Leukocyte infiltration, up-regulation of proinflammatory cytokines and severe oxidative stress caused by increased amounts of reactive oxygen species are characteristics of inflammatory bowel ...disease. The catechin (2R,3R)-2-(3,4,5-Trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol-3-(3,4,5-trihydroxybenzoate), named epigallocatechin-3-gallate, EGCG, has been demonstrated to exert anti-inflammatory and antioxidative properties, reducing reactive oxygen species in the inflamed tissues. The aim of this study was to evaluate the therapeutic effects of EGCG in a murine model of colitis induced by oral administration of dextran sodium sulfate.
Mice received a daily oral administration of 6.9mg/kg body weight EGCG or Piper nigrum (L.) alkaloid (2E,4E)-5-(1,3-benzodioxol-5-yl)-1-piperidin-1-ylpenta-2,4-dien-1-one, named piperine (2.9mg/kg body weight) or the combination of the both — piperine was used in this combination to enhance the bioavailability of EGCG.
In vivo data revealed the combination of EGCG and piperine to significantly reduce the loss of body weight, improve the clinical course and increase overall survival in comparison to untreated groups. The attenuated colitis was associated with less histological damages to the colon and reduction of tissue concentrations of malondialdehyde, the final product of lipid peroxidation. Neutrophils accumulation indicator myeloperoxidase was found to be reduced in colon tissue, while antioxidant enzymes like superoxide dismutase and glutathione peroxidase showed an increased activity. In vitro, the treatment with EGCG plus piperine enhanced the expression of SOD as well as GPO and also reduced the production of proinflammatory cytokines.
These data support the concept of anti-inflammatory properties of EGCG being generally beneficial in the DSS-model of colitis, an effect that may be mediated by its strong antioxidative potential.
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GEOZS, NUK, OILJ, SBJE, UL, UM, UPUK
Background:
Physicians can improve their relationships with patients by understanding and meeting patients’ treatment targets, leading to higher adherence to therapy and improved disease prognosis. ...In the current study, we performed a questionnaire-based survey to further understand treatment targets in patients with inflammatory bowel disease (IBD).
Methods:
We created a questionnaire based on a point-allocation scale with 10 treatment target items. A total of 234 patients with IBD Crohn’s disease (n = 129) and ulcerative colitis (n = 105) participated in three German IBD centers. Patients were asked to allocate a total of 10 points across the 10 items, with more points indicating more importance.
Results:
The most important treatment targets for patients regarding their therapy were quality of life (2.78 points), control of defecation (1.53 points), and avoidance of IBD-related surgery (1.69 points). Avoiding surgery for IBD was less important in patients who had already undergone a surgical procedure than in those who had not (1.26 points versus 1.89 points, p < 0.001). Typical treatment targets, including mucosal healing (0.52 points) and normal biochemical markers (0.39 points), were not scored high by patients. The least important item was the possibility of all-oral therapy (0.19 points in 33 patients, 0 points in 201 patients).
Conclusion:
Treatment targets for patients were primarily related to quality of life, such as therapy side effects. Knowing these targets may improve patient–physician relationships and communication, and consequently, adherence to therapy.
Thalidomide has been shown to be an effective treatment in various immunologic diseases such as Crohn's disease and rheumatoid arthritis. Its major effect is thought to be mediated by the inhibition ...of TNF-alpha, but the exact mechanism of action is still uncertain. Recent observations could demonstrate that the induction of monocyte apoptosis is a common feature of a variety of anti-inflammatory agents. Therefore, we investigated the role of thalidomide on monocyte apoptosis. Treatment with thalidomide resulted in apoptosis of human peripheral blood monocytes in a time- and dose-dependent manner as demonstrated by annexin V staining. Monocyte apoptosis required the activation of caspases, as combined stimulation by thalidomide together with the broad caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone markedly prevented monocyte cell death. Apoptosis was triggered by a CD95/CD95 ligand, TNF-RI, and TRAIL-R1 independent pathway with an inhibition of AKT-1 kinase and consecutive mitochondrial release of cytochrome c, followed by the proteolytic activation of initiator caspase-9 and effector caspase-3. Our data suggest that thalidomide-induced monocyte apoptosis is at least partially mediated by a mitochondrial signaling pathway and might contribute to the complex immunomodulatory properties of the drug.
Treatment options for inflammatory bowel disease (IBD) are incompletely helpful, and surgery is often needed. One promising class of future therapeutic agents for IBD is melanocortin-related ...peptides, which exhibit potent immunomodulatory effects. We investigated KdPT, a tripeptide derivative of the C-terminus of α–melanocyte-stimulating hormone, as an anti-inflammatory small molecule in vivo and in vitro . Intestinal inflammation was studied after oral administration of dextran sodium sulfate and in IL-10 gene–deficient mice. The effects of KdPT on key colonic epithelial cell functions were studied in vitro and in vivo by evaluating proliferation, wound healing, transepithelial resistance, and expression of tight junction proteins. Melanin assays were performed to determine the melanotropic effects of KdPT. KdPT-treated animals showed markedly reduced severity of inflammation in both colitis models. In colonic epithelial cells, KdPT increased proliferation, accelerated closure of wounds, and improved transepithelial electrical resistance after stimulation with interferon-γ/tumor necrosis factor-α. Moreover, treatment with KdPT also prevented the loss of tight junction protein expression and improved barrier function in vivo . KdPT acted independently of IL-1 receptor type I in vivo and did not affect melanogenesis in vitro . KdPT is capable of attenuating the course of experimental colitis in different models and maintains epithelial cell function. Furthermore, KdPT does not induce pigmentation, emphasizing the potential of this small molecule for the future treatment of IBD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose
The clinical course of ulcerative colitis (UC) is highly heterogeneous, with 20 to 30% of patients experiencing chronic disease activity requiring immunosuppressive or biologic therapies. The ...aim of this study was to identify predictors for a complicated disease course in an inception cohort of patients with UC.
Methods
EPICOL was a prospective, observational, inception cohort (UC diagnosis, ≤ 6 months) study in 311 patients with UC who were naive to immunosuppressants (IS)/biologics. A complicated course of disease was defined as the need for IS and/or biologic treatment (here therapy with a TNF-α antagonist) and/or UC-related hospitalisation. Patients were followed up for 24 months.
Results
Of the 307 out of 311 participants (4 patients did not meet the inclusion criteria “confirmed diagnosis of active UC within the last 6 months” (
n
= 2) and “immunosuppressive-naïve” (
n
= 2), analysis population), 209 (68.1%) versus 98 (31.9%) had an uncomplicated versus a complicated disease course, respectively. In a multivariate regression analysis, prior use of corticosteroids and prior anaemia were associated with a significantly increased risk for a complicated disease course (2.3- and 1.9-fold increase, respectively;
p
< 0.001 and
p
= 0.002). Based on these parameters, a risk model for patient stratification was developed.
Conclusion
Our study identifies anaemia and an early need for corticosteroids as predictors for a complicated course of disease in an inception cohort of patients with UC. By determining these parameters in routine clinical practice, our results may support the identification of patients who might benefit from early escalation of therapy.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Prediction of inflammatory bowel disease relapse has important implications for therapeutic strategies. Fecal S100A12 has been reported as a novel marker of intestinal inflammation. The objective was ...to investigate the utility of S100A12 as a marker for the confirmation of stable remission and prediction of relapses.
We consecutively included 147 adults and 34 children with Crohn's disease (n = 61) or ulcerative colitis (n = 120). Over a 3-year period, we collected 686 stool samples and 861 serum samples during regular follow-up visits. S100A12 and calprotectin levels were measured by an enzyme-linked immunoassay.
Fecal S100A12 correlated with S100A12 serum levels, other laboratory markers, as well as disease activity, location, and behavior. Fecal S100A12 levels in the relapse group differed significantly from those of the nonrelapse group. A baseline fecal S100A12 level of >0.5 mg/kg was significantly associated with disease relapse within 18 months. Time course analysis of fecal S100A12 before and after relapse showed a clear increase of S100A12 concentrations up to 6 months before clinical relapse. At 0.43 mg/kg, the sensitivity and specificity of S100A12 for predicting relapse already 8 to 12 weeks earlier were 70% and 83%, respectively.
Regular measurements of fecal S100A12 levels reliably detect inflammatory bowel disease relapse at an early stage, which makes the test a promising noninvasive tool for monitoring and optimizing therapy, and may reduce the need for invasive investigations during disease follow-up.
Glucocorticoids (GC) are potent anti-inflammatory and immunosuppressive agents that act on a variety of immune cells, including monocytes and macrophages. However, the exact cellular mechanisms ...underlying this anti-inflammatory capacity are still unknown. In our study, we determined the induction of apoptosis by GC in human monocytes. Peripheral blood monocytes were isolated by density centrifugation methods with a purity of >90% and were cultured in RPMI 1640 medium. Monocyte apoptosis was determined by four independent methods, including annexin-V staining, TUNEL, DNA-laddering, and typical morphology by means of transmission electron microscopy. TNF-alpha and IL-1beta were measured by ELISA. GC receptor was blocked with mifepristone. Caspase 3 was inhibited with caspase-3 inhibitor (DEVD-CHO). Stimulation with different GC at therapeutic concentrations resulted in monocyte apoptosis in a time- and dose-dependent manner. Necrosis was excluded by propidium iodide staining. Proinflammatory cytokines such as IL-1beta and TNF-alpha were down-regulated by GC treatment. Continuous treatment of monocytes with IL-1beta, but not with TNF-alpha, could almost completely prevent GC-induced cell death. The addition of mifepristone or caspase-3 inhibitor could partially abrogate GC-induced apoptosis as well as GC-induced inhibition of IL-1beta. This is the first study to demonstrate induction of apoptosis by GC in human monocytes. GC-induced monocyte apoptosis may be partially mediated through effects on IL-1beta production. It is conceivable that GC exert their anti-inflammatory capacity in various diseases, at least in part, by the induction of apoptosis in monocytes.
Glucocorticoids (GC) act as potent anti-inflammatory and immunosuppressive agents on a variety of immune cells. However, the exact mechanisms of their action are still unknown. Recently, we ...demonstrated that GC induce apoptosis in human peripheral blood monocytes. In the present study, we examined the signaling pathway in GC-induced apoptosis. Monocyte apoptosis was demonstrated by annexin V staining, DNA laddering, and electron microscopy. Apoptosis required the activation of caspases, as different caspase inhibitors prevented GC-induced cell death. In addition, the proteolytic activation of caspase-8 and caspase-3 was observed. In additional experiments, we determined the role of the death receptor CD95 in GC-induced apoptosis. CD95 and CD95 ligand (CD95L) were up-regulated in a dose- and time-dependent manner on the cell membrane and also released after treatment with GC. Costimulation with the GC receptor antagonist mifepristone diminished monocyte apoptosis as well as CD95/CD95L expression and subsequent caspase-8 and caspase-3 activation. In contrast, the caspase inhibitor N:-acetyl-Asp-Glu-Val-Asp-aldehyde suppressed caspase-3 activation and apoptosis, but did not down-regulate caspase-8 activation and expression of CD95 and CD95L. Importantly, GC-induced monocyte apoptosis was strongly abolished by a neutralizing CD95L mAb. Therefore, our data suggest that GC-induced monocyte apoptosis is at least partially mediated by an autocrine or paracrine pathway involving the CD95/CD95L system.
The inflammatory bowel diseases (IBD) are comprised of two major phenotypes, Crohn's disease (CD) and ulcerative colitis (UC). Research over the last couple of years has led to great advances in ...understanding the inflammatory bowel diseases and their underlying pathophysiologic mechanisms. From the current understanding, it is likely that chronic inflammation in IBD is due to aggressive cellular immune responses to a subset of luminal bacteria. Susceptibility to disease is thereby determined by genes encoding immune responses which are triggered by environmental stimuli. Based on extensive research over the last decade, there are several new and novel pathways and specific targets on which to focus new therapeutics. The following review summarizes the current view on the four basic tenets of the pathophysiological basis of IBD and its implications for therapies of IBD: genetics, immune dysregulation, barrier dysfunction and the role of the microbial flora.
Interactions between lymphotoxin (LT)alpha(1)beta(2) on inducer cells and the lymphotoxin beta receptor (LTbetaR) on stromal cells initiate development of lymph nodes and Peyer's patches. In this ...study, we assessed the contributions of LTalpha and LTbetaR to the development of cryptopatches (CP), aggregates of T cell precursors in the mouse small intestine. Mice genetically deficient in LTalpha or LTbetaR lacked CP. Bone marrow from LTalpha-deficient mice was unable to initiate development of CP or isolated lymphoid follicles (ILF) after transfer to CD132-null mice lacking CP and ILF. However, LTalpha-deficient bone marrow-derived cells contributed to CP formed in CD132-null mice receiving a mixture of wild-type and LTalpha-deficient bone marrow cells. Transfer of wild-type bone marrow into irradiated LTalpha-deficient mice resulted in reconstitution of both CP and ILF. However, the LT-dependent formation of CP was distinguished from the LT-dependent formation of ILF and Peyer's patches by not requiring the presence of an intact NF-kappaB-inducing kinase gene. CP but not ILF were present in the small intestine from NF-kappaB-inducing kinase-deficient alymphoplasia mice, indicating that the alternate NF-kappaB activation pathway required for other types of LTbetaR-dependent lymphoid organogenesis is dispensable for CP development. In addition, we identified VCAM-1(+) cells within both CP and ILF that are candidates for the stromal cells involved in receiving LT-dependent signals from the hemopoietic precursors recruited to CP. These findings demonstrate that interactions between cells expressing LTalpha(1)beta(2) and LTbetaR are a shared feature in the development of all small intestinal lymphoid aggregates.
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