The effect of polar head group substitution on phospholipid methylation and the beta-adrenergic response in C6 glial cells.
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ABSTRACT:
SUBMITTER: McKenzie RC
PROVIDER: S-EPMC1152815 | biostudies-other | 1985 Nov
REPOSITORIES: biostudies-other
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Project description:We have previously described the remarkable capacity of radioiodinated alkyl phospholipids to be sequestered and retained by a variety of tumors in vivo. We have already established the influence of certain structural parameters of iodinated alkyl phospholipids on tumor avidity, such as stereochemistry at the sn-2 carbon of alkylglycerol phosphocholines, meta-or para-position of iodine in the aromatic ring of phenylalkyl phosphocholines, and the length of the alkyl chain in alkyl phospholipids. In order to determine the additional structural requirements for tumor uptake and retention, three new radioiodinated alkylphospholipid analogs, 2-4, were synthesized as potential tumor imaging agents. Polar head groups were modified to determine structure-tumor avidity relationships. The trimethylammonio group in 1 was substituted with a hydrogen atom in 2, an ammonio group in 3 and a tertiary butyl group in 4. All analogs were separately labeled with iodine-125 or iodine-124 and administered to Walker 256 tumor-bearing rats or human PC-3 tumor-bearing SCID mice, respectively. Tumor uptake was assessed by gamma-camera scintigraphy (for [I-125]-labeled compounds) and high-resolution micro-PET scanning (for [I-124]-labeled compounds). It was found that structural modifications in the polar head group of alkyl phospholipids strongly influenced the tumor uptake and tissue distribution of these compounds in tumor-bearing animals. Phosphoethanolamine analog 3 (NM401) displayed a very slight accumulation in tumor as compared with phosphocholine analog 1 (NM346). Analogs 2 (NM400) and 4 (NM402) lacking the positively charged nitrogen atom failed to display any tumor uptake and localized primarily in the liver. This study provided important insights regarding structural requirements for tumor uptake and retention. Replacement of the quaternary nitrogen in the alkyl phospholipid head group with non-polar substituents resulted in loss of tumor avidity.
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Project description:1. The interactions of gangliosides with Ca(2+) and some polar-head-group requirements for establishment of particular interactions with phosphatidylcholine were studied in monolayers at the air/145mm-NaCl interface. 2. Ganglioside-Ca(2+) interactions, as revealed by surface-potential measurements, depended on the position occupied by sialosyl residues in the oligosaccharide chain. The interactions with Ca(2+) of the single sialosyl residue of monosialogangliosides occurred above 0.1mm-CaCl(2), whereas the interaction of the cation with additional sialosyl groups in di- or tri-sialogangliosides depended on the carbohydrate residue to which the sialosyl moiety was attached. The sialosyl residue bound in sialosyl-sialosyl linkage interacted very little with Ca(2+). The sialosyl residue attached to the terminal galactose of the neutral tetrasaccharide chain interacted with Ca(2+) above 1mum-CaCl(2). 3. Experiments with mixed monolayers containing dihexadecyl phosphate and hexadecyltrimethylammonium indicated that for the occurrence of interactions of polysialogangliosides with phosphatidylcholine characterized by reductions in molecular packing and surface potential both charged groups of the phospholipid and sialosyl residues with particular dipolar properties in the ganglioside are participating. 4. Possible configurations that can explain the behaviour in monolayers were inspected with space-filling molecular models. The position of the carboxylate group of sialosyl residues with respect to the interface and to the sialosyl molecular plane can explain the different orientation of the dipole-moment vector of this residue, which depends on the position to which it is linked in the oligosaccharide chain. Favoured interactions of polysialogangliosides with phosphatidylcholine may result from a configuration allowing a partial matching of two oppositely oriented electrical vectors contributed by the zwitterionic phosphocholine group and particular sialosyl groups.
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Project description:Male Sprague-Dawley rats were fed diets containing 20% (w/w) soya-bean oil, high-erucic acid rapeseed oil or low-erucic acid rapeseed oil for 0, 12 or 23 days. The type of fat present in the diet had no effect on the total phospholipid content of heart mitochondria (micrograms/mg of protein) but did influence the phospholipid class distribution. Rats fed high-erucic acid rapeseed oil for 12 or 23 days had significantly higher mitochondrial phosphatidylcholine content than rats fed soya-bean oil. Low-erucic acid rapeseed oil resulted in elevation of cardiac mitochondrial cardiolipin content after dietary treatment for 12 days. The results demonstrate in vivo that diet is a significant determinant of the phospholipid class content of subcellular membranes.
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Project description:We previously demonstrated that auraptene (AUR), a natural coumarin derived from citrus plants, exerts anti-inflammatory effects in the brain, resulting in neuroprotection in some mouse models of brain disorders. The present study showed that treatment with AUR significantly increased the release of glial cell line-derived neurotrophic factor (GDNF), in a dose- and time-dependent manner, by rat C6 glioma cells, which release was associated with increased expression of GDNF mRNA. These results suggest that AUR acted as a neuroprotective agent in the brain via not only its anti-inflammatory action but also its induction of neurotrophic factor. We also showed that (1) the AUR-induced GDNF production was inhibited by U0126, a specific inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) 1/2, and by H89, a specific inhibitor of protein kinase A (PKA); and (2) AUR induced the phosphorylation of cAMP response element-binding protein (CREB), a transcription factor located within the nucleus. These results suggest that AUR-stimulated gdnf gene expression was up-regulated through the PKA/ERK/CREB pathway in C6 cells.
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Project description:Functional substitution of the essential trace metals zinc (Zn) and cobalt (Co) within metalloenzymes has been well documented in marine diatoms and is known to be prevalent among varying genera and species. In contrast to the majority of species studied to date, we find that the polar diatom Chaetoceros RS19, originally isolated from the Ross Sea, Antarctica, has a Zn requirement that cannot be met by Co and thus does not demonstrate a Zn/Co substitution ability as assessed by growth rate. We investigate the underlying metabolic basis of Zn/Co substitution at the transporter, sensor/chaperone, and metalloenzyme level by employing metal quota, metal uptake rate, and proteomic analyses of this substitution-incapable diatom. Co appears to be transported into the cell, but not efficiently utilized by Zn metalloenzymes.
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