteristics. In addition, the effect of different concentrations of P. oleracea extract was tested on the growth of HT-29 colon cancer cells and HT-29 cancer stem cells, as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. The effects of P. oleracea extract on the expression of β-catenin, Notch1, and Notch2 in the HT-29 cells were studied using reverse transcription polymerase chain reaction and Western blotting. The tumor volume of the HT29 cells was two times larger than that of HT29 cancer stem cells. Treatment with P. oleracea extract inhibited the proliferation of both HT-29 cancer cells and HT-29 cancer stem cells at doses from 0.07 to 2.25 µg/mL. Apoptosis of HT-29 cancer cells and HT-29 cancer stem cells was assessed by flow cytometry; it was enhanced by the addition of P. oleracea extract. Finally, treatment with P. oleracea extract significantly downregulated the expression of the Notch1 and β-catenin genes in both cell types. The results of this study show that P. oleracea extract inhibits the growth of colon cancer stem cells in a dose-dependent manner. Furthermore, it inhibits the expression of the Notch1 and β-catenin genes. Taken together, this suggests that it may elicit its effects through regulatory and target genes that mediate the Notch signal transduction pathway.

Yerba mate tea and mate saponins prevented azoxymethane-induced inflammation of rat colon through suppression of NF-kB p65ser(311) signaling via IkB-a and GSK-3ß reduced phosphorylation

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Yerba mate tea (YMT) has a chemopreventive role in a variety of inflammatory diseases. The objective was to determine the capability of YMT and mate saponins to prevent azoxymethane (AOM)-induced colonic inflammation in rats. YMT (2% dry leaves, w/v, as a source of drinking fluid) (n = 15) and mat...

Caesium inhibits the colonization of Medicago truncatula by arbuscular mycorrhizal fungi

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Wiesel, Lea; Dubchak, Sergiy; Turnau, Katarzyna; Broadley, Martin R.; White, Philip J.

2015-01-01

Contamination of soils with radioisotopes of caesium (Cs) is of concern because of their emissions of harmful β and γ radiation. Radiocaesium enters the food chain through vegetation and the intake of Cs can affect the health of organisms. Arbuscular mycorrhizal (AM) fungi form mutualistic symbioses with plants through colonization of the roots and previous studies on the influence of AM on Cs concentrations in plants have given inconsistent results. These studies did not investigate the influence of Cs on AM fungi and it is therefore not known if Cs has a direct effect on AM colonization. Here, we investigated whether Cs influences AM colonization and if this effect impacts on the influence of Rhizophagus intraradices on Cs accumulation by Medicago truncatula. M. truncatula was grown with or without R. intraradices in pots containing different concentrations of Cs. Here, we present the first evidence that colonization of plants by AM fungi can be negatively affected by increasing Cs concentrations in the soil. Mycorrhizal colonization had little effect on root or shoot Cs concentrations. In conclusion, the colonization by AM fungi is impaired by high Cs concentrations and this direct effect of soil Cs on AM colonization might explain the inconsistent results reported in literature that have shown increased, decreased or unaffected Cs concentrations in AM plants. - Highlights: • Colonization of plants by arbuscular mycorrhizal fungi is negatively affected by increasing soil caesium concentrations. • Shoot caesium concentrations are not influenced by AM fungi at soil caesium concentrations above about 3 μg Cs kg −1 . • The direct effect of caesium on AM fungi might impact on the influence of AM fungi on Cs accumulation in plants. • This might explain the inconsistent results reported in literature on Cs accumulation in AM plants

Results of a phase I pilot clinical trial examining the effect of plant-derived resveratrol and grape powder on Wnt pathway target gene expression in colonic mucosa and colon cancer

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Nguyen, Anthony V; Martinez, Micaela; Stamos, Michael J; Moyer, Mary P; Planutis, Kestutis; Hope, Christopher; Holcombe, Randall F

2009-01-01

Resveratrol exhibits colon cancer prevention activity in animal models; it is purported to have this activity in humans and inhibit a key signaling pathway involved in colon cancer initiation, the Wnt pathway, in vitro. A phase I pilot study in patients with colon cancer was performed to evaluate the effects of a low dose of plant-derived resveratrol formulation and resveratrol-containing freeze-dried grape powder (GP) on Wnt signaling in the colon. Eight patients were enrolled and normal colonic mucosa and colon cancer tissue were evaluated by Wnt pathway-specific microarray and quantitative real-time polymerase chain reaction (qRT-PCR) pre- and post-exposure to resveratrol/GP. Based on the expression of a panel of Wnt target genes, resveratrol/GP did not inhibit the Wnt pathway in colon cancer but had significant (p < 0.03) activity in inhibiting Wnt target gene expression in normal colonic mucosa. The greatest effect on Wnt target gene expression was seen following ingestion of 80 g of GP per day (p < 0.001). These results were confirmed with qRT-PCR of cyclinD1 and axinII. The inhibitory effect of GP on Wnt signal throughput was confirmed in vitro with a normal colonic mucosa-derived cell line. These data suggest that GP, which contains low dosages of resveratrol in combination with other bioactive components, can inhibit the Wnt pathway in vivo and that this effect is confined to the normal colonic mucosa. Further study of dietary supplementation with resveratrol-containing foods such as whole grapes or GP as a potential colon cancer preventive strategy is warranted. NCT00256334

Gardenia jasminoides extracts and gallic acid inhibit lipopolysaccharide-induced inflammation by suppression of JNK2/1 signaling pathways in BV-2 cells

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Wen-Hung Lin

2015-06-01

Conclusion:Taken together, these results indicate that the protective mechanism of the GJ extract involves an antioxidant effect and inhibition of JNK2/1 MAP kinase and COX-2 expressions in LPS-induced inflammation of BV-2 cells.

Butyrate and bioactive proteolytic form of Wnt-5a regulate colonic epithelial proliferation and spatial development

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Uchiyama, Kazuhiko; Sakiyama, Toshio; Hasebe, Takumu; Musch, Mark W.; Miyoshi, Hiroyuki; Nakagawa, Yasushi; He, Tong-Chuan; Lichtenstein, Lev; Naito, Yuji; Itoh, Yoshito; Yoshikawa, Toshikazu; Jabri, Bana; Stappenbeck, Thaddeus; Chang, Eugene B.

2016-01-01

Proliferation and spatial development of colonic epithelial cells are highly regulated along the crypt vertical axis, which, when perturbed, can result in aberrant growth and carcinogenesis. In this study, two key factors were identified that have important and counterbalancing roles regulating these processes: pericrypt myofibroblast-derived Wnt-5a and the microbial metabolite butyrate. Cultured YAMC cell proliferation and heat shock protein induction were analzyed after butryate, conditioned medium with Wnt5a activity, and FrzB containing conditioned medium. In vivo studies to modulate Hsp25 employed intra-colonic wall Hsp25 encoding lentivirus. To silence Wnt-5a in vivo, intra-colonic wall Wnt-5a silencing RNA was used. Wnt-5a, secreted by stromal myofibroblasts of the lower crypt, promotes proliferation through canonical β-catenin activation. Essential to this are two key requirements: (1) proteolytic conversion of the highly insoluble ~40 kD Wnt-5a protein to a soluble 36 mer amino acid peptide that activates epithelial β-catenin and cellular proliferation, and (2) the simultaneous inhibition of butyrate-induced Hsp25 by Wnt-5a which is necessary to arrest the proliferative process in the upper colonic crypt. The interplay and spatial gradients of these factors insures that crypt epithelial cell proliferation and development proceed in an orderly fashion, but with sufficient plasticity to adapt to physiological perturbations including inflammation. PMID:27561676

Andrographolide sulfonate ameliorates experimental colitis in mice by inhibiting Th1/Th17 response.

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Liu, Wen; Guo, Wenjie; Guo, Lele; Gu, Yanhong; Cai, Peifen; Xie, Ning; Yang, Xiaoling; Shu, Yongqian; Wu, Xuefeng; Sun, Yang; Xu, Qiang

2014-06-01

Inflammatory bowel disease (IBD) is a chronic, relapsing and remitting condition of inflammation involves overproduction of pro-inflammatory cytokines and excessive functions of inflammatory cells. However, current treatments for IBD may have potential adverse effects including steroid dependence, infections and lymphoma. Therefore new therapies for the treatment of IBD are desperately needed. In the present study, we aimed to examine the effect of andrographolide sulfonate, a water-soluble form of andrographolide (trade name: Xi-Yan-Ping Injection), on murine experimental colitis induced by 2, 4, 6-trinitrobenzene sulfonic acid (TNBS). Andrographolide sulfonate was administrated through intraperitoneal injection to mice with TNBS-induced colitis. TNBS-induced body weight loss, myeloperoxidase activity, shortening of the colon and colonic inflammation were significantly ameliorated by andrographolide sulfonate. Both the mRNA and protein levels of pro-inflammatory cytokines were reduced by andrographolide sulfonate administration. Moreover, andrographolide sulfonate markedly suppressed the activation of p38 mitogen-activated protein kinase as well as p65 subunit of nuclear factor-κB (NF-κB). Furthermore, CD4(+) T cell infiltration as well as the differentiation of Th1 (CD4(+)IFN-γ(+)) and Th17 (CD4(+)IL17A(+)) subset were inhibited by andrographolide sulfonate. In summary, these results suggest that andrographolide sulfonate ameliorated TNBS-induced colitis in mice through inhibiting Th1/Th17 response. Our study shows that water-soluble andrographolide sulfonate may represent a new therapeutic approach for treating gastrointestinal inflammatory disorders. Copyright © 2014 Elsevier B.V. All rights reserved.

Salmonella enterica serovar Typhimurium exploits inflammation to modify swine intestinal microbiota.

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Rosanna eDrumo

2016-01-01

Full Text Available Salmonella enterica serovar Typhimurium is an important zoonotic gastrointestinal pathogen responsible for foodborne disease worldwide. It is a successful enteric pathogen because it has developed virulence strategies allowing it to survive in a highly inflamed intestinal environment exploiting inflammation to overcome colonization resistance provided by intestinal microbiota. In this study, we used piglets featuring an intact microbiota, which naturally develop gastroenteritis, as model for salmonellosis. We compared the effects on the intestinal microbiota induced by a wild type and an attenuated S. Typhimurium in order to evaluate whether the modifications are correlated with the virulence of the strain. This study showed that Salmonella alters microbiota in a virulence-dependent manner. We found that the wild type S. Typhimurium induced inflammation and a reduction of specific protecting microbiota species (SCFA-producing bacteria normally involved in providing a barrier against pathogens. Both these effects could contribute to impair colonization resistance, increasing the host susceptibility to wild type S. Typhimurium colonization. In contrast, the attenuated S. Typhimurium, which is characterized by a reduced ability to colonize the intestine, and by a very mild inflammatory response, was unable to successfully sustain competition with the microbiota.

Analgesic effect of Minocycline in rat model of inflammation-induced visceral pain

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Kannampalli, Pradeep; Pochiraju, Soumya; Bruckert, Mitchell; Shaker, Reza; Banerjee, Banani; Sengupta, Jyoti N.

2014-01-01

The present study investigates the analgesic effect of minocycline, a semi-synthetic tetracycline antibiotic, in a rat model of inflammation-induced visceral pain. Inflammation was induced in male rats by intracolonic administration of tri-nitrobenzenesulphonic acid (TNBS). Visceral hyperalgesia was assessed by comparing the viscero-motor response (VMR) to graded colorectal distension (CRD) prior and post 7 days after TNBS treatment. Electrophysiology recordings from CRD-sensitive pelvic nerve afferents (PNA) and lumbo-sacral (LS) spinal neurons were performed in naïve and inflamed rats. Colonic inflammation produced visceral hyperalgesia characterized by increase in the VMRs to CRD accompanied with simultaneous activation of microglia in the spinal cord and satellite glial cells (SGCs) in the dorsal root ganglions (DRGs). Selectively inhibiting the glial activation following inflammation by araC (Arabinofuranosyl Cytidine) prevented the development of visceral hyperalgesia. Intrathecal minocycline significantly attenuated the VMR to CRD in inflamed rats, whereas systemic minocycline produced a delayed effect. In electrophysiology experiments, minocycline significantly attenuated the mechanotransduction of CRD-sensitive PNAs and the responses of CRD-sensitive LS spinal neurons in TNBS-treated rats. While the spinal effect of minocycline was observed within 5 min of administration, systemic injection of the drug produced a delayed effect (60 min) in inflamed rats. Interestingly, minocycline did not exhibit analgesic effect in naïve, non-inflamed rats. The results demonstrate that intrathecal injection of minocycline can effectively attenuate inflammation-induced visceral hyperalgesia. Minocycline might as well act on neuronal targets in the spinal cord of inflamed rats, in addition to the widely reported glial inhibitory action to produce analgesia. PMID:24485889

Protective effect of Korean Red Ginseng extract against Helicobacter pylori-induced gastric inflammation in Mongolian gerbils

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Minkyung Bae

2014-01-01

Full Text Available Helicobacter pylori-induced gastric inflammation includes induction of inflammatory mediators interleukin (IL-8 and inducible nitric oxide synthase (iNOS, which are mediated by oxidant-sensitive transcription factor NF-κB. High levels of lipid peroxide (LPO and increased activity of myeloperoxidase (MPO, a biomarker of neutrophil infiltration, are observed in H. pylori-infected gastric mucosa. Panax ginseng Meyer, a Korean herb medicine, is widely used in Asian countries for its biological activities including anti-inflammatory efficacy. The present study aims to investigate whether Korean Red Ginseng extract (RGE inhibits H. pylori-induced gastric inflammation in Mongolian gerbils. One wk after intragastric inoculation with H. pylori, Mongolian gerbils were fed with either the control diet or the diet containing RGE (200 mg RGE/gerbil for 6 wk. The following were determined in gastric mucosa: the number of viable H. pylori in stomach; MPO activity; LPO level; mRNA and protein levels of keratinocyte chemoattractant factor (KC, a rodent IL-8 homolog, IL-1β, and iNOS; protein level of phospho-IκBα (which reflects the activation of NF-κB; and histology. As a result, RGE suppressed H. pylori-induced mRNA and protein levels of KC, IL-1β, and iNOS in gastric mucosa. RGE also inhibited H. pylori-induced phosphorylation of IκBα and increases in LPO level and MPO activity of gastric mucosa. RGE did not affect viable H. pylori colonization in the stomach, but improved the histological grade of infiltration of polymorphonuclear neutrophils, intestinal metaplasia, and hyperplasia. In conclusion, RGE inhibits H. pylori-induced gastric inflammation by suppressing induction of inflammatory mediators (KC, IL-1β, iNOS, MPO activity, and LPO level in H. pylori-infected gastric mucosa.

Navy and black bean supplementation attenuates colitis-associated inflammation and colonic epithelial damage.

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Monk, Jennifer M; Wu, Wenqing; Hutchinson, Amber L; Pauls, Peter; Robinson, Lindsay E; Power, Krista A

2018-02-27

The enriched levels of nondigestible fermentable carbohydrates and phenolic compounds found in common beans can exert immunomodulatory effects within the colon that improve gut health and mitigate the severity of colitis-associated inflammatory pathology. Prior to acute colitis onset, C57Bl/6 mice were prefed isocaloric 20% cooked navy bean (NB) or black bean (BB) diets for 3 weeks and switched to control basal diet (BD) 24 h prior to colitis induction via 5-day exposure to dextran sodium sulfate (2% w/v in drinking water)+3 days of fresh water. The severity of the acute colitis phenotype was attenuated by bean prefeeding, evidenced by reduced colon tissue inflammatory transcription factor activation (NFκB, STAT3) and inflammatory mediator levels in the colon (IL-1β, IL-6, IL-18 and MCP-1) and serum (TNFα, IL-6, IL-1β, MCP-1) versus BD (P≤.05). Additionally, biomarkers of enhanced wound repair responses were increased by bean prefeeding including colon tissue protein levels of IL-22, IL-27 and activated (i.e., GTP-bound) Cdc42 and Rac1 versus BD (P≤.05). mRNA expressions of genes involved in normal colonic epithelial function and the promotion of epithelial barrier integrity, defense and/or restitution and wound closure including MUC1, RELMβ, IgA and REG3γ were all increased in NB and BB prefed mice versus BD (P≤.05). Collectively, bean supplementation prior to colitis induction (i.e., mimicking disease relapse) primes the colonic microenvironment to attenuate the severity of the colitis inflammatory phenotype and maintain aspects of epithelial barrier function. Copyright © 2018 Elsevier Inc. All rights reserved.

Methanolic extract of white asparagus shoots activates TRAIL apoptotic death pathway in human cancer cells and inhibits colon carcinogenesis in a preclinical model

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BOUSSEROUEL, SOUAD; LE GRANDOIS, JULIE; GOSSÉ, FRANCINE; WERNER, DALAL; BARTH, STEPHAN W.; MARCHIONI, ERIC; MARESCAUX, JACQUES; RAUL, FRANCIS

2013-01-01

Shoots of white asparagus are a popular vegetable dish, known to be rich in many bioactive phytochemicals reported to possess antioxidant, and anti-inflammatory and antitumor activities. We evaluated the anticancer mechanisms of a methanolic extract of Asparagus officinalis L. shoots (Asp) on human colon carcinoma cells (SW480) and their derived metastatic cells (SW620), and Asp chemopreventive properties were also assessed in a model of colon carcinogenesis. SW480 and SW620 cell proliferation was inhibited by 80% after exposure to Asp (80 μg/ml). We demonstrated that Asp induced cell death through the activation of TRAIL DR4/DR5 death receptors leading to the activation of caspase-8 and caspase-3 and to cell apoptosis. By specific blocking agents of DR4/DR5 receptors we were able to prevent Asp-triggered cell death confirming the key role of DR4/DR5 receptors. We found also that Asp (80 μg/ml) was able to potentiate the effects of the cytokine TRAIL on cell death even in the TRAIL-resistant metastatic SW620 cells. Colon carcinogenesis was initiated in Wistar rats by intraperitoneal injections of azoxymethane (AOM), once a week for two weeks. One week after (post-initiation) rats received daily Asp (0.01%, 14 mg/kg body weight) in drinking water. After 7 weeks of Asp-treatment the colon of rats exhibited a 50% reduction of the number of preneoplastic lesions (aberrant crypt foci). In addition Asp induced inhibition of several pro-inflammatory mediators, in association with an increased expression of host-defense mediators. In the colonic mucosa of Asp-treated rats we also confirmed the pro-apoptotic effects observed in vitro including the activation of the TRAIL death-receptor signaling pathway. Taken together, our data highlight the chemopreventive effects of Asp on colon carcinogenesis and its ability to promote normal cellular homeostasis. PMID:23754197

Hydrogen sulfide lowers proliferation and induces protective autophagy in colon epithelial cells.

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Ya C Wu

Full Text Available Hydrogen sulfide (H(2S is a gaseous bacterial metabolite that reaches high levels in the large intestine. In the present study, the effect of H(2S on the proliferation of normal and cancerous colon epithelial cells was investigated. An immortalized colon epithelial cell line (YAMC and a panel of colon cancer cell lines (HT-29, SW1116, HCT116 were exposed to H(2S at concentrations similar to those found in the human colon. H(2S inhibited normal and cancerous colon epithelial cell proliferation as measured by MTT assay. The anti-mitogenic effect of H(2S was accompanied by G(1-phase cell cycle arrest and the induction of the cyclin-dependent kinase inhibitor p21(Cip. Moreover, exposure to H(2S led to features characteristic of autophagy, including increased formation of LC3B(+ autophagic vacuoles and acidic vesicular organelles as determined by immunofluorescence and acridine orange staining, respectively. Abolition of autophagy by RNA interference targeting Vps34 or Atg7 enhanced the anti-proliferative effect of H(2S. Further mechanistic investigation revealed that H(2S stimulated the phosphorylation of AMP-activated protein kinase (AMPK and inhibited the phosphorylation of mammalian target of rapamycin (mTOR and S6 kinase. Inhibition of AMPK significantly reversed H(2S-induced autophagy and inhibition of cell proliferation. Collectively, we demonstrate that H(2S inhibits colon epithelial cell proliferation and induces protective autophagy via the AMPK pathway.

Colon-available raspberry polyphenols exhibit anti-cancer effects on in vitro models of colon cancer

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McDougall Gordon

2007-01-01

Full Text Available Abstract Background There is a probable association between consumption of fruit and vegetables and reduced risk of cancer, particularly cancer of the digestive tract. This anti-cancer activity has been attributed in part to anti-oxidants present in these foods. Raspberries in particular are a rich source of the anti-oxidant compounds, such as polyphenols, anthocyanins and ellagitannins. Methods A "colon-available" raspberry extract (CARE was prepared that contained phytochemicals surviving a digestion procedure that mimicked the physiochemical conditions of the upper gastrointestinal tract. The polyphenolic-rich extract was assessed for anti-cancer properties in a series of in vitro systems that model important stages of colon carcinogenesis, initiation, promotion and invasion. Results The phytochemical composition of CARE was monitored using liquid chromatography mass spectrometry. The colon-available raspberry extract was reduced in anthocyanins and ellagitannins compared to the original raspberry juice but enriched in other polyphenols and polyphenol breakdown products that were more stable to gastrointestinal digestion. Initiation – CARE caused significant protective effects against DNA damage induced by hydrogen peroxide in HT29 colon cancer cells measured using single cell microgelelectrophoresis. Promotion – CARE significantly decreased the population of HT29 cells in the G1 phase of the cell cycle, effectively reducing the number of cells entering the cell cycle. However, CARE had no effect on epithelial integrity (barrier function assessed by recording the trans-epithelial resistance (TER of CACO-2 cell monolayers. Invasion – CARE caused significant inhibition of HT115 colon cancer cell invasion using the matrigel invasion assay. Conclusion The results indicate that raspberry phytochemicals likely to reach the colon are capable of inhibiting several important stages in colon carcinogenesis in vitro.

Oncogenic KRAS activates an embryonic stem cell-like program in human colon cancer initiation.

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Le Rolle, Anne-France; Chiu, Thang K; Zeng, Zhaoshi; Shia, Jinru; Weiser, Martin R; Paty, Philip B; Chiu, Vi K

2016-01-19

Colorectal cancer is the third most frequently diagnosed cancer worldwide. Prevention of colorectal cancer initiation represents the most effective overall strategy to reduce its associated morbidity and mortality. Activating KRAS mutation (KRASmut) is the most prevalent oncogenic driver in colorectal cancer development, and KRASmut inhibition represents an unmet clinical need. We apply a systems-level approach to study the impact of KRASmut on stem cell signaling during human colon cancer initiation by performing gene set enrichment analysis on gene expression from human colon tissues. We find that KRASmut imposes the embryonic stem cell-like program during human colon cancer initiation from colon adenoma to stage I carcinoma. Expression of miR145, an embryonic SC program inhibitor, promotes cell lineage differentiation marker expression in KRASmut colon cancer cells and significantly suppresses their tumorigenicity. Our data support an in vivo plasticity model of human colon cancer initiation that merges the intrinsic stem cell properties of aberrant colon stem cells with the embryonic stem cell-like program induced by KRASmut to optimize malignant transformation. Inhibition of the embryonic SC-like program in KRASmut colon cancer cells reveals a novel therapeutic strategy to programmatically inhibit KRASmut tumors and prevent colon cancer.

The bile acids, deoxycholic acid and ursodeoxycholic acid, regulate colonic epithelial wound healing.

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Mroz, Magdalena S; Lajczak, Natalia K; Goggins, Bridie J; Keely, Simon; Keely, Stephen J

2018-03-01

The intestinal epithelium constitutes an innate barrier which, upon injury, undergoes self-repair processes known as restitution. Although bile acids are known as important regulators of epithelial function in health and disease, their effects on wound healing processes are not yet clear. Here we set out to investigate the effects of the colonic bile acids, deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA), on epithelial restitution. Wound healing in T 84 cell monolayers grown on transparent, permeable supports was assessed over 48 h with or without bile acids. Cell migration was measured in Boyden chambers. mRNA and protein expression were measured by RT-PCR and Western blotting. DCA (50-150 µM) significantly inhibited wound closure in cultured epithelial monolayers and attenuated cell migration in Boyden chamber assays. DCA also induced nuclear accumulation of the farnesoid X receptor (FXR), whereas an FXR agonist, GW4064 (10 µM), inhibited wound closure. Both DCA and GW4064 attenuated the expression of CFTR Cl - channels, whereas inhibition of CFTR activity with either CFTR- inh -172 (10 µM) or GlyH-101 (25 µM) also prevented wound healing. Promoter/reporter assays revealed that FXR-induced downregulation of CFTR is mediated at the transcriptional level. In contrast, UDCA (50-150 µM) enhanced wound healing in vitro and prevented the effects of DCA. Finally, DCA inhibited and UDCA promoted mucosal healing in an in vivo mouse model. In conclusion, these studies suggest bile acids are important regulators of epithelial wound healing and are therefore good targets for development of new drugs to modulate intestinal barrier function in disease treatment. NEW & NOTEWORTHY The secondary bile acid, deoxycholic acid, inhibits colonic epithelial wound healing, an effect which appears to be mediated by activation of the nuclear bile acid receptor, FXR, with subsequent downregulation of CFTR expression and activity. In contrast, ursodeoxycholic acid promotes

HMGB1 Inhibition During Zymosan-Induced Inflammation: The Potential Therapeutic Action of Riboflavin.

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Mazur-Bialy, Agnieszka Irena; Pocheć, Ewa

2016-04-01

Sepsis, also known as systemic inflammatory response syndrome, is a life-threatening condition caused by a pathogenic agent and leading to multiple organ dysfunction syndrome. One of the factors responsible for the excessive intensification of the inflammatory response in the course of inflammation is high-mobility group protein B1 (HMGB1). HMG-1 is a nuclear protein which, after being released to the intercellular space, has a highly pro-inflammatory effect and acts as a late mediator of lethal damage. The purpose of this study was to examine whether the anti-inflammatory action of riboflavin is accompanied by inhibition of HMGB1 release during peritoneal inflammation and zymosan stimulation of macrophages. Peritonitis was induced in male BALB/c and C57BL/6J mice via intraperitoneal injection of zymosan (40 mg/kg). RAW 264.7 macrophages were activated with zymosan (250 µg/ml). Riboflavin (mice, 50 mg/kg; RAW 264.7, 25 µg/ml) was administered 30 min before zymosan, simultaneously with, or 2, 4, 6 h after zymosan. Additionally, mRNA expression of HMGB1 and its intracellular and serum levels were evaluated. The research showed that riboflavin significantly reduces both the expression and the release of HMGB1; however, the effect of riboflavin was time-dependent. The greatest efficacy was found when riboflavin was given 30 min prior to zymosan, and also 2 and 4 h (C57BL/6J; RAW 264.7) or 4 and 6 h (BALB/c) after zymosan. Research showed that riboflavin influences the level of HMGB1 released in the course of inflammation; however, further study is necessary to determine its mechanisms of action.

TRAIL pathway is associated with inhibition of colon cancer by protopanaxadiol

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Zhiyu Zhang

2015-01-01

Full Text Available Among important components of American ginseng, protopanaxadiol (PPD showed more active anticancer potential than other triterpenoid saponins. In this study, we determined the in vivo effects of PPD in a mouse cancer model first. Then, using human colorectal cancer cell lines, we observed significant cancer cell growth inhibition by promoting G1 cell cycle redistribution and apoptosis. Subsequently, we characterized the downstream genes targeted by PPD in HCT-116 cancer cells. Using Affymetrix high density GeneChips, we obtained the gene expression profile of the cells. Microarray data indicated that the expression levels of 76 genes were changed over two-fold after PPD, of which 52 were upregulated while the remaining 24 were downregulated. Ingenuity pathway analysis of top functions affected was carried out. Data suggested that by regulating the interactions between p53 and DR4/DR5, the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL pathway played a key role in the action of PPD, a promising colon cancer inhibitory compound.

TRAIL pathway is associated with inhibition of colon cancer by protopanaxadiol.

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Zhang, Zhiyu; Li, Zejuan; Wu, Xiaohui; Zhang, Chun-Feng; Calway, Tyler; He, Tong-Chuan; Du, Wei; Chen, Jianjun; Wang, Chong-Zhi; Yuan, Chun-Su

2015-01-01

Among important components of American ginseng, protopanaxadiol (PPD) showed more active anticancer potential than other triterpenoid saponins. In this study, we determined the in vivo effects of PPD in a mouse cancer model first. Then, using human colorectal cancer cell lines, we observed significant cancer cell growth inhibition by promoting G1 cell cycle redistribution and apoptosis. Subsequently, we characterized the downstream genes targeted by PPD in HCT-116 cancer cells. Using Affymetrix high density GeneChips, we obtained the gene expression profile of the cells. Microarray data indicated that the expression levels of 76 genes were changed over two-fold after PPD, of which 52 were upregulated while the remaining 24 were downregulated. Ingenuity pathway analysis of top functions affected was carried out. Data suggested that by regulating the interactions between p53 and DR4/DR5, the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway played a key role in the action of PPD, a promising colon cancer inhibitory compound. Copyright © 2014 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.

1,25(OH)2D3 attenuates TGF-β1/β2-induced increased migration and invasion via inhibiting epithelial-mesenchymal transition in colon cancer cells.

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Chen, Shanwen; Zhu, Jing; Zuo, Shuai; Ma, Ju; Zhang, Junling; Chen, Guowei; Wang, Xin; Pan, Yisheng; Liu, Yucun; Wang, Pengyuan

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) has been reported to inhibit proliferation and migration of multiple types of cancer cells. However, the mechanism underlying its anti-metastasis effect is not fully illustrated. In this study, the effect of 1,25(OH)2D3 on TGF-β1/β2-induced epithelial-mesenchymal transition (EMT) is tested in colon cancer cells. The results suggest that 1,25(OH)2D3 inhibited TGF-β1/β2-induced increased invasion and migration of in SW-480 and HT-29 cells. 1,25(OH)2D3 also inhibited the cadherin switch in SW-480 and HT-29 cells. TGF-β1/β2-induced increased expression of EMT-related transcription factors was also inhibited by 1,25(OH)2D3. 1,25(OH)2D3 also inhibited the secretion of MMP-2 and MMP-9 and increased expression of F-actin induced by TGF-β1/β2 in SW-480 cells. Taken together, this study suggests that the suppression of EMT might be one of the mechanisms underlying the anti-metastasis effect of 1,25(OH)2D3 in colon cancer cells. Copyright © 2015 Elsevier Inc. All rights reserved.

Glyceroneogenesis is inhibited through HIV protease inhibitor-induced inflammation in human subcutaneous but not visceral adipose tissue

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Leroyer, Stéphanie; Vatier, Camille; Kadiri, Sarah; Quette, Joëlle; Chapron, Charles; Capeau, Jacqueline; Antoine, Bénédicte

2011-01-01

Glyceroneogenesis, a metabolic pathway that participates during lipolysis in the recycling of free fatty acids to triglycerides into adipocytes, contributes to the lipid-buffering function of adipose tissue. We investigated whether glyceroneogenesis could be affected by human immunodeficiency virus (HIV) protease inhibitors (PIs) responsible or not for dyslipidemia in HIV-infected patients. We treated explants obtained from subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) depots from lean individuals. We observed that the dyslipidemic PIs nelfinavir, lopinavir and ritonavir, but not the lipid-neutral PI atazanavir, increased lipolysis and decreased glyceroneogenesis, leading to an increased release of fatty acids from SAT but not from VAT. At the same time, dyslipidemic PIs decreased the amount of perilipin and increased interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) secretion in SAT but not in VAT. Parthenolide, an inhibitor of the NFκB pathway, counteracted PI-induced increased inflammation and decreased glyceroneogenesis. IL-6 (100 ng) inhibited the activity of phosphoenolpyruvate carboxykinase, the key enzyme of glyceroneogenesis, in SAT but not in VAT. Our data show that dyslipidemic but not lipid-neutral PIs decreased glyceroneogenesis as a consequence of PI-induced increased inflammation in SAT that could have an affect on adipocytes and/or macrophages. These results add a new link between fat inflammation and increased fatty acids release and suggest a greater sensitivity of SAT than VAT to PI-induced inflammation. PMID:21068005

Dietary Modulation of Inflammation-Induced Colorectal Cancer through PPARγ

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Ashlee B. Carter

2009-01-01

Full Text Available Mounting evidence suggests that the risk of developing colorectal cancer (CRC is dramatically increased for patients with chronic inflammatory diseases. For instance, patients with Crohn's Disease (CD or Ulcerative Colitis (UC have a 12–20% increased risk for developing CRC. Preventive strategies utilizing nontoxic natural compounds that modulate immune responses could be successful in the suppression of inflammation-driven colorectal cancer in high-risk groups. The increase of peroxisome proliferator-activated receptor-γ (PPAR-γ expression and its transcriptional activity has been identified as a target for anti-inflammatory efforts, and the suppression of inflammation-driven colon cancer. PPARγ down-modulates inflammation and elicits antiproliferative and proapoptotic actions in epithelial cells. All of which may decrease the risk for inflammation-induced CRC. This review will focus on the use of orally active, naturally occurring chemopreventive approaches against inflammation-induced CRC that target PPARγ and therefore down-modulate inflammation.

TRPC3 Overexpression Promotes the Progression of Inflammation-Induced Preterm Labor and Inhibits T Cell Activation.

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Jing, Chen; Dongming, Zheng; Hong, Cui; Quan, Na; Sishi, Liu; Caixia, Liu

2018-01-01

To detect the expression of the TRPC3 channel protein in the tissues of women experiencing preterm labor and investigate its interaction with T lymphocytes, providing a theoretical basis for the clinical prevention of threatened preterm labor and the development of drug-targeted therapy. Forty-seven women experiencing preterm labor and 47 women experiencing normal full-term labor were included in this study. All included women underwent delivery via cesarean section; uterine samples were obtained at delivery. The expression of TRPC3 in uterine tissue was detected by immunohistochemistry, real-time quantitative reverse transcription-PCR, and western blot assay. Activation of T lymphocytes in peripheral blood and uterine tissue were detected by flow cytometry. A TRPC3-/- mouse model of inflammation-induced preterm labor was established; expression of TRPC3, Cav3.1, and Cav3.2 were analyzed in mouse uterine tissue. Activation of T lymphocytes in female mouse and human peripheral blood samples was determined using flow cytometry. In women experiencing preterm labor, expression of TRPC3 and the Cav3.1 and Cav3.2 proteins was significantly increased; in addition, the percentage of CD3+, CD4+, and CD8+ T cells in peripheral blood was significantly decreased. TRPC3 knockout significantly delayed the occurrence of preterm labor in mice. The muscle tension of ex vivo uterine strips was lower, Cav3.1 and Cav3.2 protein expression was lower, and the percentage of CD8+ T lymphocytes was significantly increased in wild-type mice subjected to an inflammation-induced preterm labor than in wild-type mice experiencing normal full-term labor. TRPC3 is closely related to the initiation of labor. TRPC3 relies on Cav3.1 and Cav3.2 proteins to inhibit inflammation-induced preterm labor by inhibiting the activation of T cells, in particular CD8+ T lymphocytes. © 2018 The Author(s). Published by S. Karger AG, Basel.

Diverticular Disease of the Colon: Neuromuscular Function Abnormalities.

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Bassotti, Gabrio; Villanacci, Vincenzo; Bernardini, Nunzia; Dore, Maria P

2016-10-01

Colonic diverticular disease is a frequent finding in daily clinical practice. However, its pathophysiological mechanisms are largely unknown. This condition is likely the result of several concomitant factors occurring together to cause anatomic and functional abnormalities, leading as a result to the outpouching of the colonic mucosa. A pivotal role seems to be played by an abnormal colonic neuromuscular function, as shown repeatedly in these patients, and by an altered visceral perception. There is recent evidence that these abnormalities might be related to the derangement of the enteric innervation, to an abnormal distribution of mucosal neuropeptides, and to low-grade mucosal inflammation. The latter might be responsible for the development of visceral hypersensitivity, often causing abdominal pain in a subset of these patients.

Mortality risk factor analysis in colonic perforation: would retroperitoneal contamination increase mortality in colonic perforation?

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Yoo, Ri Na; Kye, Bong-Hyeon; Kim, Gun; Kim, Hyung Jin; Cho, Hyeon-Min

2017-10-01

Colonic perforation is a lethal condition presenting high morbidity and mortality in spite of urgent surgical treatment. This study investigated the surgical outcome of patients with colonic perforation associated with retroperitoneal contamination. Retrospective analysis was performed for 30 patients diagnosed with colonic perforation caused by either inflammation or ischemia who underwent urgent surgical treatment in our facility from January 2005 to December 2014. Patient characteristics were analyzed to find risk factors correlated with increased postoperative mortality. Using the Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity (POSSUM) audit system, the mortality and morbidity rates were estimated to verify the surgical outcomes. Patients with retroperitoneal contamination, defined by the presence of retroperitoneal air in the preoperative abdominopelvic CT, were compared to those without retroperitoneal contamination. Eight out of 30 patients (26.7%) with colonic perforation had died after urgent surgical treatment. Factors associated with mortality included age, American Society of Anesthesiologists (ASA) physical status classification, and the ischemic cause of colonic perforation. Three out of 6 patients (50%) who presented retroperitoneal contamination were deceased. Although the patients with retroperitoneal contamination did not show significant increase in the mortality rate, they showed significantly higher ASA physical status classification than those without retroperitoneal contamination. The mortality rate predicted from Portsmouth POSSUM was higher in the patients with retroperitoneal contamination. Patients presenting colonic perforation along with retroperitoneal contamination demonstrated severe comorbidity. However, retroperitoneal contamination was not found to be correlated with the mortality rate.

Cholinergic anti-inflammatory pathway inhibits neointimal hyperplasia by suppressing inflammation and oxidative stress

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Dong-Jie Li

2018-05-01

Full Text Available Neointimal hyperplasia as a consequence of vascular injury is aggravated by inflammatory reaction and oxidative stress. The α7 nicotinic acetylcholine receptor (α7nAChR is a orchestrator of cholinergic anti-inflammatory pathway (CAP, which refers to a physiological neuro-immune mechanism that restricts inflammation. Here, we investigated the potential role of CAP in neointimal hyperplasia using α7nAChR knockout (KO mice. Male α7nAChR-KO mice and their wild-type control mice (WT were subjected to wire injury in left common carotid artery. At 4 weeks post injury, the injured aortae were isolated for examination. The neointimal hyperplasia after wire injury was significantly aggravated in α7nAChR-KO mice compared with WT mice. The α7nAChR-KO mice had increased collagen contents and vascular smooth muscle cells (VSMCs amount. Moreover, the inflammation was significantly enhanced in the neointima of α7nAChR-KO mice relative to WT mice, evidenced by the increased expression of tumor necrosis factor-α/interleukin-1β, and macrophage infiltration. Meanwhile, the chemokines chemokine (C-C motif ligand 2 and chemokine (CXC motif ligand 2 expression was also augmented in the neointima of α7nAChR-KO mice compared with WT mice. Additionally, the depletion of superoxide dismutase (SOD and reduced glutathione (GSH, and the upregulation of 3-nitrotyrosine, malondialdehyde and myeloperoxidase were more pronounced in neointima of α7nAChR-KO mice compared with WT mice. Accordingly, the protein expression of NADPH oxidase 1 (Nox1, Nox2 and Nox4, was also higher in neointima of α7nAChR-KO mice compared with WT mice. Finally, pharmacologically activation of CAP with a selective α7nAChR agonist PNU-282987, significantly reduced neointima formation, arterial inflammation and oxidative stress after vascular injury in C57BL/6 mice. In conclusion, our results demonstrate that α7nAChR-mediated CAP is a neuro-physiological mechanism that inhibits neointima

Vasohibin-1 suppresses colon cancer

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Liu, Shuai; Han, Bing; Zhang, Qunyuan; Dou, Jie; Wang, Fang; Lin, Wenli; Sun, Yuping; Peng, Guangyong

2015-01-01

Vasohibin-1 (VASH1) is an endogenous angiogenesis inhibitor. However, the clinical relevance of VASH1 in colon cancer and its regulations on cancer angiogenesis and cancer cell biological characteristics are still unknown. Here we showed that stromal VASH1 levels were negatively correlated with tumor size, advanced clinical stage and distant metastases in colon cancer patients. Overexpression of VASH1 in colon cancer cells induced apoptosis and senescence, inhibiting cancer cell growth and colony formation in vitro and tumor growth in vivo. In addition, knockdown of VASH1 in cancer cells promoted cell growth, adhesion and migration in vitro, and enhanced tumorigenesis and metastasis in vivo. PMID:25797264

Vasohibin-1 suppresses colon cancer.

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Liu, Shuai; Han, Bing; Zhang, Qunyuan; Dou, Jie; Wang, Fang; Lin, Wenli; Sun, Yuping; Peng, Guangyong

2015-04-10

Vasohibin-1 (VASH1) is an endogenous angiogenesis inhibitor.However, the clinical relevance of VASH1 in colon cancer and its regulations on cancer angiogenesis and cancer cell biological characteristics are still unknown. Here we showed that stromal VASH1 levels were negatively correlated with tumor size, advanced clinical stage and distant metastases in colon cancer patients. Overexpression of VASH1 in colon cancer cells induced apoptosis and senescence, inhibiting cancer cell growth and colony formation in vitro and tumor growth in vivo. In addition, knockdown of VASH1 in cancer cells promoted cell growth, adhesion and migration in vitro, and enhanced tumorigenesis and metastasis in vivo.

Inhibition of Epithelial TNF-α Receptors by Purified Fruit Bromelain Ameliorates Intestinal Inflammation and Barrier Dysfunction in Colitis

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Zhou, Zijuan; Wang, Liang; Feng, Panpan; Yin, Lianhong; Wang, Chen; Zhi, Shengxu; Dong, Jianyi; Wang, Jingyu; Lin, Yuan; Chen, Dapeng; Xiong, Yongjian; Peng, Jinyong

2017-01-01

Activation of the TNF-α receptor (TNFR) leads to an inflammatory response, and anti-TNF therapy has been administered to reduce inflammation symptoms and heal mucosal ulcers in inflammatory bowel disease (IBD). Bromelain, a complex natural mixture of proteolytic enzymes, has been shown to exert anti-inflammatory effects. This study aimed to investigate the effect of purified fruit bromelain (PFB)-induced inhibition of epithelial TNFR in a rat colitis model. Colitis was established by intracol...

Mesenchymal stem cells and conditioned medium avert enteric neuropathy and colon dysfunction in guinea pig TNBS-induced colitis.

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Robinson, Ainsley M; Sakkal, Samy; Park, Anthony; Jovanovska, Valentina; Payne, Natalie; Carbone, Simona E; Miller, Sarah; Bornstein, Joel C; Bernard, Claude; Boyd, Richard; Nurgali, Kulmira

2014-12-01

Damage to the enteric nervous system (ENS) associated with intestinal inflammation may underlie persistent alterations to gut functions, suggesting that enteric neurons are viable targets for novel therapies. Mesenchymal stem cells (MSCs) offer therapeutic benefits for attenuation of neurodegenerative diseases by homing to areas of inflammation and exhibiting neuroprotective, anti-inflammatory, and immunomodulatory properties. In culture, MSCs release soluble bioactive factors promoting neuronal survival and suppressing inflammation suggesting that MSC-conditioned medium (CM) provides essential factors to repair damaged tissues. We investigated whether MSC and CM treatments administered by enema attenuate 2,4,6-trinitrobenzene-sulfonic acid (TNBS)-induced enteric neuropathy and motility dysfunction in the guinea pig colon. Guinea pigs were randomly assigned to experimental groups and received a single application of TNBS (30 mg/kg) followed by 1 × 10(6) human bone marrow-derived MSCs, 300 μl CM, or 300 μl unconditioned medium 3 h later. After 7 days, the effect of these treatments on enteric neurons was assessed by histological, immunohistochemical, and motility analyses. MSC and CM treatments prevented inflammation-associated weight loss and gross morphological damage in the colon; decreased the quantity of immune infiltrate in the colonic wall (P ChAT, and nNOS immunoreactivity (P < 0.05); and alleviated inflammation-induced colonic dysmotility (contraction speed; P < 0.001, contractions/min; P < 0.05). These results provide strong evidence that both MSC and CM treatments can effectively prevent damage to the ENS and alleviate gut dysfunction caused by TNBS-induced colitis. Copyright © 2014 the American Physiological Society.

Complement 5a Enhances Hepatic Metastases of Colon Cancer via Monocyte Chemoattractant Protein-1-mediated Inflammatory Cell Infiltration*

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Piao, Chunmei; Cai, Lun; Qiu, Shulan; Jia, Lixin; Song, Wenchao; Du, Jie

2015-01-01

Complement 5a (C5a), a potent immune mediator generated by complement activation, promotes tumor growth; however, its role in tumor metastasis remains unclear. We demonstrate that C5a contributes to tumor metastases by modulating tumor inflammation in hepatic metastases of colon cancer. Colon cancer cell lines generate C5a under serum-free conditions, and C5a levels increase over time in a murine syngeneic colon cancer hepatic metastasis model. Furthermore, in the absence of C5a receptor or upon pharmacological inhibition of C5a production with an anti-C5 monoclonal antibody, tumor metastasis is severely impaired. A lack of C5a receptor in colon cancer metastatic foci reduces the infiltration of macrophages, neutrophils, and dendritic cells, and the role for C5a receptor on these cells were further verified by bone marrow transplantation experiments. Moreover, C5a signaling increases the expression of the chemokine monocyte chemoattractant protein-1 and the anti-inflammatory molecules arginase-1, interleukin 10, and transforming growth factor β, but is inversely correlated with the expression of pro-inflammatory molecules, which suggests a mechanism for the role of C5a in the inflammatory microenvironment required for tumor metastasis. Our results indicate a new and potentially promising therapeutic application of complement C5a inhibitor for the treatment of malignant tumors. PMID:25739439

Apple Polysaccharide inhibits microbial dysbiosis and chronic inflammation and modulates gut permeability in HFD-fed rats.

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Wang, Sheng; Li, Qian; Zang, Yue; Zhao, Yang; Liu, Nan; Wang, Yifei; Xu, Xiaotao; Liu, Li; Mei, Qibing

2017-06-01

The saying "An apple a day keeps the doctor away" has been known for over 150 years, and numerous studies have shown that apple consumption is closely associated with reduced risks of chronic diseases. It has been well accepted that dysbiosis is the reflection of various chronic diseases. Therefore, this study investigates the effects of apple polysaccharides (AP) on gut dysbiosis. High-fat diet (HFD) fed rats were treated for 14 weeks with AP. The microbiota composition, microbiota-generated short chain fatty acids (SCFAs), gut permeability and chronic inflammation were analyzed. AP treatment showed higher abundance of Bacteroidetes and Lactobacillus while lower Firmicutes and Fusobacteium. AP significantly increased total SCFAs level that contributed by acetic acid and isobutyric acid. Moreover, AP dramatically alleviated dysbiosis-associated gut permeability and chronic inflammation with decreased plasma LBP, up-regulation of Occludin, down-regulation of tumor necrosis factor a (TNF-a), monocyte chemotactic protein 1 (MCP-1), chemokine ligand 1 (CXCL-1) and interleukin 1 beta (IL-1β). The potential mechanism is due to the fact that AP reduces gut permeability, which involves the induction of autophagy in goblet cells. Therefore, AP exerts health benefits through inhibiting gut dysbiosis and chronic inflammation and modulating gut permeability in HFD-induced dysbiosis rats. Copyright © 2017 Elsevier B.V. All rights reserved.

Inhibition of G0/G1 Switch 2 Ameliorates Renal Inflammation in Chronic Kidney Disease

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Naoya Matsunaga

2016-11-01

Full Text Available Chronic kidney disease (CKD is a global health problem, and novel therapies to treat CKD are urgently needed. Here, we show that inhibition of G0/G1 switch 2 (G0s2 ameliorates renal inflammation in a mouse model of CKD. Renal expression of chemokine (C-C motif ligand 2 (Ccl2 was increased in response to p65 activation in the kidneys of wild-type 5/6 nephrectomy (5/6Nx mice. Moreover, 5/6Nx Clk/Clk mice, which carry homozygous mutations in the gene encoding circadian locomotor output cycles kaput (CLOCK, did not exhibit aggravation of apoptosis or induction of F4/80-positive cells. The renal expression of G0s2 in wild-type 5/6Nx mice was important for the transactivation of Ccl2 by p65. These pathologies were ameliorated by G0s2 knockdown. Furthermore, a novel small-molecule inhibitor of G0s2 expression was identified by high-throughput chemical screening, and the inhibitor suppressed renal inflammation in 5/6Nx mice. These findings indicated that G0s2 inhibitors may have applications in the treatment of CKD.

Diverticular colitis of the ascending colon preceding the onset of ulcerative colitis

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Maeshiro, Tatsuji; Hokama, Akira; Kinjo, Tetsu; Fujita, Jiro

2014-01-01

We present a case of diverticular colitis of the ascending colon preceding the onset of ulcerative colitis. A 58-year-old man presented with positive faecal occult blood test. Colonoscopy disclosed diverticular colitis of the ascending colon. After a year's follow-up, typical ulcerative colitis developed and diverticular colitis improved. Diverticular colitis is a newly established disorder of chronic segmental mucosal inflammation affected by diverticular disease. There is increasing recogni...

Predictors of neutrophilic airway inflammation in young smokers with asthma

DEFF Research Database (Denmark)

Westergaard, Christian Grabow; Munck, Christian; Helby, Jens

2014-01-01

by a higher degree of neutrophilic inflammation than in non-smokers. A state of neutrophilic inflammation may lead to increased steroid resistance and an accelerated loss of lung function owing to tissue destruction. The aim of this study was to elucidate predictors of neutrophilic inflammation in young...... asthmatic smokers not on steroid treatment, including analysis of tobacco history and bacterial colonization. Methods: In a cross-sectional study, 52 steroid-free, current smokers with asthma were examined with induced sputum, fractional exhaled nitric oxide (FeNO), lung function, ACQ6 score, mannitol...... smokers, neutrophilia may be induced when a certain threshold of tobacco consumption is reached....

EGFR regulation of colon cancer stem-like cells during aging and in response to the colonic carcinogen dimethylhydrazine.

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Nautiyal, Jyoti; Du, Jianhua; Yu, Yingjie; Kanwar, Shailender S; Levi, Edi; Majumdar, Adhip P N

2012-04-01

One of the most consistent pathological conditions in the gastrointestinal tract with advancing age is malignancy, particularly gastrointestinal cancers, the incidence of which increases sharply with aging. Although the reasons for the age-related rise in colorectal cancer are not fully understood, we hypothesize that aging increases susceptibility of the colon to carcinogen(s)/toxicant(s), leading to an increase in cancer stem-like cells (CSLCs) that express cancer stem cell markers, in the colonic mucosa. The current study demonstrates that aging is associated with increased expression of several colon CSLC markers [CD44, CD166, and aldehyde dehydrogenase 1 (ALDH-1)] and a higher proportion of cells expressing these markers. Aging is also accompanied by increased expression of miR-21 in colon. These increases are further increased in response to the colonic carcinogen dimethylhydrazine (DMH). Aging is also associated with increased tyrosine-phosphorylated epidermal growth factor receptor (EGFR). Inhibition of EGFR using the EGFR inhibitor cetuximab abrogated the age-related increase in CD166 and ALDH-1 as well as miRNA (miR)-21. Our results provide new evidence that aging and DMH are associated with increases in CSLC biomarkers and miR21, each of which have been linked to colorectal cancer. EGFR inhibition attenuates these changes, indicating a role for EGFR in age- and mutagen-associated changes in CSLCs.

Probiotic yeast inhibits VEGFR signaling and angiogenesis in intestinal inflammation.

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Xinhua Chen

Full Text Available Saccharomyces boulardii (Sb can protect against intestinal injury and tumor formation, but how this probiotic yeast controls protective mucosal host responses is unclear. Angiogenesis is an integral process of inflammatory responses in inflammatory bowel diseases (IBD and required for mucosal remodeling during restitution. The aim of this study was to determine whether Sb alters VEGFR (vascular endothelial growth factor receptor signaling, a central regulator of angiogenesis.HUVEC were used to examine the effects of Sb on signaling and on capillary tube formation (using the ECMatrix™ system. The effects of Sb on VEGF-mediated angiogenesis were examined in vivo using an adenovirus expressing VEGF-A(164 in the ears of adult nude mice (NuNu. The effects of Sb on blood vessel volume branching and density in DSS-induced colitis was quantified using VESsel GENeration (VESGEN software.1 Sb treatment attenuated weight-loss (p<0.01 and histological damage (p<0.01 in DSS colitis. VESGEN analysis of angiogenesis showed significantly increased blood vessel density and volume in DSS-treated mice compared to control. Sb treatment significantly reduced the neo-vascularization associated with acute DSS colitis and accelerated mucosal recovery restoration of the lamina propria capillary network to a normal morphology. 2 Sb inhibited VEGF-induced angiogenesis in vivo in the mouse ear model. 3 Sb also significantly inhibited angiogenesis in vitro in the capillary tube assay in a dose-dependent manner (p<0.01. 4 In HUVEC, Sb reduced basal VEGFR-2 phosphorylation, VEGFR-2 phosphorylation in response to VEGF as well as activation of the downstream kinases PLCγ and Erk1/2.Our findings indicate that the probiotic yeast S boulardii can modulate angiogenesis to limit intestinal inflammation and promote mucosal tissue repair by regulating VEGFR signaling.

Strawberry Phytochemicals Inhibit Azoxymethane/Dextran Sodium Sulfate-Induced Colorectal Carcinogenesis in Crj: CD-1 Mice

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Ni Shi

2015-03-01

Full Text Available Human and experimental colon carcinogenesis are enhanced by a pro-inflammatory microenvironment. Pharmacologically driven chemopreventive agents and dietary variables are hypothesized to have future roles in the prevention of colon cancer by targeting these processes. The current study was designed to determine the ability of dietary lyophilized strawberries to inhibit inflammation-promoted colon carcinogenesis in a preclinical animal model. Mice were given a single i.p. injection of azoxymethane (10 mg kg−1 body weight. One week after injection, mice were administered 2% (w/v dextran sodium sulfate in drinking water for seven days and then an experimental diet containing chemically characterized lyophilized strawberries for the duration of the bioassay. Mice fed control diet, or experimental diet containing 2.5%, 5.0% or 10.0% strawberries displayed tumor incidence of 100%, 64%, 75% and 44%, respectively (p < 0.05. The mechanistic studies demonstrate that strawberries reduced expression of proinflammatory mediators, suppressed nitrosative stress and decreased phosphorylation of phosphatidylinositol 3-kinase, Akt, extracellular signal-regulated kinase and nuclear factor kappa B. In conclusion, strawberries target proinflammatory mediators and oncogenic signaling for the preventive efficacies against colon carcinogenesis in mice. This works supports future development of fully characterized and precisely controlled functional foods for testing in human clinical trials for this disease.

Cell Growth Inhibition Effect of DsiRNA Vectorised by Pectin-Coated Chitosan-Graphene Oxide Nanocomposites as Potential Therapy for Colon Cancer

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Haliza Katas

2017-01-01

Full Text Available Colonic-targeted drug delivery system is widely explored to combat colon-related diseases such as colon cancer. Dicer-substrate small interfering RNA (DsiRNA has been explored for cancer therapy due to its potency in targeting specific gene of interest. However, its application is limited by rapid degradation and poor cellular uptake. To address this, chitosan-graphene oxide (CS-GO nanocomposite was used to deliver DsiRNA effectively into cells. Additionally, pectin was used as compatibilization agent to allow specific delivery to the colon and protect the nanocomposites from the harsh environment in the stomach and small intestine. CS-GO-DsiRNA nanocomposites were prepared by electrostatic interaction between CS and GO prior to coating with pectin. The mean particle size of CS-GO-DsiRNA-pectin nanocomposites was 554.5±124.6 nm with PDI and zeta potential of 0.47±0.19 and −10.7±3.0 mV, respectively. TEM analysis revealed smooth and spherical shape of CS-GO-DsiRNA nanocomposites and the shape became irregular after pectin coating. FTIR analysis further confirmed the successful formation of CS-GO-DsiRNA-pectin nanocomposites. Furthermore, the nanocomposites were able to entrap high amount of DsiRNA (% entrapment efficiency of 92.6±3.9% with strong binding efficiency. CS-GO-DsiRNA-pectin nanocomposites also selectively inhibited cell growth of colon cancer cell line (Caco-2 cells and were able to decrease VEGF level significantly. In a nutshell, pectin-coated DsiRNA-loaded CS-GO nanocomposites were successfully developed and they have a great potential to deliver DsiRNA to the colon effectively.

Silencing of the hTERT gene by shRNA inhibits colon cancer SW480 cell growth in vitro and in vivo.

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Ai-Qun Liu

Full Text Available Human telomerase reverse transcriptase (hTERT is the key enzyme responsible for synthesizing and maintaining the telomeres on the ends of chromosomes, and it is essential for cell proliferation. This has made hTERT a focus of oncology research and an attractive target for anticancer drug development. In this study, we designed a small interfering RNA (siRNA targeting the catalytic subunit of hTERT and tested its effects on the growth of telomerase-positive human colon carcinoma SW480 cells in vitro, as well as on the tumorigenicity of these cells in nude mice. Transient and stable transfection of hTERT siRNA into colon cancer SW480 cells suppressed hTERT expression, reduced telomerase activity and inhibited cell growth and proliferation. Knocking down hTERT expression in SW480 tumors xenografted into nude mice significantly slowed tumor growth and promoted tumor cell apoptosis. Our results suggest that hTERT is involved in carcinogenesis of human colon carcinoma, and they highlight the therapeutic potential of a hTERT knock-down approach.

Lipocalin 2 Suppresses Ocular Inflammation by Inhibiting the Activation of NF-κβ Pathway in Endotoxin-Induced Uveitis

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Wenyi Tang

2018-03-01

Full Text Available Background/Aims: Lipocalin 2 (LCN2, an important mediator of a variety of cellular processes, is involved in regulating the inflammatory response, but its roles in different inflammatory diseases are controversial. Because the role of LCN2 in ocular inflammation has been unclear until now, we explored the function of LCN2 in lipopolysaccharide (LPS-induced ocular inflammation in vivo and in vitro. Methods: Endotoxin-induced uveitis (EIU was induced in male Sprague Dawley rats by the intravitreal injection of LPS. The expression and location of LCN2 in the retina were detected with western blotting and immunohistochemistry, respectively. We determined the clinical scores for anterior inflammation, quantified the infiltrated inflammatory cells, and measured the pro-inflammatory factors to determine the anti-inflammatory effects of LCN2 in EIU eyes. Cultured primary rat Müller cells were stimulated with LPS and the expression and secretion of LCN2 were measured with real-time PCR, western blotting, and an ELISA. After Müller cells were cotreated with LPS and LCN2 or PBS, the expression and secretion of TNF-α, IL-6, and MCP-1 were examined with realtime PCR, western blotting, and ELISAs. Western blotting and immunofluorescence were used to detect the phosphorylation and cellular distribution of nuclear factor kappaB (NF-κB subunit p65. Results: In EIU, the expression of LCN2 was significantly upregulated in the retina, especially in the outer nuclear layer (mainly composed of Müller cells. LPS stimulation of cultured Müller cells also markedly elevated LCN2 expression. Intravitreal injection of LCN2 significantly reduced the clinical scores, inflammatory infiltration, and protein leakage in EIU, which correlated with the reduced levels of proinflammatory factors in the aqueous humor and retina. LCN2 treatment also reduced the expression and secretion of TNF-α, IL-6, and MCP-1 in LPS-stimulated Müller cells. LCN2 inhibited the inflammatory

δ- and γ-tocopherols inhibit phIP/DSS-induced colon carcinogenesis by protection against early cellular and DNA damages.

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Chen, Jayson X; Liu, Anna; Lee, Mao-Jung; Wang, Hong; Yu, Siyuan; Chi, Eric; Reuhl, Kenneth; Suh, Nanjoo; Yang, Chung S

2017-01-01

Tocopherols, the major forms of vitamin E, are a family of fat-soluble compounds that exist in alpha (α-T), beta (β-T), gamma (γ-T), and delta (δ-T) variants. A cancer preventive effect of vitamin E is suggested by epidemiological studies. However, past animal studies and human intervention trials with α-T, the most active vitamin E form, have yielded disappointing results. A possible explanation is that the cancer preventive activity of α-T is weak compared to other tocopherol forms. In the present study, we investigated the effects of δ-T, γ-T, and α-T (0.2% in diet) in a novel colon cancer model induced by the meat-derived dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and promoted by dextran sodium sulfate (DSS)-induced colitis in CYP1A-humanized (hCYP1A) mice. PhIP/DSS treatments induced multiple polypoid tumors, mainly tubular adenocarcinomas, in the middle to distal colon of the hCYP1A mice after 10 wk. Dietary supplementation with δ-T and γ-T significantly reduced colon tumor formation and suppressed markers of oxidative and nitrosative stress (i.e., 8-oxo-dG and nitrotyrosine) as well as pro-inflammatory mediators (i.e., NF-κB p65 and p-STAT3) in tumors and adjacent tissues. By administering δ-T at different time periods, we obtained results suggesting that the inhibitory effect of δ-T against colon carcinogenesis is mainly due to protection against early cellular and DNA damages caused by PhIP. α-T was found to be ineffective in inhibiting colon tumors and less effective in attenuating the molecular changes. Altogether, we demonstrated strong cancer preventive effects of δ-T and γ-T in a physiologically relevant model of human colon cancer. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

The influence of dibutyryl adenosine cyclic monophosphate on cell proliferation in the epithelium of the jejunal crypts, the colonic crypts and in colonic carcinomata of rat.

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Tutton, P J; Barkla, D H

1980-01-01

1. Cell proliferation in the jejunal crypts, the colonic crypts and in dimethylhydrazine (DMH)-induced adenocarcinomata of rat colon was measured using a stathmokinetic technique. 2. Dibutryl cyclic adneosine monophosphate (dibutyryl cAMP) was found to inhibit cell proliferation in colonic crypts and in colonic adenocarcinomata. 3. Dibutryl cAMP at very high doses was found to inhibit jejunal crypt cell proliferation but at lower doses was found to accelerate jejunal crypt cell proliferation. 4. Neither bilateral adrenalectomy nor chemical sympathectomy was found to abolish the ability of dibutryl cAMP to stimulate jejunal crypt cell proliferation. 5. The present results are difficult to interpret in terms of known hormonal influences on cell proliferation in the tissues examined and of established actions, of these hormones on cyclic nucleotide metabolism in other tissues.

Inhibition of Epidermal Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor Phosphorylation on Tumor-Associated Endothelial Cells Leads to Treatment of Orthotopic Human Colon Cancer in Nude Mice

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Takamitsu Sasaki

2007-12-01

Full Text Available The purpose of our study was to determine whether the dual inhibition of epidermal growth factor receptor (EGFR and vascular endothelial growth factor receptor (VEGFR signaling pathways in tumor-associated endothelial cells can inhibit the progressive growth of human colon carcinoma in the cecum of nude mice. SW620CE2 human colon cancer cells growing in culture and orthotopically in the cecum of nude mice expressed a high level of transforming growth factor alpha (TGF-α and vascular endothelial growth factor (VEGF but were negative for EGFR, human epidermal growth factor receptor 2 (HER2, VEGFR. Double immunofluorescence staining revealed that tumorassociated endothelial cells expressed EGFR, VEGFR2, phosphorylated EGFR (pEGFR, phosphorylated VEGFR (pVEGFR. Treatment of mice with either 7H-pyrrolo [2,3-d]-pyrimidine lead scaffold (AEE788; an inhibitor of EGFR and VEGFR tyrosine kinase or CPT-11 as single agents significantly inhibited the growth of cecal tumors (P < .01; this decrease was even more pronounced with AEE788 combined with CPT-11 (P < .001. AEE788 alone or combined with CPT-11 also inhibited the expression of pEGFR and pVEGFR on tumor-associated endothelial cells, significantly decreased vascularization and tumor cell proliferation, increased the level of apoptosis in both tumorassociated endothelial cells and tumor cells. These data demonstrate that targeting EGFR and VEGFR signaling on tumor-associated endothelial cells provides a viable approach for the treatment of colon cancer.

Inhibition of ROS and inflammation by an imidazopyridine derivative X22 attenuate high fat diet-induced arterial injuries.

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Li, Weixin; Wang, Lintao; Huang, Weijian; Skibba, Melissa; Fang, Qilu; Xie, Longteng; Wei, Tiemin; Feng, Zhiguo; Liang, Guang

2015-09-01

Obesity is strongly associated with the cause of structural and functional changes of the artery. Oxidative stress and inflammation play a critical role in the development of obesity-induced cardiovascular disorders. Our group previously found that an imidazopyridine derivative X22 showed excellent anti-inflammatory activity in LPS-stimulated macrophages. This study was designed to investigate the protective effects of X22 on high fat diet (HFD)-induced arterial injury and its underlying mechanisms. We observed that palmitate (PA) treatment in HUVECs induced a marked increase in reactive oxygen species, inflammation, apoptosis, and fibrosis. All of these changes were effectively suppressed by X22 treatment in a dose-dependent manner, associated with NF-κB inactivation and Nrf-2 activation. In HFD-fed rats, administration of X22 at 10mg/kg significantly decreased the arterial inflammation and oxidative stress, and eventually improved the arterial matrix remodeling and apoptosis. X22 at 10mg/kg showed a comparable bioactivity with the positive control, curcumin at 50mg/kg. The in vivo beneficial effects of X22 are also associated with its ability to increase Nrf2 expression and inhibit NF-κB activation in the artery of HFD-fed rats. Overall, these results suggest that X22 may have therapeutic potential in the treatment of obesity-induced artery injury via regulation of Nrf2-mediated oxidative stress and NF-κB-mediated inflammation. Copyright © 2015 Elsevier Inc. All rights reserved.

Lebein, a snake venom disintegrin, suppresses human colon cancer cells proliferation and tumor-induced angiogenesis through cell cycle arrest, apoptosis induction and inhibition of VEGF expression.

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Zakraoui, Ons; Marcinkiewicz, Cezary; Aloui, Zohra; Othman, Houcemeddine; Grépin, Renaud; Haoues, Meriam; Essafi, Makram; Srairi-Abid, Najet; Gasmi, Ammar; Karoui, Habib; Pagès, Gilles; Essafi-Benkhadir, Khadija

2017-01-01

Lebein, is an heterodimeric disintegrin isolated from Macrovipera lebetina snake venom that was previously characterized as an inhibitor of ADP-induced platelet aggregation. In this study, we investigated the effect of Lebein on the p53-dependent growth of human colon adenocarcinoma cell lines. We found that Lebein significantly inhibited LS174 (p53wt), HCT116 (p53wt), and HT29 (p53mut) colon cancer cell viability by inducing cell cycle arrest through the modulation of expression levels of the tumor suppression factor p53, cell cycle regulating proteins cyclin D1, CDK2, CDK4, retinoblastoma (Rb), CDK1, and cyclin-dependent kinase inhibitors p21 and p27. Interestingly, Lebein-induced apoptosis of colon cancer cells was dependent on their p53 status. Thus, in LS174 cells, cell death was associated with PARP cleavage and the activation of caspases 3 and 8 while in HCT116 cells, Lebein induced caspase-independent apoptosis through increased expression of apoptosis inducing factor (AIF). In LS174 cells, Lebein triggers the activation of the MAPK ERK1/2 pathway through induction of reactive oxygen species (ROS). It also decreased cell adhesion and migration to fibronectin through down regulation of α5β1 integrin. Moreover, Lebein significantly reduced the expression of two angiogenesis stimulators, Vascular Endothelial Growth Factor (VEGF) and Neuropilin 1 (NRP1). It inhibited the VEGF-induced neovascularization process in the quail embryonic CAM system and blocked the development of human colon adenocarcinoma in nude mice. Overall, our work indicates that Lebein may be useful to design a new therapy against colon cancer. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Milk-derived peptide Val-Pro-Pro (VPP) inhibits obesity-induced adipose inflammation via an angiotensin-converting enzyme (ACE) dependent cascade.

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Sawada, Yoko; Sakamoto, Yuri; Toh, Mariko; Ohara, Nozomi; Hatanaka, Yuiko; Naka, Ayano; Kishimoto, Yoshimi; Kondo, Kazuo; Iida, Kaoruko

2015-12-01

This study aimed to examine the effects of Val-Pro-Pro (VPP), a food-derived peptide with an angiotensin-converting enzyme (ACE) inhibitory property, on obesity-linked insulin resistance, and adipose inflammation in vivo and in vitro. C57BL/6J mice were fed high-fat high-sucrose diet and VPP (0.1% in water) for 4 months. For in vitro analysis, coculture of 3T3-L1 adipocytes overexpressing either ACE (3T3-ACE) or green fluorescent protein (3T3-GFP) and RAW264 macrophages was conducted with VPP. In diet-induced obese mice, VPP improved insulin sensitivity, concomitant with a significant decrease in tumor necrosis factor α (TNF-α) and IL-1β expression in adipose tissue, with a tendency (p = 0.06) toward decreased CC chemokine ligand 5 expression. Additionally, VPP administration inhibited macrophage accumulation and activation in fat tissues. In vitro, VPP attenuated TNF-α mRNA induced by ACE overexpression in 3T3-L1 adipocytes. TNF-α and IL-1β expression decreased following VPP treatment of RAW264 macrophage and 3T3-ACE adipocyte cocultures, but not in RAW264-3T3-GFP adipocyte cocultures. Our data suggest that VPP inhibits adipose inflammation in the interaction between adipocytes and macrophages, acting as an ACE inhibitor, thereby improving obesity-related insulin resistance. Thus, ingestion of VPP may be a viable protective and therapeutic strategy for insulin resistance and obesity-associated adipose inflammation. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Periplocin from Cortex periplocae inhibits cell growth and down-regulates survivin and c-myc expression in colon cancer in vitro and in vivo via beta-catenin/TCF signaling.

Science.gov (United States)

Zhao, Lianmei; Shan, Baoen; Du, Yanyan; Wang, Mingxia; Liu, Lihua; Ren, Feng-Zhi

2010-08-01

Cancer of the colon and rectum is the third most commonly diagnosed cancer and accounts for approximately 10% of all cancer-related deaths. Although surgical resection or radiotherapy are potentially curative for localized disease, advanced colon cancer is currently associated with poor prognosis. Therefore, the development of a new and effective chemotherapeutic agent is required to target critical pathways to induce responsiveness of colon cancer cells to death signals. Dysregulation of the beta-catenin/TCF pathway plays a central role in early activities of colorectal carcinogenesis. In this study, human colon cancer SW480 cells were used to investigate the effect of CPP (periplocin from Cortex periplocae) on the modulation of the beta-catenin/TCF signaling pathway. Our research results showed that CPP caused a dose- and time-dependent inhibition of cell growth as assessed by MTT assay and an induction in apoptosis as measured by flow cytometry and transmission electron microscopy. Furthermore, the CPP- treated cells were characterized by a decreased expression of beta-catenin protein in the total cell lysates and cytosolic and nuclear extracts. This expression alleviates the binding activity of T-cell factor (Tcf) complexes to its specific DNA-binding sites. Thus, the protein expression of the downstream elements survivin and c-myc was down-regulated. To determine the precise inhibitory mechanisms involved, further in-depth in vivo studies of CPP are warranted. In conclusion, our data suggest that CPP wields a multi-prong strategy to target the beta-catenin/Tcf signaling pathway, leading to the induction of apoptosis and inhibition of growth of colon cancer cells in vitro and in vivo. Therefore, CPP may become a potential agent against colon cancer.

Genetic Deletion and Pharmacological Inhibition of PI3Kγ Reduces Neutrophilic Airway Inflammation and Lung Damage in Mice with Cystic Fibrosis-Like Lung Disease

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Maria Galluzzo

2015-01-01

Full Text Available Purpose. Neutrophil-dominated airway inflammation is a key feature of progressive lung damage in cystic fibrosis (CF. Thus, reducing airway inflammation is a major goal to prevent lung damage in CF. However, current anti-inflammatory drugs have shown several limits. PI3Kγ plays a pivotal role in leukocyte recruitment and activation; in the present study we determined the effects of genetic deletion and pharmacologic inhibition of PI3Kγ on airway inflammation and structural lung damage in a mouse model of CF lung disease. Methods. βENaC overexpressing mice (βENaC-Tg were backcrossed with PI3Kγ-deficient (PI3KγKO mice. Tissue damage was assessed by histology and morphometry and inflammatory cell number was evaluated in bronchoalveolar lavage fluid (BALF. Furthermore, we assessed the effect of a specific PI3Kγ inhibitor (AS-605240 on inflammatory cell number in BALF. Results. Genetic deletion of PI3Kγ decreased neutrophil numbers in BALF of PI3KγKO/βENaC-Tg mice, and this was associated with reduced emphysematous changes. Treatment with the PI3Kγ inhibitor AS-605240 decreased the number of neutrophils in BALF of βENaC-Tg mice, reproducing the effect observed with genetic deletion of the enzyme. Conclusions. These results demonstrate the biological efficacy of both genetic deletion and pharmacological inhibition of PI3Kγ in reducing chronic neutrophilic inflammation in CF-like lung disease in vivo.

Inhibition of Inflammation-Associated Olfactory Loss by Etanercept in an Inducible Olfactory Inflammation Mouse Model.

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Jung, Yong Gi; Lane, Andrew P

2016-06-01

To determine the effect of a soluble human tumor necrosis factor alpha (TNF-α) receptor blocker (etanercept) on an inducible olfactory inflammation (IOI) mouse model. An in vivo study using a transgenic mouse model. Research laboratory. To study the impact of chronic inflammation on the olfactory system, a transgenic mouse model of chronic rhinosinusitis-associated olfactory loss was utilized (IOI mouse), expressing TNF-α in a temporally controlled fashion within the olfactory epithelium. In one group of mice (n = 4), etanercept was injected intraperitoneally (100 μg/dose, 3 times/week) concurrent with a 2-week period of TNF-α expression. A second group of mice (n = 2) underwent induction of TNF-α expression for 8 weeks, with etanercept treatment administered during the final 2 weeks of inflammation. Olfactory function was assayed by elecro-olfactogram (EOG), and olfactory tissue was processed for histology and immunohistochemical staining. Each group was compared with an equal-number control group. Compared with nontreated IOI mice, etanercept-treated IOI mice showed significantly improved EOG responses after 2 weeks (P loss of olfactory epithelium and no EOG response in nontreated IOI mice. However, in etanercept-treated mice, regeneration of olfactory epithelium was observed. Concomitant administration of etanercept in IOI mice results in interruption of TNF-α-induced olfactory loss and induction of neuroepithelial regeneration. This demonstrates that etanercept has potential utility as a tool for elucidating the role of TNF-α in other olfactory inflammation models. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2016.

Eleutheroside E inhibits doxorubicin-induced inflammation and ...

African Journals Online (AJOL)

Purpose: To identify the effects of eleutheroside E (EE) on apoptosis and inflammation induced by doxorubicin (DOX) in H9c2 cells and to investigate the underlying mechanisms. Methods: The effect of EE on H9c2 cell viability was determined using Cell Counting Kit-8 (CCK8). EE effect on DOX-induced apoptosis and ...

RIP3-dependent necrosis induced inflammation exacerbates atherosclerosis

Energy Technology Data Exchange (ETDEWEB)

Meng, Lingjun, E-mail: menglingjun@nibs.ac.cn [College of Biological Sciences, China Agricultural University, Beijing 100094 (China); National Institute of Biological Sciences, Beijing 102206 (China); Jin, Wei [Institute for Immunology, Tsinghua University, Beijing 100084 (China); Wang, Yuhui [Institute of Cardiovascular Sciences, Health Science Center, Peking University, Beijing 100191 (China); Huang, Huanwei; Li, Jia; Zhang, Cai [National Institute of Biological Sciences, Beijing 102206 (China)

2016-04-29

Atherothrombotic vascular disease is already the leading cause of mortality worldwide. Atherosclerosis shares features with diseases caused by chronic inflammation. More attention should concentrates on the innate immunity effect atherosclerosis progress. RIP3 (receptor-interacting protein kinase 3) act through the transcription factor named Nr4a3 (Nuclear orphan receptors) to regulate cytokine production. Deletion RIP3 decreases IL-1α production. Injection of anti-IL-1α antibody protects against the progress of atherosclerosis in ApoE −/− mice. RIP3 as a molecular switch in necrosis, controls macrophage necrotic death caused inflammation. Inhibiting necrosis will certainly reduce atherosclerosis through limit inflammation. Necrotic cell death caused systemic inflammation exacerbated cardiovascular disease. Inhibition of necrosis may yield novel therapeutic targets for treatment in years to come. - Highlights: • RIP3 regulate the Nr4a3 to control cytokine production. • Deletion RIP3 decreases IL-1a production. • Injection anti-IL-1a antibody protects against the progress of atherosclerosis. • RIP3 controls macrophage necrotic dead caused inflammation.

RIP3-dependent necrosis induced inflammation exacerbates atherosclerosis

International Nuclear Information System (INIS)

Meng, Lingjun; Jin, Wei; Wang, Yuhui; Huang, Huanwei; Li, Jia; Zhang, Cai

2016-01-01

Atherothrombotic vascular disease is already the leading cause of mortality worldwide. Atherosclerosis shares features with diseases caused by chronic inflammation. More attention should concentrates on the innate immunity effect atherosclerosis progress. RIP3 (receptor-interacting protein kinase 3) act through the transcription factor named Nr4a3 (Nuclear orphan receptors) to regulate cytokine production. Deletion RIP3 decreases IL-1α production. Injection of anti-IL-1α antibody protects against the progress of atherosclerosis in ApoE −/− mice. RIP3 as a molecular switch in necrosis, controls macrophage necrotic death caused inflammation. Inhibiting necrosis will certainly reduce atherosclerosis through limit inflammation. Necrotic cell death caused systemic inflammation exacerbated cardiovascular disease. Inhibition of necrosis may yield novel therapeutic targets for treatment in years to come. - Highlights: • RIP3 regulate the Nr4a3 to control cytokine production. • Deletion RIP3 decreases IL-1a production. • Injection anti-IL-1a antibody protects against the progress of atherosclerosis. • RIP3 controls macrophage necrotic dead caused inflammation.

De novo expression of human polypeptide N-acetylgalactosaminyltransferase 6 (GalNAc-T6) in colon adenocarcinoma inhibits the differentiation of colonic epithelium

DEFF Research Database (Denmark)

Lavrsen, Kirstine; Dabelsteen, Sally; Vakhrushev, Sergey Y

2018-01-01

Aberrant expression of O-glycans is a hallmark of epithelial cancers. Mucin type O-glycosylation is initiated by a large family of UDP-GalNAc:polypeptide N-acetyl-galactosaminyltransferases (GalNAc-Ts), that target different proteins and are differentially expressed in cells and organs. Here we...... investigated the expression patterns of all of the GalNAc-Ts in colon cancer by analysing transcriptomic data. We found that GalNAc-T6 was highly upregulated in colon adenocarcinomas but absent in normal-appearing adjacent colon tissue. The results were verified by immunohistochemistry, suggesting that Gal......NAc-T6 plays a role in colon carcinogenesis. To investigate the function of GalNAc-T6 in colon cancer, we used precise gene targeting to produce isogenic colon cancer cell lines with a knockout/-rescue system for GalNAc-T6. GalNAc-T6 expression was associated with a cancer-like, dysplastic growth pattern...

Squamosamide derivative FLZ protects dopaminergic neurons against inflammation-mediated neurodegeneration through the inhibition of NADPH oxidase activity

Directory of Open Access Journals (Sweden)

Wilson Belinda

2008-05-01

Full Text Available Abstract Background Inflammation plays an important role in the pathogenesis of Parkinson's disease (PD through over-activation of microglia, which consequently causes the excessive production of proinflammatory and neurotoxic factors, and impacts surrounding neurons and eventually induces neurodegeneration. Hence, prevention of microglial over-activation has been shown to be a prime target for the development of therapeutic agents for inflammation-mediated neurodegenerative diseases. Methods For in vitro studies, mesencephalic neuron-glia cultures and reconstituted cultures were used to investigate the molecular mechanism by which FLZ, a squamosamide derivative, mediates anti-inflammatory and neuroprotective effects in both lipopolysaccharide-(LPS- and 1-methyl-4-phenylpyridinium-(MPP+-mediated models of PD. For in vivo studies, a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-(MPTP- induced PD mouse model was used. Results FLZ showed potent efficacy in protecting dopaminergic (DA neurons against LPS-induced neurotoxicity, as shown in rat and mouse primary mesencephalic neuronal-glial cultures by DA uptake and tyrosine hydroxylase (TH immunohistochemical results. The neuroprotective effect of FLZ was attributed to a reduction in LPS-induced microglial production of proinflammatory factors such as superoxide, tumor necrosis factor-α (TNF-α, nitric oxide (NO and prostaglandin E2 (PGE2. Mechanistic studies revealed that the anti-inflammatory properties of FLZ were mediated through inhibition of NADPH oxidase (PHOX, the key microglial superoxide-producing enzyme. A critical role for PHOX in FLZ-elicited neuroprotection was further supported by the findings that 1 FLZ's protective effect was reduced in cultures from PHOX-/- mice, and 2 FLZ inhibited LPS-induced translocation of the cytosolic subunit of p47PHOX to the membrane and thus inhibited the activation of PHOX. The neuroprotective effect of FLZ demonstrated in primary neuronal

[ENT inflammation and importance of fenspiride].

Science.gov (United States)

Jankowski, R

2002-09-01

PERSISTENT INFLAMMATION: Inflammation may persist despite the eviction of the aggressive agent because of the disruption of the regulator mechanisms. In such patients, drugs such as fenspiride can be effective at several levels, from onset of inflammation, in an attempt to control its progression. INHIBITION OF NEUROPHIL MIGRATION: Could be a very interesting propriety for controlling inflammation of the human respiratory mucosa. CONTROL OF FREE RADICALS: In certain cases, clearance of free oxygen radicals by cells implicated in the inflammatory process may be overrun. Fenespiride can limit the production of free radicals, probably at the level of the producing cells. ACTION ON THE ARACHIDONIC ACID CASCADE: The mechanism and site of action of fenspiride remains to be clarified. It does not act like conventional antiinflammatory drugs by inhibiting cyclo-oxygenase. ANTIHISTAMINE ACTIVITY: Fenspiride has a certain antihistamine activity, basically by blocking H1 receptors. This action should be tested in subjects with nonspecific nasal hyperreactivity. OTHER PROPERTIES: Fenspiride also has an alpha-1-adrenolytic activity and an inhibitor effect on cyclic AMP, two properties which could have an impact on inflammatory diseases of the upper airways.

Intestinal helminth infection drives carcinogenesis in colitis-associated colon cancer.

Directory of Open Access Journals (Sweden)

Eva Pastille

2017-09-01

Full Text Available Inflammatory bowel diseases (IBD are chronic inflammatory disorders of the gastrointestinal tract, strongly associated with an increased risk of colorectal cancer development. Parasitic infections caused by helminths have been shown to modulate the host's immune response by releasing immunomodulatory molecules and inducing regulatory T cells (Tregs. This immunosuppressive state provoked in the host has been considered as a novel and promising approach to treat IBD patients and alleviate acute intestinal inflammation. On the contrary, specific parasite infections are well known to be directly linked to carcinogenesis. Whether a helminth infection interferes with the development of colitis-associated colon cancer (CAC is not yet known. In the present study, we demonstrate that the treatment of mice with the intestinal helminth Heligmosomoides polygyrus at the onset of tumor progression in a mouse model of CAC does not alter tumor growth and distribution. In contrast, H. polygyrus infection in the early inflammatory phase of CAC strengthens the inflammatory response and significantly boosts tumor development. Here, H. polygyrus infection was accompanied by long-lasting alterations in the colonic immune cell compartment, with reduced frequencies of colonic CD8+ effector T cells. Moreover, H. polygyrus infection in the course of dextran sulfate sodium (DSS mediated colitis significantly exacerbates intestinal inflammation by amplifying the release of colonic IL-6 and CXCL1. Thus, our findings indicate that the therapeutic application of helminths during CAC might have tumor-promoting effects and therefore should be well-considered.

Review article: uncomplicated diverticular disease of the colon.

Science.gov (United States)

Petruzziello, L; Iacopini, F; Bulajic, M; Shah, S; Costamagna, G

2006-05-15

Diverticular disease of the colon is the fifth most important gastrointestinal disease in terms of direct and indirect health care costs in western countries. Uncomplicated diverticular disease is defined as the presence of diverticula in the absence of complications such as perforation, fistula, obstruction and/or bleeding. The distribution of diverticula along the colon varies worldwide being almost always left-sided and directly related to age in western countries and right-sided where diet is rich in fibre. The pathophysiology of diverticular disease is complex and relates to abnormal colonic motility, changes in the colonic wall, chronic mucosal low-grade inflammation, imbalance in colonic microflora and visceral hypersensitivity. Moreover, there can be genetic factors involved in the development of colonic diverticula. The use of non-absorbable antibiotics is the mainstay of therapy in patients with mild to moderate symptoms, and the effect of fibre-supplementation alone does not appear to be significantly different from placebo, although no definite data are available. More recently, alternative treatments have been reported. Mesalazine acts as a local mucosal immunomodulator and has been shown to improve symptoms and prevent recurrence of diverticulitis. In addition, probiotics have also been shown to be beneficial by re-establishing a normal gut microflora. In this study, the current literature on uncomplicated diverticular disease of the colon is reviewed.

Streptococcus agalactiae Inhibits Candida albicans Hyphal Development and Diminishes Host Vaginal Mucosal TH17 Response.

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Yu, Xiao-Yu; Fu, Fei; Kong, Wen-Na; Xuan, Qian-Kun; Wen, Dong-Hua; Chen, Xiao-Qing; He, Yong-Ming; He, Li-Hua; Guo, Jian; Zhou, Ai-Ping; Xi, Yang-Hong; Ni, Li-Jun; Yao, Yu-Feng; Wu, Wen-Juan

2018-01-01

Streptococcus agalactiae and Candida albicans often co-colonize the female genital tract, and under certain conditions induce mucosal inflammation. The role of the interaction between the two organisms in candidal vaginitis is not known. In this study, we found that co-infection with S. agalactiae significantly attenuated the hyphal development of C. albicans , and that EFG1 -Hwp1 signal pathway of C. albicans was involved in this process. In a mouse model of vulvovaginal candidiasis (VVC), the fungal burden and the levels of pro-inflammatory cytokines, IL-1β, IL-6 and TNF-α showed a increase on co-infection with S. agalactiae , while the level of TH17 T cells and IL-17 in the cervicovaginal lavage fluid were significantly decreased. Our results indicate that S. agalactiae inhibits C. albicans hyphal development by downregulating the expression of EFG1 -Hwp1. The interaction between S. agalactiae and C. albicans may attenuate host vaginal mucosal TH17 immunity and contribute to mucosal colonization by C. albicans .

Airway fungal colonization compromises the immune system allowing bacterial pneumonia to prevail.

Science.gov (United States)

Roux, Damien; Gaudry, Stéphane; Khoy-Ear, Linda; Aloulou, Meryem; Phillips-Houlbracq, Mathilde; Bex, Julie; Skurnik, David; Denamur, Erick; Monteiro, Renato C; Dreyfuss, Didier; Ricard, Jean-Damien

2013-09-01

To study the correlation between fungal colonization and bacterial pneumonia and to test the effect of antifungal treatments on the development of bacterial pneumonia in colonized rats. Experimental animal investigation. University research laboratory. Pathogen-free male Wistar rats weighing 250-275 g. Rats were colonized by intratracheal instillation of Candida albicans. Fungal clearance from the lungs and immune response were measured. Both colonized and noncolonized animals were secondarily instilled with different bacterial species (Pseudomonas aeruginosa, Escherichia coli, or Staphylococcus aureus). Bacterial phagocytosis by alveolar macrophages was evaluated in the presence of interferon-gamma, the main cytokine produced during fungal colonization. The effect of antifungal treatments on fungal colonization and its immune response were assessed. The prevalence of P. aeruginosa pneumonia was compared in antifungal treated and control colonized rats. C. albicans was slowly cleared and induced a Th1-Th17 immune response with very high interferon-gamma concentrations. Airway fungal colonization favored the development of bacterial pneumonia. Interferon-gamma was able to inhibit the phagocytosis of unopsonized bacteria by alveolar macrophages. Antifungal treatment decreased airway fungal colonization, lung interferon-gamma levels and, consequently, the prevalence of subsequent bacterial pneumonia. C. albicans airway colonization elicited a Th1-Th17 immune response that favored the development of bacterial pneumonia via the inhibition of bacterial phagocytosis by alveolar macrophages. Antifungal treatment decreased the risk of bacterial pneumonia in colonized rats.

Blackberry extract inhibits UVB-induced oxidative damage and inflammation through MAP kinases and NF-κB signaling pathways in SKH-1 mice skin

International Nuclear Information System (INIS)

Divya, Sasidharan Padmaja; Wang, Xin; Pratheeshkumar, Poyil; Son, Young-Ok; Roy, Ram Vinod; Kim, Donghern; Dai, Jin; Hitron, John Andrew; Wang, Lei; Asha, Padmaja; Shi, Xianglin; Zhang, Zhuo

2015-01-01

Extensive exposure of solar ultraviolet-B (UVB) radiation to skin induces oxidative stress and inflammation that play a crucial role in the induction of skin cancer. Photochemoprevention with natural products represents a simple but very effective strategy for the management of cutaneous neoplasia. In this study, we investigated whether blackberry extract (BBE) reduces chronic inflammatory responses induced by UVB irradiation in SKH-1 hairless mice skin. Mice were exposed to UVB radiation (100 mJ/cm 2 ) on alternate days for 10 weeks, and BBE (10% and 20%) was applied topically a day before UVB exposure. Our results show that BBE suppressed UVB-induced hyperplasia and reduced infiltration of inflammatory cells in the SKH-1 hairless mice skin. BBE treatment reduced glutathione (GSH) depletion, lipid peroxidation (LPO), and myeloperoxidase (MPO) in mouse skin by chronic UVB exposure. BBE significantly decreased the level of pro-inflammatory cytokines IL-6 and TNF-α in UVB-exposed skin. Likewise, UVB-induced inflammatory responses were diminished by BBE as observed by a remarkable reduction in the levels of phosphorylated MAP Kinases, Erk1/2, p38, JNK1/2 and MKK4. Furthermore, BBE also reduced inflammatory mediators such as cyclooxygenase-2 (COX-2), prostaglandin E 2 (PGE 2 ), and inducible nitric oxide synthase (iNOS) levels in UVB-exposed skin. Treatment with BBE inhibited UVB-induced nuclear translocation of NF-κB and degradation of IκBα in mouse skin. Immunohistochemistry analysis revealed that topical application of BBE inhibited the expression of 8-oxo-7, 8-dihydro-2′-deoxyguanosine (8-oxodG), cyclobutane pyrimidine dimers (CPD), proliferating cell nuclear antigen (PCNA), and cyclin D1 in UVB-exposed skin. Collectively, these data indicate that BBE protects from UVB-induced oxidative damage and inflammation by modulating MAP kinase and NF-κB signaling pathways. - Highlights: • Blackberry extract inhibits UVB-induced glutathione depletion. • Blackberry

Blackberry extract inhibits UVB-induced oxidative damage and inflammation through MAP kinases and NF-κB signaling pathways in SKH-1 mice skin

Energy Technology Data Exchange (ETDEWEB)

Divya, Sasidharan Padmaja; Wang, Xin; Pratheeshkumar, Poyil; Son, Young-Ok; Roy, Ram Vinod [Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Department of Toxicology and Cancer Biology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Kim, Donghern; Dai, Jin [Department of Toxicology and Cancer Biology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Hitron, John Andrew; Wang, Lei [Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Department of Toxicology and Cancer Biology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Asha, Padmaja [National Centre for Aquatic Animal Health, Cochin University of Science and Technology, Cochin (India); Shi, Xianglin [Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Department of Toxicology and Cancer Biology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Zhang, Zhuo, E-mail: zhuo.zhang@uky.edu [Department of Toxicology and Cancer Biology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States)

2015-04-01

Extensive exposure of solar ultraviolet-B (UVB) radiation to skin induces oxidative stress and inflammation that play a crucial role in the induction of skin cancer. Photochemoprevention with natural products represents a simple but very effective strategy for the management of cutaneous neoplasia. In this study, we investigated whether blackberry extract (BBE) reduces chronic inflammatory responses induced by UVB irradiation in SKH-1 hairless mice skin. Mice were exposed to UVB radiation (100 mJ/cm{sup 2}) on alternate days for 10 weeks, and BBE (10% and 20%) was applied topically a day before UVB exposure. Our results show that BBE suppressed UVB-induced hyperplasia and reduced infiltration of inflammatory cells in the SKH-1 hairless mice skin. BBE treatment reduced glutathione (GSH) depletion, lipid peroxidation (LPO), and myeloperoxidase (MPO) in mouse skin by chronic UVB exposure. BBE significantly decreased the level of pro-inflammatory cytokines IL-6 and TNF-α in UVB-exposed skin. Likewise, UVB-induced inflammatory responses were diminished by BBE as observed by a remarkable reduction in the levels of phosphorylated MAP Kinases, Erk1/2, p38, JNK1/2 and MKK4. Furthermore, BBE also reduced inflammatory mediators such as cyclooxygenase-2 (COX-2), prostaglandin E{sub 2} (PGE{sub 2}), and inducible nitric oxide synthase (iNOS) levels in UVB-exposed skin. Treatment with BBE inhibited UVB-induced nuclear translocation of NF-κB and degradation of IκBα in mouse skin. Immunohistochemistry analysis revealed that topical application of BBE inhibited the expression of 8-oxo-7, 8-dihydro-2′-deoxyguanosine (8-oxodG), cyclobutane pyrimidine dimers (CPD), proliferating cell nuclear antigen (PCNA), and cyclin D1 in UVB-exposed skin. Collectively, these data indicate that BBE protects from UVB-induced oxidative damage and inflammation by modulating MAP kinase and NF-κB signaling pathways. - Highlights: • Blackberry extract inhibits UVB-induced glutathione depletion. �

Complement 5a Enhances Hepatic Metastases of Colon Cancer via Monocyte Chemoattractant Protein-1-mediated Inflammatory Cell Infiltration.

Science.gov (United States)

Piao, Chunmei; Cai, Lun; Qiu, Shulan; Jia, Lixin; Song, Wenchao; Du, Jie

2015-04-24

Complement 5a (C5a), a potent immune mediator generated by complement activation, promotes tumor growth; however, its role in tumor metastasis remains unclear. We demonstrate that C5a contributes to tumor metastases by modulating tumor inflammation in hepatic metastases of colon cancer. Colon cancer cell lines generate C5a under serum-free conditions, and C5a levels increase over time in a murine syngeneic colon cancer hepatic metastasis model. Furthermore, in the absence of C5a receptor or upon pharmacological inhibition of C5a production with an anti-C5 monoclonal antibody, tumor metastasis is severely impaired. A lack of C5a receptor in colon cancer metastatic foci reduces the infiltration of macrophages, neutrophils, and dendritic cells, and the role for C5a receptor on these cells were further verified by bone marrow transplantation experiments. Moreover, C5a signaling increases the expression of the chemokine monocyte chemoattractant protein-1 and the anti-inflammatory molecules arginase-1, interleukin 10, and transforming growth factor β, but is inversely correlated with the expression of pro-inflammatory molecules, which suggests a mechanism for the role of C5a in the inflammatory microenvironment required for tumor metastasis. Our results indicate a new and potentially promising therapeutic application of complement C5a inhibitor for the treatment of malignant tumors. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

The novel HDAC inhibitor AR-42-induced anti-colon cancer cell activity is associated with ceramide production

International Nuclear Information System (INIS)

Xu, Weihong; Xu, Bin; Yao, Yiting; Yu, Xiaoling; Shen, Jie

2015-01-01

In the current study, we investigated the potential activity of AR-42, a novel histone deacetylase (HDAC) inhibitor, against colon cancer cells. Our in vitro results showed that AR-42 induced ceramide production, exerted potent anti-proliferative and pro-apoptotic activities in established (SW-620 and HCT-116 lines) and primary human colon cancer cells. Exogenously-added sphingosine 1-phosphate (S1P) suppressed AR-42-induced activity, yet a cell-permeable ceramide (C4) facilitated AR-42-induced cytotoxicity against colon cancer cells. In addition, AR-42-induced ceramide production and anti-colon cancer cell activity were inhibited by the ceramide synthase inhibitor fumonisin B1, but were exacerbated by PDMP, which is a ceramide glucosylation inhibitor. In vivo, oral administration of a single dose of AR-42 dramatically inhibited SW-620 xenograft growth in severe combined immunodeficient (SCID) mice, without inducing overt toxicities. Together, these results show that AR-42 dramatically inhibits colon cancer cell proliferation in vitro and in vivo, and ceramide production might be the key mechanism responsible for its actions. - Highlights: • AR-42 is anti-proliferative against primary/established colon cancer cells. • AR-42 induces significant apoptotic death in primary/established colon cancer cells. • Ceramide production mediates AR-42-induced cytotoxicity in colon cancer cells. • AR-42 oral administration potently inhibits SW-620 xenograft growth in SCID mice

The novel HDAC inhibitor AR-42-induced anti-colon cancer cell activity is associated with ceramide production

Energy Technology Data Exchange (ETDEWEB)

Xu, Weihong; Xu, Bin; Yao, Yiting; Yu, Xiaoling [Department of Clinical Laboratory, Tongren Hospital, Shanghai (China); Shen, Jie, E-mail: tongrensj163@163.com [Department of Administrative, Tongren Hospital, No. 786 Yuyuan Road, Changning District, Shanghai (China)

2015-08-07

In the current study, we investigated the potential activity of AR-42, a novel histone deacetylase (HDAC) inhibitor, against colon cancer cells. Our in vitro results showed that AR-42 induced ceramide production, exerted potent anti-proliferative and pro-apoptotic activities in established (SW-620 and HCT-116 lines) and primary human colon cancer cells. Exogenously-added sphingosine 1-phosphate (S1P) suppressed AR-42-induced activity, yet a cell-permeable ceramide (C4) facilitated AR-42-induced cytotoxicity against colon cancer cells. In addition, AR-42-induced ceramide production and anti-colon cancer cell activity were inhibited by the ceramide synthase inhibitor fumonisin B1, but were exacerbated by PDMP, which is a ceramide glucosylation inhibitor. In vivo, oral administration of a single dose of AR-42 dramatically inhibited SW-620 xenograft growth in severe combined immunodeficient (SCID) mice, without inducing overt toxicities. Together, these results show that AR-42 dramatically inhibits colon cancer cell proliferation in vitro and in vivo, and ceramide production might be the key mechanism responsible for its actions. - Highlights: • AR-42 is anti-proliferative against primary/established colon cancer cells. • AR-42 induces significant apoptotic death in primary/established colon cancer cells. • Ceramide production mediates AR-42-induced cytotoxicity in colon cancer cells. • AR-42 oral administration potently inhibits SW-620 xenograft growth in SCID mice.

Ubiquitin-specific peptidase 22 inhibits colon cancer cell invasion by suppressing the signal transducer and activator of transcription 3/matrix metalloproteinase 9 pathway.

Science.gov (United States)

Ao, Ning; Liu, Yanyan; Bian, Xiaocui; Feng, Hailiang; Liu, Yuqin

2015-08-01

Colon cancer is associated with increased cell migration and invasion. In the present study, the role of ubiquitin-specific peptidase 22 (USP22) in signal transducer and activator of transcription 3 (STAT3)-mediated colon cancer cell invasion was investigated. The messenger RNA levels of STAT3 target genes were measured by reverse transcription-quantitative polymerase chain reaction, following USP22 knockdown by RNA interference in SW480 colon cancer cells. The matrix metalloproteinase 9 (MMP9) proteolytic activity and invasion potential of SW480 cells were measured by zymography and Transwell assay, respectively, following combined USP22 and STAT3 short interfering (si)RNA treatment or STAT3 siRNA treatment alone. Similarly, a cell counting kit-8 assay was used to detect the proliferation potential of SW480 cells. The protein expression levels of USP22, STAT3 and MMP9 were detected by immunohistochemistry in colon cancer tissue microarrays (TMAs) and the correlation between USP22, STAT3 and MMP9 was analyzed. USP22/STAT3 co-depletion partly rescued the MMP9 proteolytic activity and invasion of SW480 cells, compared with that of STAT3 depletion alone. However, the proliferation of USP22/STAT3si-SW480 cells was decreased compared with that of STAT3si-SW480 cells. USP22 expression was positively correlated with STAT3 and MMP9 expression in colon cancer TMAs. In conclusion, USP22 attenuated the invasion capacity of colon cancer cells by inhibiting the STAT3/MMP9 signaling pathway.

Eosinophils Contribute to Intestinal Inflammation via Chemoattractant Receptor-homologous Molecule Expressed on Th2 Cells, CRTH2, in Experimental Crohn's Disease.

Science.gov (United States)

Radnai, Balázs; Sturm, Eva M; Stančić, Angela; Jandl, Katharina; Labocha, Sandra; Ferreirós, Nerea; Grill, Magdalena; Hasenoehrl, Carina; Gorkiewicz, Gregor; Marsche, Gunther; Heinemann, Ákos; Högenauer, Christoph; Schicho, Rudolf

2016-09-01

Prostaglandin [PG] D2 activates two receptors, DP and CRTH2. Antagonism of CRTH2 has been shown to promote anti-allergic and anti-inflammatory effects. We investigated whether CRTH2 may play a role in Crohn's disease [CD], focusing on eosinophils which are widely present in the inflamed mucosa of CD patients and express both receptors. Using the 2,4,6-trinitrobenzenesulfonic acid [TNBS]-induced colitis model, involvement of CRTH2 in colitis was investigated by pharmacological antagonism, immunohistochemistry, Western blotting, immunoassay, and leukocyte recruitment. Chemotactic assays were performed with isolated human eosinophils. Biopsies and serum samples of CD patients were examined for presence of CRTH2 and ligands, respectively. High amounts of CRTH2-positive cells, including eosinophils, are present in the colonic mucosa of mice with TNBS colitis and in human CD. The CRTH2 antagonist OC-459, but not the DP antagonist MK0524, reduced inflammation scores and decreased TNF-α, IL-1β, and IL-6 as compared with control mice. OC-459 inhibited recruitment of eosinophils into the colon and also inhibited CRTH2-induced chemotaxis of human eosinophils in vitro. Eosinophil-depleted ΔdblGATA knockout mice were less sensitive to TNBS-induced colitis, whereas IL-5 transgenic mice with lifelong eosinophilia were more severely affected than wild types. In addition, we show that serum levels of PGD2 and Δ(12)-PGJ2 were increased in CD patients as compared with control individuals. CRTH2 plays a pro-inflammatory role in TNBS-induced colitis. Eosinophils contribute to the severity of the inflammation, which is improved by a selective CRTH2 antagonist. CRTH2 may, therefore, represent an important target in the pharmacotherapy of CD. Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Pomegranate extract and exercise provide additive benefits on improvement of immune function by inhibiting inflammation and oxidative stress in high-fat-diet-induced obesity in rats.

Science.gov (United States)

Zhao, Fei; Pang, Wentao; Zhang, Ziyi; Zhao, Jialong; Wang, Xin; Liu, Ye; Wang, Xun; Feng, Zhihui; Zhang, Yong; Sun, Wenyan; Liu, Jiankang

2016-06-01

Obesity is reported to be associated with immune dysfunction and a state of low-grade, chronic inflammation. Either pomegranate extract (PomE) or exercise (Ex) has been shown to have antiobesity, anti-inflammatory and antioxidant effects. Nevertheless, no study has addressed the additive benefits of PomE and Ex on the restoration of obesity-induced immune defects. The present work aims to study the effect of PomE and Ex as a combined intervention on immune function and the underlying mechanism involved in inflammation and oxidative stress in rats with high-fat-diet (HFD)-induced obesity. Our results demonstrate that the combination of PomE and Ex showed additive benefits on inhibition of HFD-induced body weight increase and improvement of HFD-induced immune dysfunction, including (a) attenuating the abnormality of histomorphology of the spleen, (b) increasing the ratio of the CD4+:CD8+ T cell subpopulations in splenocytes and peripheral blood mononuclear cells (PBMC), (c) inhibition of apoptosis in splenocytes and PBMC, (d) normalizing peritoneal macrophage phenotypes and (e) restoring immunomodulating factors in serum. We also find that immune dysfunction in HFD-fed rats was associated with increased inflammatory cytokine secretion and oxidative stress biomarkers, and that the combination of PomE and Ex effectively inhibited the inflammatory response and decreased oxidative damage. The effect of PomE and Ex as a combined intervention is greater than the effect of either PomE or Ex alone, showing that PomE and Ex may be additively effective in improving immune function in HFD-fed rats by inhibiting inflammation and decreasing oxidative stress. Copyright © 2016 Elsevier Inc. All rights reserved.

Time- and dose-dependent effects of curcumin on gene expression in human colon cancer cells

NARCIS (Netherlands)

Erk, M.J. van; Teuling, E.; Staal, Y.C.M.; Huybers, S.; Bladeren, P.J. van; Aarts, J.M.M.J.G.; Ommen, B. van

2004-01-01

Background. Curcumin is a spice and a coloring food compound with a promising role in colon cancer prevention. Curcumin protects against development of colon tumors in rats treated with a colon carcinogen, in colon cancer cells curcumin can inhibit cell proliferation and induce apoptosis, it is an

Time- and dose-dependent effects of curcumin on gene expression in human colon cancer cells

NARCIS (Netherlands)

Erk, van M.J.; Teuling, E.; Staal, Y.C.M.; Huybers, S.; Bladeren, van P.J.; Aarts, J.M.M.J.G.; Ommen, van B.

2004-01-01

Background: Curcumin is a spice and a coloring food compound with a promising role in colon cancer prevention. Curcumin protects against development of colon tumors in rats treated with a colon carcinogen, in colon cancer cells curcumin can inhibit cell proliferation and induce apoptosis, it is an

Time- and dose-dependent effects of curcumin on gene expression in human colon cancer cells

NARCIS (Netherlands)

Van Erk, Marjan J; Teuling, Eva; Staal, Yvonne C. M.; Huybers, Sylvie; Van Bladeren, Peter J; Aarts, Jac MMJG; Van Ommen, Ben

2004-01-01

BACKGROUND: Curcumin is a spice and a coloring food compound with a promising role in colon cancer prevention. Curcumin protects against development of colon tumors in rats treated with a colon carcinogen, in colon cancer cells curcumin can inhibit cell proliferation and induce apoptosis, it is an

Prolonged sulforaphane treatment activates survival signaling in nontumorigenic NCM460 colon cells but apoptotic signaling in tumorigenic HCT116 colon cells.

Science.gov (United States)

Zeng, Huawei; Trujillo, Olivia N; Moyer, Mary P; Botnen, James H

2011-01-01

Sulforaphane (SFN) is a naturally occurring chemopreventive agent; the induction of cell cycle arrest and apoptosis is a key mechanism by which SFN exerts its colon cancer prevention. However, little is known about the differential effects of SFN on colon cancer and normal cells. In this study, we demonstrated that SFN (15 μmol/L) exposure (72 h) inhibited cell proliferation by up to 95% in colon cancer cells (HCT116) and by 52% in normal colon mucosa-derived (NCM460) cells. Our data also showed that SFN exposure (5 and 10 μmol/L) led to the reduction of G1 phase cell distribution and an induction of apoptosis in HCT116 cells, but to a much lesser extent in NCM460 cells. Furthermore, the examination of mitogen-activated protein kinase (MAPK) signaling status revealed that SFN upregulated the phosphorylation of extracellular-regulated kinase 1/2 (ERK1/2) in NCM460 cells but not in HCT116 cells. In contrast, SFN enhanced the phosphorylation of stress-activated protein kinase (SAPK) and decreased cellular myelocytomatosis oncogene (c-Myc) expression in HCT116 cells but not NCM460 cells. Taken together, the activation of survival signaling in NCM460 cells and apoptotic signaling in HCT116 cells may play a critical role in SFN's stronger potential of inhibiting cell proliferation in colon cancer cells than in normal colon cells. Copyright © 2011, Taylor & Francis Group, LLC

Lipids Derived from Virulent Francisella tularensis Broadly Inhibit Pulmonary Inflammation via Toll-Like Receptor 2 and Peroxisome Proliferator-Activated Receptor α

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Crane, Deborah D.; Ireland, Robin; Alinger, Joshua B.; Small, Pamela

2013-01-01

Francisella tularensis is a Gram-negative facultative intracellular pathogen that causes an acute lethal respiratory disease in humans. The heightened virulence of the pathogen is linked to its unique ability to inhibit Toll-like receptor (TLR)-mediated inflammatory responses. The bacterial component and mechanism of this inhibition are unknown. Here we show that lipids isolated from virulent but not attenuated strains of F. tularensis are not detected by host cells, inhibit production of proinflammatory cytokines by primary macrophages in response to known TLR ligands, and suppress neutrophil recruitment in vivo. We further show that lipid-mediated inhibition of inflammation is dependent on TLR2, MyD88, and the nuclear hormone and fatty acid receptor peroxisome proliferator-activated receptor α (PPARα). Pathogen lipid-mediated interference with inflammatory responses through the engagement of TLR2 and PPARα represents a novel manipulation of host signaling pathways consistent with the ability of highly virulent F. tularensis to efficiently evade host immune responses. PMID:23925884

Inhibition of Pyk2 blocks lung inflammation and injury in a mouse model of acute lung injury

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Duan Yingli

2012-01-01

Full Text Available Abstract Background Proline-rich tyrosine kinase 2 (Pyk2 is essential in neutrophil degranulation and chemotaxis in vitro. However, its effect on the process of lung inflammation and edema formation during LPS induced acute lung injury (ALI remains unknown. The goal of the present study was to determine the effect of inhibiting Pyk2 on LPS-induced acute lung inflammation and injury in vivo. Methods C57BL6 mice were given either 10 mg/kg LPS or saline intratracheally. Inhibition of Pyk2 was effected by intraperitoneal administration TAT-Pyk2-CT 1 h before challenge. Bronchoalveolar lavage analysis of cell counts, lung histology and protein concentration in BAL were analyzed at 18 h after LPS treatment. KC and MIP-2 concentrations in BAL were measured by a mouse cytokine multiplex kit. The static lung compliance was determined by pressure-volume curve using a computer-controlled small animal ventilator. The extravasated Evans blue concentration in lung homogenate was determined spectrophotometrically. Results Intratracheal instillation of LPS induced significant neutrophil infiltration into the lung interstitium and alveolar space, which was attenuated by pre-treatment with TAT-Pyk2-CT. TAT-Pyk2-CT pretreatment also attenuated 1 myeloperoxidase content in lung tissues, 2 vascular leakage as measured by Evans blue dye extravasation in the lungs and the increase in protein concentration in bronchoalveolar lavage, and 3 the decrease in lung compliance. In each paradigm, treatment with control protein TAT-GFP had no blocking effect. By contrast, production of neutrophil chemokines MIP-2 and keratinocyte-derived chemokine in the bronchoalveolar lavage was not reduced by TAT-Pyk2-CT. Western blot analysis confirmed that tyrosine phosphorylation of Pyk2 in LPS-challenged lungs was reduced to control levels by TAT-Pyk2-CT pretreatment. Conclusions These results suggest that Pyk2 plays an important role in the development of acute lung injury in mice and

Tanshinone IIA Attenuates Diabetic Peripheral Neuropathic Pain in Experimental Rats via Inhibiting Inflammation

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Baojian Zhang

2018-01-01

Full Text Available Diabetic peripheral neuropathic pain (DPNP is a common and intractable complication of diabetes. Conventional therapies are always not ideal; development of novel drugs is still needed to achieve better pain relief. Recent evidences have demonstrated that inflammation is involved in the onset and maintenance of DPNP. The anti-inflammatory property of Tanshinone IIA (TIIA makes it a promising candidate to block or alter the pain perception. This study was conducted to investigate whether TIIA could attenuate DPNP in streptozotocin- (STZ- induced rats model and its potential mechanisms. TIIA was administered to STZ-induced diabetic rats at the dose of 40 mg/kg once a day for 3 weeks. The effects of TIIA on thermal hyperalgesia and mechanical allodynia were investigated using behavioral tests. The mRNA level and expression of interleukin- (IL- 1β, interleukin- (IL- 6, tumor necrosis factor- (TNF- α, and interleukin- (IL- 10 in the fourth to sixth segments of the dorsal root ganglion (L4–6 DRG were detected by quantitative real-time PCR (qPCR and Western blot. TIIA treatment significantly attenuated mechanical allodynia and thermal hyperalgesia in diabetic rats. In addition, the expression of the proinflammatory cytokines IL-1β, IL-6, and TNF-α was inhibited, and the level of the anti-inflammatory cytokine IL-10 was increased by TIIA. This study demonstrated that TIIA has significant antiallodynic and antihyperalgesic effects in a rat model of STZ-induced DPNP, and the effect may be associated with its anti-inflammation property.

The role of HMG-CoA reductase inhibition in endothelial dysfunction and inflammation

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Paolo Gelosa

2007-11-01

Full Text Available Paolo Gelosa1, Mauro Cimino2, Alice Pignieri1, Elena Tremoli1,3, Uliano Guerrini1, Luigi Sironi11Department of Pharmacological Sciences, University of Milan, Italy; 2Institute of Pharmacological Sciences, Carlo Bo University of Urbino, Italy; 3Monzino Cardiologic Center IRCCS, Milan, ItalyAbstract: Statin-induced inhibition of HMG-CoA reductase reduces cholesterol production and prevents the formation of many non-steroidal isoprenoid compounds, such as farnesylpyrophosphate and geranylgeranylpyrophosphate, that act as lipid attachments for the post-translational modification of various proteins, including the G-proteins and transcription factors involved in a number of cell processes. However, the blockade of isoprenylation elicited by statin treatment also has biological effects on cell function that go beyond the decrease in cholesterol synthesis: these are the so-called “pleiotropic” effects that mainly relate to vascular function. Endothelial dysfunction is an independent predictor of cardiovascular events that correlates with inflammation markers/mediators and robust predictors of cardiovascular diseases such as increased high-sensitivity C-reactive protein levels. The results of in vivo and in vitro studies indicate that the statins have beneficial effects unrelated to cholesterol lowering, such as improving endothelial function, increasing myocardial perfusion, and enhancing the availability of nitric oxide. This review describes the pleiotropic effects of statins that may be involved in modulating/preventing endothelial dysfunction and inflammatory processes, as well as the cellular and molecular mechanisms through which they improve endothelial function.Keywords: statins; inflammation; endothelial dysfunction; nitric oxide; HMG-CoA reductase

Inhibitory effects of meju prepared with mixed starter cultures on azoxymethane and dextran sulfate sodium-induced colon carcinogenesis in mice

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Ji-Kang Jeong

2012-01-01

Full Text Available Backgrounds: Meju is the main ingredient and the starter culture of traditional Korean fermented soybean foods; these fermented soybean products are well-known for their various health benefits, including anticancer effects. We developed the grain-type meju using probiotic mixed starter cultures to improve the qualities and functionalities of fermented soybean products, as well as the meju itself. In this study, the inhibitory effects of the grain-type meju were investigated in azoxymethane (AOM and dextran sulfate sodium (DSS-induced colon carcinogenesis mice model. Materials and Methods: AOM and DSS colon carcinogenesis was induced in female C57BL/6 mice and meju was orally administered for 4 weeks. The body weight, colon length, and colon weight of mice were determined, and colonic tissues were histologically observed. The serum levels of proinflammatory cytokines and the levels of inflammation- and apoptosis-related genes in colonic tissue were also analyzed. Results: The administration of meju using probiotic mixed starter cultures ameliorated the symptoms of colon cancer and reduced number of neoplasia, and reduced serum proinflammatory cytokine levels and iNOS and COX-2 expression levels in colonic tissue. It increased Bax and reduced Bcl-2 expression levels and increased p21 and p53 expression in colonic tissues. Conclusion: The meju showed inhibitory effects on the progression of colon cancer induced by AOM and DSS by ameliorating the symptoms of colon cancer, reducing the number of neoplasias and regulating proinflammatory cytokine levels and the expressions of inflammation- and apoptosis-related genes in the colonic tissue.

Molecular detection, quantification, and isolation of Streptococcus gallolyticus bacteria colonizing colorectal tumors: inflammation-driven potential of carcinogenesis via IL-1, COX-2, and IL-8

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Abdulamir Ahmed S

2010-09-01

Full Text Available Abstract Background Colorectal cancer (CRC has long been associated with bacteremia and/or endocarditis by Streptococcus gallolyticus member bacteria (SGMB but the direct colonization of SGMB along with its molecular carcinogenic role, if any, has not been investigated. We assessed the colonization of SGMB in CRC patients with history of bacteremia (CRC-w/bac and without history of bacteremia (CRC-wo/bac by isolating SGMB from feces, mucosal surfaces of colorectum, and colorectal tissues and detecting SGMB DNA, via PCR and in situ hybridization (ISH assays targeting SodA gene in colorectal tissues. Moreover, mRNA of IL1, IL-8, COX-2, IFN-γ, c-Myc, and Bcl-2 in colorectal tissues of studied groups was assessed via ISH and RT-PCR. Results SGMB were found to be remarkably isolated in tumorous (TU and non-tumorous (NTU tissues of CRC-w/bac, 20.5% and 17.3%, and CRC-wo/bac, 12.8% and 11.5%, respectively while only 2% of control tissues revealed SGMB (P 10 CN/g respectively, showed higher colonization in TU than in NTU and in CRC-w/bac than in CRC-wo/bac (P Conclusions The current study indicated that colorectal cancer is remarkably associated with SGMB; moreover, molecular detection of SGMB in CRC was superior to link SGMB with CRC tumors highlighting a possible direct and active role of SGMB in CRC development through most probably inflammation-based sequel of tumor development or propagation via, but not limited to, IL-1, COX-2, and IL-8.

Assessment of cytotoxicity of Portulaca oleracea Linn. against human colon adenocarcinoma and vero cell line

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Mali, Prashant Y.

2015-01-01

Background: Portulaca oleracea Linn. (Portulacaceae) is commonly known as purslane in English. In traditional system it is used to cure diarrhea, dysentery, leprosy, ulcers, asthma, and piles, reduce small tumors and inflammations. Aim: To assess cytotoxic potential of chloroform extract of P. oleracea whole plant against human colon adenocarcinoma (HCT-15) and normal (Vero) cell line. Materials and Methods: Characterization of chloroform extract of P. oleracea by Fourier transform infrared (FTIR) spectroscopy was performed. Cytotoxicity (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay was used for assessment of cytotoxic potential of chloroform extract of P. oleracea. The concentrations of 1000–0.05 μg/ml were used in the experiment. Doxorubicin was considered as standard reference drug. Results: FTIR spectrum showed the peak at 1019.52 and 1396.21 center. The 50% cell growth inhibition (IC50) of chloroform extract of P. oleracea and doxorubicin was 1132.02 μg/ml and 460.13 μg/ml against human colon adenocarcinoma and 767.60 μg/ml and 2392.71 μg/ml against Vero cell line, respectively. Conclusion: Chloroform extract of P. oleracea whole plant was less efficient or does not have cytotoxic activity against human colon adenocarcinoma cell line. It was not safe to normal Vero cell line. But, there is a need to isolate, identify, and confirm the phytoconstituents present in extract by sophisticated analytical techniques. PMID:27833374

Early administration of probiotic Lactobacillus acidophilus and/or prebiotic inulin attenuates pathogen-mediated intestinal inflammation and Smad 7 cell signaling

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Foye, Ondulla T.; Huang, I-Fei; Chiou, Christine C.; Walker, W. Allan; Shi, Hai Ning

2014-01-01

Immaturity of gut-associated immunity may contribute to pediatric mortality associated with enteric infections. A murine model to parallel infantile enteric disease was used to determine the effects of probiotic, Lactobacillus acidophilus (La), prebiotic, inulin, or both (synbiotic, syn) on pathogen-induced inflammatory responses, NF-κB, and Smad 7 signaling. Newborn mice were inoculated bi-weekly for 4 weeks with La, inulin, or syn and challenged with Citrobacter rodentium (Cr) at 5 weeks. Mouse intestinal epithelial cells (CMT93) were exposed to Cr to determine temporal alterations in NF-Kappa B and Smad 7 levels. Mice with pretreatment of La, inulin, and syn show reduced intestinal inflammation following Cr infection compared with controls, which is associated with significantly reduced bacterial colonization in La, inulin, and syn animals. Our results further show that host defense against Cr infection correlated with enhanced colonic IL-10 and transforming growth factor-β expression and inhibition of NF-κB in syn-treated mice, whereas mice pretreated with syn, La, or inulin had attenuation of Cr-induced Smad 7 expression. There was a temporal Smad 7 and NF-κB intracellular accumulation post-Cr infection and post-tumor necrosis factor stimulation in CMT93 cells. These results, therefore, suggest that probiotic, La, prebiotic inulin, or synbiotic may promote host-protective immunity and attenuate Cr-induced intestinal inflammation through mechanisms affecting NF-κB and Smad 7 signaling. PMID:22524476

Methylselenol, a selenium metabolite, plays common and different roles in cancerous colon HCT116 cell and noncancerous NCM460 colon cell proliferation.

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Zeng, Huawei; Briske-Anderson, Mary; Wu, Min; Moyer, Mary P

2012-01-01

Methylselenol is hypothesized to be a critical selenium metabolite for anticancer action, and differential chemopreventive effects of methylselenol on cancerous and noncancerous cells may play an important role. In this study, the submicromolar concentrations of methylselenol were generated by incubating methionase with seleno-L methionine, and colon-cancer-derived HCT-116 cells and noncancerous colon NCM460 cells were exposed to methylselenol. Methylselenol exposure inhibited cell growth and led to an increase in G1 and G2 fractions with a concomitant drop in S-phase and an induction of apoptosis in HCT116, but to a much lesser extent in NCM460 colon cells. Similarly, the examination of mitogen-activated protein kinase (MAPK) and cellular myelocytomatosis oncogene (c-Myc) signaling status revealed that methylselenol inhibited the phosphorylation of extracellular-regulated kinase1/2 and p38 mitogen-activated protein kinase and the expression of c-Myc in HCT116 cells, but also to a lesser extent in NCM460 cells. The other finding is that methylselenol inhibits sarcoma kinase phosphorylation in HCT116 cells. In contrast, methylselenol upregulated the phosphorylation of sarcoma and focal adhesion kinase survival signals in the noncancerous NCM460 cells. Collectively, methylselenol's stronger potential of inhibiting cell proliferation/survival signals in the cancerous HCT116 cells when compared with that in noncancerous NCM460 cells may partly explain the potential of methylselenol's anticancer action.

Integrin α6Bβ4 inhibits colon cancer cell proliferation and c-Myc activity

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Dydensborg, Anders Bondo; Teller, Inga C; Groulx, Jean-François; Basora, Nuria; Paré, Fréderic; Herring, Elizabeth; Gauthier, Rémy; Jean, Dominique; Beaulieu, Jean-François

2009-01-01

Integrins are known to be important contributors to cancer progression. We have previously shown that the integrin β4 subunit is up-regulated in primary colon cancer. Its partner, the integrin α6 subunit, exists as two different mRNA splice variants, α6A and α6B, that differ in their cytoplasmic domains but evidence for distinct biological functions of these α6 splice variants is still lacking. In this work, we first analyzed the expression of integrin α6A and α6B at the protein and transcript levels in normal human colonic cells as well as colorectal adenocarcinoma cells from both primary tumors and established cell lines. Then, using forced expression experiments, we investigated the effect of α6A and α6B on the regulation of cell proliferation in a colon cancer cell line. Using variant-specific antibodies, we observed that α6A and α6B are differentially expressed both within the normal adult colonic epithelium and between normal and diseased colonic tissues. Proliferative cells located in the lower half of the glands were found to predominantly express α6A, while the differentiated and quiescent colonocytes in the upper half of the glands and surface epithelium expressed α6B. A relative decrease of α6B expression was also identified in primary colon tumors and adenocarcinoma cell lines suggesting that the α6A/α6B ratios may be linked to the proliferative status of colonic cells. Additional studies in colon cancer cells showed that experimentally restoring the α6A/α6B balance in favor of α6B caused a decrease in cellular S-phase entry and repressed the activity of c-Myc. The findings that the α6Bβ4 integrin is expressed in quiescent normal colonic cells and is significantly down-regulated in colon cancer cells relative to its α6Aβ4 counterpart are consistent with the anti-proliferative influence and inhibitory effect on c-Myc activity identified for this α6Bβ4 integrin. Taken together, these findings point out the importance of integrin

Doenjang prepared with mixed starter cultures attenuates azoxymethane and dextran sulfate sodium-induced colitis-associated colon carcinogenesis in mice

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Ji-Kang Jeong

2014-01-01

Full Text Available Backgrounds: Doenjang is traditional Korean fermented soybean paste and widely known for its various health benefits including anticancer effect. In this study, we manufactured doenjang with the grain-type meju using probiotic mixed starter cultures of Aspegillus oryzae, Bacillus subtilis-SKm, and Lactococcus lactis-GAm to improve the qualities and beneficial properties of doenjang. Materials and Methods: The inhibitory effects of the doenjang prepared with the grain-type meju using mixed starter cultures were investigated in azoxymethane (AOM and dextran sulfate sodium (DSS-induced colon carcinogenesis mice model. AOM and DSS colon carcinogenesis was induced in female C57BL/6 mice, and doenjang was orally administered for 4 weeks. Body weight, colon length, and colon weight of mice were determined, and colonic tissues were histologically evaluated. The serum levels of proinflammatory cytokines as well as the expression of inflammation- and apoptosis-related genes in colonic tissue were also analyzed. Results: Administration of the doenjang using probiotic mixed starter cultures ameliorated the symptoms of colon cancer, and reduced the incidence of neoplasia, and reduced the levels of serum proinflammatory cytokines such as interleukin-6, and tumor necrosis factor-α and inducible nitric oxide synthase and cycloooxygenase-2 expression levels in colonic tissue. In addition, it increased Bax and reduced Bcl-2 expression levels and increased p21 and p53 expression in the colonic tissues. Conclusion: These findings indicate that the doenjang attenuated colon carcinogenesis induced by AOM and DSS by ameliorating the symptoms of colon cancer, reducing the occurrence of neoplasia, regulating proinflammatory cytokine levels, and controlling the expressions of inflammation- and apoptosis-related genes in the colonic tissue.

Longevity in mice is promoted by probiotic-induced suppression of colonic senescence dependent on upregulation of gut bacterial polyamine production.

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Mitsuharu Matsumoto

Full Text Available BACKGROUND: Chronic low-grade inflammation is recognized as an important factor contributing to senescence and age-related diseases. In mammals, levels of polyamines (PAs decrease during the ageing process; PAs are known to decrease systemic inflammation by inhibiting inflammatory cytokine synthesis in macrophages. Reductions in intestinal luminal PAs levels have been associated with intestinal barrier dysfunction. The probiotic strain Bifidobacterium animalis subsp. lactis LKM512 is known to increase intestinal luminal PA concentrations. METHODOLOGY/PRINCIPAL FINDINGS: We supplemented the diet of 10-month-old Crj:CD-1 female mice with LKM512 for 11 months, while the controls received no supplementation. Survival rates were compared using Kaplan-Meier survival curves. LKM512-treated mice survived significantly longer than controls (P<0.001; moreover, skin ulcers and tumors were more common in the control mice. We then analyzed inflammatory and intestinal conditions by measuring several markers using HPLC, ELISA, reverse transcription-quantitative PCR, and histological slices. LKM512 mice showed altered 16S rRNA gene expression of several predominant intestinal bacterial groups. The fecal concentrations of PAs, but not of short-chain fatty acids, were significantly higher in LKM512-treated mice (P<0.05. Colonic mucosal function was also better in LKM512 mice, with increased mucus secretion and better maintenance of tight junctions. Changes in gene expression levels were evaluated using the NimbleGen mouse DNA microarray. LKM512 administration also downregulated the expression of ageing-associated and inflammation-associated genes and gene expression levels in 21-month-old LKM512-treated mice resembled those in 10-month-old untreated (younger mice. CONCLUSION/SIGNIFICANCE: Our study demonstrated increased longevity in mice following probiotic treatment with LKM512, possibly due to the suppression of chronic low-grade inflammation in the colon

The influence of arachidonic acid metabolites on cell division in the intestinal epithelium and in colonic tumors.

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Petry, F M; Tutton, P J; Barkla, D H

1984-09-01

Various metabolites of arachidonic acid are now known to influence cell division. In this paper the effects on cell proliferation of arachidonic acid, some inhibitors of arachidonic acid metabolism and some analogs of arachidonic acid metabolites is described. The epithelial cell proliferation rate in the jejunum, in the descending colon and in dimethylhydrazine-induced tumors of rat colon was measured using a stathmokinetic technique. Administration of arachidonic acid resulted in retardation of cell proliferation in each of the tissues examined. A cyclooxygenase inhibitor (Flurbiprofen) prevented this effect of arachidonic acid in the jejunal crypts and in colonic tumors, but not in colonic crypts. In contrast, inhibitors of both cyclooxygenase and lipoxygenase (Benoxaprofen and BW755c) prevented the effect of arachidonic acid in the colonic crypts and reduced its effect on colonic tumours but did not alter its effect on the jejunum. An inhibitor of thromoboxane A2 synthetase (U51,605) was also able to prevent the inhibitory effect of arachidonic acid on colonic tumors. Treatment with 16,16-dimethyl PGE2 inhibited cell proliferation in jejunal crypts and in colonic tumors, as did a thromboxane A2 mimicking agent, U46619. Nafazatrom, an agent that stimulates prostacyclin synthesis and inhibits lypoxygenase, promoted cell proliferation in the jejunal crypts and colonic crypts, but inhibited cell proliferation in colonic tumours.

Goniothalamin prevents the development of chemically induced and spontaneous colitis in rodents and induces apoptosis in the HT-29 human colon tumor cell line

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Vendramini-Costa, Débora Barbosa, E-mail: vendramini.debora@gmail.com [Department of Organic Chemistry, Institute of Chemistry, University of Campinas, Campinas, SP (Brazil); Chemical, Biological and Agricultural Pluridisciplinary Research Center (CPQBA), University of Campinas, Campinas, SP (Brazil); Alcaide, Antonio [Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville (Spain); Pelizzaro-Rocha, Karin Juliane [Department of Biochemistry, Institute of Biology, University of Campinas, Campinas, SP (Brazil); Talero, Elena; Ávila-Román, Javier [Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville (Spain); Garcia-Mauriño, Sofia [Department of Plant Biology and Ecology, Faculty of Biology, University of Seville, Seville (Spain); Pilli, Ronaldo Aloise [Department of Organic Chemistry, Institute of Chemistry, University of Campinas, Campinas, SP (Brazil); Carvalho, João Ernesto de [Chemical, Biological and Agricultural Pluridisciplinary Research Center (CPQBA), University of Campinas, Campinas, SP (Brazil); Faculty of Pharmaceutical Sciences, University of Campinas, Campinas, SP (Brazil); Motilva, Virginia [Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville (Spain)

2016-06-01

Colon cancer is the third most incident type of cancer worldwide. One of the most important risk factors for colon cancer development are inflammatory bowel diseases (IBD), thus therapies focusing on IBD treatment have great potential to be used in cancer prevention. Nature has been a source of new therapeutic and preventive agents and the racemic form of the styryl-lactone goniothalamin (GTN) has been shown to be a promising antiproliferative agent, with gastroprotective, antinociceptive and anti-inflammatory effects. As inflammation is a well-known tumor promoter, the major goal of this study was to evaluate the therapeutic and preventive potentials of GTN on chemically induced and spontaneous colitis, as well as the cytotoxic effects of GTN on a human colon tumor cell line (HT-29). GTN treatments inhibited TNBS-induced acute and chronic colitis development in Wistar rats, reducing myeloperoxidase levels and inflammatory cells infiltration in the mucosa. In spontaneous-colitis using IL-10 deficient mice (C57BL/6 background), GTN prevented colitis development through downregulation of TNF-α, upregulation of SIRT-1 and inhibition of proliferation (PCNA index), without signs of toxicity after three months of treatment. In HT-29 cells, treatment with 10 μM of GTN induced apoptosis by increasing BAX/BCL2, p-JNK1/JNK1, p-P38/P38 ratios as well as through ROS generation. Caspase 8, 9 and 3 activation also occurred, suggesting caspase-dependent apoptotic pathway, culminating in PARP-1 cleavage. Together with previous data, these results show the importance of GTN as a pro-apoptotic, preventive and therapeutic agent for IBD and highlight its potential as a chemopreventive agent for colon cancer. - Highlights: • Goniothalamin (GTN) inhibits the development of TNBS-induced colitis in rats. • Moreover, GTN prevents the development of spontaneous colitis in IL-10 deficient mice. • This activity relies on downregulation of TNF-α and upregulation of SIRT-1 expression

Synergistic chondroprotective effects of curcumin and resveratrol in human articular chondrocytes: inhibition of IL-1beta-induced NF-kappaB-mediated inflammation and apoptosis.

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Csaki, Constanze; Mobasheri, Ali; Shakibaei, Mehdi

2009-01-01

Currently available treatments for osteoarthritis (OA) are restricted to nonsteroidal anti-inflammatory drugs, which exhibit numerous side effects and are only temporarily effective. Thus novel, safe and more efficacious anti-inflammatory agents are needed for OA. Naturally occurring polyphenolic compounds, such as curcumin and resveratrol, are potent agents for modulating inflammation. Both compounds mediate their effects by targeting the NF-kappaB signalling pathway. We have recently demonstrated that in chondrocytes resveratrol modulates the NF-kappaB pathway by inhibiting the proteasome, while curcumin modulates the activation of NF-kappaB by inhibiting upstream kinases (Akt). However, the combinational effects of these compounds in chondrocytes has not been studied and/or compared with their individual effects. The aim of this study was to investigate the potential synergistic effects of curcumin and resveratrol on IL-1beta-stimulated human chondrocytes in vitro using immunoblotting and electron microscopy. Treatment with curcumin and resveratrol suppressed NF-kappaB-regulated gene products involved in inflammation (cyclooxygenase-2, matrix metalloproteinase (MMP)-3, MMP-9, vascular endothelial growth factor), inhibited apoptosis (Bcl-2, Bcl-xL, and TNF-alpha receptor-associated factor 1) and prevented activation of caspase-3. IL-1beta-induced NF-kappaB activation was suppressed directly by cocktails of curcumin and resveratrol through inhibition of Ikappakappa and proteasome activation, inhibition of IkappaBalpha phosphorylation and degradation, and inhibition of nuclear translocation of NF-kappaB. The modulatory effects of curcumin and resveratrol on IL-1beta-induced expression of cartilage specific matrix and proinflammatory enzymes were mediated in part by the cartilage-specific transcription factor Sox-9. We propose that combining these natural compounds may be a useful strategy in OA therapy as compared with separate treatment with each individual

Matrix Stiffness Corresponding to Strictured Bowel Induces a Fibrogenic Response in Human Colonic Fibroblasts

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Johnson, Laura A.; Rodansky, Eva S.; Sauder, Kay L.; Horowitz, Jeffrey C.; Mih, Justin D.; Tschumperlin, Daniel J.; Higgins, Peter D.

2013-01-01

Background Crohn’s disease is characterized by repeated cycles of inflammation and mucosal healing which ultimately progress to intestinal fibrosis. This inexorable progression towards fibrosis suggests that fibrosis becomes inflammation-independent and auto-propagative. We hypothesized that matrix stiffness regulates this auto-propagation of intestinal fibrosis. Methods The stiffness of fresh ex vivo samples from normal human small intestine, Crohn’s disease strictures, and the unaffected margin were measured with a microelastometer. Normal human colonic fibroblasts were cultured on physiologically normal or pathologically stiff matrices corresponding to the physiological stiffness of normal or fibrotic bowel. Cellular response was assayed for changes in cell morphology, α-smooth muscle actin (αSMA) staining, and gene expression. Results Microelastometer measurements revealed a significant increase in colonic tissue stiffness between normal human colon and Crohn’s strictures as well as between the stricture and adjacent tissue margin. In Ccd-18co cells grown on stiff matrices corresponding to Crohn’s strictures, cellular proliferation increased. Pathologic stiffness induced a marked change in cell morphology and increased αSMA protein expression. Growth on a stiff matrix induced fibrogenic gene expression, decreased matrix metalloproteinase and pro-inflammatory gene expression, and was associated with nuclear localization of the transcriptional cofactor MRTF-A. Conclusions Matrix stiffness, representative of the pathological stiffness of Crohn’s strictures, activates human colonic fibroblasts to a fibrogenic phenotype. Matrix stiffness affects multiple pathways suggesting the mechanical properties of the cellular environment are critical to fibroblast function and may contribute to autopropagation of intestinal fibrosis in the absence of inflammation, thereby contributing to the intractable intestinal fibrosis characteristic of Crohn’s disease. PMID

Intra-amniotic Ureaplasma parvum-Induced Maternal and Fetal Inflammation and Immune Responses in Rhesus Macaques.

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Senthamaraikannan, Paranthaman; Presicce, Pietro; Rueda, Cesar M; Maneenil, Gunlawadee; Schmidt, Augusto F; Miller, Lisa A; Waites, Ken B; Jobe, Alan H; Kallapur, Suhas G; Chougnet, Claire A

2016-11-15

 Although Ureaplasma species are the most common organisms associated with prematurity, their effects on the maternal and fetal immune system remain poorly characterized.  Rhesus macaque dams at approximately 80% gestation were injected intra-amniotically with 10 7 colony-forming units of Ureaplasma parvum or saline (control). Fetuses were delivered surgically 3 or 7 days later. We performed comprehensive assessments of inflammation and immune effects in multiple fetal and maternal tissues.  Although U. parvum grew well in amniotic fluid, there was minimal chorioamnionitis. U. parvum colonized the fetal lung, but fetal systemic microbial invasion was limited. Fetal lung inflammation was mild, with elevations in CXCL8, tumor necrosis factor (TNF) α, and CCL2 levels in alveolar washes at day 7. Inflammation was not detected in the fetal brain. Significantly, U. parvum decreased regulatory T cells (Tregs) and activated interferon γ production in these Tregs in the fetus. It was detected in uterine tissue by day 7 and induced mild inflammation and increased expression of connexin 43, a gap junction protein involved with labor.  U. parvum colonized the amniotic fluid and caused uterine inflammation, but without overt chorioamnionitis. It caused mild fetal lung inflammation but had a more profound effect on the fetal immune system, decreasing Tregs and polarizing them toward a T-helper 1 phenotype. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Prostaglandin E2 produced by Entamoeba histolytica binds to EP4 receptors and stimulates interleukin-8 production in human colonic cells.

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Dey, Indranil; Chadee, Kris

2008-11-01

Entamoeba histolytica pathogenesis in the colon occurs in a stepwise fashion. It begins with colonization of the mucin layer, which is followed by stimulation of a proinflammatory response that causes nonspecific tissue damage that may facilitate parasite invasion of the underlying colonic mucosa. Unfortunately, the parasite and/or host factors that stimulate a proinflammatory response in the gut are poorly understood. In this study, we found that live E. histolytica or secretory or proteins (SP) and soluble ameba components (SAP) can markedly increase interleukin-8 (IL-8) mRNA expression and protein production in colonic epithelial cells. The IL-8-stimulating molecule produced by live amebae was identified as prostaglandin E(2) (PGE(2)) as trophozoites treated with cyclooxygenase inhibitors inhibited the biosynthesis of PGE(2) and eliminated IL-8 production induced by live parasites or ameba components. Moreover, using specific prostaglandin EP2 and EP4 receptor agonists and antagonists, we found that PGE(2) binds exclusively through EP4 receptors in colonic epithelial cells to stimulate IL-8 production. Silencing of EP4 receptors with EP4 small interfering RNA completely eliminated SP- and SAP-induced IL-8 production. These studies identified bioactive PGE(2) as a one of the major virulence factors produced by E. histolytica that can stimulate the potent neutrophil chemokine and activator IL-8, which can trigger an acute host inflammatory response. Thus, the induction of IL-8 production in response to E. histolytica-derived PGE(2) may be a mechanism that explains the initiation and amplification of acute inflammation associated with intestinal amebiasis.

The selective vitamin D receptor agonist, elocalcitol, reduces endometriosis development in a mouse model by inhibiting peritoneal inflammation.

Science.gov (United States)

Mariani, Margherita; Viganò, Paola; Gentilini, Davide; Camisa, Barbara; Caporizzo, Elvira; Di Lucia, Pietro; Monno, Antonella; Candiani, Massimo; Somigliana, Edgardo; Panina-Bordignon, Paola

2012-07-01

Endometriosis, which is characterized by the growth of endometrial tissue at ectopic locations as well as vascular development and inflammation, is still an unmet clinical need since an optimal drug that allows for both pain and infertility management does not exist. Since both the eutopic and the ectopic endometrium express the vitamin D receptor (VDR), and VDR agonists are endowed with anti-proliferative and anti-inflammatory properties, we evaluated the effect of elocalcitol, a VDR agonist with low calcaemic liability, in a mouse model of experimentally induced endometriosis. Endometriosis was induced by injection of syngeneic endometrial tissue fragments into adult Balb/c female mice. After having confirmed by immunohistochemistry that endometriotic lesions developing in mice expressed VDR, the mice were administered with elocalcitol (100 μg/kg) or vehicle orally, once a day, for various durations of time. In this model, elocalcitol was able to reduce total lesion weight up to 70% upon treatment for 1 week before and 2 weeks after disease induction. Interestingly, a therapeutic effect was also observed on already established lesions. Elocalcitol was shown to reduce the capacity of mouse endometrial cells to adhere to collagen. In addition in treated mice, a decreased state of peritoneal inflammation was demonstrated by the inhibition of macrophage recruitment and inflammatory cytokine secretion. The VDR agonist elocalcitol inhibits lesion development in a validated mouse model of endometriosis, and exerts a protective effect on both the implantation and organization of transferred endometrial tissue. These preliminary data in mice provide a sound rationale for further testing in primate models and eventually in humans.

Effect of hydroxyapatite particle size, morphology and crystallinity on proliferation of colon cancer HCT116 cells

Energy Technology Data Exchange (ETDEWEB)

Dey, Sangeeta; Das, Mitun, E-mail: mitun@cgcri.res.in; Balla, Vamsi Krishna

2014-06-01

The aim of the present work is to chemically and physically characterize the synthesized Hydroxyapatite (HAp) micro and nanoparticles and to explore the inhibitory effect of nano-HAps on the in vitro growth of human colon cancerous cells HCT116. HAp powder was synthesized using three different routes to achieve micro and nanosized powders, with different morphologies and crystallinity. The synthesized powders were characterized using X-ray diffraction, FTIR spectroscopy and scanning electron microscope. The results showed that the average crystallite size of HAp powder varies from 11 nm to 177 nm and respective crystallinity of powder found to be in the range of 0.12 and 0.92. The effect of these physico-chemical properties of HAp powders on human colon cancer HCT116 cells inhibition was determined in vitro. It was found that decreasing the HAp powder crystallite size between 11 nm and 22 nm significantly increases the HCT116 cell inhibition. Our results demonstrate that apart from HAp powder size their crystallinity and morphology also play an important role in cellular inhibition of human colon cancer cells. - Highlights: • Chemically synthesized hydroxyapatite micro and nano-particles with different morphologies and crystallinity. • In vitro cell–material interaction showed that hydroxyapatite nano-particles inhibit colon cancer cells. • Human colon cancer cell inhibition also depends on crystallinity and morphology of HAp powder.

Predictive utility of cyclo-oxygenase-2 expression by colon and rectal cancer.

Science.gov (United States)

Lobo Prabhu, Kristel C; Vu, Lan; Chan, Simon K; Phang, Terry; Gown, Allen; Jones, Steven J; Wiseman, Sam M

2014-05-01

Cyclo-oxygenase-2 (COX-2), an inducible enzyme expressed in areas of inflammation, is a target of interest for colorectal cancer therapy. Currently, the predictive significance of COX-2 in colorectal cancer remains unclear. Tissue microarrays were constructed using 118 colon cancer and 85 rectal cancer specimens; 44 synchronous metastatic colon cancer and 22 rectal cancer lymph nodes were also evaluated. COX-2 expression was assessed by immunohistochemistry. Univariate analysis was used to determine the predictive significance of clinicopathologic variables. Overall survival, disease-specific survival, and disease-free survival were the main outcomes examined. COX-2 was found to be expressed in 93% of colon cancers and 87% of rectal cancers. Decreased COX-2 expression was related to decreased disease-specific survival (P = .016) and decreased disease-free survival (P = .019) in the rectal cancer cohort but not in the colon cancer cohort. COX-2 expression has predictive utility for management of rectal but not colon cancer. Copyright © 2014 Elsevier Inc. All rights reserved.

Dietary intervention with green dwarf banana flour (Musa sp AAA) prevents intestinal inflammation in a trinitrobenzenesulfonic acid model of rat colitis.

Science.gov (United States)

Scarminio, Viviane; Fruet, Andrea C; Witaicenis, Aline; Rall, Vera L M; Di Stasi, Luiz C

2012-03-01

Dietary products are among the therapeutic approaches used to modify intestinal microflora and to promote protective effects during the intestinal inflammatory process. Because the banana plant is rich in resistant starch, which is used by colonic microbiota for the anaerobic production of the short-chain fatty acids that serve as a major fuel source for colonocytes: first, green dwarf banana flour produces protective effects on the intestinal inflammation acting as a prebiotic and, second, combination of this dietary supplementation with prednisolone presents synergistic effects. For this, we used the trinitrobenzenesulphonic acid (TNBS) model of rat colitis. Our results revealed that the protective effect produced by a combination of 10% green dwarf banana flour with prednisolone was more pronounced than those promoted by a single administration of prednisolone or a diet containing 10% or 20% banana flour. This beneficial effect was associated with an improvement in the colonic oxidative status because the banana flour diet prevented the glutathione depletion and inhibited myeloperoxidase activity and lipid peroxidation. In addition, the intestinal anti-inflammatory activity was associated with an inhibition of alkaline phosphatase activity, a reduction in macroscopic and microscopic scores, and an extension of the lesions. In conclusion, the dietary use of the green dwarf banana flour constitutes an important dietary supplement and complementary medicine product to prevention and treatment of human inflammatory bowel disease. Copyright © 2012 Elsevier Inc. All rights reserved.

Anaplasma phagocytophilum Dihydrolipoamide Dehydrogenase 1 Affects Host-Derived Immunopathology during Microbial Colonization

Czech Academy of Sciences Publication Activity Database

Chen, G.; Severo, M. S.; Sakhon, O. S.; Choy, A.; Herron, M. J.; Felsheim, R. F.; Wiryawan, H.; Liao, J.; Johns, J. L.; Munderloh, U. G.; Sutterwala, F. S.; Kotsyfakis, Michalis; Pedra, J. H. F.

2012-01-01

Roč. 80, č. 9 (2012), s. 3194-3205 ISSN 0019-9567 Institutional support: RVO:60077344 Keywords : ricketsia * microbial colonization * immunopathology * inflammation * signaling pathways Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.074, year: 2012 http://iai. asm .org/content/80/9/3194

Members of native coral microbiota inhibit glycosidases and thwart colonization of coral mucus by an opportunistic pathogen.

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Krediet, Cory J; Ritchie, Kim B; Alagely, Ali; Teplitski, Max

2013-05-01

The outcome of the interactions between native commensal microorganisms and opportunistic pathogens is crucial to the health of the coral holobiont. During the establishment within the coral surface mucus layer, opportunistic pathogens, including a white pox pathogen Serratia marcescens PDL100, compete with native bacteria for available nutrients. Both commensals and pathogens employ glycosidases and N-acetyl-glucosaminidase to utilize components of coral mucus. This study tested the hypothesis that specific glycosidases were critical for the growth of S. marcescens on mucus and that their inhibition by native coral microbiota reduces fitness of the pathogen. Consistent with this hypothesis, a S. marcescens transposon mutant with reduced glycosidase and N-acetyl-glucosaminidase activities was unable to compete with the wild type on the mucus of the host coral Acropora palmata, although it was at least as competitive as the wild type on a minimal medium with glycerol and casamino acids. Virulence of the mutant was modestly reduced in the Aiptasia model. A survey revealed that ∼8% of culturable coral commensal bacteria have the ability to inhibit glycosidases in the pathogen. A small molecular weight, ethanol-soluble substance(s) produced by the coral commensal Exiguobacterium sp. was capable of the inhibition of the induction of catabolic enzymes in S. marcescens. This inhibition was in part responsible for the 10-100-fold reduction in the ability of the pathogen to grow on coral mucus. These results provide insight into potential mechanisms of commensal interference with early colonization and infection behaviors in opportunistic pathogens and highlight an important function for the native microbiota in coral health.

Hath1 inhibits proliferation of colon cancer cells probably through up-regulating expression of Muc2 and p27 and down-regulating expression of cyclin D1.

Science.gov (United States)

Zhu, Dai-Hua; Niu, Bai-Lin; Du, Hui-Min; Ren, Ke; Sun, Jian-Ming; Gong, Jian-Ping

2012-01-01

Previous studies showed that Math1 homologous to human Hath1 can cause mouse goblet cells to differentiate. In this context it is important that the majority of colon cancers have few goblet cells. In the present study, the potential role of Hath1 in colon carcinogenesis was investigated. Sections of paraffin-embedded tissues were used to investigate the goblet cell population of normal colon mucosa, mucosa adjacent colon cancer and colon cancer samples from 48 patients. Hath1 and Muc2 expression in these samples were tested by immunohistochemistry, quantitative real-time reverse transcription -PCR and Western blotting. After the recombinant plasmid, pcDNA3.1(+)-Hath1 had been transfected into HT29 colon cancer cells, three clones were selected randomly to test the levels of Hath1 mRNA, Muc2 mRNA, Hath1, Muc2, cyclin D1 and p27 by quantitative real-time reverse transcription-PCR and Western blotting. Moreover, the proliferative ability of HT29 cells introduced with Hath1 was assessed by means of colony formation assay and xenografting. Expression of Hath1, Muc2, cyclin D1 and p27 in the xenograft tumors was also detected by Western blotting. No goblet cells were to be found in colon cancer and levels of Hath1 mRNA and Hath1, Muc2 mRNA and Muc2 were significantly down-regulated. Hath1 could decrease cyclin D1, increase p27 and Muc2 in HT29 cells and inhibit their proliferation. Hath1 may be an anti-oncogene in colon carcinogenesis.

Diagnosis of ulcerative colitis before onset of inflammation by multivariate modeling of genome-wide gene expression data

DEFF Research Database (Denmark)

Olsen, Jørgen; Gerds, Thomas A; Seidelin, Jakob B

2009-01-01

Background: Endoscopically obtained mucosal biopsies play an important role in the differential diagnosis between ulcerative colitis (UC) and Crohn's disease (CD), but in some cases where neither macroscopic nor microscopic signs of inflammation are present the biopsies provide only inconclusive...... biopsies from 78 patients were included. A diagnostic model was derived with the random forest method based on 71 biopsies from 60 patients. The model-internal out-of-bag performance measure yielded perfect classification. Furthermore, the model was validated in independent 18 noninflamed biopsies from 18...... of random forest modeling of genome-wide gene expression data for distinguishing quiescent and active UC colonic mucosa versus control and CD colonic mucosa.(Inflamm Bowel Dis 2009)....

STAT3 signaling pathway is necessary for cell survival and tumorsphere forming capacity in ALDH+/CD133+ stem cell-like human colon cancer cells

International Nuclear Information System (INIS)

Lin, Li; Fuchs, James; Li, Chenglong; Olson, Veronica; Bekaii-Saab, Tanios; Lin, Jiayuh

2011-01-01

Highlights: ► The phosphorylated or activated form of STAT3 was expressed in colon cancer stem-like cells. ► STAT3 inhibitor, FLLL32 inhibits P-STAT3 and STAT3 target genes in colon cancer stem-like cells. ► Inhibition of STAT3 resulted in decreased cell viability and reduced numbers of tumorspheres. ► STAT3 is required for survival and tumorsphere forming capacity in colon cancer stem-like cells. ► Targeting STAT3 in cancer stem-like cells may offer a novel treatment approach for colon cancer. -- Abstract: Persistent activation of Signal Transducers and Activators of Transcription 3 (STAT3) is frequently detected in colon cancer. Increasing evidence suggests the existence of a small population of colon cancer stem or cancer-initiating cells may be responsible for tumor initiation, metastasis, and resistance to chemotherapy and radiation. Whether STAT3 plays a role in colon cancer-initiating cells and the effect of STAT3 inhibition is still unknown. Flow cytometry was used to isolate colon cancer stem-like cells from three independent human colon cancer cell lines characterized by both aldehyde dehydrogenase (ALDH)-positive and CD133-positive subpopulation (ALDH + /CD133 + ). The effects of STAT3 inhibition in colon cancer stem-like cells were examined. The phosphorylated or activated form of STAT3 was expressed in colon cancer stem-like cells and was reduced by a STAT3-selective small molecular inhibitor, FLLL32. FLLL32 also inhibited the expression of potential STAT3 downstream target genes in colon cancer stem-like cells including survivin, Bcl-XL, as well as Notch-1, -3, and -4, which may be involved in stem cell function. Furthermore, FLLL32 inhibited cell viability and tumorsphere formation as well as induced cleaved caspase-3 in colon cancer stem-like cells. FLLL32 is more potent than curcumin as evidenced with lower IC50 in colon cancer stem-like cells. In summary, our results indicate that STAT3 is a novel therapeutic target in colon cancer stem

Protein-bound polysaccharide from Phellinus linteus inhibits tumor growth, invasion, and angiogenesis and alters Wnt/β-catenin in SW480 human colon cancer cells

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Park Hae-Duck

2011-07-01

Full Text Available Abstract Background Polysaccharides extracted from the Phellinus linteus (PL mushroom are known to possess anti-tumor effects. However, the molecular mechanisms responsible for the anti-tumor properties of PL remain to be explored. Experiments were carried out to unravel the anticancer effects of PL. Methods The anti-cancer effects of PL were examined in SW480 colon cancer cells by evaluating cell proliferation, invasion and matrix metallo-proteinase (MMP activity. The anti-angiogenic effects of PL were examined by assessing human umbilical vein endothelial cell (HUVEC proliferation and capillary tube formation. The in vivo effect of PL was evaluated in an athymic nude mouse SW480 tumor engraft model. Results PL (125-1000 μg/mL significantly inhibited cell proliferation and decreased β-catenin expression in SW480 cells. Expression of cyclin D1, one of the downstream-regulated genes of β-catenin, and T-cell factor/lymphocyte enhancer binding factor (TCF/LEF transcription activity were also significantly reduced by PL treatment. PL inhibited in vitro invasion and motility as well as the activity of MMP-9. In addition, PL treatment inhibited HUVEC proliferation and capillary tube formation. Tumor growth of SW480 cells implanted into nude mice was significantly decreased as a consequence of PL treatment, and tumor tissues from treated animals showed an increase in the apoptotic index and a decrease in β-catenin expression. Moreover, the proliferation index and microvessel density were significantly decreased. Conclusions These data suggest that PL suppresses tumor growth, invasion, and angiogenesis through the inhibition of Wnt/β-catenin signaling in certain colon cancer cells.

Management of colon stents based on Bernoulli's principle.

Science.gov (United States)

Uno, Yoshiharu

2017-03-01

The colonic self-expanding metal stent (SEMS) has been widely used for "bridge to surgery" and palliative therapy. However, if the spread of SEMS is insufficient, not only can a decompression effect not be obtained but also perforation and obstructive colitis can occur. The mechanism of occurrence of obstructive colitis and perforation was investigated by flow dynamics. Bernoulli's principle was applied, assuming that the cause of inflammation and perforation represented the pressure difference in the proximal lumen and stent. The variables considered were proximal lumen diameter, stent lumen diameter, flow rate into the proximal lumen, and fluid density. To model the right colon, the proximal lumen diameter was set at 50 mm. To model the left-side colon, the proximal lumen diameter was set at 30 mm. For both the right colon model and the left-side colon model, the difference in pressure between the proximal lumen and the stent was less than 20 mmHg, when the diameter of the stent lumen was 14 mm or more. Both the right colon model and the left-side colon model were 30 mmHg or more at 200 mL s -1 when the stent lumen was 10 mm or less. Even with an inflow rate of 90-110 mL s -1 , the pressure was 140 mmHg when the stent lumen diameter was 5 mm. In theory, in order to maintain the effectiveness of SEMS, it is necessary to keep the diameter of the stent lumen at 14 mm or more.

The Interleukin-6 inflammation pathway from cholesterol to aging – Role of statins, bisphosphonates and plant polyphenols in aging and age-related diseases

Directory of Open Access Journals (Sweden)

Omoigui Sota

2007-03-01

Full Text Available Abstract We describe the inflammation pathway from Cholesterol to Aging. Interleukin 6 mediated inflammation is implicated in age-related disorders including Atherosclerosis, Peripheral Vascular Disease, Coronary Artery Disease, Osteoporosis, Type 2 Diabetes, Dementia and Alzheimer's disease and some forms of Arthritis and Cancer. Statins and Bisphosphonates inhibit Interleukin 6 mediated inflammation indirectly through regulation of endogenous cholesterol synthesis and isoprenoid depletion. Polyphenolic compounds found in plants, fruits and vegetables inhibit Interleukin 6 mediated inflammation by direct inhibition of the signal transduction pathway. Therapeutic targets for the control of all the above diseases should include inhibition of Interleukin-6 mediated inflammation.

Azithromycin and erythromycin ameliorate the extent of colonic damage induced by acetic acid in rats

International Nuclear Information System (INIS)

Mahgoub, Afaf; El-Medany, Azza; Mustafa, Ali; Arafah, Maha; Moursi, Mahmoud

2005-01-01

Ulcerative colitis is a common inflammatory bowel disease (IBD) of unknown etiology. Recent studies have revealed the role of some microorganisms in the initiation and perpetuation of IBD. The role of antibiotics in the possible modulation of colon inflammation is still uncertain. In this study, we evaluated the effects of two macrolides, namely azithromycin and erythromycin, at different doses on the extent and severity of ulcerative colitis caused by intracolonic administration of 3% acetic acid in rats. The lesions and the inflammatory response were assessed by histology and measurement of myeloperoxidase (MPO) activity, nitric oxide synthetase (NOS) and tumor necrosis factor alpha (TNFα) in colonic tissues. Inflammation following acetic acid instillation was characterized by oedema, diffuse inflammatory cell infiltration and necrosis. Increase in MPO, NOS and TNFα was detected in the colonic tissues. Administration of either azithromycin or erythromycin at different dosage (10, 20 and 40 mg/kg orally, daily for 5 consecutive days) significantly (P < 0.05) reduced the colonic damage, MPO and NOS activities as well as TNFα level. This reduction was highly significant with azithromycin when given at a dose of 40 mg/kg. It is concluded that azithromycin and erythromycin may have a beneficial therapeutic role in ulcerative colitis

Diverticular colitis of the ascending colon preceding the onset of ulcerative colitis.

Science.gov (United States)

Maeshiro, Tatsuji; Hokama, Akira; Kinjo, Tetsu; Fujita, Jiro

2014-06-30

We present a case of diverticular colitis of the ascending colon preceding the onset of ulcerative colitis. A 58-year-old man presented with positive faecal occult blood test. Colonoscopy disclosed diverticular colitis of the ascending colon. After a year's follow-up, typical ulcerative colitis developed and diverticular colitis improved. Diverticular colitis is a newly established disorder of chronic segmental mucosal inflammation affected by diverticular disease. There is increasing recognition of such cases with diverticular colitis preceding ulcerative colitis. There may be a possible pathogenic relationship between the two diseases. 2014 BMJ Publishing Group Ltd.

Ketamine Exhibits Different Neuroanatomical Profile After Mammalian Target of Rapamycin Inhibition in the Prefrontal Cortex: the Role of Inflammation and Oxidative Stress.

Science.gov (United States)

Abelaira, Helena M; Réus, Gislaine Z; Ignácio, Zuleide M; Dos Santos, Maria Augusta B; de Moura, Airam B; Matos, Danyela; Demo, Júlia P; da Silva, Júlia B I; Danielski, Lucineia G; Petronilho, Fabricia; Carvalho, André F; Quevedo, João

2017-09-01

Studies indicated that mammalian target of rapamycin (mTOR), oxidative stress, and inflammation are involved in the pathophysiology of major depressive disorder (MDD). Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been identified as a novel MDD therapy; however, the antidepressant mechanism is not fully understood. In addition, the effects of ketamine after mTOR inhibition have not been fully investigated. In the present study, we examined the behavioral and biochemical effects of ketamine in the prefrontal cortex (PFC), hippocampus, amygdala, and nucleus accumbens after inhibition of mTOR signaling in the PFC. Male adult Wistar rats received pharmacological mTOR inhibitor, rapamycin (0.2 nmol) or vehicle into the PFC and then a single dose of ketamine (15 mg/kg, i.p.). Immobility was assessed in forced swimming tests, and then oxidative stress parameters and inflammatory markers were evaluated in the brain and periphery. mTOR activation in the PFC was essential to ketamine's antidepressant-like effects. Ketamine increased lipid damage in the PFC, hippocampus, and amygdala. Protein carbonyl was elevated in the PFC, amygdala, and NAc after ketamine administration. Ketamine also increased nitrite/nitrate in the PFC, hippocampus, amygdala, and NAc. Myeloperoxidase activity increased in the hippocampus and NAc after ketamine administration. The activities of superoxide dismutase and catalase were reduced after ketamine administration in all brain areas studied. Inhibition of mTOR signaling pathways by rapamycin in the PFC was required to protect against oxidative stress by reducing damage and increasing antioxidant enzymes. Finally, the TNF-α level was increased in serum by ketamine; however, the rapamycin plus treatment group was not able to block this increase. Activation of mTOR in the PFC is involved in the antidepressant-like effects of ketamine; however, the inhibition of this pathway was able to protect certain brain areas against

Docosahexaenoic acid ester of phloridzin inhibit lipopolysaccharide-induced inflammation in THP-1 differentiated macrophages.

Science.gov (United States)

Sekhon-Loodu, Satvir; Ziaullah; Rupasinghe, H P Vasantha

2015-03-01

Phloridzin or phlorizin (PZ) is a predominant phenolic compound found in apple and also used in various natural health products. Phloridzin shows poor absorption and cellular uptake due to its hydrophilic nature. The aim was to investigate and compare the effect of docosahexaenoic acid (DHA) ester of PZ (PZ-DHA) and its parent compounds (phloridzin and DHA), phloretin (the aglycone of PZ) and cyclooxygenase inhibitory drugs (diclofenac and nimesulide) on production of pro-inflammatory biomarkers in inflammation-induced macrophages by lipopolysaccharide (LPS)-stimulation. Human THP-1 monocytes were seeded in 24-well plates (5×10(5)/well) and treated with phorbol 12-myristate 13-acetate (PMA, 0.1μg/mL) for 48h to induce macrophage differentiation. After 48h, the differentiated macrophages were washed with Hank's buffer and treated with various concentrations of test compounds for 4h, followed by the LPS-stimulation (18h). Pre-exposure of PZ-DHA ester was more effective in reducing tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2) protein levels compared to DHA and nimesulide. However, diclofenac was the most effective in reducing prostaglandin (PGE2) level by depicting a dose-dependent response. However, PZ-DHA ester and DHA were the most effective in inhibiting the activation of nuclear factor-kappa B (NF-κB) among other test compounds. Our results suggest that PZ-DHA ester might possess potential therapeutic activity to treat inflammation related disorders such as type 2 diabetes, asthma, atherosclerosis and inflammatory bowel disease. Copyright © 2015 Elsevier B.V. All rights reserved.

Overexpression of Long Non-Coding RNA TUG1 Promotes Colon Cancer Progression.

Science.gov (United States)

Zhai, Hui-Yuan; Sui, Ming-Hua; Yu, Xiao; Qu, Zhen; Hu, Jin-Chen; Sun, Hai-Qing; Zheng, Hai-Tao; Zhou, Kai; Jiang, Li-Xin

2016-09-16

BACKGROUND Colon cancer is one of the most prevalent and deadly cancers worldwide. It is still necessary to further define the mechanisms and explore therapeutic targets of colon cancer. Dysregulation of long noncoding RNAs (lncRNAs) has been shown to be correlated with diverse biological processes, including tumorigenesis. This study aimed to characterize the biological mechanism of taurine-upregulated gene 1 (TUG1) in colon cancer. MATERIAL AND METHODS qRT-PCR was used to analyze the expression level of TUG1 and p63 in 75 colon cancer tissues and the matched adjacent non-tumor tissue. In vitro, cultured colon cancer cell lines HCT-116 and LoVo were used as cell models. TUG1 and p63 were silenced via transferring siRNA into HCT-116 or LoVo. The effects of TUG1 were investigated by examining cell proliferation, apoptosis, and migration. RESULTS Among the 75 colon cancer cases, the expression of TUG1 was significantly higher in colon cancer tissues compared with the matched adjacent non-tumor tissue, while p63 expression was lower in the tumor tissue. In HCT-116 and LoVo, the expression of TUG1 was significantly increased by p63 siRNA transfection. Furthermore, down-regulation of TUG1 by siRNA significantly inhibited the cell proliferation and promoted colon cancer cell apoptosis. In addition, inhibition of TUG1 expression significantly blocked the cell migration ability of colon cancer cells. CONCLUSIONS LncRNA TUG1 may serve as a potential oncogene for colon cancer. Overexpressed TUG1 may contribute to promoting cell proliferation and migration in colon cancer cells.

Streptococcus agalactiae Inhibits Candida albicans Hyphal Development and Diminishes Host Vaginal Mucosal TH17 Response

Directory of Open Access Journals (Sweden)

Xiao-Yu Yu

2018-02-01

Full Text Available Streptococcus agalactiae and Candida albicans often co-colonize the female genital tract, and under certain conditions induce mucosal inflammation. The role of the interaction between the two organisms in candidal vaginitis is not known. In this study, we found that co-infection with S. agalactiae significantly attenuated the hyphal development of C. albicans, and that EFG1-Hwp1 signal pathway of C. albicans was involved in this process. In a mouse model of vulvovaginal candidiasis (VVC, the fungal burden and the levels of pro-inflammatory cytokines, IL-1β, IL-6 and TNF-α showed a increase on co-infection with S. agalactiae, while the level of TH17 T cells and IL-17 in the cervicovaginal lavage fluid were significantly decreased. Our results indicate that S. agalactiae inhibits C. albicans hyphal development by downregulating the expression of EFG1-Hwp1. The interaction between S. agalactiae and C. albicans may attenuate host vaginal mucosal TH17 immunity and contribute to mucosal colonization by C. albicans.

A characterization of anaerobic colonization and associated mucosal adaptations in the undiseased ileal pouch.

LENUS (Irish Health Repository)

Smith, F M

2012-02-03

INTRODUCTION: The resolution of pouchitis with metronidazole points to an anaerobic aetiology. Pouchitis is mainly seen in patients with ulcerative colitis pouches (UCP). We have recently found that sulphate reducing bacteria (SRB), a species of strict anaerobe, colonize UCP exclusively. Herein, we aimed to correlate levels of different bacterial species (including SRB) with mucosal inflammation and morphology. METHODS: Following ethical approval, fresh faecal samples and mucosal biopsies were taken from 9 patients with UCP and 5 patients with familial adenomatous polyposis pouches (FAPP). For the purposes of comparison, faecal samples and mucosal biopsies were also taken from the stomas of 7 of the 9 patients with UC (UCS). Colonization by four types of strict anaerobes (SRB, Clostridium perfringens, Bifidobacteria and Bacteroides) as well as by three types of facultative anaerobes (Enterococci, Coliforms and Lactobacilli) was evaluated. Inflammatory scores and mucosal morphology were assessed histologically in a blinded fashion by a pathologist. RESULTS: In general, strict anaerobes predominated over facultative in the UCP (P = 0.041). SRB were present in UCP exclusively. Even after exclusion of SRB from total bacterial counts, strict anaerobes still predominated. In the UCS, facultative anaerobes predominated. Strict and facultative anaerobes were present at similar levels in the FAPP. Enterococci were present at significantly reduced levels in the UCP when compared with the UCS (P = 0.031). When levels of SRB and other anaerobic species were individually correlated with mucosal inflammation and morphology, no trends were observed. CONCLUSION: We have previously identified that SRB exclusively colonize UCP. In addition we have now identified a novel increase in the strict\\/facultative anaerobic ratio within the UCP compared to UCS. These stark differences in bacterial colonization, however, appear to have limited impact on mucosal inflammation or morphology.

The α-cyclodextrin complex of the Moringa isothiocyanate suppresses lipopolysaccharide-induced inflammation in RAW 264.7 macrophage cells through Akt and p38 inhibition.

Science.gov (United States)

Giacoppo, Sabrina; Rajan, Thangavelu Soundara; Iori, Renato; Rollin, Patrick; Bramanti, Placido; Mazzon, Emanuela

2017-06-01

In the last decades, a growing need to discover new compounds for the prevention and treatment of inflammatory diseases has led researchers to consider drugs derived from natural products as a valid option in the treatment of inflammation-associated disorders. The purpose of the present study was to investigate the anti-inflammatory effects of a new formulation of Moringa oleifera-derived 4-(α-L-rhamnopyranosyloxy)benzyl isothiocyanate as a complex with alpha-cyclodextrin (moringin + α-CD) on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells, a common model used for inflammation studies. In buffered/aqueous solution, the moringin + α-CD complex has enhanced the water solubility and stability of this isothiocyanate by forming a stable inclusion system. Our results showed that moringin + α-CD inhibits the production of inflammatory mediators in LPS-stimulated macrophages by down-regulation of pro-inflammatory cytokines (TNF-α and IL-1β), by preventing IκB-α phosphorylation, translocation of the nuclear factor-κB (NF-κB), and also via the suppression of Akt and p38 phosphorylation. In addition, as a consequence of upstream inhibition of the inflammatory pathway following treatment with moringin + α-CD, the modulation of the oxidative stress (results focused on the expression of iNOS and nitrotyrosine) and apoptotic pathway (Bax and Bcl-2) was demonstrated. Therefore, moringin + α-CD appears to be a new relevant helpful tool to use in clinical practice for inflammation-associated disorders.

Noscapine induces mitochondria-mediated apoptosis in human colon cancer cells in vivo and in vitro

International Nuclear Information System (INIS)

Yang, Zi-Rong; Liu, Meng; Peng, Xiu-Lan; Lei, Xiao-Fei; Zhang, Ji-Xiang; Dong, Wei-Guo

2012-01-01

Highlights: ► Noscapine inhibited cell viability of colon cancer in a time- and dose- dependent manner. ► G 2 /M phase arrest and chromatin condensation and nuclear fragmentation were induced. ► Noscapine promoted apoptosis via mitochondrial pathways. ► Tumorigenicity was inhibited by noscapine. -- Abstract: Noscapine, a phthalide isoquinoline alkaloid derived from opium, has been widely used as a cough suppressant for decades. Noscapine has recently been shown to potentiate the anti-cancer effects of several therapies by inducing apoptosis in various malignant cells without any detectable toxicity in cells or tissues. However, the mechanism by which noscapine induces apoptosis in colon cancer cells remains unclear. The signaling pathways by which noscapine induces apoptosis were investigated in colon cancer cell lines treated with various noscapine concentrations for 72 h, and a dose-dependent inhibition of cell viability was observed. Noscapine effectively inhibited the proliferation of LoVo cells in vitro (IC 50 = 75 μM). This cytotoxicity was reflected by cell cycle arrest at G 2 /M and subsequent apoptosis, as indicated by increased chromatin condensation and fragmentation, the upregulation of Bax and cytochrome c (Cyt-c), the downregulation of survivin and Bcl-2, and the activation of caspase-3 and caspase-9. Moreover, in a xenograft tumor model in mice, noscapine injection clearly inhibited tumor growth via the induction of apoptosis, which was demonstrated using a TUNEL assay. These results suggest that noscapine induces apoptosis in colon cancer cells via mitochondrial pathways. Noscapine may be a safe and effective chemotherapeutic agent for the treatment of human colon cancer.

NoxO1 Controls Proliferation of Colon Epithelial Cells

Directory of Open Access Journals (Sweden)

Franziska Moll

2018-05-01

Full Text Available AimReactive oxygen species (ROS produced by enzymes of the NADPH oxidase family serve as second messengers for cellular signaling. Processes such as differentiation and proliferation are regulated by NADPH oxidases. In the intestine, due to the exceedingly fast and constant renewal of the epithelium both processes have to be highly controlled and balanced. Nox1 is the major NADPH oxidase expressed in the gut, and its function is regulated by cytosolic subunits such as NoxO1. We hypothesize that the NoxO1-controlled activity of Nox1 contributes to a proper epithelial homeostasis and renewal in the gut.ResultsNoxO1 is highly expressed in the colon. Knockout of NoxO1 reduces the production of superoxide in colon crypts and is not subsidized by an elevated expression of its homolog p47phox. Knockout of NoxO1 increases the proliferative capacity and prevents apoptosis of colon epithelial cells. In mouse models of dextran sulfate sodium (DSS-induced colitis and azoxymethane/DSS induced colon cancer, NoxO1 has a protective role and may influence the population of natural killer cells.ConclusionNoxO1 affects colon epithelium homeostasis and prevents inflammation.

Piroxicam decreases postirradiation colonic neoplasia in the rat.

Science.gov (United States)

Northway, M G; Scobey, M W; Cassidy, K T; Geisinger, K R

1990-12-01

This study evaluated the effects of the nonsteroidal antiinflammatory agent piroxicam on chronic radiation proctitis in the rat. Forty female Wistar rats received a 2250-cGy dose of irradiation to the distal 2 cm of the colon. Twenty received piroxicam 8.0 mg/kg orally 30 minutes before exposure and 24 hours after exposure; 20 rats served as irradiated controls. All animals were evaluated by colonoscopy 1 and 3 weeks postexposure and every third week until death or killing at 1 year. At killing, colons were removed for light microscopic examination. One year postirradiation results showed no differences in mortality, vascular changes, acute inflammation, colitis cystica profunda, or rectal stricture between the control and piroxicam-treated groups. However, at 1 year postirradiation the control group demonstrated neoplasia in 15 of 19 animals compared with eight of 20 animals in the piroxicam-treated group. The first endoscopic appearance of colonic neoplasm occurred at 15 weeks postirradiation in one control irradiated rat whereas the first evidence of endoscopic neoplasm in the piroxicam-treated group did not occur until 36 weeks postirradiation. Histologic examination documented a tendency toward a greater presence of adenocarcinomas in the control group compared with the piroxicam-treated group. The authors conclude that piroxicam treatment significantly decreased the incidence of colonic neoplasia in general as well as delayed the endoscopic appearance of colonic neoplasia in rats after pelvic irradiation.

Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease

Science.gov (United States)

Zhang, Liping; Rajan, Vik; Lin, Eugene; Hu, Zhaoyong; Han, H. Q.; Zhou, Xiaolan; Song, Yanping; Min, Hosung; Wang, Xiaonan; Du, Jie; Mitch, William E.

2011-01-01

Chronic kidney disease (CKD) and several other catabolic conditions are characterized by increased circulating inflammatory cytokines, defects in IGF-1 signaling, abnormal muscle protein metabolism, and progressive muscle atrophy. In these conditions, no reliable treatments successfully block the development of muscle atrophy. In mice with CKD, we found a 2- to 3-fold increase in myostatin expression in muscle. Its pharmacological inhibition by subcutaneous injections of an anti-myostatin peptibody into CKD mice (IC50 ∼1.2 nM) reversed the loss of body weight (≈5–7% increase in body mass) and muscle mass (∼10% increase in muscle mass) and suppressed circulating inflammatory cytokines vs. results from CKD mice injected with PBS. Pharmacological myostatin inhibition also decreased the rate of protein degradation (16.38±1.29%; Pmyostatin expression via a NF-κB-dependent pathway, whereas muscle cells exposed to myostatin stimulated IL-6 production via p38 MAPK and MEK1 pathways. Because IL-6 stimulates muscle protein breakdown, we conclude that CKD increases myostatin through cytokine-activated pathways, leading to muscle atrophy. Myostatin antagonism might become a therapeutic strategy for improving muscle growth in CKD and other conditions with similar characteristics.—Zhang, L., Rajan, V., Lin, E., Hu, Z., Han, H.Q., Zhou, X., Song, Y., Min, H., Wang, X., Du, J., Mitch, W. E. Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease. PMID:21282204

Management of colonic diverticular disease with poorly absorbed antibiotics and other therapies

Science.gov (United States)

Sopeña, Federico; Lanas, Angel

2011-01-01

Colonic diverticular disease is common in Western countries and its prevalence increases with age. The large majority of patients (80–85%) will remain entirely asymptomatic throughout their life. In symptomatic cases, most patients will have diverticulosis without inflammation while the remainder will have diverticulitis with or without complications. About 1–2% will require hospitalization and 0.5% will require surgery. Factors predicting the development of symptoms remain to be identified. However, it is generally recognized that diverticular disease is probably related to complex interactions between colon structure, intestinal motility, diet, and genetic features. Epidemiologic studies have demonstrated an association between diverticulosis and diets that are low in fiber and high in refined carbohydrates. Although the causes of symptom development are still unclear, it is thought that previous episodes of intestinal inflammation may play a role. Changes in intestinal microflora could be one of the putative mechanisms responsible for low-grade inflammation. In patients with uncomplicated diverticulosis, a diet abundant in fruit and vegetables is recommended. The current therapeutic approaches in preventing recurrence of symptoms are based on nonabsorbable antibiotics, mesalazine, and/or probiotics. Cyclic rifaximin administration seems to be an adequate approach to relieving symptoms and preventing acute diverticulitis in patients with symptomatic diverticulosis. PMID:22043229

Malignant transformation of colonic epithelial cells by a colon-derived long noncoding RNA

International Nuclear Information System (INIS)

Franklin, Jeffrey L.; Rankin, Carl R.; Levy, Shawn; Snoddy, Jay R.; Zhang, Bing; Washington, Mary Kay; Thomson, J. Michael; Whitehead, Robert H.; Coffey, Robert J.

2013-01-01

Highlights: •Non-coding RNAs are found in the colonic crypt progenitor compartment. •Colonocytes transformed by ncNRFR are highly invasive and metastatic. •ncNRFR has a region similar to the miRNA, let-7 family. •ncNRFR expression alters let-7 activity as measured by reporter construct. •ncNRFR expression upregulates let-7b targets. -- Abstract: Recent progress has been made in the identification of protein-coding genes and miRNAs that are expressed in and alter the behavior of colonic epithelia. However, the role of long non-coding RNAs (lncRNAs) in colonic homeostasis is just beginning to be explored. By gene expression profiling of post-mitotic, differentiated tops and proliferative, progenitor-compartment bottoms of microdissected adult mouse colonic crypts, we identified several lncRNAs more highly expressed in crypt bottoms. One identified lncRNA, designated non-coding Nras functional RNA (ncNRFR), resides within the Nras locus but appears to be independent of the Nras coding transcript. Stable overexpression of ncNRFR in non-transformed, conditionally immortalized mouse colonocytes results in malignant transformation, as determined by growth in soft agar and formation of highly invasive tumors in nude mice. Moreover, ncNRFR appears to inhibit the function of the tumor suppressor let-7. These results suggest precise regulation of ncNRFR is necessary for proper cell growth in the colonic crypt, and its misregulation results in neoplastic transformation

The Carcinogenic Agent Azoxymethane (AOM) Enhances Early Inflammation-induced Colon Crypt Pathology

DEFF Research Database (Denmark)

Venning, Freja Albjerg; Claesson, Mogens Helweg; Kissow, Hannelouise

2013-01-01

Severe combined immunodeficiency (SCID) mice transplanted with CD4+ T cells depleted of CD25+ regulatory T cells develop colitis within 2-3 weeks after the T cell transfer. In the present study we studied the effect of the carcinogen azoxymethane (AOM) on the colon crypt pathology of normal SCID...

Loss of hepatocyte-nuclear-factor-4alpha affects colonic ion transport and causes chronic inflammation resembling inflammatory bowel disease in mice.

Directory of Open Access Journals (Sweden)

Mathieu Darsigny

Full Text Available BACKGROUND: Hnf4alpha, an epithelial specific transcriptional regulator, is decreased in inflammatory bowel disease and protects against chemically-induced colitis in mice. However, the precise role of this factor in maintaining normal inflammatory homeostasis of the intestine remains unclear. The aim of this study was to evaluate the sole role of epithelial Hnf4alpha in the maintenance of gut inflammatory homeostasis in mice. METHODOLOGY/PRINCIPAL FINDINGS: We show here that specific epithelial deletion of Hnf4alpha in mice causes spontaneous chronic intestinal inflammation leading to focal areas of crypt dropout, increased cytokines and chemokines secretion, immune cell infiltrates and crypt hyperplasia. A gene profiling analysis in diseased Hnf4alpha null colon confirms profound genetic changes in cell death and proliferative behaviour related to cancer. Among the genes involved in the immune protection through epithelial barrier function, we identify the ion transporter claudin-15 to be down-modulated early in the colon of Hnf4alpha mutants. This coincides with a significant decrease of mucosal ion transport but not of barrier permeability in young animals prior to the manifestation of the disease. We confirm that claudin-15 is a direct Hnf4alpha gene target in the intestinal epithelial context and is down-modulated in mouse experimental colitis and inflammatory bowel disease. CONCLUSION: Our results highlight the critical role of Hnf4alpha to maintain intestinal inflammatory homeostasis during mouse adult life and uncover a novel function for Hnf4alpha in the regulation of claudin-15 expression. This establishes Hnf4alpha as a mediator of ion epithelial transport, an important process for the maintenance of gut inflammatory homeostasis.

Effect of entacapone on colon motility and ion transport in a rat model of Parkinson’s disease

Science.gov (United States)

Li, Li-Sheng; Liu, Chen-Zhe; Xu, Jing-Dong; Zheng, Li-Fei; Feng, Xiao-Yan; Zhang, Yue; Zhu, Jin-Xia

2015-01-01

AIM: To study the effects of entacapone, a catechol-O-methyltransferase inhibitor, on colon motility and electrolyte transport in Parkinson’s disease (PD) rats. METHODS: Distribution and expression of catechol-O-methyltransferase (COMT) were measured by immunohistochemistry and Western blotting methods. The colonic smooth muscle motility was examined in vitro by means of a muscle motility recording device. The mucosal electrolyte transport of PD rats was examined by using a short-circuit current (ISC) technique and scanning ion-selective electrode technique (SIET). Intracellular detection of cAMP and cGMP was accomplished by radioimmunoassay testing. RESULTS: COMT was expressed in the colons of both normal and PD rats, mainly on the apical membranes of villi and crypts in the colon. Compared to normal controls, PD rats expressed less COMT. The COMT inhibitor entacapone inhibited contraction of the PD rat longitudinal muscle in a dose-dependent manner. The β2 adrenoceptor antagonist ICI-118,551 blocked this inhibitory effect by approximately 67% (P fluid, as well as pretreatment using adenylate cyclase inhibitor MDL12330A. As an inhibitor of prostaglandin synthetase, indomethacin can inhibit entacapone-induced ISC by 45% (P < 0.01). When SIET was applied to measure Cl- flux changes, this provided similar results. Entacapone significantly increased intracellular cAMP content in the colonic mucosa, which was greatly inhibited by indomethacin. CONCLUSION: COMT expression exists in rat colons. The β2 adrenoceptor is involved in the entacapone-induced inhibition of colon motility. Entacapone induces cAMP-dependent Cl- secretion in the PD rat. PMID:25834315

Nasal bacterial colonization in cases of idiopathic epistaxis in children.

Science.gov (United States)

Kamble, Payal; Saxena, Sonal; Kumar, Sunil

2015-11-01

To evaluate the role of nasal bacterial colonization in cases of idiopathic epistaxis in children. A descriptive, hospital based, observational study in our hospital was conducted on total 112 pediatric patients in the age group 4-16 years. Group A (control): 56 patients with no epistaxis; Group B (epistaxis): 56 patients with idiopathic epistaxis. A swab for microbiological evaluation was taken from the anterior nasal cavity of each child. A highly significant association between nasal colonization with pathological Staphylococcus aureus and idiopathic epistaxis was found. The presence of pathological S. aureus colonization in the anterior nasal cavity was also associated with statistically significant number of crusting and presence of dilated blood vessels on the anterior nasal septum of children in epistaxis group. Nasal bacterial colonization with S. aureus leads to a sequence of pathological events i.e. low grade inflammation, crusting and new vessel formation. This leads to irritation in nasal cavity resulting in digital trauma and subsequently epistaxis and thus it plays an important role in causing idiopathic epistaxis in children. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Titanocene–Gold Complexes Containing N-Heterocyclic Carbene Ligands Inhibit Growth of Prostate, Renal, and Colon Cancers in Vitro

Science.gov (United States)

2016-01-01

We report on the synthesis, characterization, and stability studies of new titanocene complexes containing a methyl group and a carboxylate ligand (mba = −OC(O)-p-C6H4-S−) bound to gold(I)–N-heterocyclic carbene fragments through the thiolate group: [(η5-C5H5)2TiMe(μ-mba)Au(NHC)]. The cytotoxicities of the heterometallic compounds along with those of novel monometallic gold–N-heterocyclic carbene precursors [(NHC)Au(mbaH)] have been evaluated against renal, prostate, colon, and breast cancer cell lines. The highest activity and selectivity and a synergistic effect of the resulting heterometallic species was found for the prostate and colon cancer cell lines. The colocalization of both titanium and gold metals (1:1 ratio) in PC3 prostate cancer cells was demonstrated for the selected compound 5a, indicating the robustness of the heterometallic compound in vitro. We describe here preliminary mechanistic data involving studies on the interaction of selected mono- and bimetallic compounds with plasmid (pBR322) used as a model nucleic acid and the inhibition of thioredoxin reductase in PC3 prostate cancer cells. The heterometallic compounds, which are highly apoptotic, exhibit strong antimigratory effects on the prostate cancer cell line PC3. PMID:27182101

Diverticular disease of the right colon

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Boutross-Tadross Odette

2011-10-01

Full Text Available Abstract Background The incidence of colonic diverticular disease varies with national origin, cultural background and diet. The frequency of this disease increases with advancing age. Right-sided diverticular disease is uncommon and reported to occur in 1-2% of surgical specimens in European and American series. In contrast the disease is more prevalent and reported in 43-50% of specimens in Asian series. Various lines of evidence suggest this variation may represent hereditary differences. The aim of the study is to report all cases of right sided diverticular disease underwent surgical resection or identified during pathological examination of right hemicoloectomy specimens Methods A retrospective review of all surgical specimens with right sided colonic diverticular disease selected from a larger database of all colonic diverticulosis and diverticulitis surgical specimen reported between January 1993 and December 2010 at the Pathology Department McMaster University Medical Centre Canada. The clinical and pathological features of these cases were reviewed Results The review identified 15 cases of right colon diverticulosis. The clinical diagnoses of these cases were appendicitis, diverticulitis or adenocarcinoma. Eight cases of single congenital perforated diverticuli were identified and seven cases were incidental multiple acquired diverticuli found in specimen resected for right side colonic carcinomas/large adenomas. Laparotomy or laparoscopic assisted haemicolectomies were done for all cases. Pathological examination showed caecal wall thickening with inflammation associated with perforated diverticuli. Histology confirmed true solitary diverticuli that exhibited in two cases thick walled vessels in the submucosa and muscular layer indicating vascular malformation/angiodysplasia. Acquired diverticuli tend to be multiple and are mostly seen in specimens resected for neoplastic right colon diseases. Conclusion Single true diverticular

Diverticular disease of the right colon.

Science.gov (United States)

Radhi, Jasim M; Ramsay, Jennifer A; Boutross-Tadross, Odette

2011-10-06

The incidence of colonic diverticular disease varies with national origin, cultural background and diet. The frequency of this disease increases with advancing age. Right-sided diverticular disease is uncommon and reported to occur in 1-2% of surgical specimens in European and American series. In contrast the disease is more prevalent and reported in 43-50% of specimens in Asian series. Various lines of evidence suggest this variation may represent hereditary differences. The aim of the study is to report all cases of right sided diverticular disease underwent surgical resection or identified during pathological examination of right hemicoloectomy specimens A retrospective review of all surgical specimens with right sided colonic diverticular disease selected from a larger database of all colonic diverticulosis and diverticulitis surgical specimen reported between January 1993 and December 2010 at the Pathology Department McMaster University Medical Centre Canada. The clinical and pathological features of these cases were reviewed The review identified 15 cases of right colon diverticulosis. The clinical diagnoses of these cases were appendicitis, diverticulitis or adenocarcinoma. Eight cases of single congenital perforated diverticuli were identified and seven cases were incidental multiple acquired diverticuli found in specimen resected for right side colonic carcinomas/large adenomas. Laparotomy or laparoscopic assisted haemicolectomies were done for all cases. Pathological examination showed caecal wall thickening with inflammation associated with perforated diverticuli. Histology confirmed true solitary diverticuli that exhibited in two cases thick walled vessels in the submucosa and muscular layer indicating vascular malformation/angiodysplasia. Acquired diverticuli tend to be multiple and are mostly seen in specimens resected for neoplastic right colon diseases. Single true diverticular disease of the right colon is usually of congenital type and affects

STAT3 signaling pathway is necessary for cell survival and tumorsphere forming capacity in ALDH{sup +}/CD133{sup +} stem cell-like human colon cancer cells

Energy Technology Data Exchange (ETDEWEB)

Lin, Li, E-mail: lin.796@osu.edu [Center for Childhood Cancer, The Research Institute at Nationwide Children' s Hospital, Department of Pediatrics, Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43205 (United States); Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030 (China); Fuchs, James; Li, Chenglong [Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210 (United States); Olson, Veronica [Center for Childhood Cancer, The Research Institute at Nationwide Children' s Hospital, Department of Pediatrics, Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43205 (United States); Bekaii-Saab, Tanios [Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43210 (United States); Lin, Jiayuh, E-mail: lin.674@osu.edu [Center for Childhood Cancer, The Research Institute at Nationwide Children' s Hospital, Department of Pediatrics, Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43205 (United States)

2011-12-16

Highlights: Black-Right-Pointing-Pointer The phosphorylated or activated form of STAT3 was expressed in colon cancer stem-like cells. Black-Right-Pointing-Pointer STAT3 inhibitor, FLLL32 inhibits P-STAT3 and STAT3 target genes in colon cancer stem-like cells. Black-Right-Pointing-Pointer Inhibition of STAT3 resulted in decreased cell viability and reduced numbers of tumorspheres. Black-Right-Pointing-Pointer STAT3 is required for survival and tumorsphere forming capacity in colon cancer stem-like cells. Black-Right-Pointing-Pointer Targeting STAT3 in cancer stem-like cells may offer a novel treatment approach for colon cancer. -- Abstract: Persistent activation of Signal Transducers and Activators of Transcription 3 (STAT3) is frequently detected in colon cancer. Increasing evidence suggests the existence of a small population of colon cancer stem or cancer-initiating cells may be responsible for tumor initiation, metastasis, and resistance to chemotherapy and radiation. Whether STAT3 plays a role in colon cancer-initiating cells and the effect of STAT3 inhibition is still unknown. Flow cytometry was used to isolate colon cancer stem-like cells from three independent human colon cancer cell lines characterized by both aldehyde dehydrogenase (ALDH)-positive and CD133-positive subpopulation (ALDH{sup +}/CD133{sup +}). The effects of STAT3 inhibition in colon cancer stem-like cells were examined. The phosphorylated or activated form of STAT3 was expressed in colon cancer stem-like cells and was reduced by a STAT3-selective small molecular inhibitor, FLLL32. FLLL32 also inhibited the expression of potential STAT3 downstream target genes in colon cancer stem-like cells including survivin, Bcl-XL, as well as Notch-1, -3, and -4, which may be involved in stem cell function. Furthermore, FLLL32 inhibited cell viability and tumorsphere formation as well as induced cleaved caspase-3 in colon cancer stem-like cells. FLLL32 is more potent than curcumin as evidenced with lower

The influence of androgens, anti-androgens, and castration on cell proliferation in the jejunal and colonic crypt epithelia, and in dimethylhydrazine-induced adenocarcinoma of rat colon.

Science.gov (United States)

Tutton, P J; Barkla, D H

1982-01-01

Androgenic hormones have previously been shown to promote cell proliferation in the small intestine of rat and androgen receptors have been demonstrated in carcinomata of the large intestine of rat. In this study the influence of testosterone and of castration on epithelial cell proliferation in the small intestine, the large intestine and in dimethylhydrazine-induced colonic tumours is compared. Cell proliferation in the small intestine and in colonic tumours was accelerated by testosterone treatment, and cell proliferation in colonic tumours, but not in the small intestine, was retarded following castration. Cell proliferation in colonic tumours was also inhibited by the anti-androgenic drug, Flutamide. Testosterone and castration each failed to influence cell proliferation in the colonic crypt epithelium of both normal and carcinogen-treated animals.

Nanoparticles containing a liver X receptor agonist inhibit inflammation and atherosclerosis.

Science.gov (United States)

Zhang, Xue-Qing; Even-Or, Orli; Xu, Xiaoyang; van Rosmalen, Mariska; Lim, Lucas; Gadde, Suresh; Farokhzad, Omid C; Fisher, Edward A

2015-01-28

Liver X receptor (LXR) signaling pathways regulate lipid metabolism and inflammation, which has generated widespread interest in developing synthetic LXR agonists as potential therapeutics for the management of atherosclerosis. In this study, it is demonstrated that nanoparticles (NPs) containing the synthetic LXR agonist GW3965 (NP-LXR) exert anti-inflammatory effects and inhibit the development of atherosclerosis without causing hepatic steatosis. These NPs are engineered through self-assembly of a biodegradable diblock poly(lactide-co-glycolide)-b-poly(ethylene glycol) (PLGA-b-PEG) copolymer. NP-LXR is significantly more effective than free GW3965 at inducing LXR-target gene expression and suppressing inflammatory factors in macrophages in vitro and in vivo. Additionally, the NPs elicit negligible lipogenic gene stimulation in the liver. Using the Ldlr (-/-) mouse model of atherosclerosis, abundant colocalization of fluorescently labeled NPs within plaque macrophages following systemic administration is seen. Notably, six intravenous injections of NP-LXR over 2 weeks markedly reduce the CD68-positive cell (macrophage) content of plaques (by 50%) without increasing total cholesterol or triglycerides in the liver and plasma. Together, these findings identify GW3965-encapsulated PLGA-b-PEG NPs as a promising nanotherapeutic approach to combat atherosclerosis, providing the benefits of LXR agonists without their adverse effects on hepatic and plasma lipid metabolism. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Low concentration of copper inhibits colonization of soil by the arbuscular mycorrhizal fungus Glomus intraradices and radically changes the microbial community structure

DEFF Research Database (Denmark)

Hagerberg, David; Manique, Nina; Brandt, Kristian K.

2011-01-01

. To avoid indirect effects through the plant, copper was only added to root-free microcosm compartments. [Cu]bio was measured using a Pseudomonas fluorescens biosensor strain. In the range of 0–1.5 μg g−1 [Cu]bio, a log–log linear relationship between added copper and [Cu]bio was found. Microbial...... colonization of the root-free compartment was evaluated by whole-cell fatty acid analysis (WCFA) and amplified rDNA restriction analysis (ARDRA). The WCFA analysis showed that the AM fungus soil colonization was severely inhibited by Cu with a 50% reduction of mycorrhizal growth at 0.26 μg g−1 [Cu......]bio. The growth of other main microbial groups was not significantly affected by copper. However, ARDRA analysis showed a very strong effect of copper on the bacterial community composition probably caused by an increased proportion of Cu-resistant bacteria. Our results suggest that problems with plant yield may...

Down-regulation of LRP1B in colon cancer promoted the growth and migration of cancer cells.

Science.gov (United States)

Wang, Zhiqiang; Sun, Peng; Gao, Chun; Chen, Ji; Li, Jun; Chen, Zhonghao; Xu, Ming; Shao, Jun; Zhang, Yunpeng; Xie, Jiang

2017-08-01

Aberrant activation of beta-catenin/TCF signaling is one of the hallmarks of colon cancer. It is of great interest to study the mechanism for the regulation of beta-catenin/TCF signaling. In this study, it was found that LRP1B was down-regulated in colon cancer tissues and inhibited the growth, migration and metastasis of colon cancer cells. The molecular mechanism study revealed that LRP1B interacted with DVL2, inhibited the interaction between DVL2 and Axin, and negatively regulated beta-catenin/TCF signaling. Taken together, our study demonstrated the suppressive roles of LRP1B in the progression of colon cancer, implicating that restoring the function of LRP1B would be a promising strategy for the treatment of colon cancer. Copyright © 2017. Published by Elsevier Inc.

Changes in colonic motility induced by sennosides in dogs: evidence of a prostaglandin mediation.

OpenAIRE

Staumont, G; Fioramonti, J; Frexinos, J; Bueno, L

1988-01-01

The effects of sennosides on colonic motility were investigated in eight conscious dogs chronically fitted with two strain gauge transducers in the proximal colon, an intracolonic silicone catheter and a polyethylene catheter implanted in a branch of the right colonic artery. Oral sennosides (30 mg/kg) inhibited colonic motility for 12 to 18 h after a three to six hours delay, and associated with giant contractions and diarrhoea. The minimal oral dose of sennosides to produce such changes var...

Noscapine induces mitochondria-mediated apoptosis in human colon cancer cells in vivo and in vitro

Energy Technology Data Exchange (ETDEWEB)

Yang, Zi-Rong; Liu, Meng; Peng, Xiu-Lan; Lei, Xiao-Fei; Zhang, Ji-Xiang [Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province (China); Dong, Wei-Guo, E-mail: dongwg1966@yahoo.com.cn [Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province (China)

2012-05-11

Highlights: Black-Right-Pointing-Pointer Noscapine inhibited cell viability of colon cancer in a time- and dose- dependent manner. Black-Right-Pointing-Pointer G{sub 2}/M phase arrest and chromatin condensation and nuclear fragmentation were induced. Black-Right-Pointing-Pointer Noscapine promoted apoptosis via mitochondrial pathways. Black-Right-Pointing-Pointer Tumorigenicity was inhibited by noscapine. -- Abstract: Noscapine, a phthalide isoquinoline alkaloid derived from opium, has been widely used as a cough suppressant for decades. Noscapine has recently been shown to potentiate the anti-cancer effects of several therapies by inducing apoptosis in various malignant cells without any detectable toxicity in cells or tissues. However, the mechanism by which noscapine induces apoptosis in colon cancer cells remains unclear. The signaling pathways by which noscapine induces apoptosis were investigated in colon cancer cell lines treated with various noscapine concentrations for 72 h, and a dose-dependent inhibition of cell viability was observed. Noscapine effectively inhibited the proliferation of LoVo cells in vitro (IC{sub 50} = 75 {mu}M). This cytotoxicity was reflected by cell cycle arrest at G{sub 2}/M and subsequent apoptosis, as indicated by increased chromatin condensation and fragmentation, the upregulation of Bax and cytochrome c (Cyt-c), the downregulation of survivin and Bcl-2, and the activation of caspase-3 and caspase-9. Moreover, in a xenograft tumor model in mice, noscapine injection clearly inhibited tumor growth via the induction of apoptosis, which was demonstrated using a TUNEL assay. These results suggest that noscapine induces apoptosis in colon cancer cells via mitochondrial pathways. Noscapine may be a safe and effective chemotherapeutic agent for the treatment of human colon cancer.

A Zinc Chelator TPEN Attenuates Airway Hyperresponsiveness Airway Inflammation in Mice In Vivo

Directory of Open Access Journals (Sweden)

Satoru Fukuyama

2011-01-01

Conclusions: In pulmonary allergic inflammation induced in mice immunized with antigen without alum, zinc chelator inhibits airway inflammation and hyperresponsiveness. These findings suggest that zinc may be a therapeutic target of allergic asthma.

G Protein-coupled pH-sensing Receptor OGR1 Is a Regulator of Intestinal Inflammation.

Science.gov (United States)

de Vallière, Cheryl; Wang, Yu; Eloranta, Jyrki J; Vidal, Solange; Clay, Ieuan; Spalinger, Marianne R; Tcymbarevich, Irina; Terhalle, Anne; Ludwig, Marie-Gabrielle; Suply, Thomas; Fried, Michael; Kullak-Ublick, Gerd A; Frey-Wagner, Isabelle; Scharl, Michael; Seuwen, Klaus; Wagner, Carsten A; Rogler, Gerhard

2015-06-01

A novel family of proton-sensing G protein-coupled receptors, including OGR1, GPR4, and TDAG8, was identified to be important for physiological pH homeostasis and inflammation. Thus, we determined the function of proton-sensing OGR1 in the intestinal mucosa. OGR1 expression in colonic tissues was investigated in controls and patients with IBD. Expression of OGR1 upon cell activation was studied in the Mono Mac 6 (MM6) cell line and primary human and murine monocytes by real-time PCR. Ogr1 knockout mice were crossbred with Il-10 deficient mice and studied for more than 200 days. Microarray profiling was performed using Ogr1 and Ogr1 (WT) residential peritoneal macrophages. Patients with IBD expressed higher levels of OGR1 in the mucosa than non-IBD controls. Treatment of MM6 cells with TNF, led to significant upregulation of OGR1 expression, which could be reversed by the presence of NF-κB inhibitors. Kaplan-Meier survival analysis showed a significantly delayed onset and progression of rectal prolapse in female Ogr1/Il-10 mice. These mice displayed significantly less rectal prolapses. Upregulation of gene expression, mediated by OGR1, in response to extracellular acidification in mouse macrophages was enriched for inflammation and immune response, actin cytoskeleton, and cell-adhesion gene pathways. OGR1 expression is induced in cells of human macrophage lineage and primary human monocytes by TNF. NF-κB inhibition reverses the induction of OGR1 expression by TNF. OGR1 deficiency protects from spontaneous inflammation in the Il-10 knockout model. Our data indicate a pathophysiological role for pH-sensing receptor OGR1 during the pathogenesis of mucosal inflammation.

VESGEN Mapping of Bioactive Protection against Intestinal Inflammation: Application to Human Spaceflight and ISS Experiments

Science.gov (United States)

Parsons-Wingerter, P. A.; Chen, X.; Kelly, C. P.; Reinecker, H. C.

2011-01-01

Challenges to successful space exploration and colonization include adverse physiological reactions to micro gravity and space radiation factors. Constant remodeling of the microvasculature is critical for tissue preservation, wound healing, and recovery after ischemia. Regulation of the vascular system in the intestine is particularly important to enable nutrient absorption while maintaining barrier function and mucosal defense against micro biota. Although tremendous progress has been made in understanding the molecular circuits regulating neovascularization, our knowledge of the adaptations of the vascular system to environmental challenges in the intestine remains incomplete. This is in part because of the lack of methods to observe and quantify the complex processes associated with vascular responses in vivo. Developed by GRC as a mature beta version, pre-release research software, VESsel GENeration Analysis (VESGEN) maps and quantifies the fractal-based complexity of vascular branching for novel insights into the cytokine, transgenic and therapeutic regulation of angiogenesis, lymphangiogenesis and microvascular remodeling. Here we demonstrate that VESGEN can be used to characterize the dynamic vascular responses to acute intestinal inflammation and mucosal recovery from in vivo confocal microscopic 3D image series. We induced transient intestinal inflammation in mice by DSS treatment and investigated whether the ability of the pro biotic yeast Saccharomyces boulardii (Sb) to protect against intestinal inflammation was due to regulation of vascular remodeling. A primary characteristic of inflammation is excessive neovascularization (angiogenesis) resulting in fragile vessels prone to bleeding. Morphological parameters for triplicate specimens revealed that Sb treatment greatly reduced the inflammatory response of vascular networks by an average of 78%. This resulted from Sb inhibition of vascular endothelial growth factor receptor signaling, a major

PLK1 has tumor-suppressive potential in APC-truncated colon cancer cells.

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Raab, Monika; Sanhaji, Mourad; Matthess, Yves; Hörlin, Albrecht; Lorenz, Ioana; Dötsch, Christina; Habbe, Nils; Waidmann, Oliver; Kurunci-Csacsko, Elisabeth; Firestein, Ron; Becker, Sven; Strebhardt, Klaus

2018-03-16

The spindle assembly checkpoint (SAC) acts as a molecular safeguard in ensuring faithful chromosome transmission during mitosis, which is regulated by a complex interplay between phosphatases and kinases including PLK1. Adenomatous polyposis coli (APC) germline mutations cause aneuploidy and are responsible for familial adenomatous polyposis (FAP). Here we study the role of PLK1 in colon cancer cells with chromosomal instability promoted by APC truncation (APC-ΔC). The expression of APC-ΔC in colon cells reduces the accumulation of mitotic cells upon PLK1 inhibition, accelerates mitotic exit and increases the survival of cells with enhanced chromosomal abnormalities. The inhibition of PLK1 in mitotic, APC-∆C-expressing cells reduces the kinetochore levels of Aurora B and hampers the recruitment of SAC component suggesting a compromised mitotic checkpoint. Furthermore, Plk1 inhibition (RNAi, pharmacological compounds) promotes the development of adenomatous polyps in two independent Apc Min/+ mouse models. High PLK1 expression increases the survival of colon cancer patients expressing a truncated APC significantly.

Capecitabine treatment of HCT-15 colon cancer cells induces ...

African Journals Online (AJOL)

HCT-15 cells caused condensation of DNA and induced apoptosis in a concentration- ... Conclusion: Capecitabine treatment causes inhibition of colon cancer growth via the mitochondrial ... fluoropyrimidine aimed to selectively transfer 5-.

Plumbagin, a vitamin K3 analogue ameliorate malaria pathogenesis by inhibiting oxidative stress and inflammation.

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Gupta, Amit Chand; Mohanty, Shilpa; Saxena, Archana; Maurya, Anil Kumar; Bawankule, Dnyaneshwar U

2018-03-22

Plumbagin, a vitamin K3 analogue is the major active constituent in several plants including root of Plumbago indica Linn. This compound has been shown to exhibit a wide spectrum of pharmacological activities. The present investigation was to evaluate the ameliorative effects of plumbagin (PL) against severe malaria pathogenesis due to involvement of oxidative stress and inflammatory response in Plasmodium berghei infected malaria in mice. Malaria pathogenesis was induced by intra-peritoneal injection of P. berghei infected red blood cells into the Swiss albino mice. PL was administered orally at doses of 3, 10 and 30 mg/kg/day following Peter's 4 day suppression test. Oral administration of PL showed significant reduction of parasitaemia and increase in mean survival time. PL treatment is also attributed to significant increase in the blood glucose and haemoglobin level when compared with vehicle-treated infected mice. Significant inhibition in level of oxidative stress and pro-inflammation related markers were observed in PL treated group. The trend of inhibition in oxidative stress markers level after oral treatment of PL was MPO > LPO > ROS in organ injury in P. berghei infected mice. This study showed that plumbagin is able to ameliorate malaria pathogenesis by augmenting anti-oxidative and anti-inflammatory mechanism apart from its effect on reducing parasitaemia and increasing mean survival time of malaria-induced mice.

Suppression of Inflammation and Arthritis by Orally Administrated Cardiotoxin from Naja naja atra

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Cao-Xin Chen

2015-01-01

Full Text Available Cardiotoxin (CTX from Naja naja atra venom (NNAV reportedly had analgesic effect in animal models but its role in inflammation and arthritis was unknown. In this study, we investigated the analgesic, anti-inflammatory, and antiarthritic actions of orally administered CTX-IV isolated from NNAV on rodent models of inflammation and adjuvant arthritis. CTX had significant anti-inflammatory effects in models of egg white induced nonspecific inflammation, filter paper induced rat granuloma formation, and capillary osmosis tests. CTX significantly reduced the swelling of paw induced by egg white, the inflammatory exudation, and the formation of granulomas. CTX reduced the swelling of paw, the AA clinical scores, and pathological alterations of joint. CTX significantly decreased the number of the CD4 T cells and inhibited the expression of relevant proinflammatory cytokines IL-17 and IL-6. CTX significantly inhibited the secretion of proinflammatory cytokine IL-6 and reduced the level of p-STAT3 in FLS. These results suggest that CTX inhibits inflammation and inflammatory pain and adjuvant-induced arthritis. CTX may be a novel therapeutic drug for treatment of arthritis.

FXR silencing in human colon cancer by DNA methylation and KRAS signaling.

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Bailey, Ann M; Zhan, Le; Maru, Dipen; Shureiqi, Imad; Pickering, Curtis R; Kiriakova, Galina; Izzo, Julie; He, Nan; Wei, Caimiao; Baladandayuthapani, Veerabhadran; Liang, Han; Kopetz, Scott; Powis, Garth; Guo, Grace L

2014-01-01

Farnesoid X receptor (FXR) is a bile acid nuclear receptor described through mouse knockout studies as a tumor suppressor for the development of colon adenocarcinomas. This study investigates the regulation of FXR in the development of human colon cancer. We used immunohistochemistry of FXR in normal tissue (n = 238), polyps (n = 32), and adenocarcinomas, staged I-IV (n = 43, 39, 68, and 9), of the colon; RT-quantitative PCR, reverse-phase protein array, and Western blot analysis in 15 colon cancer cell lines; NR1H4 promoter methylation and mRNA expression in colon cancer samples from The Cancer Genome Atlas; DNA methyltransferase inhibition; methyl-DNA immunoprecipitation (MeDIP); bisulfite sequencing; and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) knockdown assessment to investigate FXR regulation in colon cancer development. Immunohistochemistry and quantitative RT-PCR revealed that expression and function of FXR was reduced in precancerous lesions and silenced in a majority of stage I-IV tumors. FXR expression negatively correlated with phosphatidylinositol-4, 5-bisphosphate 3 kinase signaling and the epithelial-to-mesenchymal transition. The NR1H4 promoter is methylated in ~12% colon cancer The Cancer Genome Atlas samples, and methylation patterns segregate with tumor subtypes. Inhibition of DNA methylation and KRAS silencing both increased FXR expression. FXR expression is decreased early in human colon cancer progression, and both DNA methylation and KRAS signaling may be contributing factors to FXR silencing. FXR potentially suppresses epithelial-to-mesenchymal transition and other oncogenic signaling cascades, and restoration of FXR activity, by blocking silencing mechanisms or increasing residual FXR activity, represents promising therapeutic options for the treatment of colon cancer.

Changes in colonic motility induced by sennosides in dogs: evidence of a prostaglandin mediation.

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Staumont, G; Fioramonti, J; Frexinos, J; Bueno, L

1988-01-01

The effects of sennosides on colonic motility were investigated in eight conscious dogs chronically fitted with two strain gauge transducers in the proximal colon, an intracolonic silicone catheter and a polyethylene catheter implanted in a branch of the right colonic artery. Oral sennosides (30 mg/kg) inhibited colonic motility for 12 to 18 h after a three to six hours delay, and associated with giant contractions and diarrhoea. The minimal oral dose of sennosides to produce such changes varied from 5 to 15 mg/kg. Intracolonic sennosides at the minimal effective dose and at 30 mg/kg reproduced the effects of oral sennosides, but with a shorter latency (0.5-1.5 h). Intracolonic PGE2 (100 micrograms/kg) in viscous gel medium or intra-arterial PGE2 (10 micrograms/h) inhibited colonic motility and induced giant contractions often associated with defecation. The colonic motor changes induced by intracolonic sennosides at the minimal effective dose, but not those induced by intracolonic PGE2, were blocked by intra-arterial indomethacin (10 micrograms/h) or piroxicam (5 micrograms/h). These results suggest that colonic motor actions of sennosides are mediated through a local prostaglandins synthesis, as they were blocked by cyclooxygenase inhibitor and reproduced by PGE2. PMID:3197991

1-L-MT, an IDO inhibitor, prevented colitis-associated cancer by inducing CDC20 inhibition-mediated mitotic death of colon cancer cells.

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Liu, Xiuting; Zhou, Wei; Zhang, Xin; Ding, Yang; Du, Qianming; Hu, Rong

2018-04-01

Indoleamine 2,3-dioxygenase 1 (IDO1), known as IDO, catabolizes tryptophan through kynurenine pathway, whose activity is correlated with impaired clinical outcome of colorectal cancer. Here we showed that 1-L-MT, a canonical IDO inhibitor, suppressed proliferation of human colorectal cancer cells through inducing mitotic death. Our results showed that inhibition of IDO decreased the transcription of CDC20, which resulted in G2/M cycle arrest of HCT-116 and HT-29. Furthermore, 1-L-MT induced mitochondria injuries and caused apoptotic cancer cells. Importantly, 1-L-MT protected mice from azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon carcinogenesis, with reduced mortality, tumor number and size. What is more, IDO1-/- mice exhibited fewer tumor burdens and reduced proliferation in the neoplastic epithelium, while, 1-L-MT did not exhibit any further protective effects on IDO-/- mice, confirming the critical role of IDO and the protective effect of 1-L-MT-mediated IDO inhibition in CRC. Furthermore, 1-L-MT also alleviated CRC in Rag1-/- mice, demonstrating the modulatory effects of IDO independent of its role in modulating adaptive immunity. Taken together, our findings validated that the anti-proliferation effect of 1-L-MT in vitro and the prevention of CRC in vivo were through IDO-induced cell cycle disaster of colon cancer cells. Our results identified 1-L-MT as a promising candidate for the chemoprevention of CRC. © 2018 UICC.

Piroxicam decreases postirradiation colonic neoplasia in the rat

International Nuclear Information System (INIS)

Northway, M.G.; Scobey, M.W.; Cassidy, K.T.; Geisinger, K.R.

1990-01-01

This study evaluated the effects of the nonsteroidal antiinflammatory agent piroxicam on chronic radiation proctitis in the rat. Forty female Wistar rats received a 2250-cGy dose of irradiation to the distal 2 cm of the colon. Twenty received piroxicam 8.0 mg/kg orally 30 minutes before exposure and 24 hours after exposure; 20 rats served as irradiated controls. All animals were evaluated by colonoscopy 1 and 3 weeks postexposure and every third week until death or killing at 1 year. At killing, colons were removed for light microscopic examination. One year postirradiation results showed no differences in mortality, vascular changes, acute inflammation, colitis cystica profunda, or rectal stricture between the control and piroxicam-treated groups. However, at 1 year postirradiation the control group demonstrated neoplasia in 15 of 19 animals compared with eight of 20 animals in the piroxicam-treated group. The first endoscopic appearance of colonic neoplasm occurred at 15 weeks postirradiation in one control irradiated rat whereas the first evidence of endoscopic neoplasm in the piroxicam-treated group did not occur until 36 weeks postirradiation. Histologic examination documented a tendency toward a greater presence of adenocarcinomas in the control group compared with the piroxicam-treated group. The authors conclude that piroxicam treatment significantly decreased the incidence of colonic neoplasia in general as well as delayed the endoscopic appearance of colonic neoplasia in rats after pelvic irradiation. 41 references

Piroxicam decreases postirradiation colonic neoplasia in the rat

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Northway, M.G.; Scobey, M.W.; Cassidy, K.T.; Geisinger, K.R. (Wake Forest Univ., Winston Salem, NC (USA))

1990-12-01

This study evaluated the effects of the nonsteroidal antiinflammatory agent piroxicam on chronic radiation proctitis in the rat. Forty female Wistar rats received a 2250-cGy dose of irradiation to the distal 2 cm of the colon. Twenty received piroxicam 8.0 mg/kg orally 30 minutes before exposure and 24 hours after exposure; 20 rats served as irradiated controls. All animals were evaluated by colonoscopy 1 and 3 weeks postexposure and every third week until death or killing at 1 year. At killing, colons were removed for light microscopic examination. One year postirradiation results showed no differences in mortality, vascular changes, acute inflammation, colitis cystica profunda, or rectal stricture between the control and piroxicam-treated groups. However, at 1 year postirradiation the control group demonstrated neoplasia in 15 of 19 animals compared with eight of 20 animals in the piroxicam-treated group. The first endoscopic appearance of colonic neoplasm occurred at 15 weeks postirradiation in one control irradiated rat whereas the first evidence of endoscopic neoplasm in the piroxicam-treated group did not occur until 36 weeks postirradiation. Histologic examination documented a tendency toward a greater presence of adenocarcinomas in the control group compared with the piroxicam-treated group. The authors conclude that piroxicam treatment significantly decreased the incidence of colonic neoplasia in general as well as delayed the endoscopic appearance of colonic neoplasia in rats after pelvic irradiation. 41 references.

3',5'-Cyclic diguanylic acid (c-di-GMP) inhibits basal and growth factor-stimulated human colon cancer cell proliferation

International Nuclear Information System (INIS)

Karaolis, David K.R.; Cheng, Kunrong; Lipsky, Michael; Elnabawi, Ahmed; Catalano, Jennifer; Hyodo, Mamoru; Hayakawa, Yoshihiro; Raufman, Jean-Pierre

2005-01-01

The novel cyclic dinucleotide, 3',5'-cyclic diguanylic acid, cGpGp (c-di-GMP), is a naturally occurring small molecule that regulates important signaling mechanisms in prokaryotes. Recently, we showed that c-di-GMP has 'drug-like' properties and that c-di-GMP treatment might be a useful antimicrobial approach to attenuate the virulence and pathogenesis of Staphylococcus aureus and prevent or treat infection. In the present communication, we report that c-di-GMP (≤50 μM) has striking properties regarding inhibition of cancer cell proliferation in vitro. c-di-GMP inhibits both basal and growth factor (acetylcholine and epidermal growth factor)-induced cell proliferation of human colon cancer (H508) cells. Toxicity studies revealed that exposure of normal rat kidney cells and human neuroblastoma cells to c-di-GMP at biologically relevant doses showed no lethal cytotoxicity. Cyclic dinucleotides, such as c-di-GMP, represent an attractive and novel 'drug-platform technology' that can be used not only to develop new antimicrobial agents, but also to develop novel therapeutic agents to prevent or treat cancer

A crucial role for CDC42 in senescence-associated inflammation and atherosclerosis.

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Takashi K Ito

Full Text Available Risk factors for atherosclerosis accelerate the senescence of vascular endothelial cells and promote atherogenesis by inducing vascular inflammation. A hallmark of endothelial senescence is the persistent up-regulation of pro-inflammatory genes. We identified CDC42 signaling as a mediator of chronic inflammation associated with endothelial senescence. Inhibition of CDC42 or NF-κB signaling attenuated the sustained up-regulation of pro-inflammatory genes in senescent human endothelial cells. Endothelium-specific activation of the p53/p21 pathway, a key mediator of senescence, also resulted in up-regulation of pro-inflammatory molecules in mice, which was reversed by Cdc42 deletion in endothelial cells. Likewise, endothelial-specific deletion of Cdc42 significantly attenuated chronic inflammation and plaque formation in atherosclerotic mice. While inhibition of NF-κB suppressed the pro-inflammatory responses in acute inflammation, the influence of Cdc42 deletion was less marked. Knockdown of cdc-42 significantly down-regulated pro-inflammatory gene expression and restored the shortened lifespan to normal in mutant worms with enhanced inflammation. These findings indicate that the CDC42 pathway is critically involved in senescence-associated inflammation and could be a therapeutic target for chronic inflammation in patients with age-related diseases without compromising host defenses.

Inhibition of lipopolysaccharide induced acute inflammation in lung by chlorination

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Zhang, Jinshan; Xue, Jinling; Xu, Bi; Xie, Jiani [Environmental Simulation and Pollution Control State Key Joint Laboratory, School of Environment, Tsinghua University, Beijing 100084 (China); Qiao, Juan, E-mail: qjuan@tsinghua.edu.cn [Department of Chemistry, Tsinghua University, Beijing 100084 (China); Lu, Yun, E-mail: luyun@tsinghua.edu.cn [Environmental Simulation and Pollution Control State Key Joint Laboratory, School of Environment, Tsinghua University, Beijing 100084 (China)

2016-02-13

Highlights: • Chlorination is effective to reduce the inflammation inducing capacity of LPS in lung. • LAL-detected endotoxin activity is not correlated to the potency of inflammation induction. • Alkyl chain of LPS was chlorinated in chlorination process. • LPS aggregate size decreases after chlorination. - Abstract: Lipopolysaccharide (LPS, also called endotoxin) is a pro-inflammatory constituent of gram negative bacteria and cyanobacteria, which causes a potential health risk in the process of routine urban application of reclaimed water, such as car wash, irrigation, scenic water refilling, etc. Previous studies indicated that the common disinfection treatment, chlorination, has little effect on endotoxin activity removal measured by Limulus amebocyte lysate (LAL) assay. However, in this study, significant decrease of acute inflammatory effects was observed in mouse lung, while LAL assay still presented a moderate increase of endotoxin activity. To explore the possible mechanisms, the nuclear magnetic resonance (NMR) results showed the chlorination happened in alkyl chain of LPS molecules, which could affect the interaction between LPS and LPS-binding protein. Also the size of LPS aggregates was found to drop significantly after treatment, which could be another results of chlorination caused polarity change. In conclusion, our observation demonstrated that chlorination is effective to reduce the LPS induced inflammation in lung, and it is recommended to use health effect-based methods to assess risk removal of water treatment technologies.

Inhibition of lipopolysaccharide induced acute inflammation in lung by chlorination

International Nuclear Information System (INIS)

Zhang, Jinshan; Xue, Jinling; Xu, Bi; Xie, Jiani; Qiao, Juan; Lu, Yun

2016-01-01

Highlights: • Chlorination is effective to reduce the inflammation inducing capacity of LPS in lung. • LAL-detected endotoxin activity is not correlated to the potency of inflammation induction. • Alkyl chain of LPS was chlorinated in chlorination process. • LPS aggregate size decreases after chlorination. - Abstract: Lipopolysaccharide (LPS, also called endotoxin) is a pro-inflammatory constituent of gram negative bacteria and cyanobacteria, which causes a potential health risk in the process of routine urban application of reclaimed water, such as car wash, irrigation, scenic water refilling, etc. Previous studies indicated that the common disinfection treatment, chlorination, has little effect on endotoxin activity removal measured by Limulus amebocyte lysate (LAL) assay. However, in this study, significant decrease of acute inflammatory effects was observed in mouse lung, while LAL assay still presented a moderate increase of endotoxin activity. To explore the possible mechanisms, the nuclear magnetic resonance (NMR) results showed the chlorination happened in alkyl chain of LPS molecules, which could affect the interaction between LPS and LPS-binding protein. Also the size of LPS aggregates was found to drop significantly after treatment, which could be another results of chlorination caused polarity change. In conclusion, our observation demonstrated that chlorination is effective to reduce the LPS induced inflammation in lung, and it is recommended to use health effect-based methods to assess risk removal of water treatment technologies.

Curcumin inhibits growth potential by G1 cell cycle arrest and induces apoptosis in p53-mutated COLO 320DM human colon adenocarcinoma cells.

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Dasiram, Jade Dhananjay; Ganesan, Ramamoorthi; Kannan, Janani; Kotteeswaran, Venkatesan; Sivalingam, Nageswaran

2017-02-01

Curcumin, a natural polyphenolic compound and it is isolated from the rhizome of Curcuma longa, have been reported to possess anticancer effect against stage I and II colon cancer. However, the effect of curcumin on colon cancer at Dukes' type C metastatic stage III remains still unclear. In the present study, we have investigated the anticancer effects of curcumin on p53 mutated COLO 320DM human colon adenocarcinoma cells derived from Dukes' type C metastatic stage. The cellular viability and proliferation were assessed by trypan blue exclusion assay and MTT assay, respectively. The cytotoxicity effect was examined by lactate dehydrogenase (LDH) cytotoxicity assay. Apoptosis was analyzed by DNA fragmentation analysis, Hoechst and propidium iodide double fluorescent staining and confocal microscopy analysis. Cell cycle distribution was performed by flow cytometry analysis. Here we have observed that curcumin treatment significantly inhibited the cellular viability and proliferation potential of p53 mutated COLO 320DM cells in a dose- and time-dependent manner. In addition, curcumin treatment showed no cytotoxic effects to the COLO 320DM cells. DNA fragmentation analysis, Hoechst and propidium iodide double fluorescent staining and confocal microscopy analysis revealed that curcumin treatment induced apoptosis in COLO 320DM cells. Furthermore, curcumin caused cell cycle arrest at the G1 phase, decreased the cell population in the S phase and induced apoptosis in COLO 320DM colon adenocarcinoma cells. Together, these data suggest that curcumin exerts anticancer effects and induces apoptosis in p53 mutated COLO 320DM human colon adenocarcinoma cells derived from Dukes' type C metastatic stage. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Methyl Sartortuoate Inhibits Colon Cancer Cell Growth by Inducing Apoptosis and G2/M-Phase Arrest.

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Lan, Qiusheng; Li, Shoufeng; Lai, Wei; Xu, Heyang; Zhang, Yang; Zeng, Yujie; Lan, Wenjian; Chu, Zhonghua

2015-08-17

The potential anti-neoplastic activity of terpenoids is of continued interest. In this study, we investigate whether methyl sartortuoate, a terpenoid isolated from soft coral, induced cell cycle arrest and apoptosis in a human colon cancer cell line. Culture studies found that methyl sartortuoate inhibited colon cancer cell (LoVo and RKO) growth and caused apoptotic death in a concentration- and time-dependent manner, by activation of caspase-8, caspase-9, caspase-3, p53 and Bax, and inactivation of B-cell lymphoma 2 (Bcl-2) apoptosis regulating proteins. Methyl sartortuoate treatment led to reduced expression of cdc2 and up-regulated p21 and p53, suggesting that Methyl sartortuoate induced G2-M arrest through modulation of p53/p21/cdc2 pathways. Methyl sartortuoate also up-regulated phospho-JNK and phospho-p38 expression levels. This resulted in cell cycle arrest at the G2-M phase and apoptosis in LoVo and RKO cells. Treatment with the JNK inhibitor SP600125 and the p38 MAPK inhibitor SB203580 prevented methyl sartortuoate-induced apoptosis in LoVo cells. Moreover, methyl sartortuoate also prevented neoplasm growth in NOD-SCID nude mice inoculated with LoVo cells. Taken together, these findings suggest that methyl sartortuoate is capable of leading to activation of caspase-8, -9, -3, increasing p53 and Bax/Bcl-2 ratio apoptosis through MAPK-dependent apoptosis and results in G2-M phase arrest in LoVo and RKO cells. Thus, methyl sartortuoate may be a promising anticancer candidate.

SiRNA-mediated IGF-1R inhibition sensitizes human colon cancer SW480 cells to radiation

International Nuclear Information System (INIS)

Yavari, Kamal; Taghikhani, Mohammad; Mesbah-Namin, Seyed A.; Maragheh, Mohammad Ghannadi; Babaei, Mohammad Hosein; Arfaee, Ali Jabbary; Madani, Hossein; Mirzaei, Hamid Reza

2010-01-01

Purpose. Insulin like growth factor receptor 1 (IGF-1R) is well-documented to play a key role in radiation response and tumor radiosensitivity, thus offering an attractive clinic drug target to enhance tumor sensitivity to anti-cancer radiotherapy. Material and methods. Human colon carcinoma SW480 cells were transfected with the specific small interference RNA (siRNA) expression vector (pkD-shRNA-IGF-1R-V2) designed to target IGF-1R mRNA. The expression of IGF-1R mRNA and its protein among the transfected and untransfected cells were detected by semi-quantitative RT-PCR and ELISA assay. The changes in cell radiosensitivity were examined by MTT assay. Results. Transfection of mammalian expression vector pkD containing IGF-1R siRNA was shown to reduce IGF-1R mRNA levels by up to 95%. ELISA assay detected a similar inhibition of IGF-1R protein levels in cells transfected with IGF-1R siRNA. SW480 cells transfected with the expression vector for siRNA significantly rendered cells more sensitive to radiation and the highest radiation enhancement ratio was 2.02 ± 0.08. Conclusion. These data provide the first evidence that specific siRNA fragment (pkD-shRNA-IGF-1R-V2) targeting human IGF-1R mRNA is able to enhance colon cancer radiosensitivity. Also results indicated that, combining IGF-1R siRNA and radiation significantly enhances antitumor efficacy compared with either modality alone

Imaging colon cancer development in mice: IL-6 deficiency prevents adenoma in azoxymethane-treated Smad3 knockouts

Science.gov (United States)

Harpel, Kaitlin; Leung, Sarah; Faith Rice, Photini; Jones, Mykella; Barton, Jennifer K.; Bommireddy, Ramireddy

2016-02-01

The development of colorectal cancer in the azoxymethane-induced mouse model can be observed by using a miniaturized optical coherence tomography (OCT) imaging system. This system is uniquely capable of tracking disease development over time, allowing for the monitoring of morphological changes in the distal colon due to tumor development and the presence of lymphoid aggregates. By using genetically engineered mouse models deficient in Interleukin 6 (IL-6) and Smad family member 3 (Smad3), the role of inflammation on tumor development and the immune system can be elucidated. Smad3 knockout mice develop inflammatory response, wasting, and colitis associated cancer while deficiency of proinflammatory cytokine IL-6 confers resistance to tumorigenesis. We present pilot data showing that the Smad3 knockout group had the highest tumor burden, highest spleen weight, and lowest thymus weight. The IL-6 deficiency in Smad3 knockout mice prevented tumor development, splenomegaly, and thymic atrophy. This finding suggests that agents that inhibit IL-6 (e.g. anti-IL-6 antibody, non-steroidal anti-inflammatory drugs [NSAIDs], etc.) could be used as novel therapeutic agents to prevent disease progression and increase the efficacy of anti-cancer agents. OCT can also be useful for initiating early therapy and assessing the benefit of combination therapy targeting inflammation.

Inhibition of Acute Phase Inflammation by Laminaria japonica through Regulation of iNOS-NF-κB Pathway

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Seong Kyu Park

2013-01-01

Full Text Available Laminaria japonica has been frequently used as food supplements in many of the Asian countries and as a drug in traditional oriental medicine. This research investigated the effects of Laminaria japonica extract (LJE on acute phase inflammation in a carrageenan-induced paw edema model, as assessed by histomorphometric and immunohistochemical analyses. The effect of LJE was also evaluated in Raw264.7 cells stimulated with lipopolysaccharide (LPS in the aspect of the inhibition of nitric oxide (NO, prostaglandin E2 (PGE2, and proinflammatory cytokines production. NO, PGE2, tumor necrosis factor (TNF-α, interleukin-1β, and interleukin-6 contents were assayed by ELISA, and inducible NO synthase (iNOS and cyclooxygenase (COX-2 expressions were determined by western blot analyses. In rats, LJE treatment inhibited carrageenan-induced paw edema formation and infiltration of inflammatory cells in H&E staining. LJE treatment prevented the ability of LPS to increase the levels of iNOS and COX-2 protein in a concentration-dependent manner. Consistently, LJE suppressed the production of TNF-α, interleukin-1β, and interleukin-6. Treatment of the cells with LJE caused inhibition of inhibitor of κBα phosphorylation induced by LPS, suggesting LJE repression of nuclear factor-κB activity by LPS. In conclusion, this study shown here may be of help to understand the action mechanism of LJE and the anti-inflammatory use of L. japonica.

Absence of mucosal inflammation in uncomplicated diverticular disease.

Science.gov (United States)

Elli, Luca; Roncoroni, Leda; Bardella, Maria Teresa; Terrani, Claudia; Bonura, Antonella; Ciulla, Michele; Marconi, Stefano; Piodi, Luca

2011-07-01

Uncomplicated diverticular disease is a common condition in patients older than 50 years. Symptoms are aspecific and overlapping with those of irritable bowel syndrome. Nowadays, patients are often treated with antinflammatory drugs (5-aminosalicilic acid). Our purpose was to evaluate the presence of inflammation in the colonic mucosa of patients with symptomatic uncomplicated diverticular disease compared with subjects without diverticula. Endoscopic biopsies of colon from 10 patients with symptomatic uncomplicated diverticular disease and 10 from subjects without diverticula (controls) were taken. Specimens were homogenised and IL2, IL4, IL5, IL8, IL10, IL12p70, IL13, IFN gamma, TNF alfa (searchlight multiplex technique), TGF beta, transglutaminase type 2 and caspase 9 were measured. Histochemistry for transglutaminase type 2 and TUNEL were performed on the histological sections, in addition to morphologic evaluation, as markers of tissue remodelling and apoptosis. For statistical analysis Student's t test and Spearman correlation test were used. No histological differences were detected between the patients with an uncomplicated diverticular disease and controls. Mean values of mucosal cytokines and of the other tested parameters did not show statistically significant differences between patients with uncomplicated diverticular disease and controls. Even if based on a small number of patients, the study demonstrates the absence of inflammation in the mucosa of subjects affected by uncomplicated diverticular disease.

Inhibition of Epithelial TNF-α Receptors by Purified Fruit Bromelain Ameliorates Intestinal Inflammation and Barrier Dysfunction in Colitis.

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Zhou, Zijuan; Wang, Liang; Feng, Panpan; Yin, Lianhong; Wang, Chen; Zhi, Shengxu; Dong, Jianyi; Wang, Jingyu; Lin, Yuan; Chen, Dapeng; Xiong, Yongjian; Peng, Jinyong

2017-01-01

Activation of the TNF-α receptor (TNFR) leads to an inflammatory response, and anti-TNF therapy has been administered to reduce inflammation symptoms and heal mucosal ulcers in inflammatory bowel disease (IBD). Bromelain, a complex natural mixture of proteolytic enzymes, has been shown to exert anti-inflammatory effects. This study aimed to investigate the effect of purified fruit bromelain (PFB)-induced inhibition of epithelial TNFR in a rat colitis model. Colitis was established by intracolonic administration of 2, 4, 6-trinitrobenzene sulfonic acid. Expression of TNFR1 and TNFR2 was measured by quantitative RT-PCR and western blotting. The effect of PFB on colitis was evaluated by examining the inflammatory response and intestinal epithelial barrier function. Our results showed that both TNFR1 and TNFR2 expression were significantly increased in a colitis model, and the increase was significantly reversed by PFB. Colitis symptoms, including infiltration of inflammatory cells, cytokine profiles, epithelial cell apoptosis, and epithelial tight junction barrier dysfunction were significantly ameliorated by PFB. Compared with fruit bromelain and stem bromelain complex, the inhibition of TNFR2 induced by PFB was stronger than that exhibited on TNFR1. These results indicate that PFB showed a stronger selective inhibitory effect on TNFR2 than TNFR1. In other words, purification of fruit bromelain increases its selectivity on TNFR2 inhibition. High expression of epithelial TNFRs in colitis was significantly counteracted by PFB, and PFB-induced TNFR inhibition ameliorated colitis symptoms. These results supply novel insights into potential IBD treatment by PFB.

Strawberry-Tree Honey Induces Growth Inhibition of Human Colon Cancer Cells and Increases ROS Generation: A Comparison with Manuka Honey.

Science.gov (United States)

Afrin, Sadia; Forbes-Hernandez, Tamara Y; Gasparrini, Massimiliano; Bompadre, Stefano; Quiles, José L; Sanna, Gavino; Spano, Nadia; Giampieri, Francesca; Battino, Maurizio

2017-03-11

Honey is a natural product known to modulate several biological activities including cancer. The aim of the present study was to examine the phytochemical content and the antioxidant activity of Strawberry tree ( Arbutus unedo ) honey (STH) and its cytotoxic properties against human colon adenocarcinoma (HCT-116) and metastatic (LoVo) cell lines in comparison with Manuka ( Leptospermum scoparium ) honey (MH). Several unifloral STH and MH were analyzed for their phenolic, flavonoid, amino acid and protein contents, as well as their radical scavenging activities. STH from the Berchidda area showed the highest amount of phenolic, flavonoid, amino acid and protein content, and antioxidant capacity compared to MH. Both STH and MH induced cytotoxicity and cell death in a dose- and time-dependent manner in HCT-116 and LoVo cells, with less toxicity on non-cancer cells. Compared to MH, STH showed more effect at lower concentrations on HCT-116 and LoVo cells. In addition, both honeys increased intracellular reactive oxygen species (ROS) generation. In HCT-116 cells, STH and MH induced similar ROS production but in LoVo cells STH induced a higher percentage of ROS compared to MH. Our results indicate that STH and MH can induce cell growth inhibition and ROS generation in colon adenocarcinoma and metastatic cells, which could be due to the presence of phytochemicals with antioxidant properties. These preliminary results are interesting and suggest a potential chemopreventive action which could be useful for further studies in order to develop chemopreventive agents for colon cancer.

Strawberry-Tree Honey Induces Growth Inhibition of Human Colon Cancer Cells and Increases ROS Generation: A Comparison with Manuka Honey

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Sadia Afrin

2017-03-01

Full Text Available Honey is a natural product known to modulate several biological activities including cancer. The aim of the present study was to examine the phytochemical content and the antioxidant activity of Strawberry tree (Arbutus unedo honey (STH and its cytotoxic properties against human colon adenocarcinoma (HCT-116 and metastatic (LoVo cell lines in comparison with Manuka (Leptospermum scoparium honey (MH. Several unifloral STH and MH were analyzed for their phenolic, flavonoid, amino acid and protein contents, as well as their radical scavenging activities. STH from the Berchidda area showed the highest amount of phenolic, flavonoid, amino acid and protein content, and antioxidant capacity compared to MH. Both STH and MH induced cytotoxicity and cell death in a dose- and time-dependent manner in HCT-116 and LoVo cells, with less toxicity on non-cancer cells. Compared to MH, STH showed more effect at lower concentrations on HCT-116 and LoVo cells. In addition, both honeys increased intracellular reactive oxygen species (ROS generation. In HCT-116 cells, STH and MH induced similar ROS production but in LoVo cells STH induced a higher percentage of ROS compared to MH. Our results indicate that STH and MH can induce cell growth inhibition and ROS generation in colon adenocarcinoma and metastatic cells, which could be due to the presence of phytochemicals with antioxidant properties. These preliminary results are interesting and suggest a potential chemopreventive action which could be useful for further studies in order to develop chemopreventive agents for colon cancer.

Rocuronium Bromide Inhibits Inflammation and Pain by Suppressing Nitric Oxide Production and Enhancing Prostaglandin E2 Synthesis in Endothelial Cells.

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Baek, Sang Bin; Shin, Mal Soon; Han, Jin Hee; Moon, Sang Woong; Chang, Boksoon; Jeon, Jung Won; Yi, Jae Woo; Chung, Jun Young

2016-12-01

Rocuronium bromide is a nondepolarizing neuromuscular blocking drug and has been used as an adjunct for relaxation or paralysis of the skeletal muscles, facilitation of endotracheal intubation, and improving surgical conditions during general anesthesia. However, intravenous injection of rocuronium bromide induces injection pain or withdrawal movement. The exact mechanism of rocuronium bromide-induced injection pain or withdrawal movement is not yet understood. We investigated whether rocuronium bromide treatment is involved in the induction of inflammation and pain in vascular endothelial cells. For this study, calf pulmonary artery endothelial (CPAE) cells were used, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, Western blot, nitric oxide detection, and prostaglandin E 2 immunoassay were conducted. Rocuronium bromide treatment inhibited endothelial nitric oxide synthase and suppressed nitric oxide production in CPAE cells. Rocuronium bromide activated cyclooxygenase-2, inducible nitric oxide synthase and increased prostaglandin E 2 synthesis in CPAE cells. Rocuronium bromide induced inflammation and pain in CPAE cells. Suppressing nitric oxide production and enhancing prostaglandin E 2 synthesis might be associated with rocuronium bromide-induced injection pain or withdrawal movement.

Dietary supplementation of resveratrol attenuates chronic colonic inflammation in mice.

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Sánchez-Fidalgo, Susana; Cárdeno, Ana; Villegas, Isabel; Talero, Elena; de la Lastra, Catalina Alarcón

2010-05-10

Ulcerative colitis is a nonspecific inflammatory disorder characterized by oxidative and nitrosative stress, leucocyte infiltration and upregulation of inflammatory mediators. Resveratrol is a polyphenolic compound found in grapes and wine, with multiple pharmacological actions, mainly anti-inflammatory, antioxidant, antitumour and immunomodulatory activities. The aim of this study was to investigate the effect of dietary resveratrol on chronic dextran sulphate sodium (DSS)-induced colitis. Six-week-old mice were randomized into two dietary groups: one standard diet and the other enriched with resveratrol at 20mg/kg of diet. After 30days, mice were exposed to 3% DSS for 5days developing acute colitis that progressed to severe chronic inflammation after 21days of water. Our results demonstrated that resveratrol group significantly attenuated the clinical signs such as loss of body weight, diarrhea and rectal bleeding improving results from disease activity index and inflammatory score. Moreover, the totality of resveratrol-fed animals survived and finished the treatment while animals fed with standard diet showed a mortality of 40%. Three weeks after DSS removal, the polyphenol caused substantial reductions of the rise of pro-inflammatory cytokines, TNF-alpha and IL-1beta and an increase of the anti-inflammatory cytokine IL-10. Also resveratrol reduced prostaglandin E synthase-1 (PGES-1), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) proteins expression, via downregulation of p38, a mitogen-activated protein kinases (MAPK) signal pathway. We conclude that resveratrol diet represents a novel approach to the treatment of chronic intestinal inflammation. Copyright 2010 Elsevier B.V. All rights reserved.

Therapeutic effect of angiogenesis inhibitor combined with radiotherapy on liver metastasis model of colon cancer

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Jin Liugen; Zhou Shifu

2005-01-01

Objective: To observe the therapeutic effect of angiogenesis inhibitor combined with radiotherapy on liver metastasis model of colon cancer. Methods: Nude mice liver metastasis model of colon cancer was established with human colon cancer cells line (LS174T) inoculated into mice' spleen and followed by splenectomy. Angiogenesis inhibitor 2-ME and radiotherapy were administered after-wads. The growth inhibition effect on metastases and neovessel was examined. Results: The incidences of liver metastasis were 100% in this intrasplenic injection model. The mean weight and microvessel density 4 weeks after inoculation were 53.6 ± 4.7 mg, 8.4 ± 1.7 in treatment group as compared to 173.9 ± 11.6 mg, 41.2 ± 6.3 in control group respectively. Conclusion: 2-ME combined with radiotherapy has significant inhibition on the growth of liver metastases. Angiogenesis inhibition is one of the mechanisms of its efficiency. (authors)

HMG-CoA reductase regulates CCL17-induced colon cancer cell migration via geranylgeranylation and RhoA activation

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Al-Haidari, Amr A.; Syk, Ingvar; Thorlacius, Henrik

2014-01-01

Highlights: • Simvastatin blocked CCL17-induced and CCR4-dependent RhoA activation in HT29 cells. • CCL17/CCR4-mediated migration of colon cancer cells was antagonised by simvastatin. • Cell migration recovered by adding Mevalonate and geranylgeranyl pyrophosphate. • Targeting HMG-CoA reductase might be useful to inhibit colon cancer metastasis. - Abstract: Background: Simvastatin is widely used to lower cholesterol levels in patients with cardiovascular diseases, although accumulating evidence suggests that statins, such as simvastatin, also exert numerous anti-tumoral effects. Aim: The aim of this study was to examine the effect of simvastatin on colon cancer cell migration. Methods: Migration assays were performed to evaluate CCL17-induced colon cancer cell (HT-29) chemotaxis. In vitro tumor growth and apoptosis were assessed using a proliferation assay and annexin V assay, respectively. Active RhoA protein levels in CCL17-stimulated colon cancer cells were quantified using a G-LISA assay. Results: We found that simvastatin dose-dependently decreased CCL17-induced colon cancer cell migration. Simvastatin had no effect on colon cancer cell proliferation or apoptosis. Inhibition of beta chemokine receptor 4, CCR4, reduced CCL17-evoked activation of RhoA in colon cancer cells. Moreover, administration of mevalonate reversed the inhibitory effect of simvastatin on CCL17-induced colon cancer cell migration. Interestingly, co-incubation with geranylgeranyl pyrophosphate (GGPP) antagonized the inhibitory impact of simvastatin on colon cancer cell migration triggered by CCL17. Moreover, we observed that simvastatin decreased CCL17-induced activation of RhoA in colon cancer cells. Administration of mevalonate and GGPP reversed the inhibitory effect of simvastatin on CCL17-provoked RhoA activation in colon cancer cells. Conclusions: Taken together, our findings show for the first time that HMG-CoA reductase regulates CCL17-induced colon cancer cell migration via

[In vitro and in vivo effects of mango pulp (Mangifera indica cv. Azucar) in colon carcinogenesis].

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Corrales-Bernal, Andrea; Amparo Urango, Luz; Rojano, Benjamín; Maldonado, Maria Elena

2014-03-01

Mango pulp contains ascorbic acid, carotenoids, polyphenols, terpenoids and fiber which are healthy and could protect against colon cancer. The aim of this study was to evaluate the antiproliferative and preventive capacity of an aqueous extract of Mangifera indica cv. Azúcar on a human colon adenocarcinoma cell line (SW480) and in a rodent model of colorectal cancer, respectively. The content of total phenolics, flavonoids and carotenoids were also analyzed in the extract. SW480 cell growth was inhibited in a dose and time dependent manner by 22.3% after a 72h exposure to the extract (200 µg/ mL). Colon carcinogenesis was initiated in Balb/c mice by two intra-peritoneal injections of azoxymethane (AOM) at the third and fourth week of giving mango in drinking water (0.3%, 0.6%, 1.25%). After 10 weeks of treatment, in the colon of mice receiving 0.3% mango, aberrant crypt foci formation was inhibited more than 60% (p=0,05) and the inhibition was dose-dependent when compared with controls receiving water. These results show that mango pulp, a natural food, non toxic, part of human being diet, contains bioactive compounds able to reduce growth of tumor cells and to prevent the appearance of precancerous lesions in colon during carcinogenesis initiation.

Inhibition of allergic dermal inflammation by the novel imidazopyridazine derivative TAK-427 in a guinea pig experimental model of eczema.

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Fukuda, Shigeru; Midoro, Katsuo; Kamei, Takayuki; Gyoten, Michiyo; Kawano, Yasuhiko; Ashida, Yasuko; Nagaya, Hideaki

2002-12-01

Antigen challenge by patch ovalbumin emulsion induced an eczema-like skin lesion in epicutaneously sensitized guinea pigs. Diseased skin sites were macroscopically characterized by manifestations of dermatitis, such as erythema, edema, and papules, and microscopically characterized by acanthosis, spongiosis, and dermal infiltration by eosinophils. Using such lesions as a model of eczema, we evaluated the potential value of TAK-427 [2-[6-[[3-[4-(diphenylmethoxy)piperidino]propyl]amino] imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionic acid dihydrate] as a therapeutic agent for atopic dermatitis by comparing it with dexamethasone and antihistamines. TAK-427 (0.3-30 mg/kg, p.o.) and dexamethasone (3 and 10 mg/kg, p.o.) inhibited eosinophil infiltration into the skin and ameliorated the dermatitis manifestations and epidermal damage. By contrast, none of the antihistamines tested (azelastine, ketotifen, terfenadine, and cetirizine) suppressed the eosinophil infiltration or dermatitis manifestations. To elucidate the mechanism by which TAK-427 inhibited the development of eczema, we investigated cytokine expression in the affected skin. Both TAK-427 and dexamethasone suppressed the increased mRNA expression of interleukin (IL)-13, granulocyte-macrophage colony-stimulating factor, IL-1alpha, tumor necrosis factor-alpha, interferon-gamma, and IL-8, but not IL-10, suggesting that TAK-427 inhibits allergic inflammation of the skin leading to the development of eczema by inhibiting the expression of proinflammatory cytokines after antigen challenge.

Obesity-related colon cancer: dietary factors and their mechanisms of anticancer action.

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Zeng, Huawei; Lazarova, Darina L

2012-02-01

Overweight/obesity is an epidemic in the US as well as in other developed countries, affecting two-thirds of Americans and an estimated 2.3 billion people worldwide. Obesity increases the risk for Type 2 diabetes, cardiovascular disease and cancer. For example, epidemiological studies have established a strong association between obesity and colon cancer. It is generally accepted that metabolic changes associated with overweight/obesity, particularly abdominal obesity and changes in adipocyte function, contribute to the increased risk of colon cancer. Understanding the mechanisms underlying this association is important for the development of preventive strategies for colon cancer. Part of these preventive strategies may be based on dietary factors, such as vitamins, minerals (e.g. selenium), fibre, phytochemicals and phenolic compounds. These anticancer nutrients may counteract the molecular changes associated with obesity. The present article reviews the evidence that inflammation and insulin resistance induced by obesity are the molecular mediators of the association between obesity and colon cancer. We also evaluate the evidence for the ability of dietary factors to target the obesity-induced changes and, thus, protect against colon cancer. © 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd.

Maresin 1 Inhibits TRPV1 in Temporomandibular Joint-Related Trigeminal Nociceptive Neurons and TMJ Inflammation-Induced Synaptic Plasticity in the Trigeminal Nucleus

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Chul-Kyu Park

2015-01-01

Full Text Available In the trigeminal system, disruption of acute resolution processing may lead to uncontrolled inflammation and chronic pain associated with the temporomandibular joint (TMJ. Currently, there are no effective treatments for TMJ pain. Recently, it has been recognized that maresin 1, a newly identified macrophage-derived mediator of inflammation resolution, is a potent analgesic for somatic inflammatory pain without noticeable side effects in mice and a potent endogenous inhibitor of transient receptor potential vanilloid 1 (TRPV1 in the somatic system. However, the molecular mechanisms underlying the analgesic actions of maresin 1 on TMJ pain are unclear in the trigeminal system. Here, by performing TMJ injection of a retrograde labeling tracer DiI (a fluorescent dye, I showed that maresin 1 potently inhibits capsaicin-induced TRPV1 currents and neuronal activity via Gαi-coupled G-protein coupled receptors in DiI-labeled trigeminal nociceptive neurons. Further, maresin 1 blocked TRPV1 agonist-evoked increases in spontaneous excitatory postsynaptic current frequency and abolished TMJ inflammation-induced synaptic plasticity in the trigeminal nucleus. These results demonstrate the potent actions of maresin 1 in regulating TRPV1 in the trigeminal system. Thus, maresin 1 may serve as a novel endogenous inhibitor for treating TMJ-inflammatory pain in the orofacial region.

Bifidobacterium breve alters immune function and ameliorates DSS-induced inflammation in weanling rats.

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Izumi, Hirohisa; Minegishi, Mario; Sato, Yohei; Shimizu, Takashi; Sekine, Kazunori; Takase, Mitsunori

2015-10-01

Bifidobacterium breve M-16V (M16V) is a probiotic bacterial strain with a long tradition of use in neonatal intensive care units in some countries. Previous study showed that the effects of M16V administration on gene expression were greater during the weaning period than in the neonatal period and were greater in the colon than in the small intestine and spleen, suggesting that M16V has anti-inflammatory effects. In this study, we evaluated the effects of inflammation during the weaning period and the effects of M16V on normal and inflammatory conditions. From postnatal day (PD) 21 to 34, weanling rats were administered of 2.5 × 10(9) of M16V daily, and colitis was induced by administration of 2% dextran sulfate sodium from PD28 to 35. Colitis severity, immune function, and microbiota were investigated. Colitis caused a reduction in body weight gain, colon shortening, poor nutritional status, anemia, changes in blood and spleen lymphocyte populations, spleen T-cell malfunctions, and alterations in colon microbiota. M16V administration improved some but not all of the changes induced by colitis. M16V could suppress inflammation and, therefore, can be considered a safe strain to use not only during the neonatal period but also the weaning period.

Ethanol extracts from Portulaca oleracea L. attenuated ischemia/reperfusion induced rat neural injury through inhibition of HMGB1 induced inflammation

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Zheng, Chenggang; Liu, Chen; Wang, Wanyin; Tang, Gusheng; Dong, Liwei; Zhou, Juan; Zhong, Zhengrong

2016-01-01

It is well demonstrated that the high mobility group box 1 (HMGB1) mediated inflammation has been implicated as one of the important causes for brain damage induced by cerebral ischemia/reperfusion (I/R). In the present study, we assessed the neuro-protective and anti-inflammation effects of the ethanol extracts from Portulaca oleracea L. (EEPO) against cerebral I/R injury in the rat transient middle cerebral artery occlusion (tMCAO) model. Rats were administrated with their respective treatment for 7 days before the MCA occlusion. After that, rats were intraperitoneal injection with chloral hydrate and sacrificed by decapitation, then the serum and brain tissue were collected. The neurological deficit score, infarct size and brain edema were tested. The levels of serum cytokine as TNF-α, IL-1β, INF-γ, IL-6, and HMGB1 and LDH were detected. The protein level of tissue or nucleus HMGB1, IκB and p-p65 were tested, too. The results showed that pretreatment with EEPO significantly decreased the neurological deficit score, infarct size and brain edema. Moreover, EEPO decreased rat serum cytokine level and rat right cortices p-p65 and IκB protein level. In conclusion all these results suggested that pretreatment with EEFPO provided significant protection against cerebral I/R injury in rats might by virtue of its anti-inflammation property through inhibition of increase of neuleus HMGB1. PMID:27904702

Broadleaf Mahonia attenuates granulomatous lobular mastitis-associated inflammation by inhibiting CCL-5 expression in macrophages

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Wang, Zhiyu; Wang, Neng; Liu, Xiaoyan; Wang, Qi; Xu, Biao; Liu, Pengxi; Zhu, Huayu; Chen, Jianping; Situ, Honglin; Lin, Yi

2018-01-01

Granulomatous lobular mastitis (GLM) is a type of chronic mammary inflammation with unclear etiology. Currently systematic corticosteroids and methitrexate are considered as the main drugs for GLM treatment, but a high toxicity and risk of recurrence greatly limit their application. It is therefore an urgent requirement that safe and efficient natural drugs are found to improve the GLM prognosis. Broadleaf Mahonia (BM) is a traditional Chinese herb that is believed to have anti-inflammatory properties according to ancient records of traditional Chinese medicine. The present study investigated this belief and demonstrated that BM significantly inhibited the expression of interleukin-1β (IL-1β), IL-6, cyclooxygenase-2 and inducible nitric oxide synthase in RAW264.7 cells, but had little influence on the cell viability, cell cycle and apoptosis. Meanwhile, the lipopolysaccharide-induced elevation of reactive oxygen species and nitric oxide was also blocked following BM treatment, accompanied with decreased activity of nuclear factor-κB and MAPK signaling. A cytokine array further validated that BM exhibited significant inhibitory effects on several chemoattractants, including chemokine (C-C motif) ligand (CCL)-2, CCL-3, CCL-5 and secreted tumor necrosis factor receptor 1, among which CCL-5 exhibited the highest inhibition ratio in cell and clinical GLM specimens. Collectively, the results show that BM is a novel effective anti-inflammatory herb in vitro and ex vivo, and that CCL-5 may be closely associated with GLM pathogenesis. PMID:29138800

Broadleaf Mahonia attenuates granulomatous lobular mastitis‑associated inflammation by inhibiting CCL‑5 expression in macrophages.

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Wang, Zhiyu; Wang, Neng; Liu, Xiaoyan; Wang, Qi; Xu, Biao; Liu, Pengxi; Zhu, Huayu; Chen, Jianping; Situ, Honglin; Lin, Yi

2018-01-01

Granulomatous lobular mastitis (GLM) is a type of chronic mammary inflammation with unclear etiology. Currently systematic corticosteroids and methitrexate are considered as the main drugs for GLM treatment, but a high toxicity and risk of recurrence greatly limit their application. It is therefore an urgent requirement that safe and efficient natural drugs are found to improve the GLM prognosis. Broadleaf Mahonia (BM) is a traditional Chinese herb that is believed to have anti‑inflammatory properties according to ancient records of traditional Chinese medicine. The present study investigated this belief and demonstrated that BM significantly inhibited the expression of interleukin‑1β (IL‑1β), IL‑6, cyclooxygenase‑2 and inducible nitric oxide synthase in RAW264.7 cells, but had little influence on the cell viability, cell cycle and apoptosis. Meanwhile, the lipopolysaccharide‑induced elevation of reactive oxygen species and nitric oxide was also blocked following BM treatment, accompanied with decreased activity of nuclear factor‑κB and MAPK signaling. A cytokine array further validated that BM exhibited significant inhibitory effects on several chemoattractants, including chemokine (C‑C motif) ligand (CCL)‑2, CCL‑3, CCL‑5 and secreted tumor necrosis factor receptor 1, among which CCL‑5 exhibited the highest inhibition ratio in cell and clinical GLM specimens. Collectively, the results show that BM is a novel effective anti‑inflammatory herb in vitro and ex vivo, and that CCL‑5 may be closely associated with GLM pathogenesis.

Antifibrotic Mechanism of Pinocembrin: Impact on Oxidative Stress, Inflammation and TGF-β /Smad Inhibition in Rats.

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Said, Marwa M; Azab, Samar S; Saeed, Noha M; El-Demerdash, Ebtehal

2018-03-01

The present study aimed to elucidate the potential antifibrotic effects of pinocembrin (PIN), a flavanone found abundantly in honey and propolis, by studying its effect on different oxidative stress, inflammatory and fibrosis markers in an experimental model of CCl4-induced liver fibrosis. PIN (20 mg/kg) was given orally 3 times/week for 6 consecutive weeks alternating with CCl4 (0.5 mL/kg, 1:1 mixture with corn oil, i. p.) twice weekly. Different hepatotoxicity indices, oxidative stress, inflammatory and liver fibrosis markers were assessed. PIN significantly restored liver transaminases and total cholesterol to normal levels. Also, PIN ameliorated oxidative stress injury evoked by CCl4 as evidenced by inhibition of reduced glutathione depletion and lipid peroxidation as well as elevation of antioxidant enzyme superoxide dismutase (SOD). Further, PIN upregulated the nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2), thereby inducing the expression and activity of the cytoprotective enzyme hemeoxygenase-1 (HO-1). Moreover, PIN alleviated pro-inflammatory cytokines such as TNF-α via inhibiting nuclear factor-κB (NF-κB) activation. As markers of fibrosis, collagen and α-SMA expression increased markedly in the CCl4 group and PIN prevented these alterations. In addition, PIN down-regulated TGFβ1 and p-Smad2/3, thereby inhibiting TGFβ1/Smad signaling pathway. These results suggest that PIN possess potent antifibrotic effects that can be explained on its antioxidant properties. It ameliorates oxidative stress and inflammation during induction of fibrogenesis via its ability to augment celular antioxidant defenses, activating Nrf2-mediated HO-1 expression and modulating NF-κB and TGF-β1/Smad signaling pathway.

Nasal Bacterial Colonization in Pediatric Epistaxis: The Role of Topical Antibacterial Treatment

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Mukaddder Korkmaz

2016-04-01

Full Text Available Background: Epistaxis is a common problem in childhood. It has been shown that children with recurrent epistaxis are more likely to have nasal colonization with Staphylococcus aureus. It has been suggested that low-grade inflammation, crusting and increased vascularity due to bacterial colonization contributes to the development of epistaxis in children. Aims: This study aimed to investigate the nasal colonization and treatment outcome in pediatric epistaxis patients. Study Design: Retrospective cross-sectional study. Methods: Charts of the pediatric patients referred to our university hospital otolaryngology outpatient clinics for the evaluation of epistaxis were reviewed. The patients whose nasal cultures had been taken at the first clinical visit comprised the study group. Results: Staphylococcus aureus was the most common bacteria grown. The presence of crusting and hypervascularity was not dependent on the type of bacterial growth and there was no relation between hypervascularity and crusting of the nasal mucosa. Thirty-six patients were evaluated for the outcome analysis. Resolution of bleeding was not dependent on nasal colonization; in patients with colonization, there was no difference between topical antibacterial and non-antibacterial treatments. Conclusion: Despite the high colonization rates, topical antibacterial treatment was not found superior to non-antibacterial treatment. Our study does not support the belief that bacterial colonization results in hypervascularity of the septal mucosa causing epistaxis since no relation was found between nasal colonization, hypervascularity and crusting. The role of bacterial colonization in pediatric epistaxis need to be further investigated and treatment protocols must be determined accordingly.

Induced terpene accumulation in Norway spruce inhibits bark beetle colonization in a dose-dependent manner.

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Tao Zhao

Full Text Available Tree-killing bark beetles (Coleoptera, Scolytinae are among the most economically and ecologically important forest pests in the northern hemisphere. Induction of terpenoid-based oleoresin has long been considered important in conifer defense against bark beetles, but it has been difficult to demonstrate a direct correlation between terpene levels and resistance to bark beetle colonization.To test for inhibitory effects of induced terpenes on colonization by the spruce bark beetle Ips typographus (L. we inoculated 20 mature Norway spruce Picea abies (L. Karsten trees with a virulent fungus associated with the beetle, Ceratocystis polonica (Siem. C. Moreau, and investigated induced terpene levels and beetle colonization in the bark.Fungal inoculation induced very strong and highly variable terpene accumulation 35 days after inoculation. Trees with high induced terpene levels (n = 7 had only 4.9% as many beetle attacks (5.1 vs. 103.5 attacks m(-2 and 2.6% as much gallery length (0.029 m m(-2 vs. 1.11 m m(-2 as trees with low terpene levels (n = 6. There was a highly significant rank correlation between terpene levels at day 35 and beetle colonization in individual trees. The relationship between induced terpene levels and beetle colonization was not linear but thresholded: above a low threshold concentration of ∼100 mg terpene g(-1 dry phloem trees suffered only moderate beetle colonization, and above a high threshold of ∼200 mg terpene g(-1 dry phloem trees were virtually unattacked.This is the first study demonstrating a dose-dependent relationship between induced terpenes and tree resistance to bark beetle colonization under field conditions, indicating that terpene induction may be instrumental in tree resistance. This knowledge could be useful for developing management strategies that decrease the impact of tree-killing bark beetles.

Development of Novel Promiscuous Anti-Chemokine Peptibodies for Treating Autoimmunity and Inflammation

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Michal Abraham

2017-11-01

Full Text Available Chemokines and their receptors play critical roles in the progression of autoimmunity and inflammation. Typically, multiple chemokines are involved in the development of these pathologies. Indeed, targeting single chemokines or chemokine receptors has failed to achieve significant clinical benefits in treating autoimmunity and inflammation. Moreover, the binding of host atypical chemokine receptors to multiple chemokines as well as the binding of chemokine-binding proteins secreted by various pathogens can serve as a strategy for controlling inflammation. In this work, promiscuous chemokine-binding peptides that could bind and inhibit multiple inflammatory chemokines, such as CCL2, CCL5, and CXCL9/10/11, were selected from phage display libraries. These peptides were cloned into human mutated immunoglobulin Fc-protein fusions (peptibodies. The peptibodies BKT120Fc and BKT130Fc inhibited the ability of inflammatory chemokines to induce the adhesion and migration of immune cells. Furthermore, BKT120Fc and BKT130Fc also showed a significant inhibition of disease progression in a variety of animal models for autoimmunity and inflammation. Developing a novel class of antagonists that can control the courses of diseases by selectively blocking multiple chemokines could be a novel way of generating effective therapeutics.

Memory Deficits Induced by Inflammation Are Regulated by α5-Subunit-Containing GABAA Receptors

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Dian-Shi Wang

2012-09-01

Full Text Available Systemic inflammation causes learning and memory deficits through mechanisms that remain poorly understood. Here, we studied the pathogenesis of memory loss associated with inflammation and found that we could reverse memory deficits by pharmacologically inhibiting α5-subunit-containing γ-aminobutyric acid type A (α5GABAA receptors and deleting the gene associated with the α5 subunit. Acute inflammation reduces long-term potentiation, a synaptic correlate of memory, in hippocampal slices from wild-type mice, and this reduction was reversed by inhibition of α5GABAA receptor function. A tonic inhibitory current generated by α5GABAA receptors in hippocampal neurons was increased by the key proinflammatory cytokine interleukin-1β through a p38 mitogen-activated protein kinase signaling pathway. Interleukin-1β also increased the surface expression of α5GABAA receptors in the hippocampus. Collectively, these results show that α5GABAA receptor activity increases during inflammation and that this increase is critical for inflammation-induced memory deficits.

Effects of adsorbed and templated nanosilver in mesoporous calcium-silicate nanoparticles on inhibition of bacteria colonization of dentin

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Fan W

2014-11-01

Full Text Available Wei Fan,1,* Daming Wu,1,* Franklin R Tay,2 Tengjiao Ma,1 Yujie Wu,1 Bing Fan1 1The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, People’s Republic of China; 2Department of Endodontics, Georgia Regents University, Augusta, Georgia, USA *These authors contributed equally to this work Abstract: Mesoporous calcium-silicate nanoparticles (MCSNs are advanced biomaterials for controlled drug delivery and mineralization induction. Nanosilver-incorporated MCSNs (Ag-MCSNs were prepared in the present study using both the adsorption and template methods. Both versions of Ag-MCSNs showed characteristic morphology of mesoporous materials and exhibited sustained release of ions over time. In antibacterial testing against planktonic Enterococcus faecalis, Ag-MCSNs showed significantly better antibacterial effects when compared with MCSNs (P<0.05. The Ag-MCSNs aggregated on the dentin surface of root canal walls and infiltrated into dentinal tubules after ultrasound activation, significantly inhibiting the adherence and colonization of E. faecalis on dentin (P<0.05. Despite this, Ag-MCSNs with templated nanosilver showed much lower cytotoxicity than Ag-MCSNs with adsorbed nanosilver (P<0.05. The results of the present study indicated that nanosilver could be incorporated into MCSNs using the template method. The templated nanosilver could release silver ions and inhibit the growth and colonization of E. faecalis both in the planktonic form and as biofilms on dentin surfaces as absorbed nanosilver. Templated Ag-MCSNs may be developed into a new intracanal disinfectant for root canal disinfection due to their antibacterial ability and low cytotoxicity, and as controlled release devices for other bioactive molecules to produce multifunctional biomaterials. Keywords: antibacterial effect, mesoporosity

miR-4458 suppresses glycolysis and lactate production by directly targeting hexokinase2 in colon cancer cells

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Qin, Yaguang; Cheng, Chuanyao; Lu, Hong, E-mail: honglu6512@163.com; Wang, Yaqiu

2016-01-01

miR-4458, a new tumor-suppressor, was reported to down-regulated in human hepatocellular carcinoma. The expression status, roles and inhibitory mechanisms of miR-4458 in other tumors still need to be clarified. The aim of this study is to investigate the effects of miR-4458 and to elucidate the potential mechanism in colon cancer cells. Using bioinformatic databases, we predicted that hexokinase2 (HK2), a rate-limiting enzyme in the glycolytic pathway, was a target of miR-4458, so the effects of miR-4458 on glycolysis and lactate production was assessed in colon cancer cells. We found that miR-4458 was down-regulated and HK2 was up-regulated in colon cancer cells. Overexpression of miR-4458 inhibited proliferation, glycolysis, and lactate production under both normoxic and hypoxic conditions. Luciferase activity assays showed that HK2 was a direct target of miR-4458. Moreover, knockdown of HK2 by specific RNAi also suppressed proliferation, glycolysis, and lactate production under both normoxic and hypoxic conditions. In conclusion, our findings suggested that miR-4458 inhibited the progression of colon cancer cells by inhibition of glycolysis and lactate production via directly targeting HK2 mRNA. - Highlights: • miR-4458 is down-regulated in colon cancer cells. • miR-4458 suppresses proliferation, glycolysis, and lactate production. • HK2 is a target of miR-4458. • HK2 knockdown inhibits proliferation, glycolysis, and lactate production.

Effect of Aging on Periodontal Inflammation, Microbial Colonization, and Disease Susceptibility.

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Wu, Y; Dong, G; Xiao, W; Xiao, E; Miao, F; Syverson, A; Missaghian, N; Vafa, R; Cabrera-Ortega, A A; Rossa, C; Graves, D T

2016-04-01

Periodontitis is a chronic inflammatory disease induced by a biofilm that forms on the tooth surface. Increased periodontal disease is associated with aging. We investigated the effect of aging on challenge by oral pathogens, examining the host response, colonization, and osteoclast numbers in aged versus young mice. We also compared the results with mice with lineage-specific deletion of the transcription factor FOXO1, which reduces dendritic cell (DC) function. Periodontitis was induced by oral inoculation of Porphyromonas gingivalis and Fusobacterium nucleatum in young (4 to 5 mo) and aged (14 to 15 mo) mice. Aged mice as well as mice with reduced DC function had decreased numbers of DCs in lymph nodes, indicative of a diminished host response. In vitro studies suggest that reduced DC numbers in lymph nodes of aged mice may involve the effect of advanced glycation end products on DC migration. Surprisingly, aged mice but not mice with genetically altered DC function had greater production of antibody to P. gingivalis, greater IL-12 expression, and more plasma cells in lymph nodes following oral inoculation as compared with young mice. The greater adaptive immune response in aged versus young mice was linked to enhanced levels of P. gingivalis and reduced bacterial diversity. Thus, reduced bacterial diversity in aged mice may contribute to increased P. gingivalis colonization following inoculation and increased periodontal disease susceptibility, reflected by higher TNF levels and osteoclast numbers in the periodontium of aged versus young mice. © International & American Associations for Dental Research 2016.

The Composition of Colonic Commensal Bacteria According to Anatomical Localization in Colorectal Cancer

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Liuyang Zhao

2017-02-01

Full Text Available Colorectal cancer (CRC is a multistage disease resulting from complex factors, including genetic mutations, epigenetic changes, chronic inflammation, diet, and lifestyle. Recent accumulating evidence suggests that the gut microbiota is a new and important player in the development of CRC. Imbalance of the gut microbiota, especially dysregulated gut bacteria, contributes to colon cancer through mechanisms of inflammation, host defense modulations, oxidative stress, and alterations in bacterial-derived metabolism. Gut commensal bacteria are anatomically defined as four populations: luminal commensal bacteria, mucus-resident bacteria, epithelium-resident bacteria, and lymphoid tissue-resident commensal bacteria. The bacterial flora that are harbored in the gastrointestinal (GI tract vary both longitudinally and cross-sectionally by different anatomical localization. It is notable that the translocation of colonic commensal bacteria is closely related to CRC progression. CRC-associated bacteria can serve as a non-invasive and accurate biomarker for CRC diagnosis. In this review, we summarize recent findings on the oncogenic roles of gut bacteria with different anatomical localization in CRC progression.

Bisphosphonates Inhibit Pain, Bone Loss, and Inflammation in a Rat Tibia Fracture Model of Complex Regional Pain Syndrome.

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Wang, Liping; Guo, Tian-Zhi; Hou, Saiyun; Wei, Tzuping; Li, Wen-Wu; Shi, Xiaoyou; Clark, J David; Kingery, Wade S

2016-10-01

Bisphosphonates are used to prevent the bone loss and fractures associated with osteoporosis, bone metastases, multiple myeloma, and osteogenesis deformans. Distal limb fractures cause regional bone loss with cutaneous inflammation and pain in the injured limb that can develop into complex regional pain syndrome (CRPS). Clinical trials have reported that antiresorptive bisphosphonates can prevent fracture-induced bone loss, inhibit serum inflammatory cytokine levels, and alleviate CRPS pain. Previously, we observed that the inhibition of inflammatory cytokines or adaptive immune responses attenuated the development of pain behavior in a rat fracture model of CRPS, and we hypothesized that bisphosphonates could prevent pain behavior, trabecular bone loss, postfracture cutaneous cytokine upregulation, and adaptive immune responses in this CRPS model. Rats underwent tibia fracture and cast immobilization for 4 weeks and were chronically administered either subcutaneously perfused alendronate or oral zoledronate. Behavioral measurements included hindpaw von Frey allodynia, unweighting, warmth, and edema. Bone microarchitecture was measured by microcomputed tomography, and bone cellular activity was evaluated by static and dynamic histomorphometry. Spinal cord Fos immunostaining was performed, and skin cytokine (tumor necrosis factor, interleukin [IL]-1, IL-6) and nerve growth factor (NGF) levels were determined by enzyme immunoassay. Skin and sciatic nerve immunoglobulin levels were determined by enzyme immunoassay. Rats with tibia fractures developed hindpaw allodynia, unweighting, warmth, and edema, increased spinal Fos expression and trabecular bone loss in the lumbar vertebra and bilateral distal femurs as measured by microcomputed tomography, increased trabecular bone resorption and osteoclast surface with decreased bone formation rates, increased cutaneous inflammatory cytokine and NGF expression, and elevated immunocomplex deposition in skin and nerve

The Streptococcus pneumoniae Competence Regulatory System Influences Respiratory Tract Colonization ▿

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Kowalko, J. E.; Sebert, M. E.

2008-01-01

The Streptococcus pneumoniae ComDE two-component signaling system controls the development of genetic competence in the bacterium and affects virulence in models of pneumonia and bacteremia. We have investigated the impact of the competence pathway during colonization of the nasopharynx, the principal ecological niche of the pneumococcus. Previous work showed that deletion of the pneumococcal CiaRH signaling system inhibited colonization and increased expression of genes required for competen...

Controlling the complement system in inflammation.

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Kirschfink, M

1997-12-01

Inappropriate or excessive activation of the complement system can lead to harmful, potentially life-threatening consequences due to severe inflammatory tissue destruction. These consequences are clinically manifested in various disorders, including septic shock, multiple organ failure and hyperacute graft rejection. Genetic complement deficiencies or complement depletion have been proven to be beneficial in reducing tissue injury in a number of animal models of severe complement-dependent inflammation. It is therefore believed that therapeutic inhibition of complement is likely to arrest the process of certain diseases. Attempts to efficiently inhibit complement include the application of endogenous soluble complement inhibitors (C1-inhibitor, recombinant soluble complement receptor 1- rsCR1), the administration of antibodies, either blocking key proteins of the cascade reaction (e.g. C3, C5), neutralizing the action of the complement-derived anaphylatoxin C5a, or interfering with complement receptor 3 (CR3, CD18/11b)-mediated adhesion of inflammatory cells to the vascular endothelium. In addition, incorporation of membrane-bound complement regulators (DAF-CD55, MCP-CD46, CD59) has become possible by transfection of the correspondent cDNA into xenogeneic cells. Thereby, protection against complement-mediated inflammatory tissue damage could be achieved in various animal models of sepsis, myocardial as well as intestinal ischemia/reperfusion injury, adult respiratory distress syndrome, nephritis and graft rejection. Supported by results from first clinical trials, complement inhibition appears to be a suitable therapeutic approach to control inflammation. Current strategies to specifically inhibit complement in inflammation have been discussed at a recent meeting on the 'Immune Consequences of Trauma, Shock and Sepsis', held from March 4-8, 1997, in Munich, Germany. The Congress (chairman: E. Faist, Munich, Germany), which was held in close cooperation with various

Inflammation, Adenoma and Cancer: Objective Classification of Colon Biopsy Specimens with Gene Expression Signature

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Orsolya Galamb

2008-01-01

Full Text Available Gene expression analysis of colon biopsies using high-density oligonucleotide microarrays can contribute to the understanding of local pathophysiological alterations and to functional classification of adenoma (15 samples, colorectal carcinomas (CRC (15 and inflammatory bowel diseases (IBD (14. Total RNA was extracted, amplified and biotinylated from frozen colonic biopsies. Genome-wide gene expression profile was evaluated by HGU133plus2 microarrays and verified by RT-PCR. We applied two independent methods for data normalization and used PAM for feature selection. Leave one-out stepwise discriminant analysis was performed. Top validated genes included collagenIVα1, lipocalin-2, calumenin, aquaporin-8 genes in CRC; CD44, met proto-oncogene, chemokine ligand-12, ADAM-like decysin-1 and ATP-binding casette-A8 genes in adenoma; and lipocalin-2, ubiquitin D and IFITM2 genes in IBD. Best differentiating markers between Ulcerative colitis and Crohn's disease were cyclin-G2; tripartite motif-containing-31; TNFR shedding aminopeptidase regulator-1 and AMICA. The discriminant analysis was able to classify the samples in overall 96.2% using 7 discriminatory genes (indoleamine-pyrrole-2,3-dioxygenase, ectodermal-neural cortex, TIMP3, fucosyltransferase-8, collectin sub-family member 12, carboxypeptidase D, and transglutaminase-2. Using routine biopsy samples we successfully performed whole genomic microarray analysis to identify discriminative signatures. Our results provide further insight into the pathophysiological background of colonic diseases. The results set up data warehouse which can be mined further.

FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis

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Verbeke, Len; Mannaerts, Inge; Schierwagen, Robert; Govaere, Olivier; Klein, Sabine; Vander Elst, Ingrid; Windmolders, Petra; Farre, Ricard; Wenes, Mathias; Mazzone, Massimiliano; Nevens, Frederik; van Grunsven, Leo A.; Trebicka, Jonel; Laleman, Wim

2016-01-01

Hepatic inflammation drives hepatic stellate cells (HSC), resulting in liver fibrosis. The Farnesoid-X receptor (FXR) antagonizes inflammation through NF-κB inhibition. We investigated preventive and therapeutic effects of FXR agonist obeticholic acid (OCA) on hepatic inflammation and fibrosis in toxic cirrhotic rats. Cirrhosis was induced by thioacetamide (TAA) intoxication. OCA was given during or after intoxication with vehicle-treated rats as controls. At sacrifice, fibrosis, hemodynamic and biochemical parameters were assessed. HSC activation, cell turn-over, hepatic NF-κB activation, pro-inflammatory and pro-fibrotic cytokines were determined. The effect of OCA was further evaluated in isolated HSC, Kupffer cells, hepatocytes and liver sinusoidal endothelial cells (LSEC). OCA decreased hepatic inflammation and fibrogenesis during TAA-administration and reversed fibrosis in established cirrhosis. Portal pressure decreased through reduced intrahepatic vascular resistance. This was paralleled by decreased expression of pro-fibrotic cytokines (transforming growth-factor β, connective tissue growth factor, platelet-derived growth factor β-receptor) as well as markers of hepatic cell turn-over, by blunting effects of pro-inflammatory cytokines (e.g. monocyte chemo-attractant protein-1). In vitro, OCA inhibited both LSEC and Kupffer cell activation; while HSC remained unaffected. This related to NF-κB inhibition via up-regulated IκBα. In conclusion, OCA inhibits hepatic inflammation in toxic cirrhotic rats resulting in decreased HSC activation and fibrosis. PMID:27634375

Inflammation arising from obesity reduces taste bud abundance and inhibits renewal.

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Kaufman, Andrew; Choo, Ezen; Koh, Anna; Dando, Robin

2018-03-01

Despite evidence that the ability to taste is weakened by obesity and can be rescued with weight loss intervention, few studies have investigated the molecular effects of obesity on the taste system. Taste bud cells undergo continual turnover even in adulthood, exhibiting an average life span of only a few weeks, tightly controlled by a balance of proliferation and cell death. Recent data reveal that an acute inflammation event can alter this balance. We demonstrate that chronic low-grade inflammation brought on by obesity reduces the number of taste buds in gustatory tissues of mice-and is likely the cause of taste dysfunction seen in obese populations-by upsetting this balance of renewal and cell death.

[Changes of expression of miR-155 in colitis-associated colonic carcinogenesis].

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Li, Weiwei; Han, Wenxiao; Zhao, Xinhua; Wang, Hongying

2014-04-01

To investigate the changes of miR-155 and its target genes in colitis-associated carcinogenesis. Colitis-associated colon cancer was induced by azoxymethane (AOM) and dextran sulfate sodium (DSS) in C57BL/6 mice. Mice of three different stages during the development of colon cancer were obtained, named AD1, AD2 and AD3, respectively. A control group of mice without any treatment and a DSS only group representing chronic inflammation without cancer were set up as well. Colon tissue was collected and expression of miR-155 in the colon tissues was measured by real-time fluorescent quantitative PCR. TargetScan and PicTar were used to predict potential target genes of miR-155, which were then preliminarily screened with our gene expression microarray database of AOM-DSS mouse model. Regular PCR was used to confirm the changes of the expression of these potential target genes in AOM-DSS mouse model. Colitis-associated colon cancer was effectively induced by azoxymethane and dextran sulfate sodium in C57BL/6 mice. Histological examination revealed that the evolution process was sequentially from normal, mild dysplasia, moderate dysplasia, and severe dysplasia to adenocarcinoma in the AOM-DSS mouse model. The level of miR-155 was gradually elevated with the formation of colitis-associated colon cancer. There was no significant difference between the levels of miR-155 expression in the DSS group (0.005 6 ± 0.003 7) and control group (0.012 0 ± 0.005 1) (P > 0.05), but the level of miR-155 in the AD3 group (0.054 4 ± 0.027 0) was significantly higher than that of the DSS group (0.005 6 ± 0.003 7)(P Bcorl1, Cacna1c, Rspo2 and Foxo3 were potential target genes of miR-155 in the AOM-DSS mouse model. Changes of Kcna1 and Cacna1c in the AOM-DSS mouse model were validated to be consistent with the changes obtained with the gene expression microarray. The up-regulation of miR-155 is related to colitis-associated carcinogenesis, but is irrelevant to chronic inflammation in the

Illicium verum Extract and Trans-Anethole Attenuate Ovalbumin-Induced Airway Inflammation via Enhancement of Foxp3+ Regulatory T Cells and Inhibition of Th2 Cytokines in Mice

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Yoon-Young Sung

2017-01-01

Full Text Available Illicium verum is used in traditional medicine to treat inflammation. The study investigates the effects of IVE and its component, trans-anethole (AET, on airway inflammation in ovalbumin- (OVA- induced asthmatic mice. Asthma was induced in BALB/c mice by systemic sensitization to OVA, followed by intratracheal, intraperitoneal, and aerosol allergen challenges. IVE and AET were orally administered for four weeks. We investigated the effects of treatment on airway hyperresponsiveness, IgE production, pulmonary eosinophilic infiltration, immune cell phenotypes, Th2 cytokine production in bronchoalveolar lavage, Th1/Th2 cytokine production in splenocytes, forkhead box protein 3 (Foxp3 expression, and lung histology. IVE and AET ameliorated OVA-driven airway hyperresponsiveness (p<0.01, pulmonary eosinophilic infiltration (p<0.05, mucus hypersecretion (p<0.01, and IL-4, IL-5, IL-13, and CCR3 production (p<0.05, as well as IgE levels (p<0.01. IVE and AET increased Foxp3 expression in lungs (p<0.05. IVE and AET reduced IL-4 and increased IFN-γ production in the supernatant of splenocyte cultures (p<0.05. Histological studies showed that IVE and AET inhibited eosinophilia and lymphocyte infiltration in lungs (p<0.01. These results indicate that IVE and AET exert antiasthmatic effects through upregulation of Foxp3+ regulatory T cells and inhibition of Th2 cytokines, suggesting that IVE may be a potential therapeutic agent for allergic lung inflammation.

Genetic variation in 15-hydroxyprostaglandin dehydrogenase and colon cancer susceptibility.

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Cheryl L Thompson

Full Text Available 15-Hydroxyprostaglandin dehydrogenase (15-PGDH is a metabolic antagonist of COX-2, catalyzing the degradation of inflammation mediator prostaglandin E2 (PGE2 and other prostanoids. Recent studies have established the 15-PGDH gene as a colon cancer suppressor.We evaluated 15-PDGH as a colon cancer susceptibility locus in a three-stage design. We first genotyped 102 single-nucleotide polymorphisms (SNPs in the 15-PGDH gene, spanning ∼50 kb up and down-stream of the coding region, in 464 colon cancer cases and 393 population controls. We then genotyped the same SNPs, and also assayed the expression levels of 15-PGDH in colon tissues from 69 independent patients for whom colon tissue and paired germline DNA samples were available. In the final stage 3, we genotyped the 9 most promising SNPs from stages 1 and 2 in an independent sample of 525 cases and 816 controls (stage 3.In the first two stages, three SNPs (rs1365611, rs6844282 and rs2332897 were statistically significant (p<0.05 in combined analysis of association with risk of colon cancer and of association with 15-PGDH expression, after adjustment for multiple testing. For one additional SNP, rs2555639, the T allele showed increased cancer risk and decreased 15-PGDH expression, but just missed statistical significance (p-adjusted = 0.063. In stage 3, rs2555639 alone showed evidence of association with an odds ratio (TT compared to CC of 1.50 (95% CI = 1.05-2.15, p = 0.026.Our data suggest that the rs2555639 T allele is associated with increased risk of colon cancer, and that carriers of this risk allele exhibit decreased expression of 15-PGDH in the colon.

Identification of colonic fibroblast secretomes reveals secretory factors regulating colon cancer cell proliferation.

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Chen, Sun-Xia; Xu, Xiao-En; Wang, Xiao-Qing; Cui, Shu-Jian; Xu, Lei-Lei; Jiang, Ying-Hua; Zhang, Yang; Yan, Hai-Bo; Zhang, Qian; Qiao, Jie; Yang, Peng-Yuan; Liu, Feng

2014-10-14

Stromal microenvironment influences tumor cell proliferation and migration. Fibroblasts represent the most abundant stromal constituents. Here, we established two pairs of normal fibroblast (NF) and cancer-associated fibroblast (CAF) cultures from colorectal adenocarcinoma tissues and the normal counterparts. The NFs and CAFs were stained positive for typical fibroblast markers and inhibited colon cancer (CC) cell proliferation in in vitro cocultures and in xenograft mouse models. The fibroblast conditioned media were analyzed using LC-MS and 227 proteins were identified at a false discovery rate of 1.3%, including 131 putative secretory and 20 plasma membrane proteins. These proteins were enriched for functional categories of extracellular matrix, adhesion, cell motion, inflammatory response, redox homeostasis and peptidase inhibitor. Secreted protein acidic and rich in cysteine, transgelin, follistatin-related protein 1 (FSTL1) and decorin was abundant in the fibroblast secretome as confirmed by Western blot. Silencing of FSTL1 and transgelin in colonic fibroblast cell line CCD-18Co induced an accelerated proliferation of CC cells in cocultures. Exogenous FSTL1 attenuates CC cell proliferation in a negative fashion. FSTL1 was upregulated in CC patient plasma and cancerous tissues but had no implication in prognosis. Our results provided novel insights into the molecular signatures and modulatory role of CC associated fibroblasts. In this study, a label-free LC-MS was performed to analyze the secretomes of two paired primary fibroblasts, which were isolated from fresh surgical specimen of colorectal adenocarcinoma and adjacent normal colonic tissues and exhibited negative modulatory activity for colon cancer cell growth in in vitro cocultures and in vivo xenograph mouse models. Follistatin-related protein 1 was further revealed to be one of the stroma-derived factors of potential suppression role for colon cancer cell proliferation. Our results provide novel

GLP-1 nanomedicine alleviates gut inflammation.

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Anbazhagan, Arivarasu N; Thaqi, Mentor; Priyamvada, Shubha; Jayawardena, Dulari; Kumar, Anoop; Gujral, Tarunmeet; Chatterjee, Ishita; Mugarza, Edurne; Saksena, Seema; Onyuksel, Hayat; Dudeja, Pradeep K

2017-02-01

The gut hormone, glucagon like peptide-1 (GLP-1) exerts anti-inflammatory effects. However, its clinical use is limited by its short half-life. Previously, we have shown that GLP-1 as a nanomedicine (GLP-1 in sterically stabilized phospholipid micelles, GLP-1-SSM) has increased in vivo stability. The current study was aimed at testing the efficacy of this GLP-1 nanomedicine in alleviating colonic inflammation and associated diarrhea in dextran sodium sulfate (DSS) induced mouse colitis model. Our results show that GLP-1-SSM treatment markedly alleviated the colitis phenotype by reducing the expression of pro-inflammatory cytokine IL-1β, increasing goblet cells and preserving intestinal epithelial architecture in colitis model. Further, GLP-1-SSM alleviated diarrhea (as assessed by luminal fluid) by increasing protein expression of intestinal chloride transporter DRA (down regulated in adenoma). Our results indicate that GLP-1 nanomedicine may act as a novel therapeutic tool in alleviating gut inflammation and associated diarrhea in inflammatory bowel disease (IBD). Published by Elsevier Inc.

MicroRNA-215 suppresses cell proliferation, migration and invasion of colon cancer by repressing Yin-Yang 1

International Nuclear Information System (INIS)

Chen, Zehong; Han, Siqi; Huang, Wensheng; Wu, Jialin; Liu, Yuyi; Cai, Shirong; He, Yulong; Wu, Suijing; Song, Wu

2016-01-01

Colorectal cancer is one of the most common malignant tumors worldwide with rising incidence. MicroRNAs are small non-coding RNAs that implicate in multiple physiological or pathological processes. The aberrant expression of miRNA-215 (miR-215) has been illustrated in various types of cancers. However, the expression of miR-215 in human colon cancer and the biological roles of it remain largely unknown. We conducted this study to explore the expression and the function of miR-215 in human colon cancer. The results showed that miR-215 was remarkably downregulated in colon cancer tissues and cell lines. Overexpression of miR-215 by miR-215 mimic significantly inhibited colon cancer cell proliferation, migration and invasion while knockdown of miR-215 by miR-215 inhibitor exerted reverse effects. Furthermore, we newly identified Yin-Yang 1(YY1) as a direct target of miR-215 which could rescue the effects of miR-215 on colon cancer cells. In summary, our investigation revealed that miR-215 was downregulated in colon cancer and it suppressed colon cancer cell proliferation, migration and invasion by directly targeting YY1. - Highlights: • MiR-215 expression was decreased in colon cancer tissues and cell lines. • Mir-215 inhibited colon cancer cell proliferation, migration and invasion. • MiR-215 targeted YY1 directly. • The effects of miR-215 on colon cancer cells were mediated by YY1.

Retinoic acid morpholine amide (RAMA) inhibits expression of Fas ligand through EP1 receptor in colon cancer cells.

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Chen, Shao-Xuan; Du, Shi-Yu; Wang, Yun-Ting; Zhao, Hong-Chuan; Zhang, Yan-Li; Yao, Li

2016-01-01

Among the members of tumour necrosis factor family Fas ligand on binding to its receptor strongly induces apoptosis of tumour-infiltrating lymphocytes (TIL). Thus, FasL acts as an inhibitor of anti-tumour immune response. The present study demonstrates that retinoic acid morpholine amide (RAMA) significantly suppresses FasL expression in colon cancer cells in a dose- and time-dependent manner. The suppression of FasL mRNA and proteins was significant at a concentration of 30 μM after 48 h in CLT85 and HT26 colon cancer cells. There was around 2.6- and 3.2-fold decrease in FasL mRNA after incubation with 30 μM of RAMA in CLT85 cells and HT26 cells, respectively. The results from Western blot showed a decrease in FasL mRNA and protein expression in both CLT85 and HT26 cells after suppression of cyclooxygenase (COX)-2 and COX-1 by RNAi. However, when COX-2-specific silencer RNA (siCOX-2)- and siCOX-1-treated CLT85 and HT26 cells were exposed to RAMA, inhibition of FasL expression was further suppressed. The siCOX-2-treated CLT85 and HT26 cells on exposure to RAMA showed ∼87 and ∼54 % reduction in FasL mRNA, respectively. Co-culture of Jurkat T cells with RAMA-treated HT26 and CLT85 cells decreased the viability of Jurkat T cells by only 2 and 4.3 %, respectively, compared to 19.5 and 37.3 % in control HT26 and CLT85 cells. The results from real-time reverse transcription polymerase chain reaction (RT-PCR) and immunoblotting showed that suppression of EP1 prevented RAMA-induced FasL suppression in CLT85 cells at both the mRNA and protein levels. Thus, RAMA can be a potent therapeutic agent for the treatment of colon tumours.

Electrolyte transport in distal colon of sodium-depleted rats: Effect of sodium repletion

International Nuclear Information System (INIS)

Turnamian, S.G.; Binder, H.J.

1988-01-01

Dietary sodium depletion increases plasma aldosterone level and, as a result, induces amiloride-sensitive electrogenic sodium absorption and electrogenic potassium secretion and stimulates Na + -K + -ATPase activity in rat distal colon, while inhibiting electroneutral sodium chloride absorption. To assess the events that occur as the aldosterone-stimulated colon reverts to normal, unidirectional 22 Na and 36 Cl fluxes were measured under voltage-clamp conditions across isolated distal colonic mucosa of rats that were initially dietary sodium depleted for 7 days and then sodium repleted for varying periods of time before the study. Within 8 h of dietary sodium repletion, plasma aldosterone level and Na + -K + -ATPase activity declined to normal, amiloride-sensitive electrogenic sodium absorption decreased by >90%, and active electrogenic potassium secretion also decreased markedly. In contrast, electroneutral sodium chloride absorption did not completely return to levels seen in normal animals until ∼64-68 h. These results demonstrate that maintenance of electrogenic sodium absorption and potassium secretion are directly dependent on elevated plasma aldosterone levels. The inhibition of electroneutral sodium absorption, although initiated by excess aldosterone, persists after normalization of the plasma aldosterone level, thereby implying that the inhibition is dependent on additional factor(s)

Phosphodiesterase-4 inhibition as a therapeutic approach to treat capillary leakage in systemic inflammation.

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Schick, Martin Alexander; Wunder, Christian; Wollborn, Jakob; Roewer, Norbert; Waschke, Jens; Germer, Christoph-Thomas; Schlegel, Nicolas

2012-06-01

In sepsis and systemic inflammation, increased microvascular permeability and consecutive breakdown of microcirculatory flow significantly contribute to organ failure and death. Evidence points to a critical role of cAMP levels in endothelial cells to maintain capillary endothelial barrier properties in acute inflammation. However, approaches to verify this observation in systemic models are rare. Therefore we tested here whether systemic application of the phosphodiesterase-4-inhibitors (PD-4-Is) rolipram or roflumilast to increase endothelial cAMP was effective to attenuate capillary leakage and breakdown of microcirculatory flow in severe lipopolysaccharide (LPS)-induced systemic inflammation in rats. Measurements of cAMP in mesenteric microvessels demonstrated significant LPS-induced loss of cAMP levels which was blocked by application of rolipram. Increased endothelial cAMP by application of either PD-4-I rolipram or roflumilast led to stabilization of endothelial barrier properties as revealed by measurements of extravasated FITC-albumin in postcapillary mesenteric venules. Accordingly, microcirculatory flow in mesenteric venules was significantly increased following PD-4-I treatment and blood gas analyses indicated improved metabolism. Furthermore application of PD-4-I after manifestation of LPS-induced systemic inflammation and capillary leakage therapeutically stabilized endothelial barrier properties as revealed by significantly reduced volume resuscitation for haemodynamic stabilization. Accordingly microcirculation was significantly improved following treatment with PD-4-Is. Our results demonstrate that inflammation-derived loss of endothelial cAMP contributes to capillary leakage which was blocked by systemic PD-4-I treatment. Therefore these data suggest a highly clinically relevant and applicable approach to stabilize capillary leakage in sepsis and systemic inflammation.

Aldosterone induction of electrogenic sodium transport in the apical membrane vesicles of rat distal colon

International Nuclear Information System (INIS)

Rajendran, V.M.; Kashgarian, M.; Binder, H.J.

1989-01-01

Na-H exchange is present in apical membrane vesicles (AMV) isolated from distal colon of normal rats. Because in intact tissue aldosterone both induces amiloride-sensitive electrogenic sodium transport and inhibits electroneutral sodium absorption, these studies with AMV were designed to establish the effect of aldosterone on sodium transport. An outward-directed proton gradient stimulated 22Na uptake in AMV isolated from distal colon of normal and dietary sodium depleted (with elevated aldosterone levels) experimental rats. Unlike normal AMV, proton gradient-dependent 22Na uptake in experimental AMV was inhibited when uptake was measured under voltage-clamped conditions. 10 microM amiloride inhibited the initial rate of proton gradient-dependent 22Na uptake in AMV of normal and experimental rats by 30 and 75%, respectively. In contrast, 1 mM amiloride produced comparable inhibition (90 and 80%) of 22Na uptake in normal and experimental AMV. Intravesicular-negative potential stimulated 22Na uptake in experimental but not in normal AMV. This increase was inhibited by 90% by 10 microM amiloride. An analogue of amiloride, 5-(N-ethylisopropyl) amiloride (1 microM), a potent inhibitor of electroneutral Na-H exchange in AMV of normal rat distal colon, did not alter potassium diffusion potential-dependent 22Na uptake. Increasing sodium concentration saturated proton gradient-dependent 22Na uptake in normal AMV. However, in experimental AMV, 22Na uptake stimulated by both proton gradient and potassium diffusion potential did not saturate as a function of increasing sodium concentration. We conclude from these results that an electrically sensitive conductive channel, not electroneutral Na-H exchange, mediates 22Na uptake in AMV isolated from the distal colon of aldosterone rats

Treatment of colon cancer with oncolytic herpes simplex virus in preclinical models.

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Yang, H; Peng, T; Li, J; Wang, Y; Zhang, W; Zhang, P; Peng, S; Du, T; Li, Y; Yan, Q; Liu, B

2016-05-01

Cancer stem cells (CSCs), which are a rare population in any type of cancer, including colon cancer, are tumorigenic and responsible for cancer recurrence and metastasis. CSCs have been isolated from a number of different solid tumors recently, although the isolation of CSCs in colon cancer is still challenging. We cultured colon cancer cells in stem cell medium to obtain colonosphere cells. These cells possessed the characteristics of CSCs, with a high capacity of tumorigenicity, migration and invasion in vitro and in vivo. The isolation and identification of CSCs have provided new targets for the therapeutics. Oncolytic herpes simplex viruses (oHSV) are an effective strategy for killing colon cancer cells in preclinical models. Here, we examined the efficacy of an oncolytic herpes simplex virus type 2 (oHSV2) in killing colon cancer cells and colon cancer stem-like cells (CSLCs). oHSV2 was found to be highly cytotoxic to the adherent and sphere cells in vitro, and oHSV2 treatment in vivo significantly inhibited tumor growth. This study demonstrates that oHSV2 is effective against colon cancer cells and colon CSLCs and could be a promising strategy for treating colon cancer patients.

Combination of gefitinib and DNA methylation inhibitor decitabine exerts synergistic anti-cancer activity in colon cancer cells.

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Yun-feng Lou

Full Text Available Despite recent advances in the treatment of human colon cancer, the chemotherapy efficacy against colon cancer is still unsatisfactory. In the present study, effects of concomitant inhibition of the epidermal growth factor receptor (EGFR and DNA methyltransferase were examined in human colon cancer cells. We demonstrated that decitabine (a DNA methyltransferase inhibitor synergized with gefitinib (an EGFR inhibitor to reduce cell viability and colony formation in SW1116 and LOVO cells. However, the combination of the two compounds displayed minimal toxicity to NCM460 cells, a normal human colon mucosal epithelial cell line. The combination was also more effective at inhibiting the AKT/mTOR/S6 kinase pathway. In addition, the combination of decitabine with gefitinib markedly inhibited colon cancer cell migration. Furthermore, gefitinib synergistically enhanced decitabine-induced cytotoxicity was primarily due to apoptosis as shown by Annexin V labeling that was attenuated by z-VAD-fmk, a pan caspase inhibitor. Concomitantly, cell apoptosis resulting from the co-treatment of gefitinib and decitabine was accompanied by induction of BAX, cleaved caspase 3 and cleaved PARP, along with reduction of Bcl-2 compared to treatment with either drug alone. Interestingly, combined treatment with these two drugs increased the expression of XIAP-associated factor 1 (XAF1 which play an important role in cell apoptosis. Moreover, small interfering RNA (siRNA depletion of XAF1 significantly attenuated colon cancer cells apoptosis induced by the combination of the two drugs. Our findings suggested that gefitinib in combination with decitabine exerted enhanced cell apoptosis in colon cancer cells were involved in mitochondrial-mediated pathway and induction of XAF1 expression. In conclusion, based on the observations from our study, we suggested that the combined administration of these two drugs might be considered as a novel therapeutic regimen for treating colon

Colon cancer

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Colorectal cancer; Cancer - colon; Rectal cancer; Cancer - rectum; Adenocarcinoma - colon; Colon - adenocarcinoma; Colon carcinoma ... eat may play a role in getting colon cancer. Colon cancer may be linked to a high-fat, ...

VEGF controls lung Th2 inflammation via the miR-1-Mpl (myeloproliferative leukemia virus oncogene)-P-selectin axis.

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Takyar, Seyedtaghi; Vasavada, Hema; Zhang, Jian-ge; Ahangari, Farida; Niu, Naiqian; Liu, Qing; Lee, Chun Geun; Cohn, Lauren; Elias, Jack A

2013-09-23

Asthma, the prototypic Th2-mediated inflammatory disorder of the lung, is an emergent disease worldwide. Vascular endothelial growth factor (VEGF) is a critical regulator of pulmonary Th2 inflammation, but the underlying mechanism and the roles of microRNAs (miRNAs) in this process have not been defined. Here we show that lung-specific overexpression of VEGF decreases miR-1 expression in the lung, most prominently in the endothelium, and a similar down-regulation occurs in lung endothelium in Th2 inflammation models. Intranasal delivery of miR-1 inhibited inflammatory responses to ovalbumin, house dust mite, and IL-13 overexpression. Blocking VEGF inhibited Th2-mediated lung inflammation, and this was restored by antagonizing miR-1. Using mRNA arrays, Argonaute pull-down assays, luciferase expression assays, and mutational analysis, we identified Mpl as a direct target of miR-1 and showed that VEGF controls the expression of endothelial Mpl during Th2 inflammation via the regulation of miR-1. In vivo knockdown of Mpl inhibited Th2 inflammation and indirectly inhibited the expression of P-selectin in lung endothelium. These experiments define a novel VEGF-miR-1-Mpl-P-selectin effector pathway in lung Th2 inflammation and herald the utility of miR-1 and Mpl as potential therapeutic targets for asthma.

Inflammation in Diabetic Retinopathy