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A new cerebroside, asperiamide A, and adenosine were produced from a marine fungus, identified as Asperillus sp., collected in the Mei Zhou Gulf, China. Two-dimensional NMR methods, FAB-MS, were used to established the structure of the new compound.
A new cerebroside and three known cycloartan triterpenes were isolated from fruits of Ailanthus altissima Swingle. Their structures were identified as 1-O-beta-D-glucopyranosyl-(2S, 3R, 4E, 9E)-2-(2'R-hydroxyhexadecenoy)-4, 9-octadecadiene-1, 3-diol (1), 9, 19-cyclolanost-23 (Z)-ene-3beta, 25-diol (2), cycloart-25-ene-3beta, 24R-diol (3), and cycloart-25-ene-3beta, 24S-diol (4) by means of chemical and spectroscopic analysis. Compounds 2, 3, and 4 were isolated from genus Ailanthus for the first time. The analgesic activity of 1 was also evaluated.
Saponification of cerebroside sulfate (sulfatide) by refluxing with 1 N KOH in 90% n-butanol for 1 h yielded ceramide, sphingosine, lysosulfatide (psychosine-3'-sulfate ester) and a hitherto unknown compound. The latter compound was identified as 3,6-anhydrogalactosyl sphingosine (3',6'-anhydropsychosine) from its mass spectrum. The structure of lysosulfatide was confirmed by reacylating it to sulfatide by condensing it with lignoceroyl chloride. The resulting sulfatide, which was chromatographically identical to control sulfatides, was not oxidized by periodate. The sulfatide was also permethylated and methanolyzed. The sugar moiety obtained was identified as methyl 2,4,6-tri-O-methylgalactoside by gas-liquid chromatography and thin-layer chromatography. The presence of the sulfate group in lysosulfatide was further confirmed by IR spectroscopy and the presence of radioactivity when it was prepared from [35S]sulfatide. The effect of the sulfate group on cleavage of the galactoside linkage and on the formation of the 3,6-anhydro derivative is discussed.
A myelination parameter of the chick optic pathway has been investigated: the activity of cerebroside sulfotransferase. Evidence is presented for a somatofugal progression of the enzyme activity peak along the optic nerve, chiasm, optic tract, tectum anterior, and tectum posterior. The enzyme activity appears on the fifteenth embryonic day and reaches a maximum in the nerve two days before hatching. One day after hatching, the peak is found in the chiasm, and three days after that in the optic tract. The peak is found in the tectum anterior on the tenth day. The results suggest a somatofugal progression of myelination.
Fatty acids of cerebrosides, sulphatides and sphingomyelin from normal human sural nerve, by comparison with brain, show a diminution of long-chained fatty acids as well as unsaturated fatty acids. The findings in brachial plexus are intermediate. In cases of peripheral neuropathy from various causes sphingomyelin fatty acid composition reveals pronounced loss of long-chained fatty acids, a phenomenon that is probably unspecific and may be associated with all forms of demyelination. Problems associated with the limited amount of nervous tissue available from biopsy specimens are discussed.
Cerebroside-beta-glucosidase (acid beta-glucosidase) activity was determined in the forebrain from three patients with the infantile type of Gaucher disease, six patients with the Norrbottnian type and one patient with a mixed infantile/Norrbottnian type. The forebrain from ten subjects, aged 3 months to 20 years, served as controls. The activity was assayed with the natural substrate, (glucose-6-3H) nervonoylglucosylsphingosine and the artificial fluorogenic 4-methyl-umbelliferyl-beta-glucoside. The average residual activities of beta-glucosidase were 12% in the Norrbottnian type and 5% in the infantile type when determined with natural or artificial substrate. Optimum discrimination of the two types of Gaucher disease was obtained with the natural substrate.
Golgi-enriched fractions were prepared from brainstems of 17-day-old rats by first floating off myelin, then fractionating the remaining pellet by a series of differential and density gradient centrifugations in sucrose. Fractions enriched in Golgi membranes were recovered at 0.46/0.76 M and 0.76/0.87 M interfaces on the final sucrose gradient as indicated by morphology and the biochemical markers thiamine pyrophosphatase and [3H]fucose-labeled glycoprotein. Morphology of the two fractions indicated very little contamination with myelin lamellae; however, the presence of significant levels of 2',3'-cyclic nucleotidase in the lighter fraction suggested a contribution from oligodendroglial or myelin-related membranes. Cerebroside sulfotransferase was highly enriched in the lighter Golgi-enriched fraction relative to the denser fraction, the post-34,880 X g microsomes, and the myelin-like fraction. In contrast, ceramide galactosyl transferase was more evenly distributed among the fractions. Our results show a more highly localized distribution of sulfatide synthesis than of galactocerebroside synthesis, probably in Golgi membranes or oligodendroglia-related membranes with similar properties.
Snell dwarf mice (dw/dw) and normal mice (+/?) were injected with thyroxine (T4) (1 microgram/animal, four injections) and growth hormone (GH) (20 micrograms/animal, four injections) from the 5th to the 15th day of life. In the untreated dw/dw mouse brain, the specific activities of UDP-galactose:ceramide galactosyltransferase (CGalT), PAPS:cerebroside sulfotransferase (CST), and 2', 3'-cyclic nucleotide 3'-phosphohydrolase (CNP) were decreased by 28, 25, and 37%, respectively, compared with the control untreated +/? mice. The major effect of T4 was an increase of the brain CNP in the +/? mice (+40%) and dw/dw mice (+111%). The treatment with T4 also brought to normal the level of CGalT in dw/dw brain; a somewhat less marked effect on CST was observed. The treatment with GH had a great stimulatory effect on CNP: the specific activity of this enzyme increased by 40 and 69% in +/? and dw/dw mouse brain, respectively. On the contrary, no effect of GH on the CGalT activity was observed in this study. Our results suggest that T4 and GH may have both independent and complementary actions on the myelin-associated enzymes during the early postnatal period of brain development.
To obtain an understanding of the importance of the neuronal cytoskeleton in Schwann cell metabolism, an antimicrotubular agent (colchicine) was injected into the rat sciatic nerve 24 or 48 h before incubation of the nerve with labeled precursor: [35S]sulfate, [14C]galactose, or [3H]-galactose. Colchicine inhibited the incorporation of 35S radioactivity into sulfatides and, to a lesser extent, into proteins. With galactose as the radioactive precursor, synthesis of cerebrosides was reduced by colchicine injection, whereas incorporation of radioactivity into phosphatidylserine and phosphatidylcholine increased. Intraneural injection of lumicolchicine had no effect. The effects of colchicine on the metabolism of the Schwann cell are discussed in relation to its action on microtubules.
Cell-mediated cytotoxic reactions against myelin basic protein (MBP), encephalitogenic peptide, cerebrosides and gangliosides were studied in 165 MS cases. The cytotoxicity, which is detectable only in the autologous system, is mediated by T lymphocytes bearing antigens reactive with antibody OKT8. The cytotoxicity is highest during active MS regardless of whether it is relapsing or chronic progressive. During inactive MS cytotoxicity is significantly less and remains virtually unchanged at a low level over long periods. The degree of cytotoxicity is thus, predominantly, dependent on the activity stage of the disease. Further, there is a correlation with the severity of the clinical deficiencies. The pathogenetic significance of cytotoxic reactions can be recognized by the close correlation between the stage and course of MS, which can be demonstrated both statistically and individually.
Cultured fibroblasts derived from patients with late infantile metachromatic leukodystrophy incorporated arylsulfatase A from the growth medium. Upon exposure to cerebroside sulfate, they exhibited patterns of uptake and hydrolysis indistinguishable from cells derived from control subjects. Furthermore, inclusion granules formed in the metachromatic leukodystrophy fibroblasts upon exposure to sulfatides were cleared by subsequent supplementation of the growth medium with arylsulfatase A.
The mycoparasite Humicola fuscoatra NRRL 22980 was isolated from a sclerotium of Aspergillus flavus that had been buried in a cornfield near Tifton, Ga. When grown on autoclaved rice, this fungus produced the antifungal metabolites monorden, monocillin IV, and a new monorden analog. Each metabolite produced a clear zone of inhibition surrounding paper assay disks on agar plates seeded with conidia of A. flavus. Monorden was twice as inhibitory to A. flavus mycelium extension (MIC > 28 microg/ml) as monocillin IV (MIC > 56 microg/ml). Cerebrosides C and D, metabolites known to potentiate the activity of cell wall-active antibiotics, were separated from the ethyl acetate extract but were not inhibitory to A. flavus when tested as pure compounds. This is the first report of natural products from H. fuscoatra.
A fragment distinct from the heavy and light chains was obtained by treatment of Clostridium botulinum type B neurotoxin with chymotrypsin. Enzyme-linked immunosorbent assay and immunoblotting analysis with monoclonal antibodies showed that the fragment consisted of the light chain and part of the heavy chain (H-1 fragment) linked together by a disulfide bond. Monoclonal antibodies reacting to the heavy chain but not to the fragment were thought to recognize the epitopes on the remaining portion (H-2 fragment) of the heavy chain, being easily digested by chymotrypsin. Thus, the antigenic structure of type B neurotoxin resembles those of type A and E neurotoxins. The chymotrypsin-induced fragment bound to cerebroside and free fatty acids but not to gangliosides. The manner of binding of type B neurotoxin to gangliosides and free fatty acids was different from those of type A and E neurotoxins. Such differences in the reactivities to lipids may be related to the finding that each neurotoxin binds to a type-specific site on the neural membrane.
On examination in the first weeks after onset of the disease, cell-mediated cytotoxicity against encephalitogenic peptide, myelin basic protein (MBP), cerebrosides and gangliosides was demonstrable in 32 (76%) of 42 patients with optic neuritis (ON). 14 patients with ON and concomitant neurological symptoms (ON/MS) had positive findings with all antigens, especially with the encephalitogenic peptide. The cytotoxic reactions against all antigens showed a close correlation with the course of ON: when the disease improved, the cytotoxicity decreased and became negative on average 4 months after ON onset. As previously reported, cell-mediated cytotoxicity against the above-mentioned antigens, especially the encephalitogenic peptide, may be considered as a pathogenetic factor in multiple sclerosis (MS). A positive reaction with this antigen in patients with ON only probably indicates the first manifestations of MS.
[(14)C]Stearic acid-labeled cerebroside sulfate (CS) was presented to cultured skin fibroblasts in the media. After endocytosis into control cells 86% was readily metabolized to galactosylceramide, ceramide, and stearic acid, which was reutilized in the synthesis of the major lipids found in cultured fibroblasts. Uptake and metabolism of the [(14)C]CS into cells from typical and atypical patients and carriers of metachromatic leukodystrophy (MLD), Krabbe disease, and Farber disease were observed. Cells from patients with late infantile MLD could not metabolize the CS at all, while cells from an adult MLD patient and from a variant MLD patient could metabolize approximately 40 and 15%, respectively, of the CS taken up. These results are in contrast to the in vitro results that demonstrated a severe deficiency of arylsulfatase A in the late infantile and adult patient and a partial deficiency (21-27% of controls) in the variant MLD patient. Patients with Krabbe disease could metabolize nearly 40% of the galactosylceramide produced in the lysosomes from the CS. This is in contrast to the near zero activity for galactosylceramidase measured in vitro. Carriers of Krabbe disease with galactosylceramidase activity near half normal in vitro and those with under 10% of normal activity were found to metabolize galactosylceramide in cells significantly slower than controls. This provides a method for differentiating affected patients from carriers with low enzyme activity in vitro. Cells from patients with Farber disease could catabolize only approximately 15% of the ceramide produced from galactosylceramide. This technique provides a method for the identification of typical and atypical patients and carriers of three genetic diseases using one substrate.
With pulse-chase study of 1-[14C]stearic acid-labeled cerebroside sulfate (14C-CS) and subsequent subcellular fractionation by Percoll gradient, the metabolism of CS and translocation of its metabolites in human skin fibroblasts from controls, metachromatic leukodystrophy (MLD), and globoid cell leukodystrophy (GLD) were studied. In control skin fibroblasts, CS was transported to lysosome and metabolized there to galactosylceramide (GalCer) and ceramide (Cer) within 1 h. During the chase period, radioactivity was increased at plasma membrane plus Golgi as phospholipids and no accumulation of GalCer or Cer was found in lysosome. In MLD fibroblasts, 95% of 14C-CS taken up was unhydrolyzed at 24 h-chase and accumulated at not only lysosome but also plasma membrane. In GLD fibroblasts, GalCer was accumulated throughout the subcellular fractions and more accumulated mainly at plasma membrane plus Golgi with longer pulse. This translocation of lipid from lysosome seems to have considerable function, even in lipidosis, which may result in an imbalance of the sphingolipid pattern on the cell surface and these changes might be one of causes of neuronal dysfunction in sphingolipidosis.
Rat epididymal fat cells were isolated and incubated with 25 microunits insulin/ml for 15 minutes. Insulin induced a significant shift in the saturated/unsaturated fatty acid ratio of the cerebroside fraction isolated from fat cell ghosts. This change was due to a decrease of saturated fatty acids and an increase of unsaturated fatty acids which were hydrolyzed from the isolated lipids. There were no significant changes in the amount of phospholipids isolated from the fat cell ghosts after this period of incubation with insulin or of fatty acids associated with them. Isolated adipocytes were also incubated with 8 x 10(-8) M dexamethasone for 2 1/2 hours. Insulin (25 microunits/ml) was then added, and the incubation continued for 15 minutes. Dexamethasone treated cells did not show a statistically significant insulin stimulated decrease in the saturated/unsaturated fatty acid ratio. These studies demonstrate an insulin induced change in membrane lipids which appeared to be partially blocked by previous exposure to dexamethasone.
We previously reported the isolation of a novel cerebroside (1-O-(beta-D-glucopyranosyl)-(2S,3R,4E,8Z)-2-N-palmityloc tadecasphinga-4,8-diene; LCC) from the fruits of Lycium chinense MILL. (Solanaceae) which protected primary cultured rat hepatocytes from the toxicity induced by carbon tetrachloride (CCl4). The present study was conducted to determine the mechanism(s) by which LCC might exert its hepatoprotective activity. To determine the effect of LCC on the glutathione (GSH) redox system, we measured the activities of enzymes involved in the system as well as the levels of hepatic mitochondrial GSH and malondialdehyde (MDA). The hepatotoxicant, CCl4, routinely decreased levels of total and reduced GSH. The levels of these compounds were significantly maintained at the levels of the control cultures following treatment with LCC. The decreased activities of glutathione reductase and glutathione peroxidase in CCl4-injured rat hepatocytes were significantly increased by the treatment of LCC. Furthermore, the elevated levels of MDA seen in CCl4-injured rat hepatocytes were reduced after treatment with LCC in a concentration dependent manner over a range of 1-10 microM. From these results, we postulate that LCC may preserve the hepatic mitochondrial level of GSH by scavenging reactive oxygen species produced during CCl4-induced toxicity and thereby reduce lipid peroxidation and cellular damage.