Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the relation of type 2 diabetes mellitus to parkinsonian signs in older persons. Participants were 1030 women and men (mean age 80.3 y, education 14.5 y, Mini-Mental State Examination 27.9) without dementia or Parkinson disease, enrolled in the Rush Memory and Aging Project, an epidemiologic study of aging. We used separate linear and logistic regression models, adjusted for age, sex, and education, to examine the relation of diabetes, identified by history and medication inspection, to each of the scores of global parkinsonian signs and 4 separate parkinsonian signs. Diabetes was present in 140 (14%) participants. Most participants had mild parkinsonian signs. Diabetes was associated with a more severe global parkinsonian signs score (beta=0.20, SE=0.10, P=0.05) and postural reflex impairment-gait disturbance (beta=0.40, SE=0.17, P=0.02), but not with bradykinesia, rigidity, or tremor. Associations were no longer significant after controlling for vascular risk factors or conditions, particularly body mass index and congestive heart failure. Overall, there was no evidence that vascular variables modified the relation of diabetes to parkinsonian signs. In summary, we found that diabetes was associated with parkinsonian signs, especially postural reflex impairment-gait disturbance, and that vascular factors may play a role in this association.
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PMID:Diabetes and parkinsonian signs in older persons. 1754 40

Amyloid formation has been implicated in a wide range of human diseases including Alzheimer's disease, Parkinson's disease, and type 2 diabetes. In type 2 diabetes, islet amyloid polypeptide (IAPP, also known as amylin) forms cytotoxic amyloid deposits in the pancreas, and these are believed to contribute to the pathology of the disease. The mechanism of islet amyloid formation is not understood; however, recent proposals have invoked a role for incompletely processed proIAPP. In this model, incompletely processed proIAPP containing the N-terminal pro region is excreted and binds to heparan sulfate proteoglycans (HSPGs) of the basement membrane thereby establishing a high local concentration which can act as a seed for amyloid formation. Here we report biophysical proof-of-principle experiments designed to test the viability of this model. The model predicts that interactions with HSPGs should accelerate amyloid formation by the proIAPP processing intermediate, and this is indeed what is observed. Interaction with heparan sulfate leads to the rapid formation of an intermediate state with partial helical content which then converts, on a slower time scale, to amyloid fibrils. TEM shows that fibrils formed by the proIAPP processing intermediate in the presence and in the absence of heparan sulfate have the classic features of amyloid. Fibrils formed by the proIAPP processing intermediate are competent to seed amyloid formation by mature IAPP. The seeding experiments support a second major premise of the model, namely, that fibrils formed by the processing intermediate are capable of seeding amyloid formation by the mature peptide.
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PMID:Amyloid formation by pro-islet amyloid polypeptide processing intermediates: examination of the role of protein heparan sulfate interactions and implications for islet amyloid formation in type 2 diabetes. 1792 51

Foods contain many bioactive compounds that can improve humans' health, helping to decrease the risk of cataract, macular degeneration, cardiovascular and neurological diseases, osteoporosis, and cancer. Regular practice of exercise and physical activity could also help to drive away aging-associated diseases (obesity, osteoporosis, type 2 diabetes, hypertension, Alzheimer's disease, Parkinson's disease, dementia, and stroke). Exercise recommendations to promote both women's and men's health and disease conditions that hinder exercise practice are described. Health promotion practices should focus on both dietary intake of functional foods and regular practice of exercise within the framework of a healthy lifestyle.
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PMID:Functional foods and physical activities in health promotion of aging people. 1798 Sep 78

A 79-year old woman was admitted with disturbed consciousness (JCS II-30). She had been given a diagnosis of type 2 diabetes 7 years previously, and was being treated with oral hypoglycemic agents. She also suffered Alzheimer's disease and Parkinson's disease. Plasma glucose and HbA1c upon admission was 676mg/dl and 9.7%, respectively. Serum Na was 153mEq/l. Urine ketone body test was negative and metabolic acidosis was not observed. Hyperglycemic hyperosmolar non-ketotic coma (HHNC) was diagnosed, and treatment was started immediately with normal saline infusion. Continuous infusion of regular insulin was needed to lower blood glucose. Disturbed consciousness and dehydration improved by the third hospital day. However, she became bedridden afterwards and received tube feeding. Up to 46 units of insulin was needed daily to control blood glucose. Urine C-peptide secretion was very low (10microg/day), suggesting that insulin therapy was essential for glycemic control long before admission. It is thought that a number of elderly diabetic patients who need insulin therapy do not receive or continue it for various reasons. Discussion is necessary to grasp the actual situation and defensive actions that can be taken.
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PMID:[An elderly case of hyperglycemic hyperosmolar non-ketotic coma (HHNC)]. 1819 60

Catalytic cleavage of the backbone of a protein related to a disease may cure the disease. Owing to the catalytic nature of the protein inactivation, the drug dosage and the side effects can be reduced with the catalytic drugs. Catalytic drugs can be designed even for proteins lacking active sites. Effective artificial proteases have been designed for proteins or oligomers of oligopeptides. The Co(III) complex of cyclen has been used as the catalytic center for peptide hydrolysis. Binding sites of the catalysts that recognize the targets have been searched by using various kinds of chemical libraries. Some of the artificial metalloproteases reported till date offer a new therapeutic option for amyloidoses (e.g. Alzheimer's disease, type 2 diabetes mellitus, Parkinson's disease, mad cow's disease, etc.).
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PMID:Metal complexes as artificial proteases: toward catalytic drugs. 1826 72

Sirtuins have emerged as therapeutic targets to treat age-related diseases. There are seven human Sirtuins (SIRT1-7) that display diversity in cellular localization and function. Growing evidence suggests that small-molecule activators of SIRT1 may counteract age-related afflictions such as type 2 diabetes. Alternatively, inhibitors of SIRT2 may be useful in the treatment of neurodegenerative diseases such as Parkinson's disease. Recent discoveries of small-molecule and protein modulators of Sirtuin deacetylation activity have provided enormous insight into the biological and molecular functions of Sirtuins and have validated their potential as therapeutics.
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PMID:The Sirtuin family: therapeutic targets to treat diseases of aging. 1828 81

Amyloid formation has been implicated in more than 20 different human diseases, including Alzheimer's disease, Parkinson's disease, and type 2 diabetes. The development of inhibitors of amyloid is a topic of considerable interest, both because of their potential therapeutic applications and because they are useful mechanistic probes. Recent studies have highlighted the potential use of rifampicin as an inhibitor of amyloid formation by a variety of polypeptides; however, there are conflicting reports on its ability to inhibit amyloid formation by islet amyloid polypeptide (IAPP). IAPP is the cause of islet amyloid in type 2 diabetes. We show that rifampicin does not prevent amyloid formation by IAPP and does not disaggregate preformed IAPP amyloid fibrils;, instead, it interferes with standard fluorescence-based assays of amyloid formation. Rifampicin is unstable in aqueous solution and is readily oxidized. However, the effects of oxidized and reduced rifampicin are similar, in that neither prevents amyloid formation by IAPP. Furthermore, use of a novel p-cyanoPhe analogue of IAPP shows that rifampicin does not significantly affect the kinetics of IAPP amyloid formation. The implications for the development of amyloid inhibitors are discussed as are the implications for studies of the toxicity of islet amyloid. The work also demonstrates the utility of p-cyanoPhe IAPP for the screening of inhibitors. The data indicate that rifampicin cannot be used to test the relative toxicity of IAPP fibrils and prefibril aggregates of IAPP.
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PMID:Rifampicin does not prevent amyloid fibril formation by human islet amyloid polypeptide but does inhibit fibril thioflavin-T interactions: implications for mechanistic studies of beta-cell death. 1845 28

The presence of fibrillar protein deposits (amyloid) of human islet amyloid polypeptide (hIAPP) in the pancreatic islets of Langerhans is thought to be related to death of the insulin-producing islet beta-cells in type 2 diabetes mellitus (DM2). The mechanism of hIAPP-induced beta-cell death is not understood. However, there is growing evidence that hIAPP-induced disruption of beta-cell membranes is the cause of hIAPP cytotoxicity. Amyloid cytotoxicity by membrane damage has not only been suggested for hIAPP, but also for peptides and proteins related to other misfolding diseases, like Alzheimer's disease, Parkinson's disease, and prion diseases. Here we review the interaction of hIAPP with membranes, and discuss recent progress in the field, with a focus on hIAPP structure and on the proposed mechanisms of hIAPP-induced membrane damage in relation to beta-cell death in DM2.
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PMID:Recent insights in islet amyloid polypeptide-induced membrane disruption and its role in beta-cell death in type 2 diabetes mellitus. 1848 16

In 1983, it was reported that certain drug users with a history of exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a contaminant of an illicitly produced meperidine analogue, developed an irreversible syndrome resembling idiopathic Parkinson disease (PD). Soon thereafter, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine's active metabolite, 1-methyl-4-phenylpyridine, was shown to be a complex I inhibitor. Activity of complex I (the point of entry for most electrons that traverse the mitochondrial electron transport chain) has been found to be impaired in the substantia nigra pars compacta and also in other brain tissues in PD patients. In 2006, high temporal and spatial resolution phosphorous functional magnetic resonance spectroscopy was used to demonstrate that, in 20 PD patients, mitochondrial dysfunction extended to the visual cortex. Epidemiologic studies have implicated a number of apparently disparate exogenous factors in the causation of PD. For example, exposure to certain pesticides and herbicides (many known to inhibit electron transport chain activity) increases PD risk. Parkinson disease risk can be doubled, tripled, or more in individuals with repeated head injuries. Over time, PD risk is almost doubled in men and women with prior type 2 diabetes mellitus. Nevertheless, despite evidence that certain exogenous and/or developmental factors play a role in causation of PD, their potential effect on PD incidence is greatly overshadowed by that of advancing age. In 1 prospective study, PD incidence rate in subjects at least 85 years old was about 14 times that observed in subjects aged 56 to 65 years. The dramatic effect of aging on PD risk may be explained in part by the fact that mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra pars compacta neurons. High levels of these mutations are associated with electron transport chain deficiency, a situation that favors increased oxidative damage, Lewy body formation, and apoptotic cell death. Systematic study of the effects of putative risk factors in animal models of parkinsonism may be expected to improve our understanding of PD's complex pathogenesis.
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PMID:Parkinson disease: primacy of age as a risk factor for mitochondrial dysfunction. 1880 67

Catalytic drugs based on target-selective artificial proteases have been proposed as a new paradigm in drug design. Peptide-cleavage agents selective for pathogenic proteins of Alzheimer's disease, type 2 diabetes mellitus or Parkinson's disease have been prepared using the Co(III) aqua complex (Co(III)cyclen) of 1,4,7,10-tetraazacyclododecane as the catalytic center. In the present study, the Co(III) aqua complex (Co(III)oxacyclen) of 1-oxa-4,7,10-triazacyclododecane was examined in search of an improved catalytic center for peptide-cleavage agents. An X-ray crystallographic study of [Co(oxacyclen)(CO(3))](ClO(4)), titration of Co(III)oxacyclen, and kinetic studies on the cleavage of albumin, gamma-globulin, lysozyme, and myoglobin by Co(III)oxacyclen were carried out. Considerably higher proteolytic activity was observed for Co(III)oxacyclen in comparison with Co(III)cyclen, indicating that better target-selective artificial metalloproteases would be obtained using Co(III)oxacyclen as the catalytic center. The improved proteolytic activity was attributed to either steric effects or the increased Lewis acidity of the Co(III) center. The kinetic data also predicted that side effects due to the cleavage of nontarget proteins by a catalytic drug based on Co(III)oxacyclen would be insignificant.
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PMID:Proteolytic activity of Co(III) complex of 1-oxa-4,7,10-triazacyclododecane: a new catalytic center for peptide-cleavage agents. 1883 52


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