Danuta Owczarek

Diet and nutritional factors in inflammatory bowel diseases

Inflammatory bowel disease (IBD) development is affected by complex interactions between environmental factors, changes in intestinal flora, various predisposing genetic properties and changes in the immune system. Dietary factors seem to play an underestimated role in the etiopathogenesis and course of the disease. However, research about food and IBD is conflicting. An excessive consumption of sugar, animal fat and linoleic acid is considered a risk factor for IBD development, whereas a high fiber diet and citrus fruit consumption may play a protective role. Also, appropriate nutrition in particular periods of the disease may facilitate achieving or prolonging remissions and most of all, improve the quality of life for patients. During disease exacerbation, a low fiber diet is recommended for most patients. In the remission time, an excessive consumption of alcohol and sulfur products may have a negative effect on the disease course. Attempts are also made at employing diets composed in detail in order to supplement IBD therapy. A diet with a modified carbohydrate composition, a semi-vegetarian diet and a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols are under investigation. Due to chronic inflammation as well as side effects of chronically used medications, patients with IBD are also at increased risk of nutritional factor deficiencies, including iron, calcium, vitamin D, vitamin B12, folic acid, zinc, magnesium and vitamin A. It should also be remembered that there is no single common diet suitable for all IBD patients; each of them is unique and dietary recommendations must be individually developed for each patient, depending on the course of the disease, past surgical procedures and type of pharmacotherapy.

Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), arginine, and 8‐iso‐prostaglandin F2α (8‐iso‐PGF2α) level in patients with inflammatory bowel diseases

Background: Intestinal microvessels of patients with inflammatory bowel disease (IBD) show microvascular endothelial dysfunction. It may contribute to reduced perfusion, poor ulcer healing, and sustained chronic inflammation. The aim of the study was to assess endothelial dysfunction and oxidative stress markers in patients with IBD. Methods: Serum levels of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), arginine, and 8‐iso‐prostaglandin F2&agr; (8‐iso‐PGF2&agr;) were measured in 31 consecutive patients with ulcerative colitis (UC) and 32 with Crohns disease (CD). Apparently healthy subjects served as age‐ and sex‐matched controls. Associations between these markers and the disease activity and laboratory variables were evaluated. Results: ADMA, SDMA, and 8‐iso‐PGF2&agr; levels were increased in the IBD group as compared to the control group and higher in patients with CD than UC (P < 0.05 for all comparisons). Arginine levels were similar in all the groups. In the CD and UC groups ADMA and SDMA showed positive correlation with 8‐iso‐PGF2&agr; (r from 0.47–0.67; P < 0.01 for all comparisons). ADMA and SDMA correlated positively with the CD activity (r = 0.4, P = 0.025; r = 0.4, P = 0.024, respectively) and the 8‐iso‐PGF2&agr; level correlated positively with the UC activity (r = 0.4, P = 0.026). Conclusions: This is the first study to show that in patients with IBD there is enhanced ADMA generation that might be associated with oxidative stress, and these effects are more pronounced in the CD group. (Inflamm Bowel Dis 2010;)

Met-enkephalins in patients with inflammatory bowel diseases

PURPOSE Opioid peptides provide a link between the neuroendocrine and immune systems. They modify the inflammatory process through their effect on the synthesis and secretion of cytokines and on the proliferation of leukocytes to the inflammatory lesion. The evaluation analyzed changes in free met-enkephalin concentration values in the serum and colon mucosal biopsy specimens of patients with inflammatory bowel disease (IBD). MATERIAL AND METHODS In serum and colon mucosal biopsy specimens, free met-enkephalin levels were determined in 43 patients with ulcerative colitis (UC) and 38 individuals with Crohns disease (CD). The evaluation analyzed the effect of disease activity, inflammatory lesions of the colon and laboratory parameters, on the level of the investigated marker. The control group consisted of 45 healthy volunteers. RESULTS Serum free met-enkephalin levels were depressed in patients with CD (85.4pg/ml) and UC (101.5pg/ml) as compared to the controls (119.4pg/ml). Met-enkephalin levels in colonic biopsies collected from inflammatory lesions in IBD patients were significantly higher as compared to sections without inflammatory lesions (6.59pg/mg vs. 2.89pg/mg, p < 0.01 in the CD group and 6.12pg/mg vs. 3.47pg/mg, p < 0.05 in the UC group) and their level correlated with disease activity. CONCLUSIONS The present investigation is the first study that demonstrates changes in free met-enkephalin levels in IBD that may play a role in the pathogenesis and course of the disease. Further studies are necessary to assess the anti-inflammatory effect of opioid peptides.

Reduced plasma fibrin clot permeability and susceptibility to lysis in patients with inflammatory bowel disease: a novel prothrombotic mechanism.

Background:Inflammatory bowel disease (IBD) is associated with an increased risk of thromboembolism. Its mechanism is still unclear. Altered fibrin clot properties have been reported in patients with thromboembolism and those with chronic inflammatory states. We investigated whether fibrin characteristics are abnormal in IBD. Methods:Ex vivo plasma fibrin clot permeability (Ks), compaction, turbidity, and efficiency of fibrinolysis were assessed in 85 consecutive patients with IBD, including 47 with ulcerative colitis (UC) and 38 with Crohns disease (CD), all with no history of thromboembolism. Forty-eight patients matched for age and sex served as controls. Results:Compared with controls, patients with UC and CD had 29.5% and 35.7% lower Ks associated with 13.8% and 23.1% lower compaction, respectively (all P < 0.001). Patients with UC and CD had higher maximum clot absorbance (+8.9%, P = 0.008, and +15.2%, P < 0.0001, respectively), higher maximum D-dimer released from clots (D-Dmax, +27.0%, P = 0.01, and +28.7%, P < 0.0001, respectively), and prolonged clot lysis time (+19.0%, P < 0.0001, and +25.5%, P < 0.0001, respectively). Lag phase was similar in both group of patients. D-Dmax was the only parameter that differed between patients in the UC and CD groups, being higher in CD (P = 0.04). The multiple linear regression model showed that in patients with UC, but not with CD, Ks, compaction, lysis time, and D-Dmax were all independently associated with disease activity. In patients with CD, Ks and lysis time were independently predicted by fibrinogen and C-reactive protein. Conclusions:Both UC and CD are characterized by formation of dense fibrin networks relatively resistant to lysis. Prothrombotic clot phenotype might represent a novel mechanism increasing thrombotic risk in IBD.

HGF, sIL-6R and TGF-β1 Play a Significant Role in the Progression of Multiple Myeloma.

Background. In the last few years, it has been widely reported that proinflammatory and angiogenic cytokines are important for the development and progression of multiple myeloma (MM). Objectives. To further validate and acquire more insight into this view we decided to check whether plasma levels of certain cytokines and their soluble receptors differ between MM patients and healthy subjects. Patients and Methods. The study was conducted in 76 MM patients aged 22 to 77 years (60±10 years) and 35 healthy controls aged 20 to 63 years (33±10 years). Plasma levels of interleukin-6 (IL-6), b-fibroblast growth factor (b-FGF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1), as well as soluble receptors for IL-6 (sIL-6R) and VEGF (sVEGF-R2) were measured using enzyme-linked immunosorbent assay (ELISA). Results. Significantly higher plasma levels of IL-6 (13.65±42.61 vs. 1.04±1.12 pg/ml, p=0.006), HGF (2174±2714 vs. 648±130 pg/ml, p<0.001), b-FGF (7.92±10.78 vs. 2.54±5.38 pg/ml, p<0.001) and sIL-6R (37.1±14.2 vs. 25.3±6.4 ng/ml, p=0.003) were observed in MM patients vs. healthy controls, respectively. Plasma sVEGF-R2 was significantly lower in MM patients than in controls (7518±2119 vs. 8725±1281 pg/ml, respectively; p<0.001). We observed an inverse correlation between length of treatment and the level of sIL-6R, and TGF-β1 in plasma. Conclusions. Plasma levels of HGF, b-FGF, IL-6 and sIL-6R in MM patients were higher when compared to the control group. Antineoplastic therapy leads to a time-dependent decrease in plasma levels of sIL-6R, and TGF-β1 in MM patients. Blood plasma level of HGF is an optimal measure to differentiate patients in whom disease is progressing versus patients who respond to therapy.

Endothelial dysfunction in inflammatory bowel diseases: Pathogenesis, assessment and implications

Endothelial dysfunction is considered one of the etiological factors of inflammatory bowel disease (IBD). An inflammatory process leads to functional and structural changes in the vascular endothelium. An increase of leukocyte adhesiveness and leukocyte diapedesis, as well as an increased vascular smooth muscle tone and procoagulant activity is observed. Structural changes of the vascular endothelium comprise as well capillary and venule remodeling and proliferation of endothelial cells. Hypoxia in the inflammatory area stimulates angiogenesis by up-regulation of vascular endothelial growth factor, fibroblast growth factor and tumor necrosis factor-α. Inflammatory mediators also alter the lymphatic vessel function and impair lymph flow, exacerbating tissue edema and accumulation of dead cells and bacteria. The endothelial dysfunction might be diagnosed by the use of two main methods: physical and biochemical. Physical methods are based on the assessment of large arteries vasodilatation in response to an increased flow and receptors stimulation. Flow-mediated vasodilatation (FMD) is the method that is the most widely used; however, it is less sensitive in detecting early changes of the endothelium function. Most of the studies demonstrated a decrease of FMD in IBD patients but no changes in the carotic intima-media thickness. Biochemical methods of detecting the endothelial dysfunction are based on the assessment of the synthesis of compounds produced both by the normal and damaged endothelium. The endothelial dysfunction is considered an initial step in the pathogenesis of atherosclerosis in the general population. In IBD patients, the risk of cardiovascular diseases is controversial. Large, prospective studies are needed to establish the role of particular medications or dietary elements in the endothelial dysfunction as well to determine the real risk of cardiovascular diseases.

Interactions between medications employed in treating benign prostatic hyperplasia and food − A short review

Benign prostatic hyperplasia (BPH) is the most common disease in elderly men. BPH symptoms include frequent urination, urgent tenesmus and urination at night, a weak and interrupted urine flow and a sense of incomplete emptying of the bladder. Alpha- 1 adrenergic receptor antagonists and 5 α-reductase inhibitors form the most important groups of medications employed in BPH. Appropriately managed BPH patients shall be subject to counselling on interactions between agents belonging to these groups, and on particular components of the food they have. The present review has been aimed at assessing potential effects of consumed food, alcohol and fruit juices on the pharmacokinetics and pharmacodynamics of medications for benign prostatic hyperplasia. The authors reviewed the English PubMed database covering the years 1991-2015. Additionally, a digital version of Stockley Drugs Interaction and other electronic databases such as drugs.com and Medscape were also researched; characterisation charts for particular medical products were also analyzed. Pharmacokinetics of extended-release forms of alfuzosin, doxazosin, tamsulosin and silodosin is well known to be food-sensitive. Alfuzosin, tamsulosin and silodosin due to their likely interaction with grapefruit juice and citrus fruits, may intensify adverse effects of the drugs. Alpha-1 adrenergic receptor antagonists are known to interact with alcohol, leading to orthostatic hypotension. For 5 alpha-reductase inhibitors, such as finasteride, or dutasteride, the pharmacokinetic effect due to consumed food is of no clinical importance and thus they may be taken regardless of meals. As in general grapefruit juice and alcohol tend to significantly affect the efficacy and safety of the applied drug therapy, it is highly advisable to be knowledgeable on the subject in order to educate patients.

Geldanamycin and Its Derivatives Inhibit the Growth of Myeloma Cells and Reduce the Expression of the MET Receptor.

Introduction. Geldanamycin (GA) is an ansamycin antibiotic that exhibits potent anti-neoplastic properties. The aim of this study was to assess the impact of GA and its derivatives on the growth and invasiveness of myeloma cell lines and CD138+ cells derived from the bone marrow of patients with multiple myeloma. Materials and methods. We evaluated cell proliferation, survival, apoptosis, cell cycle of myeloma cells, and the expression of cell surface proteins after incubation with geldanamycin or its derivatives. Results. GA and its analogs have an effect on myeloma cells by inhibiting their growth in a time and dose-dependent manner. Myeloma cell lines demonstrated decreased proliferation after incubation with 10 nM of GA or 100 nM GA analogs. The first significant effects of GA on U266 cells was observed after 24 hours. After 24 hours, U266 cells incubated with 100 nM GA were in both early and late stages of apoptosis; 17AEP and 17DMAG caused apoptosis of similar intensity to GA. It has been observed that GA and its derivatives cause caspase-3 activation. Analysis of the activity of AKT and MAP 42/44 kinases was performed by incubating U266 cells for 24 and 48 hours in100 nM of GA and its derivatives. After 24 hours incubation, no significant changes in protein expression were observed, while after 48 hours, the strongest changes were seen in AKT protein expression after incubation with GA and 17AEP-GA. In studies of the cell cycle, it was found that 100 nM 17AEP-GA and 17-DMAP-GA cause cell cycle abnormalities. We observed a nearly two-fold increase in U266 cells in the G1 phase and a simultaneous decrease in the percentage of cells in the G2/M phase, indicating that cells were halted in the G1 phase. In the case of the INA6 cells, proliferation was halted in both the G1 and G2/M phases. Conclusions. GA and the analogues that we tested can inhibit myeloma cell growth by induction of apoptosis and blockage of cell cycle progression, and have an effect on the down-regulation of the MET receptor. The GA derivatives tested, despite their modifications still retain strong anticancer properties. Specifically, two analogues of GA, 17AEP-GA and 17DMAG due to their properties can be more effective and safer chemotherapeutic agents than 17AAG, which is currently used and described in literature.

Intrahepatic expression of genes related to metabotropic receptors in chronic hepatitis.

AIM To screen for genes related to metabotropic receptors that might be involved in the development of chronic hepatitis. METHODS Assessment of 20 genes associated with metabotropic receptors was performed in liver specimens obtained by punch biopsy from 12 patients with autoimmune and chronic hepatitis type B and C. For this purpose, a microarray with low integrity grade and with oligonucleotide DNA probes complementary to target transcripts was used. Evaluation of gene expression was performed in relation to transcript level, correlation between samples and grouping of clinical parameters used in chronic hepatitis assessment. Clinical markers of chronic hepatitis included alanine and aspartate aminotransferase, γ-glutamyltranspeptidase, alkaline phosphatase and cholinesterase activity, levels of iron ions, total cholesterol, triglycerides, albumin, glucose, hemoglobin, platelets, histological analysis of inflammatory and necrotic status, fibrosis according to METAVIR score, steatosis, as well as anthropometric body mass index, waist/hip index, percentage of adipose tissue and liver size in ultrasound examination. Gender, age, concomitant diseases and drugs were also taken into account. Validation of oligonucleotide microarray gene expression results was done with the use of quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS The highest (0.002 < P < 0.046) expression among genes encoding main components of metabotropic receptor pathways, such as the α subunit of G-coupled protein, phosphoinositol-dependent protein kinase or arrestin was comparable to that of angiotensinogen synthesized in the liver. Carcinogenesis suppressor genes, such as chemokine ligand 4, transcription factor early growth response protein 1 and lysophosphatidic acid receptor, were characterized by the lowest expression (0.002 < P < 0.046), while the factor potentially triggering hepatic cancer, transcription factor JUN-B, had a 20-fold higher expression. The correlation between expression of genes of protein kinases PDPK1, phosphoinositide 3-kinase and protein kinase A (Spearmans coefficient range: 0.762-0.769) confirmed a functional link between these enzymes. Gender (P = 0.0046) and inflammation severity, measured by alanine aminotransferase activity (P = 0.035), were characterized by diverse metabotropic receptor gene expression patterns. The Pearsons coefficient ranging from -0.35 to 0.99 from the results of qRT-PCR and microarray indicated that qRT-PCR had certain limitations as a validation tool for oligonucleotide microarray studies. CONCLUSION A microarray-based analysis of hepatocyte metabotropic G-protein-related gene expression can reveal the molecular basis of chronic hepatitis.

Concomitant carcinoid tumor and papillary urothelial neoplasm of low malignant potential in a patient with Crohn's disease: a case report.

Patients with a long-term history of inflammatory bowel diseases show an increased risk of developing colorectal cancers. In the case of Crohns disease, such an increased risk is also associated with other malignant tumors. The report presents a very rare case of a concomitant carcinoid tumor and papillary urothelial neoplasm of low malignant potential in a 35-year-old patient with diagnosed Crohns disease complicated by an enterovesical fistula. The carcinoid tumor and papillary urothelial neoplasm of low malignant potential were diagnosed by postoperative histopathology. In patients with Crohns disease, concomitant occurrence of various malignancies may be observed even earlier in life.