Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024523 (malabsorption)
 7,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Standard pharmacologic management of cystic fibrosis is discussed and the role of new agents in the treatment of this disease is explored. Cystic fibrosis is a recessive, fatal genetic disease involving multiple organ systems, in which patients develop pancreatic insufficiency, malabsorption, and repeated pulmonary infections. Pharmacotherapy to date has included broad-spectrum antimicrobials and aggressive nutritional management with microencapsulated pancreatic enzymes. Acute pulmonary exacerbations, caused by Pseudomonas aeruginosa, require combination i.v. antimicrobial therapy for 14 to 21 days. With the recent discovery of the genetic defect responsible for cystic fibrosis, as well as the cellular mechanism, new pharmacologic approaches are being explored to improve treatment. Aerosolized amiloride is being tested to modify the basic defect in the chloride channel. Dornase, a new mucolytic, is used to decrease sputum viscosity and increase mucociliary clearance. Leukoprotease inhibitors are currently being evaluated for decreasing the acute inflammatory reaction in the lung. Gene therapy has been promising, but its role in the management of cystic fibrosis is many years away. Drug therapy for cystic fibrosis has been primarily directed at treating infections with antibiotics and supplementing digestive enzymes and vitamins. New agents and gene therapy may substantially change the morbidity and mortality of this disease.
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PMID:Pharmacologic management of cystic fibrosis. 830 66

Cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel highly expressed in epithelial cells of the gastrointestinal tract. Mutations in the CFTR gene cause cystic fibrosis (CF), a disease characterized by pancreatic insufficiency, fat malabsorption, and steatorrhea. Despite the administration of pancreatic enzymes to normalize malabsorption, CF patients still experienced lipid fecal loss, nutritional deficiencies, and abnormalities in serum lipid profile, suggesting the presence of intrinsic defects in the intestinal handling of nutrients. The objective of the present study was to assess the impact of CFTR gene knockdown on intracellular lipid metabolism of the intestinal Caco-2/15 cell line. Partial CFTR gene inactivation led to cellular lipid accretion of phospholipids, triglycerides, and cholesteryl esters. Likewise, secretion of these lipid fractions was significantly increased following CFTR gene manipulation. As expected from these findings, the output of triglyceride-rich lipoproteins showed the same increasing pattern. Investigation of the mechanisms underlying these changes revealed that CFTR knockdown resulted in raised levels of apolipoproteins in cells and media and microsomal transfer protein activity, two important factors for the efficient assembly and secretion of lipoproteins. Similarly, scrutiny of the enzymatic monoacylglycerol acyltransferase and diacylglycerol acyltransferase, which exhibit dynamic function in triacylglycerol resynthesis and chylomicron formation in enterocytes, revealed a significant augmentation in their activity. Conversely, cholesterol uptake mediated by Niemann-Pick C1 like 1, Scavenger Receptor Class B Type I, and ATP-binding cassette G8 remains unaffected by genetic modification of CFTR. Collectively, these results highlight the role played by CFTR in intestinal handling of lipids and may suggest that factors other than defective CFTR are responsible for the abnormal intracellular events leading to fat malabsorption in CF patients.
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PMID:CFTR knockdown stimulates lipid synthesis and transport in intestinal Caco-2/15 cells. 1980 59

Cystic fibrosis (CF) is the most common autosomal recessive disease among Caucasians. It is due to a mutation in the cftr gene, which encodes the CF transmembrane conductance regulator (CFTR), a chloride channel located in the plasma membrane of mucus-secreting epithelial cells. Numerous other functions of the CFTR protein were identified recently. The survival gains achieved in CF patients over the last 30 years have led to the emergence of delayed complications, one of which is bone disease. The fracture risk is increased from late adolescence onward. Vertebral fractures have an estimated prevalence of 14% among CF patients and can cause severe respiratory complications. Bone mineral density (BMD) is below the age-specific range. Among young adults with CF, 23.5% have BMD values below the cutoff for osteoporosis. Z-scores, which are decreased in children with CF compared to healthy controls, diminish further in adolescence as a result of inadequate peak bone mass accumulation. Studies have shown increased bone resorption, most notably during infectious episodes, and disturbances in bone formation. The numerous pathophysiological mechanisms that contribute to diminish bone strength in CF patients include exocrine pancreatic failure with malabsorption, protein-calorie malnutrition, inflammation related to recurrent infection, and deficiencies in vitamins D and K. In addition, many recent studies support a role for abnormal CFTR function in the osteoblast dysfunction seen in CF. Appropriate diagnostic and therapeutic management of osteoporosis in CF patients is crucial. Risk factors for osteoporosis should be corrected to the extent possible. Oral bisphosphonate therapy may deserve consideration, particularly in adults.
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PMID:Bone disease in cystic fibrosis: what's new? 2123

Cystic fibrosis (CF) is a multisystemic autosomal recessive disease caused by a defect in the expression of CFTR protein, i.e. chloride channel present in the apical membrane of respiratory, digestive, reproductive and sweat glands epithelium. It primarily occurs in the Caucasians, while being considerably or excep tionally rare in persons of other races. Absence, deficit or structural and functional abnormalities of CFTR protein lead to mucosal hyperconcentration in the respiratory, digestive and reproductive systems and malabsorption of chloride and sodium in the sweat glands. Thus, the clinical features of patients' with CF are predominated by respiratory, digestive and reproductive disorders, as well as the tendency to dehydration in the condition of increased sweating. Beside genotype variations, the degree of disease manifestation is also essentially influenced by various exogenous factors, such as the frequency and severity of respiratory infections, the level of aero-pollution, quality of immunoprophylaxis, patients' nutritional condition and other. Chloride concentration of over 60 mmol/L in sweat, a high level of immunoreactive chymotrypsinogen in blood and the verification of homozygous mutation of CFTR gene are the basic methods in the diagnostics of the disease. CF belongs to the group of severe and complex chronic diseases, and therefore requires multidisciplinary therapeutic approach. Owing to the improvement of healthcare provision, most patients with CF now survive into adulthood. In addition, their quality of life is also considerably improved.
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PMID:Cystic fibrosis. 2265 Jan 16

Cystic fibrosis (CF) is caused by mutations in the CFTR chloride channel. Deletion of phenylalanine 508 (F508del), the most frequent CF mutation, impairs CFTR trafficking and gating. F508del-CFTR mistrafficking may be corrected by acting directly on mutant CFTR itself or by modulating expression/activity of CFTR-interacting proteins, that may thus represent potential drug targets. To evaluate possible candidates for F508del-CFTR rescue, we screened a siRNA library targeting known CFTR interactors. Our analysis identified RNF5 as a protein whose inhibition promoted significant F508del-CFTR rescue and displayed an additive effect with the investigational drug VX-809. Significantly, RNF5 loss in F508del-CFTR transgenic animals ameliorated intestinal malabsorption and concomitantly led to an increase in CFTR activity in intestinal epithelial cells. In addition, we found that RNF5 is differentially expressed in human bronchial epithelia from CF vs. control patients. Our results identify RNF5 as a target for therapeutic modalities to antagonize mutant CFTR proteins.
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PMID:Genetic Inhibition Of The Ubiquitin Ligase Rnf5 Attenuates Phenotypes Associated To F508del Cystic Fibrosis Mutation. 2618 66

Cystic fibrosis (CF) is an autosomal recessive genetic disease that occurs in approximately 1 in 2,500 white live births. It is less common in nonwhite individuals. A dysfunctional epithelial chloride channel leads to excessively thick mucus affecting multiple organ systems. Common issues include mucous plugging of the airway, lung inflammation, chronic pulmonary infections, intestinal malabsorption, and malnutrition. Universal screening of newborns for CF is recommended in many countries. CF can be diagnosed based on clinical evidence of disease along with genetic testing or other laboratory evidence of chloride channel dysfunction. Pulmonary system dysfunction causes the most morbidity and mortality. Pulmonary function testing is the primary modality used to monitor CF progression. Therapies include chest physiotherapy, mucolytics, antibiotics, anti-inflammatory drugs, targeted therapies, and vaccines. Dysfunction of the exocrine pancreas and gastrointestinal tract leads to malabsorption, malnutrition, and intestinal obstruction. Nutrition should be optimized with adequate calories, pancreatic enzymes, and appropriate dietary supplements. Complications, including acute pulmonary exacerbations, gastrointestinal conditions, chronic rhinosinusitis, CF-related diabetes, osteoporosis, infertility, and psychosocial issues, must be managed. At the appropriate time, lung transplantation and end-of-life issues must be addressed.
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PMID:Respiratory Conditions Update: Cystic Fibrosis. 2757 34