Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alpha-1-antitrypsin deficiency results from point mutations that distort the structure of the protein to allow a unique protein-protein interaction that we have termed loopsheet polymerisation. Polymers of Z alpha 1-antitrypsin accumulate within hepatocytes to form inclusion bodies that are associated with juvenile cirrhosis and hepatocellular carcinoma. The lack of circulating protein predisposes the Z alpha 1-antitrypsin homozygote to emphysema. This process also occurs in other members of the serine proteinase inhibitor (serpin) superfamily, antithrombin, C1-inhibitor and alpha 1-antichymotrypsin, in association with thrombosis, angioedema and chronic obstructive pulmonary disease, respectively, and we have recently shown that it underlies a novel inclusion body dementia. The interaction provides a useful paradigm for other 'conformational diseases' such as Huntington's disease, Creutzfeldt-Jakob disease and the amyloidoses.
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PMID:Alpha-1-antitrypsin deficiency, the serpinopathies and conformational disease. 1090 27

The serpin superfamily of serine proteinase inhibitors has a central role in controlling proteinases in many biological pathways in a wide range of species. The inhibitory function of the serpins involves a marked conformational transition, but this inherent molecular flexibility also renders the serpins susceptible to point mutations that result in aberrant intermolecular linkage and polymer formation. The effects of such protein aggregation are cumulative, with a progressive loss of cellular function that results in diseases as diverse as cirrhosis and emphysema. The recent recognition that mutations in a serpin can also result in late-onset dementia provides insights into changes that underlie other conformational diseases, such as the amyloidoses, the prion encephalopathies and Huntington and Alzheimer diseases.
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PMID:Serpinopathies and the conformational dementias. 1236 Feb 34

Repeating intermolecular protein association by means of beta-sheet expansion is the mechanism underlying a multitude of diseases including Alzheimer's, Huntington's and Parkinson's and the prion encephalopathies. A family of proteins, known as the serpins, also forms large stable multimers by ordered beta-sheet linkages leading to intracellular accretion and disease. These 'serpinopathies' include early-onset dementia caused by mutations in neuroserpin, liver cirrhosis and emphysema caused by mutations in alpha(1)-antitrypsin (alpha(1)AT), and thrombosis caused by mutations in antithrombin. Serpin structure and function are quite well understood, and the family has therefore become a model system for understanding the beta-sheet expansion disorders collectively known as the conformational diseases. To develop strategies to prevent and reverse these disorders, it is necessary to determine the structural basis of the intermolecular linkage and of the pathogenic monomeric state. Here we report the crystallographic structure of a stable serpin dimer which reveals a domain swap of more than 50 residues, including two long antiparallel beta-strands inserting in the centre of the principal beta-sheet of the neighbouring monomer. This structure explains the extreme stability of serpin polymers, the molecular basis of their rapid propagation, and provides critical new insights into the structural changes which initiate irreversible beta-sheet expansion.
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PMID:Crystal structure of a stable dimer reveals the molecular basis of serpin polymerization. 1897 12

Excess iron is found in brain nuclei from neurodegenerative patients (with Parkinson's, Alzheimer's and Huntington's diseases) and also in the liver and spleen of cirrhosis, hemochromatosis and thalassaemia patients. Ferritin, the iron-storing protein of mammals, is known to darken T(2)-weighted MR images. Understanding NMR tissue behavior may make it possible to detect those diseases, to follow their evolution and finally to establish a protocol for non-invasive measurement of an organ's iron content using MRI methods. In this preliminary work, the MR relaxation properties of embalmed iron-containing tissues were studied as well as their potential correlation with the iron content of these tissues. Relaxometric measurements (T(1) and T(2)) of embalmed samples of brain nuclei (caudate nucleus, dentate nucleus, globus pallidus, putamen, red nucleus and substantia nigra), liver and spleen from six donors were made at different magnetic fields (0.00023-14 T). The influence of the inter-echo time on transverse relaxation was also studied. Moreover, iron content of tissues was determined by inductively coupled plasma atomic emission spectroscopy. In brain nuclei, 1/T(2) increases quadratically with the field and depends on the inter-echo time in CPMG sequences at high fields, both features compatible with an outer sphere relaxation theory. In liver and spleen, 1/T(2) increases linearly with the field and depends on the inter-echo time at all fields. In our study, a correlation between 1/T(2) and iron concentration is observed. Explaining the relaxation mechanism for these tissues is likely to require a combination of several models. The value of 1/T(2) at high field could be used to evaluate iron accumulation in vivo. In the future, confirmation of those features is expected to be achieved from measurements of fresh (not embalmed) human tissues.
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PMID:Variable-field relaxometry of iron-containing human tissues: a preliminary study. 1957 79

Increasing metabolic syndromes including type-2 diabetes mellitus, obesity, and steatohepatitis are serious problems in most countries in the world. Neurodegenerative diseases such as Alzheimer, Parkinson's, and Huntington's diseases are increasing in many countries. However, therapy for these diseases is not sufficient yet. Thus, effective chemotherapy for these diseases is being expected. Conophylline is an alkaloid isolated from the leaves of Ervatamia microphylla and related plants. It was found to induce beta-cell differentiation in the precursor pancreatic cells. Oral administration of this compound ameliorated type-2 diabetes mellitus model in mice and rats. Later, fibrosis of the pancreatic islets was found to be greatly reduced by conophylline in the pancreatic islets. It also inhibited chemically induced liver cirrhosis. Further study indicated that conophylline inhibited non-alcoholic steatohepatitis in the model mice. On the one hand, loss of autophagy often causes protein aggregation to give neural cell death. Conophylline was found to activate autophagy in cultured neural cells. Activation of autophagy ameliorated cellular models of Parkinson's and Huntington's diseases. Thus, conophylline is likely to be useful for the development of chemotherapy for metabolic and neurodegenerative diseases.
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PMID:Therapeutic activity of plant-derived alkaloid conophylline on metabolic syndrome and neurodegenerative disease models. 2924 16

Prion diseases are a group of neurodegenerative diseases associated with the misfolding of the cellular prion protein (PrPC) into the infectious form (PrPSc). There are currently no treatments for prion disease. Bile acids have the ability to protect hepatocytes from apoptosis and are neuroprotective in animal models of other protein-folding neurodegenerative diseases, including Huntington's, Parkinson's, and Alzheimer's disease. Importantly, bile acids are approved for clinical use in patients with cirrhosis and have recently been shown to be safe and possibly effective in pilot trials of patients with amyotrophic lateral sclerosis (ALS). We previously reported that the bile acid ursodeoxycholic acid (UDCA), given early in disease, prolonged incubation periods in male RML-infected mice. Here, we expand on this result to include tauro-ursodeoxycholic acid (TUDCA) treatment trials and delayed UDCA treatment. We demonstrate that despite a high dose of TUDCA given early in disease, there was no significant difference in incubation periods between treated and untreated cohorts, regardless of sex. In addition, delayed treatment with a high dose of UDCA resulted in a significant shortening of the average survival time for both male and female mice compared to their sex-matched controls, with evidence of increased BiP, a marker of apoptosis, in treated female mice. Our findings suggest that treatment with high-dose TUDCA provides no therapeutic benefit and that delayed treatment with high-dose UDCA is ineffective and could worsen outcomes.
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PMID:High Dose and Delayed Treatment with Bile Acids Ineffective in RML Prion-Infected Mice. 2978 43