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)

Idiopathic Parkinson's disease is a common movement disorder characterized by a loss of dopaminergic neurons in the substantia nigra. Its pathogenesis is postulated to involve complex interactions between genetic susceptibility and environmental exposures. The IGF2-INS-TH gene cluster on the telomeric end of human chromosome 11 is a gene rich region expressing several proteins important for dopamine neuron homeostasis. We used a haplotyping approach to determine whether common genetic variation in the IGF2-INS-TH cluster influences the risk of idiopathic Parkinson's disease in a Caucasian case-control group recruited from Brisbane, Australia. Three tagging polymorphisms, the SNPs, rs680 and rs689 and the microsatellite, HUMTH01, were genotyped in 215 cases and 215 age- and gender-matched controls. Eight common haplotypes accounted for 91% of the genetic variation in our control group and one haplotype, IGF2-INS-TH*6, was significantly under-represented among the cases with idiopathic Parkinson's disease (OR = 0.42, 95% CI = 0.25-0.72, P-value = 0.001). Analysis of the individual polymorphisms showed that the IGF2-rs680 alternate 'A' allele accounted for the majority of the protective effect. Our findings suggest that common genetic variants in the IGF2-INS-TH cluster modify susceptibility to idiopathic Parkinson's disease.
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PMID:Haplotype analysis of the IGF2-INS-TH gene cluster in Parkinson's disease. 1808 51

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

Neuronal death is a common feature in neurodegenerative diseases including Alzheimer disease (AD) and Parkinson disease (PD). This occurs over years, not the minutes of classically defined apoptosis, and neurons show both responses of apoptosis and regeneration, evidenced by accumulated oxidative insult and attempts at cell cycle re-entry. There is recent evidence suggesting that several known gene mutations in causing familial AD (amyloid beta protein precursor, presenilin-1, or presenilin-2 gene) and familial PD (Parkin, PINK-1, or DJ-1 gene) are associated with increased oxidative stress. Also, several known genetic (e.g. Apolipoprotein Eepsilon4 variant) and environmental (e.g. metals or pesticides exposure) risk factors of sporadic AD and/or PD are associated with increased oxidative stress. In concord, patients at the preclinical stages of AD and PD as well as cellular and animal models of the diseases provide consistent evidence that oxidative insult is a significant early event in the pathological cascade of AD and PD. In contrast to the general aspects of the pathological hallmarks, aggregation of the disease-specific proteins such as amyloid-beta, tau, and alpha-synuclein may act as a compensatory (survival) response against the oxidative insult via the mechanism that the disease-specific structures sequester redox-active metals. Expanding knowledge of the molecular mechanisms of organism longevity indicates that pro-longevity gene products such as forkhead transcription factors and sirtuins are involved in the insulin-like signaling pathway and oxidative stress resistance against aging. An enhancement of the pro-longevity signaling (e.g. caloric restriction) may be a promising approach as anti-oxidative strategy against age-associated neurodegenerative diseases.
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PMID:Neuronal death and survival under oxidative stress in Alzheimer and Parkinson diseases. 1822 Jul 80

Controlling iron/oxygen chemistry in biology depends on multiple genes, regulatory messenger RNA structures, signaling pathways and protein catalysts. Ferritin synthesis is regulated by cytokines (tumor necrosis factor-alpha and interleukin-1alpha) at various levels (transcriptional, post-transcriptional, translational) during development, cellular differentiation, proliferation and inflammation. The cellular response by cytokines to infection stimulates the expression of ferritin genes. The immunological actions of ferritin include binding to T lymphocytes, suppression of the delayed-type hypersensitivity, suppression of antibody production by B lymphocytes, and decreased phagocytosis of granulocytes. Thyroid hormone, insulin and insulin growth factor-1 are involved in the regulation of ferritin at the mRNA level. Ferritin and iron homeostasis are implicated in the pathogenesis of many disorders, including diseases involved in iron acquisition, transport and storage (primary hemochromatosis) as well as in atherosclerosis, Parkinson's disease, Alzheimer disease, and restless leg syndrome. Mutations in the ferritin gene cause the hereditary hyperferritinemia-cataract syndrome and neuroferritinopathy. Hyperferritinemia is associated with inflammation, infections and malignancies, and in systemic lupus erythematosus correlates with disease activity. Some evidence points to the importance of hyperferritinemia in dermatomyositis and multiple sclerosis, but further mechanistic investigations are warranted.
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PMID:Hyperferritinemia in autoimmunity. 1830 May 83

The incidence of neurodegenerative diseases is higher in postmenopausal women that young women. In this sense, Alzheimer's and Parkinson's diseases, ischemic brain injury and memory or cognitive dysfunction increase dramatically when the ovarian function declines. On the other hand, insulin resistance represents an independent factor in the etiology of age-associated coronary and cerebrovascular disease. Therefore, depression, neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and memory or cognitive dysfunction should be considered, in some cases, a result of metabolic syndrome, and that postmenopausal women are more vulnerable that young women to these diseases Several studies have suggested that the molecular mechanism by which estradiol exerts its neuroprotective effects involves activation of the PI3-k signalling pathway, which is activated by insulin and IGF-1. Therefore, it seems possible that ERalpha can interact with these signalling pathways, mainly with PI3-k and IRS-1, to promote neuroprotective effects in the brain. In particular, IGF-I seems to be particularly important in the process of neuroprotection; it can reverse age-related effects and attenuate the age-related decrease in cerebral glucose utilization. Moreover, gonadal hormones have been found to regulate IGF-I receptor. Therefore, it seems clear that the interaction of both systems plays a role in the prevention of neuronal age-related effects. These findings suggest that by interacting with some components of the IGF-I signalling pathway, ERalpha affects the actions of IGF-I in the brain and suggest future avenues of research. The relationship between insulin resistance states associated with aging in females, and the cross-talk between estradiol and proteins includes in the IRS-1/PI3-k/Akt and IGF-1-IR signalling pathways, will lead to a more complete understanding of the precise mechanism underlying estradiol-mediated neuroprotection. Numerous clinical studies have demonstrated that the incidence of neurodegenerative diseases in higher in postmenopausal women that young women. In this sense, Alzheimer's and Parkinson's disease, ischemic brain injury and memory or cognitive dysfunction increase dramatically when the ovarian function declines. Moreover, estrogen replacement therapy seems to be a good element in order to decrease the risk and/or severity of neurodegenerative conditions, and it would be able to improve some aspects related to memory and learning process.
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PMID:Neuroprotective effects of estrogens: cross-talk between estrogen and intracellular insulin signalling. 1847 10

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

We report the generation of functional dopaminergic neurons from human embryonic stem cells (hESCs) using a growth factor mediated multistep EB protocol and its therapeutic effects in vivo. Embryoid bodies (EBs) were cultured in insulin-transferrin-selenium fibronectin (ITSFn) media for the selection of neural precursor cells (NPC). The selected cells on exposure to N2 media supplemented with EGF, bFGF initially aggregated to generate spontaneous free floating neurospheres and on exposure to signaling molecules Shh and FGF-8 differentiated into dopaminergic neurons (40% TH+ cells/total neurons). The differentiated NPC expressed dopaminergic specific markers both at cellular and molecular levels. They secreted detectable levels of dopamine into the culture supernatant. The most unique feature of our protocol is the generation of free floating neurospheres which can be expanded for a longer period without losing their capability to differentiate into DA neurons. Further, transplantation of NPCs into the substantia nigra of 6-OHDA lesioned rat model of Parkinson's disease elicited significant reversal of lesion induced motor deficits which was sustained upto the end of 1 year long study period. Immunohistochemical studies of the grafted area one year post transplantation revealed that transplanted hESC derived neural precursor cells survived, integrated in vivo and differentiated into dopaminergic neurons without teratoma formation. In summary, our results encourage the potential use of hESC derived dopaminergic neurons for future clinical application in Parkinson's disease.
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PMID:One year survival and significant reversal of motor deficits in parkinsonian rats transplanted with hESC derived dopaminergic neurons. 1856 28

Evidence suggests inflammation, mitochondria dysfunction, and oxidative stress play major roles in Parkinson's disease (PD), where the primary pathology is the significant loss of dopaminergic neurons in the substantia nigra (SN). Current methods used to treat PD focus mainly on replacing dopamine in the nigrostriatal system. However, with time these methods fail and worsen the symptoms of the disease. This implies there is more to the treatment of PD than just restoring dopamine or the dopaminergic neurons, and that a broader spectrum of factors must be changed in order to restore environmental homeostasis. Pharmacological agents that can protect against progressive neuronal degeneration, increase the level of dopamine in the nigrostriatal system, or restore the dopaminergic system offer various avenues for the treatment of PD. Drugs that reduce inflammation, restore mitochondrial function, or scavenge free radicals have also been shown to offer neuroprotection in various animal models of PD. The activation of peroxisome proliferator receptor- gamma (PPAR-gamma ) has been associated with altering insulin sensitivity, increasing dopamine, inhibiting inflammation, altering mitochondrial bioenergetics, and reducing oxidative stress - a variety of factors that are altered in PD. Therefore, PPAR-gamma activation may offer a new clinically relevant treatment approach to neuroinflammation and PD related neurodegeneration. This review will summarize the current understanding of the role of PPAR-gamma agonists in neuroinflammation and discuss their potential for the treatment of PD.
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PMID:Agonism of Peroxisome Proliferator Receptor-Gamma may have Therapeutic Potential for Neuroinflammation and Parkinson's Disease. 1861 52

Endoplasmic reticulum (ER) stress is involved in the pathogenesis of several diseases including Alzheimer disease and Parkinson disease. Many recent studies have shown that ER stress is related to the pathogenesis of diabetes mellitus, and with the death of pancreatic beta-cells, insulin resistance, and the death of the vascular cells in the retina. Diabetic retinopathy is a major complication of diabetes and results in death of both neural and vascular cells. Because the death of the neurons directly affects visual function, the precise mechanism causing the death of neurons in early diabetic retinopathy must be determined. The ideal therapy for preventing the onset and the progression of diabetic retinopathy would be to treat the factors involved with both the vascular and neuronal abnormalities in diabetic retinopathy. In this review, we present evidence that ER stress is involved in the death of both retinal neurons and vascular cells in diabetic eyes, and thus reducing or blocking ER stress may be a potential therapy for preventing the onset and the progression of diabetic retinopathy.
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PMID:Endoplasmic reticulum stress and diabetic retinopathy. 1862 65

Peroxisome proliferator-activated receptors (PPARs) are well studied for their peripheral physiological and pathological impact, but they also play an important role for the pathogenesis of various disorders of the central nervous system (CNS) like multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's, and Parkinson's disease. The observation that PPARs are able to suppress the inflammatory response in peripheral macrophages and in several models of human autoimmune diseases lead to the idea that PPARs might be beneficial for CNS disorders possessing an inflammatory component. The neuroinflammatory response during the course of Alzheimer's disease (AD) is triggered by the neurodegeneration and the deposition of the beta-amyloid peptide in extracellular plaques. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been considered to delay the onset and reduce the risk to develop Alzheimer's disease, while they also directly activate PPARgamma. This led to the hypothesis that NSAID protection in AD may be partly mediated by PPARgamma. Several lines of evidence have supported this hypothesis, using AD-related transgenic cellular and animal models. Stimulation of PPARgamma receptors by synthetic agonist (thiazolidinediones) inducing anti-inflammatory, anti-amyloidogenic, and insulin sensitising effects may account for the observed effects. Several clinical trials already revealed promising results using PPAR agonists, therefore PPARs represent an attractive therapeutic target for the treatment of AD.
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PMID:PPARs in Alzheimer's Disease. 1864 13


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