Inhibition of diacylglycerol: CDPcholine cholinephosphotransferase activity by dimethylaminoethyl<i>p</i>‐clorophenoxyacetate

Parthasarathy, S.; Cady, R. K.; Kraushaar, D. S.; Sládek, Norman E.; Baumann, Wolfgang J.

doi:10.1007/bf02533260

Cited by 20 publications

(4 citation statements)

References 11 publications

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“…centrophenoxine) is a nootropic drug that is marketed as a memory enhancer. This drug, which readily crosses the blood-brain barrier, has been reported to inhibit enzymes involved in PC biosynthesis [ 36 , 37 ], increase acetylcholine, scavenges radicals [ 38 ], and ameliorate rotenone-induced motor dysfunction in rodents [ 34 , 35 ]. MFX rapidly hydrolyzes into 4-chlorophenoxyacetic acid and dimethylethanolamine (DMAE) at neutral pH, and DMAE is considered to be the active product because of its ability to scavenge hydroxyl radicals [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Chemical Compensation of Mitochondrial Phospholipid Depletion in Yeast and Animal Models of Parkinson’s Disease

Wang

Zhang

et al. 2016

PLoS ONE

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We have been investigating the role that phosphatidylethanolamine (PE) and phosphatidylcholine (PC) content plays in modulating the solubility of the Parkinson’s disease protein alpha-synuclein (α-syn) using Saccharomyces cerevisiae and Caenorhabditis elegans. One enzyme that synthesizes PE is the conserved enzyme phosphatidylserine decarboxylase (Psd1/yeast; PSD-1/worms), which is lodged in the inner mitochondrial membrane. We previously found that decreasing the level of PE due to knockdown of Psd1/psd-1 affects the homeostasis of α-syn in vivo. In S. cerevisiae, the co-occurrence of low PE and α-syn in psd1Δ cells triggers mitochondrial defects, stress in the endoplasmic reticulum, misprocessing of glycosylphosphatidylinositol-anchored proteins, and a 3-fold increase in the level of α-syn. The goal of this study was to identify drugs that rescue this phenotype. We screened the Prestwick library of 1121 Food and Drug Administration-approved drugs using psd1Δ + α-syn cells and identified cyclosporin A, meclofenoxate hydrochloride, and sulfaphenazole as putative protective compounds. The protective activity of these drugs was corroborated using C. elegans in which α-syn is expressed specifically in the dopaminergic neurons, with psd-1 depleted by RNAi. Worm populations were examined for dopaminergic neuron survival following psd-1 knockdown. Exposure to cyclosporine, meclofenoxate, and sulfaphenazole significantly enhanced survival at day 7 in α-syn-expressing worm populations whereby 50–55% of the populations displayed normal neurons, compared to only 10–15% of untreated animals. We also found that all three drugs rescued worms expressing α-syn in dopaminergic neurons that were deficient in the phospholipid cardiolipin following cardiolipin synthase (crls-1) depletion by RNAi. We discuss how these drugs might block α-syn pathology in dopaminergic neurons.

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Section: Discussionmentioning

confidence: 99%

Chemical Compensation of Mitochondrial Phospholipid Depletion in Yeast and Animal Models of Parkinson’s Disease

Wang

Zhang

et al. 2016

PLoS ONE

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“…Males Sprague-Dawley rats weighing 250 -300 g were killed by CO 2 inhalation prior to isolating the microsomes (41). Each rat was placed on its back and a midline incision was made in the abdomen.…”

Section: Isolation Of Microsomes From Rat Intestinementioning

confidence: 99%

Dietary oxidized fatty acids: an atherogenic risk?

Penumetcha

Khan

Parthasarathy

2000

Journal of Lipid Research

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Previous studies have suggested that heated fat that contains oxidized fatty acids in the diet might contribute to the presence of oxidized components in circulating lipoproteins. On the other hand, studies in our laboratory showed that cultured cells such as smooth muscle cells take up oxidized fatty acids poorly. Because intestinal cells are morphologically quite distinct, we studied the uptake of oxidized linoleic acid by Caco-2 and smooth muscle cells (control). When 16-day-old Caco-2 cells were incubated with oxidized linoleic acid (ox-linoleic acid), its uptake was comparable to that of unoxidized linoleic acid (unox-linoleic acid) or that of oleic acid (40-58, 70, and 55%, respectively). In contrast, the uptake of ox-linoleate by smooth muscle cells was about 3%. To determine whether the brush border structure of Caco-2 cells was responsible for increased uptake of oxidized fatty acids, we compared uptake in 4-and 16-day-old cells. The uptake of unox-linoleate and oleic acid (18:1) was comparable for the 4-and 16-day cells. In addition, saturation and competition experiments showed that the uptake of ox-linoleate by Caco-2 cells is not saturable even at 150 M and that this uptake is diluted in the presence of unox-linoleate. In esterification experiments utilizing rat intestinal microsomes, we show that both ox-and unox-linoleate are esterified equally well. In summary, dietary oxidized fatty acids can be absorbed by the intestine and incorporated into lipoproteins and could potentially impose an oxidative stress and exacerbate atherogenesis. -

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“…Increasing effectiveness in ChoPTase inhibition is observed in the series CPIB, SaH-42-348, tibric acid, S-321328, WY-14643, S-8527, and DH-990, with IC50 ranging from 22 mM (CPIB) to 0.3 mM (DH-990). LLAcylTase inhibition by the hypolipidemic drugs follows the same general pattern, but IC50 concentrations range from 9 mM (CPIB) to 40 ,uM (DH-990). The agents inhibit ChoPTase (K;, 25-0.25 mM) and LLAcylTase (K;, 10-0.025 mM) noncompetitively.…”

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confidence: 94%

“…We previously reported (40,41) that two of the key enzymes ofphosphatidylcholine synthesis in mammalian systems-namely, cholinephosphotransferase (ChoPTase; CDPcholine:1,2-diacylglycerol cholinephosphotransferase, EC 2.7.8.2) (42) and lysolecithin acyltransferase (LLAcylTase; acyl-CoA:1-acylglycero-3-phosphocholine O-acyltransferase, EC 2.3.1.23) (43)-are inhibited by centrophenoxine (CPO; N,N-dimethylaminoethyl p-chlorophenoxyacetate) and neophenoxine (NPO; (N,Ndimethylaminoethyl p-chlorophenoxyethyl ether). The structural similarity of CPO and clofibrate prompted us to study the effect of clofibric acid (CPIB; p-chlorophenoxyisobutyric acid) and several other hypolipidemic drugs on the two enzymes of choline phospholipid metabolism.…”

mentioning

confidence: 99%