Human diseases Cystic fibrosis

If the protein fails to fold properly, its shape is incorrect and it cannot perform its intended function. Aberrations in protein folding appear to contribute to human diseases. Among these are Alzheimer s disease, prion diseases, emphysema and cirrhosis, amyelotrophic lateral sclerosis (Lou Gehrig s disease), cystic fibrosis, some tumors, and osteogenesis imperfecta (King et al., 2002). The prion that seems to cause ovine transmissible spongiform encephalopathy, for instance, appears as a pleated sheet rather than a smooth helix. 

In experimental animals, vitamin E deficiency results in resorption of femses and testicular atrophy. Dietary deficiency of vitamin E in humans is unknown, though patients with severe fat malabsorption, cystic fibrosis, and some forms of chronic fiver disease suffer deficiency because they are unable to absorb the vitamin or transport it, exhibiting nerve and muscle membrane damage. Premamre infants are born with inadequate reserves of the vitamin. Their erythrocyte membranes are abnormally fragile as a result of peroxidation, which leads to hemolytic anemia. 

Human leukocyte elastase is a protease that degrades elastin and other connective tissue components. It is implicated in the pathogenesis of pulmonary emphysema and other inflammatory diseases such as rheumatoid arthritis and cystic fibrosis. Porcine pancreatic elastase has often been used as a model for HLE. Both enzymes have a small primary binding site Si. 

Damage to connective caused by leakage of elastases leads to damage associated with inflammatory diseases, such as pulmonary emphysema, adult respiratory distress syndrome, septic shock, cystic fibrosis, carcinogenesis, chronic bronchitis, and rheumatoid arthritis. Compounds that directly inhibit elastase or its release from human neutrophils are of enormous pharmaceutical and cosmetological interest in the development of new anti-inflammatory drugs. A possible source for elastase inhibitors are the medicinal Asteraceae and Droseraceae, particularly those used as traditional medicine in Asia. 

Nonpeptide receptors Adenosine Aj Human cDNA Cardiac arrhythmia, asthma, myocardial ischemia, obesity, pain, renal disease, sleep apnea, stroke, cancer, inflammation, glaucoma, cystic fibrosis, Alzheimer s disease, Parkinson s disease Bradycardia, lipolysis inhibition, reduction of glomerular filtration and natriuresis, tubero-glomerular feedback, antinociception, renal vasodilatation-constriction, reduction of central cholinergic and noradrenergic nerve activity, presynaptic inhibition of excitatory neuro transmission... 

Angiotensin-II AT, Human cDNA Artherosderosis, cardiac hypertrophy, congestive heart failure, hypertension, myocardial infarction, renal disease, cancer, diabetes, obesity, glaucoma, cystic fibrosis, Alzheimer s disease, Parkinson s disease Smooth muscle contraction, cell proliferation and migration, aldosterone and ADH release, central and peripheral sympathetic stimulation, extracellular matrix formation, tubular sodium retention, neuroprotection... 

Patients suffering from cystic fibrosis often use various aerosolized drugs. To reduce the viscosity of the mucus in the airways, recombinant human deoxyribonuclease is used. This enzyme is the first recombinant protein that has been developed for specific delivery to the lungs via the airways. It has a local action on the mucus in the airways and its absorption is minimal. Another drug that decreases the viscosity of the mucus is acetylcysteine. Aerosolized antibiotics are a further group of therapeutics that is widely used by cystic fibrosis patients. Solutions of antibiotics like tobramycin or colistin are used in nebulizers to prevent exacerbation of the disease. Pentamidine has been used for the prophylaxis of Pneumocystis pneumonia in patients infected with HIV virus, while chronic rejection of lung transplants provided a reason to develop an aerosol formulation of cyclosporine A. 

Although ER protein degradation seems not be essential for yeast cells, the breakdown of mutated and thus malfolded ER proteins is often associated with severe diseases in human (Ciechanover, 1998 Plemper and Wolf, 1999). The importance of this process in the understanding of genetic disorders like cystic fibrosis and a 1-antitrypsin deficiency has been outlined above. In the following we will give further examples on how viruses or toxins may misuse the machinery for the ER protein degradation to interfere with cellular processes. 

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