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

Polymorphic N-acetyltransferase (NAT2) is involved in the metabolism of several compounds relevant in pharmacology or toxicology, with diverse clinical consequences. Inter-ethnic variations in distribution of the acetylation phenotype are significant. The caffeine test is most often used to assess the acetylation phenotype and to identify rapid and slow acetylators. The NAT2 phenotype could account for the increased risk of certain side effects in slow acetylators treated with isoniazid (particularly peripheral neuropathies and lupus erythematosus), although therapeutic efficacy seems to be independent of the acetylation status. Hypersensibility reactions with sulfonamides (including Lyell and Stevens-Johnson syndromes) are more frequent in slow acetylators, who also show poor tolerance to sulfasalazine and dapsone. In contrast, myelotoxicity induced by amonafide is more frequent in rapid acetylators, probably because of increased production of a toxic metabolite of the drug. In carcinogenesis, NAT2 may play a protective role against bladder cancer, although studies have shown contradictory results. Slow acetylators may have a risk of developing primitive liver cancer. For lung cancer, data are not conclusive, but slow acetylation status may predispose to mesothelioma in subjects exposed to asbestos. No relation has been found between acetylation phenotype and breast cancer. Contradictory results were reported on its role in colorectal cancer. Non-smoking type 1 diabetics may be at increased risk of nephropathy if they are rapid acetylators. Parkinson's disease may be more frequent among slow acetylators, but again, data have shown contradictory results. Finally, a poor acetylator phenotype may predispose to atopic diseases.
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PMID:[Clinical relevance of N-acetyltransferase type 2 (NAT2) genetic polymorphism]. 1261 Nov 96

Synucleins are emerging as central player in the fundamental neural processes and in the formation of pathologically insoluble deposits characteristic of Alzheimer's disease and Parkinson's disease. However, gamma Synuclein (SNCG) is also highly associated with breast cancer and ovarian cancer progression. Whereas most studies of this group of proteins have been directed to the elucidation of their role in the formation of depositions in brain tissue, the normal cellular function of this highly conserved synuclein family remains largely unknown. A notable finding in this study is that SNCG, identified previously as a breast cancer-specific gene 1, strongly stimulated the ligand-dependent transcriptional activity of estrogen receptor-alpha (ER-alpha) in breast cancer cells. Augmentation of SNCG expression stimulated transcriptional activity of ER-alpha, whereas compromising endogenous SNCG expression suppressed ER-alpha signaling. The SNCG-stimulated ER-alpha signaling was demonstrated in three different cell systems including ER-alpha-positive and SNCG-negative MCF-7 cells, ER-alpha-positive and SNCG-positive T47D cells, and SNCG-negative and ER-alpha-negative MDA-MB-435 cells. The SNCG-mediated stimulation of ER-alpha transcriptional activity is consistent with its stimulation of the ligand-dependent cell growth. Whereas overexpression of SNCG stimulated the ligand-dependent cell proliferation, suppression of endogenous SNCG expression significantly inhibited cell growth in response to estrogen. The stimulatory effect of SNCG on ERalpha-regulated gene expression and cell growth can be effectively inhibited by antiestrogens. These data indicate that SNCG is required for efficient ER-alpha signaling and, thus, stimulated hormone-responsive mammary tumors.
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PMID:Stimulation of estrogen receptor signaling by gamma synuclein. 1287 81

Women undergoing chemotherapy for breast cancer are often administered dopamine antagonist adjuvant medications that may increase levels of prolactin potentially increasing the risk of cancer. Using nationwide computerized registers of death data for the years 1991 through 1996 we examined 12,430,473 deaths of persons over 40 years of age and extracted 144,364 cases with Parkinson's disease (PD), a dopamine deficient population. Patients with PD had lower rates of breast and other types of malignancies, even in the presence of depression and suicide.
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PMID:Are dopamine antagonists a risk factor for breast cancer? An answer from Parkinson's disease. 1465 14

Among 14,088 patients, with a primary diagnosis of Parkinson's disease during the period 1977-98 identified from the National Register of Patients, 1282 cancers were subsequently recorded in the Danish Cancer Registry, compared with 1464 expected, with a standardised incidence ratio (SIR) of 0.88 (95% confidence interval (CI), 0.8-0.9). Significantly reduced risks were found for smoking-related cancers, for example, cancers of the lung (SIR, 0.38), larynx (0.47) and urinary bladder (0.52), although moderate reductions in risk were also seen for several nonsmoking-related cancers. In contrast, increased risks were seen for malignant melanoma (SIR, 1.95; 95% CI, 1.4-2.6), nonmelanocytic skin cancer (1.25; 1.1-1.4) and breast cancer (1.24; 1.0-1.5). The observed cancer pattern supports the hypothesis that constituents of tobacco smoke inhibit or delay the development of Parkinson's disease, but a low smoking prevalence appears to be only part of the explanation for the decreased cancer incidence. The increased relative risks of melanoma and nonmelanoma skin cancer are not likely to be artefactual, but further investigations of potential mechanisms are warranted.
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PMID:Atypical cancer pattern in patients with Parkinson's disease. 1558 88

Human kallikreins are serine proteases that comprise a recently identified large and closely related 15-member family. The kallikreins include both regulatory- and degradative-type proteases, impacting a variety of physiological processes including regulation of blood pressure, neuronal health, and the inflammatory response. While the function of the majority of the kallikreins remains to be elucidated, two members are useful biomarkers for prostate cancer and several others are potentially useful biomarkers for breast cancer, Alzheimer's, and Parkinson's disease. Human tissue kallikrein (human K1) is the best functionally characterized member of this family, and is known to play an important role in blood pressure regulation. As part of this function, human K1 exhibits unique dual-substrate specificity in hydrolyzing low molecular weight kininogen between both Arg-Ser and Met-Lys sequences. We report the X-ray crystal structure of mature, active recombinant human apo K1 at 1.70 A resolution. The active site exhibits structural features intermediate between that of apo and pro forms of known kallikrein structures. The S2 to S2' pockets demonstrate a variety of conformational changes in comparison to the porcine homolog of K1 in complex with peptide inhibitors, including the displacement of an extensive solvent network. These results indicate that the binding of a peptide substrate contributes to a structural rearrangement of the active-site Ser 195 resulting in a catalytically competent juxtaposition with the active-site His 57. The solvent networks within the S1 and S1' pockets suggest how the Arg-Ser and Met-Lys dual substrate specificity of human K1 is accommodated.
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PMID:1.70 A X-ray structure of human apo kallikrein 1: structural changes upon peptide inhibitor/substrate binding. 1565 Oct 49

Female sexual dysfunction (FSD) is a multifactorial set of conditions associated with multiple anatomical, physiological, biological, medical and psychological factors that can have major impact on self-esteem, quality of life, mood and relationships. Studies indicate that FSD is commonly seen in women who report a low level of satisfaction with partner relationship and in women with male partners who have erectile dysfunction. This complexity of FSD is augmented by the presence of chronic disease. Negative sexual effects are widely reported in studies of women with chronic diseases (such as metabolic syndrome, diabetes mellitus, chronic kidney disease, cancer, spinal cord injury, lupus, rheumatic diseases, Parkinson's disease, fibromyalgia and chronic pain) as compared to a general healthy female population. Physical problems, emotional problems and partnership difficulties arising from disease-related stress contribute to less active and less enjoyable sex life. Chronic pain, fatigue, low self-esteem as well as use of medications might reduce sexual function. These effects of chronic diseases on female sexual function still remain largely unstudied. The study by Manor and Zohar published in this issue of Harefuah draws our attention to the sexual dysfunction of women with breast cancer and examines their needs for information regarding their sexual function. In the absence of definite treatment evidence, psychological counseling, improved vaginal lubrication, low dose of hormonal therapy can be used to relieve FSD. Physicians must consider integrating diagnosis of their female patients' sexual needs and dysfunction, especially women with chronic diseases. Patients' education and counseling may contribute to a better quality of life in spite of their chronic disease.
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PMID:[Female sexual function and chronic disease]. 1650 15

Estrogens can be converted to electrophilic metabolites, particularly the catechol estrogen-3,4-quinones, estrone(estradiol)-3,4-quinone [E(1)(E(2))-3,4-Q], which react with DNA to form depurinating adducts. These adducts are released from DNA to generate apurinic sites. Error-prone repair of this damage leads to the mutations that initiate breast, prostate, and other types of cancer. The reaction of E(1)(E(2))-3,4-Q with DNA forms the depurinating adducts 4-hydroxyE(1)(E(2))-1-N3adenine [4-OHE(1)(E(2))-1-N3Ade] and 4-OHE(1)(E(2))-1-N7guanine(Gua). These two adducts constitute >99% of the total DNA adducts formed. The E(1)(E(2))-2,3-Q forms small amounts of the depurinating 2-OHE(1)(E(2))-6-N3Ade adducts. Reaction of the quinones with DNA occurs more abundantly when estrogen metabolism is unbalanced. Such an imbalance is the result of overexpression of estrogen-activating enzymes and/or deficient expression of deactivating (protective) enzymes. Excessive formation of E(1)(E(2))-3,4-Q is the result of this imbalance. Oxidation of catechols to semiquinones and quinones is a mechanism of tumor initiation not only for endogenous estrogens, but also for synthetic estrogens such as hexestrol and diethylstilbestrol, a human carcinogen. This mechanism is also involved in the initiation of leukemia by benzene, rat olfactory tumors by naphthalene, and neurodegenerative diseases such as Parkinson's disease by dopamine. In fact, dopamine quinone reacts with DNA similarly to the E(1)(E(2))-3,4-Q, forming analogous depurinating N3Ade and N7Gua adducts. The depurinating adducts that migrate from cells and can be found in body fluids can also serve as biomarkers of cancer risk. In fact, a higher level of estrogen-DNA adducts has been found in the urine of men with prostate cancer and in women with breast cancer compared to healthy controls. This unifying mechanism of the origin of cancer and other diseases suggests preventive strategies based on the level of depurinating DNA adducts that generate the first critical step in the initiation of diseases.
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PMID:Catechol quinones of estrogens in the initiation of breast, prostate, and other human cancers: keynote lecture. 1726 77

There is substantial evidence based on well designed epidemiologic studies for low cancer rates in patients with Parkinson disease (PD). This risk reduction cannot be attributed to the recognized low life-long incidence of smoking in patients with PD, as not only smoking-related cancers but also non-smoking-related ones are less common in PD. Whereas the risk for most cancers appears to be relatively low in patients with PD, breast cancer and melanomas occur more frequently in the PD population as compared with controls. The relationship between this peculiar pattern of cancer rates and PD might be related to the involvement of common genes in both diseases. Mutations in parkin gene, for example, have been reported in several types of cancer. Furthermore, genes involved in familial forms of PD appear to be abnormally expressed in cancers. Thus, parkin and PINK1 might be tumor suppressor genes, whereas DJ-1 is an oncogene. Cell survival signals may differ owing to mutated genes and represent two opposite extremes such as cell proliferation in cancer and cell death due to apoptosis in PD. Unraveling the link between PD and cancer may open a therapeutic window for both diseases.
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PMID:Are Parkinson disease patients protected from some but not all cancers? 1900 Dec 59

Nuclear factor-kappaB (NF-kappaB) is responsible for the expression by regulating many genes for immune response, cell adhesion, differentiation, proliferation, angiogenesis and apoptosis. The function of NF-kappaB is inhibited by binding to NF-kappaB inhibitor (IkappaB), and imbalance of NF-kappaB and IkappaB has been associated with development of many diseases, including tumours. In this review, we focus on polymorphisms of the NFKB and NFKBI genes in relation to development of common inflammatory diseases including ulcerative colitis (UC), Crohn's disease (CD), rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, giant cell arthritis, type 1 diabetes, multiple sclerosis, celiac disease, and Parkinson's disease, as well as susceptibility of several cancers, such as oral squamous cell carcinoma, colorectal cancer (CRC), hepatocellular carcinoma, breast cancer and myeloma.
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PMID:NFKB and NFKBI polymorphisms in relation to susceptibility of tumour and other diseases. 1770 19

DJ-1 was initially identified by us as a novel oncogene and has later been found to be a causative gene for familial Parkinson's disease PARK7. DJ-1 plays role in transcriptional regulation and in oxidative stress function, and loss of its function is thought to be related to onset age, mode of progression and clinical severity of both familial and sporadic forms of Parkinson's disease (PD). DJ-1 is localized both in the cytoplasm and nucleus, and it has been reported to be secreted into the serum or plasma of patients with breast cancer, melanoma, familial amyloidotic polyneuropathy and stroke. In this study, levels of DJ-1 secreted into the serum of healthy controls and patients with sporadic PD were examined by using a DJ-1 ELISA kit, and the level of oxidative stress in the serum was also measured. The results showed that DJ-1 was secreted into the serum of both healthy controls and PD patients. There was no significant difference between the levels of secreted DJ-1 in two groups, and correlations of levels of secreted DJ-1 with age, clinical severity of PD and level of oxidative stress were not found.
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PMID:Secretion of DJ-1 into the serum of patients with Parkinson's disease. 1816 23


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