Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021390 (inflammatory bowel disease)
 23,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vitamin D-deficient IL-10 knockout (KO) mice develop accelerated inflammatory bowel disease (IBD). Removing dietary calcium from the diets of vitamin D-deficient IL-10 KO mice increased the severity of IBD. The mice fed either calcium or active vitamin D (1 alpha,25-dihydroxyvitamin D3, 1,25D3), developed an intermediate form of IBD, while the mice fed both calcium and 1,25D3 had the mildest form of IBD. TNF-alpha secretion from Con A-stimulated splenocytes was reduced by dietary calcium or 1,25D3 treatment. The IL-10 KO mice that received both high calcium diets and 1,25D3 treatments had the lowest TNF-alpha production. In the colons, a TNF-alpha-inducing transcription factor, LPS-induced TNF-alpha factor (LITAF), was inhibited by 1,25D3, but not by calcium. The inhibition of several TNF-alpha-related genes was associated with the decreased colitis in 1,25D3-treated IL-10 KO mice. Furthermore, fulminating IBD in vitamin D receptor/IL-10 double-KO mice corresponded with the increased expression of TNF-alpha and LITAF in the colon. Our results suggest that dietary calcium has independent effects on IBD severity and that 1,25D3 and high calcium together result in the maximal suppression of experimental IBD. The data support a model where dietary calcium and 1,25D3 treatment directly and indirectly inhibit the TNF-alpha pathway and suppress IBD.
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PMID:Calcium and 1 alpha,25-dihydroxyvitamin D3 target the TNF-alpha pathway to suppress experimental inflammatory bowel disease. 1559 22

During inflammatory bowel disease, reactive oxygen metabolites are released by phagocytes reacting with intraluminal NH3 to produce monochloramine (NH2Cl). NH2Cl is assumed to play role in the pathogenesis of inflammation-associated diarrhoea, as it is able to induce intestinal secretion. The aim of the present study was to determine the action sites of NH2Cl in rat colonic epithelium with Ussing chamber and fura-2 experiments. In intact mucosa, NH2Cl (5.10(-6)-10(-4) mol.l(-1)) evoked a concentration-dependent increase in short-circuit current (Isc), consistent with the induction of anion secretion, as demonstrated by anion substitution and transport blocker experiments. When the apical membrane was permeabilised by the ionophore nystatin, two basolateral action sites of NH2Cl (5.10(-5) mol.l(-1)) could be identified, i.e. an increase in the K+ conductance and a stimulation of the Na+-K+ pump. When tissues were basolaterally depolarised by a high K+ concentration, the stimulation of an apical Cl- conductance by NH2Cl was observed. In isolated colonic crypts loaded with the Ca2+-sensitive fluorescent dye fura-2, NH2Cl (5.10(-5) mol.l(-1)) evoked an increase in the intracellular Ca2+ concentration. This increase was independent from the presence of Ca2+ in the extracellular medium, but was inhibited by blockade of intracellular sarcoplasmatic, endoplasmatic Ca2+-ATPases with cyclopiazonic acid (10(-5) mol.l(-1)). The NH2Cl-evoked Ca2+ release was sensitive against inhibition of ryanodine receptors with ruthenium red (5.10(-5) mol.l(-1)) and against inhibition of inositol-1,4,5-trisphosphate (IP3) receptors with 2-aminoethoxydiphenylborate (10(-4) mol.l(-1)). Both blockers also inhibited the NH2Cl-induced increase in Isc. These results indicate that an intracellular Ca2+ release via ryanodine and/or IP3 receptors is involved in oxidant stimulation of anion secretion in rat colon.
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PMID:Stimulation of colonic anion secretion by monochloramine: action sites. 1561 20

A key feature of inflammatory bowel disease (IBD) is disruption of the intestinal epithelial barrier by unknown mechanisms. Integrity of the epithelial barrier is determined by an apical junctional complex that is composed of tight junction (TJ) and adherens junction (AJ). Previous observations have suggested that alterations in the apical junctional complex occur in IBD. Localization studies in mucosal biopsies from IBD patients have revealed disappearance of key TJ (occludin, JAM1, ZO1, claudin 1) and AJ (E-cadherin, beta-catenin) proteins from intercellular junctions. In vitro experiments examining the effects of inflammatory cytokines on model intestinal epithelial monolayers suggest that disruption of the epithelial barrier is associated with internalization of transmembrane TJ proteins, JAM1, ocdudin and claudins 1/4. The mechanism(s) of internalization of intercellular junctions can be modelled in vitro by calcium depletion of confluent epithelial cell monolayers. Using this model, we have observed rapid, orchestrated endocytosis of all AJ and TJ proteins into a subapical cytoplasmic compartment that is independent of caveolae/lipid rafts and macropinocytosis. However, inhibitors of clathrin-mediated endocytosis effectively block internalization of AJs and TJs, and junctional proteins colocalize with clathrin. Interestingly, internalized AJ and TJ proteins enter early endosomes followed by movement to organelles that do not label with markers of late and recycling endosomes, lysosomes or Golgi but appear to represent a unique storage compartment that colocalizes with t-SNARE protein, syntaxin 4. A better understanding of the mechanisms of junctional internalization and recycling will likely provide new insights into the mechanisms of altered barrier function in IBD.
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PMID:The epithelium in inflammatory bowel disease: potential role of endocytosis of junctional proteins in barrier disruption. 1566 38

Hypercalcemia has been described in patients with a number of granulomatous diseases, including sarcoidosis and mycobacterial infection. Disordered vitamin D metabolism is the root cause for the elevated serum calcium levels. A similar mechanism of abnormal vitamin D metabolism explained the hypercalcemia occurring in patients with lymphoma. Crohn's disease is a granulomatous disorder that is more commonly associated with hypocalcemia caused by poor calcium intake and decreased intestinal calcium absorption related to vitamin D deficiency as a consequence of malabsorption. A man with Crohn's disease who presented with hypercalcemia and acute renal failure is described. Biochemical parameters showed an elevated 1,25-dihydroxyvitamin D level, with a low-normal 25-hydroxyvitamin D level and decreased parathyroid hormone level. Inflammatory bowel disease had been clinically active during the preceding 2 months. With resolution of gastrointestinal symptoms, serum calcium, vitamin D, and parathyroid hormone levels returned to normal. Serum creatinine levels decreased toward normal. Angiotensin-converting enzyme (ACE) levels have been reported to be elevated in patients with sarcoidosis, particularly in the setting of active disease with hypercalcemia. Controversy exists about ACE levels in the face of active Crohn's disease: 1 report noted elevated levels, whereas other publications reported depressed levels. Our patient had an elevated ACE level in the setting of active bowel disease and hypercalcemia, and ACE levels returned to normal with resolution of gastrointestinal symptoms.
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PMID:Hypercalcemia due to excess 1,25-dihydroxyvitamin D in Crohn's disease. 1569 36

Severe electrolyte imbalance is rarely the cause of cardiac decompensation. We report the case of a young patient with acute left ventricular failure due to severe hypocalcaemia secondary to the intestinal malabsorption of calcium with inflammatory bowel disease. The interesting feature of this case was the rapid haemodynamic deterioration and the total reversal within one week following correction of the hypocalcaemia.
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PMID:[Acute cardiomyopathy and severe hypocalcaemia]. 1572 24

Decreased bone mineral density is a frequent finding in patients with inflammatory bowel disease. Factors contributing to this are: 1) malabsorption of vitamin D, calcium and possibly vitamin K and other nutrients, 2) treatment with corticosteroids, 3) inflammatory cytokines in inflammatory bowel disease, and 4) hypogonadism induced by the inflammatory bowel disease. Among patients with Crohn's disease from 32% to 38% have osteopenia (Z-scores <-1), and among patients with ulcerative colitis 23% to 25% have osteopenia. The mean deficit was 0.44+/-0.08 Z-scores in the spine in Crohn's disease and 0.34+/-0.08 in ulcerative colitis. A similar deficit was seen in the hip in both conditions. From these deficits, an increase in overall fracture risk of 1.1-1.3 should be expected. The observed excess fracture risk was limited compared to the general population in both Crohn's disease (RR=1.2, 95% CI: 0.9-1.6 for any fracture and 2.2, 95% CI: 1.2-4.0 for spine fractures) and ulcerative colitis (RR=1.1, 95% CI: 1-1.2 for any fracture, and 1.5, 95% CI: 0.9-2.5 for spine fractures). The observed excess fracture risk was close to that expected from the changes in BMD. Despite the limited excess fracture risk, a relatively large percentage of all fractures may be attributable to corticosteroid use among users of corticosteroids.
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PMID:Prevalence and pathogenesis of osteoporosis in patients with inflammatory bowel disease. 1578 32

Osteoporosis is a frequent finding in patients with Crohn's disease and ulcerative colitis. The prevalence of vertebral fractures in those patients with significantly reduced bone mineral density is up to 22%. Factors contributing to osteoporosis in inflammatory bowel disease (IBD) patients are treatment with glucocorticoids, increased cytokine production by the inflammation itself, malabsorption and possibly hypogonadism. Therefore, consequent treatment of the underlying IBD and minimising therapy with systemic glucocorticoids, as well as the adequate intake of calcium and vitamin D, may be very important measures to prevent bone loss in IBD. In patients with osteoporosis associated with Crohn's disease or ulcerative colitis, various treatment strategies, such as sodium fluoride and aminobisphosphonates, are discussed. Unfortunately, interventional studies in secondary osteoporosis are often limited by the small study population. The efficacy in prevention of vertebral fractures is not proven in any of the described treatment modalities in these patients. Therefore, guidelines are based on data using bone density as the most accepted surrogate marker and treatment guidelines are based on data from patients with postmenopausal and steroid-induced osteoporosis.
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PMID:Diagnosis and management of osteoporosis in inflammatory bowel disease. 1578 33

There is evidence from both observational studies and clinical trials that calcium malnutrition and hypovitaminosis D are predisposing conditions for various common chronic diseases. In addition to skeletal disorders, calcium and vitamin D deficits increase the risk of malignancies, particularly of colon, breast and prostate gland, of chronic inflammatory and autoimmune diseases (e.g. insulin-dependent diabetes mellitus, inflammatory bowel disease, multiple sclerosis), as well as of metabolic disorders (metabolic syndrome, hypertension). The aim of the present review was to provide improved understanding of the molecular and cellular processes by which deficits in calcium and vitamin D cause specific changes in cell and organ functions and thereby increase the risk for chronic diseases of different aetiology. 1,25-Dihydroxyvitamin D(3) and extracellular Ca(++) are both key regulators of proliferation, differentiation and function at the cellular level. However, the efficiency of vitamin D receptor-mediated intracellular signalling is limited by the negative effects of hypovitaminosis D on extrarenal 25-hydroxyvitamin D-1alpha-hydroxylase activity and thus on the production of 1,25-dihydroxyvitamin D(3). Calcium malnutrition eventually causes a decrease in calcium concentration in extracellular fluid compartments, resulting in organ-specific modulation of calcium-sensing receptor activity. Hence, attenuation of signal transduction from the ligand-activated vitamin D receptor and calcium-sensing receptor seems to be the prime mechanism by which calcium and vitamin D insufficiencies cause perturbation of cellular functions in bone, kidney, intestine, mammary and prostate glands, endocrine pancreas, vascular endothelium, and, importantly, in the immune system. The wide range of diseases associated with deficits in calcium and vitamin D in combination with the high prevalence of these conditions represents a special challenge for preventive medicine.
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PMID:Vitamin D and calcium deficits predispose for multiple chronic diseases. 1586 41

Claudin proteins comprise a recently described family of tight junction proteins that differentially regulate paracellular permeability. Since other tight junction proteins show alterations in distribution or expression in inflammatory bowel disease (IBD) we assessed expression of claudins (CL) 2, 3 and 4 in IBD. CL 2 was strongly expressed along the inflamed crypt epithelium, whilst absent or barely detectable in normal colon. In contrast, CL 3 and 4 were present throughout normal colonic epithelium and were reduced or redistributed in the diseased surface epithelium. In a T84-cell culture model of the gut barrier, paracellular permeability decreased with time after plating and correlated with a marked decrease in the expression of CL 2. Addition of IFNgamma/TNFalpha led to further decreases in CL 2 and 3, the redistrbution of CL 4 and a marked increase in paracellular permeability. Conversely, IL-13 dramatically increased CL 2, with little effect on CL 3 or 4, but also resulted in increased paracellular permeability. Expression of CL 2 did not correlate with proliferation or junctional reorganisation after calcium ion depletion. Re-expression of CL 2 in response to IL-13 was inhibited by phophatidylinositol 3 kinase inhibitor, LY294002, which also restored the ion permeability to previous levels. CL 2 expression could be stimulated in the absence of IL-13 by activation of phospho-Akt in the phophatidylinositol 3 kinase pathway. These results suggest that INFgamma/TNFalpha and IL-13 have differential effects on CL 2, 3 and 4 in tight junctions, which may lead to increased permeability via different mechanisms.
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PMID:Inflammatory processes have differential effects on claudins 2, 3 and 4 in colonic epithelial cells. 1600 10

Colorectal cancer (CRC) is the second leading cause of cancer death in Argentina. The cumulative lifetime risk of developing CRC for both men and women is 4-6%. Despite advances in the management of this disease, the 5-year survival rate is about 60% because only 35% of patients are diagnosed when the disease is localized. Risk factors for CRC include age, diet and life style factors, personal or family history of adenomas or CRC and personal history of inflammatory bowel disease. Scientific evidence shows that primary and secondary prevention, through screening programs, permit to reduce incidence and mortality significantly. Chemopreventive agents, including nonsteroidal antiinflammatory drugs, folate, and calcium, have been shown to have some preventive effect. Physical inactivity and excess body weight are consistent risk factors for CRC. Tobacco exposure, diet high in red meat and low in vegetables and alcohol consumption, probably in combination with a diet low in folate, appear to increase risk. The dietary fiber and risk of CRC has been studied but the results are still inconclusive. Screening for CRC is cost-effective compared with no screening, but a single optimal strategy cannot be determined from the currently available data. The advantages and disadvantages or limitations of screening modalities for CRC are analyzed. The literature and clinical practice guidelines are reviewed, with an emphasis on advances and evolving screening methods and recommendations for patients with average, moderate and high-risk CRC.
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PMID:[Prevention of colorectal cancer]. 1612 87


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