A brevifoliol analogue from the Himalyan yew Taxus wallichiana.
The needles of Taxus wallichiana gave a new brevifoliol derivative whose structure was established by spectral data.
India↗
Biomedical subjects
R P Sharma
Publications and source records attributed to R P Sharma.
Altered dopamine turnover in murine hypothalamus after low-dose continuous oral administration of aluminum.
Aluminum, a known neurotoxic substance, has been suggested as a possible contributing factor in the pathogenesis of Alzheimer's disease. Ground-water pollution by aluminum has been recently reported. In the current study groups of 5 male BALB/c mice were administered aluminum ammonium sulfate in drinking water ad libitum at 0, 5, 25, and 125 mg/L aluminum for 4 weeks. At the termination of aluminum exposure, their brains were removed and dissected into cerebrum, cerebellum, medulla oblongata, midbrain, corpus striatum, and hypothalamus. The concentration of norepinephrine (NE), dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA), were determined in each brain area. DA, DOPAC, and HVA levels were lower in the hypothalamus of aluminum-treated mice, most notably in the low-dose group, as compared with control. No marked alterations in NE, 5-HT, and 5-HIAA levels were detected in any brain region. Changes in the concentration of DA and its metabolites measured in the hypothalamus suggest an inhibition of DA synthesis by aluminum.
Administration, Oral↗
Biological activity of the labdane diterpenes.
Biological activity of diterpenes of the labdane skeleton, isolated from the terrestrial plants and marine sources during the last ten years has been reviewed.
Adenosine↗
Increased responsiveness to intravenous lipopolysaccharide challenge in steers grazing endophyte-infected tall fescue compared with steers grazing endophyte-free tall fescue.
Fescue toxicosis in cattle occurs as a result of consumption of ergot alkaloids in endophyte-infected (E+, Neotyphodium coenophialum) tall fescue (Festuca arundinacea). The condition is characterized by pyrexia, decreased weight gains, rough hair coats, and decreased calving rates. The objective of this experiment was to investigate whether steers grazing E+ fescue have altered host response to lipopolysaccharide (endotoxin, LPS) challenge compared with steers grazing endophyte-free (E-) fescue. Angus steers (n=8) had continuously grazed either E+ (n=4) or E- (n=4) tall fescue grass for 8 months prior to the experiment. The E+ steers had lower body weight, depressed average daily gain, and decreased basal serum prolactin compared with the E- steers prior to LPS administration. Each steer received a single bolus i.v. injection of LPS (0.2 microgram/kg body weight; Escherichia coli; 026:B6) dissolved in sterile saline, and blood was serially collected every 30 min for 4 h and at 24 h post LPS administration. LPS increased serum tumor necrosis factor-alpha (TNF-alpha), cortisol, and haptoglobin but decreased plasma glucose and IGF-I. Importantly, however, TNF-alpha, cortisol, and IGF-I responses to LPS were greater in E+ compared with E- steers. These results indicated that animals grazing E+ fescue had altered integrated metabolic host response compared with animals grazing E- fescue. Potentially, combined exposure to E+ fescue and a bacterial LPS could have greater deleterious effects on the animal compared with exposure to only one of the two and would likely lead to increased catabolism.
Animals↗
Effect of vitamin C and E in modulating peripheral vascular response to local cold stimulus in man at high altitude.
At high altitude (HA), cold stress is aggravated by hypoxia, perhaps due to the increased formation of free radicals which trigger oxidative stress. This may be one of the contributing factors for adverse effects including disturbances in microcirculation and capillary permeability resulting in decreased peripheral blood flow. This leads to altered cold-induced-vasodilatation (CIVD) response on exposure to HA. The present study was conducted on 40 male volunteers (4 groups of 10 each) to evaluate the utility of supplementation of vitamin C (500 mg/d)and vitamin E (400 mg/d) singly, as well as in combination, in modulating peripheral vascular response by assessing CIVD response under local cold stimulus both at Delhi (200 m) and at HA (3,700 m). On exposure to 3,700 m, decreased CIVD response was observed in all the groups. The responses were better in vitamin supplemented groups, in general, as compared to the placebo group. The best CIVD response was seen in the vitamin C (singly)-treated group. Administration of vitamin C and E together did not result in any additional benefit. Facilitation of CIVD response due to supplementation of vitamin C may be attributed to its (a) antioxidant effect, and (b) major physiological functions of increased metabolism and thermogenic properties, facilitation of collagen synthesis, restoration of intercellular substances and better maintenance of the rheological status of the blood. Hence, vitamin C is effective for improving peripheral blood flow and thereby reduces the incidence of cold injuries during acclimatization or outdoor duties at HA.
Adaptation, Physiological↗
A decrease of reelin expression as a putative vulnerability factor in schizophrenia.
Postmortem prefrontal cortices (PFC) (Brodmann's areas 10 and 46), temporal cortices (Brodmann's area 22), hippocampi, caudate nuclei, and cerebella of schizophrenia patients and their matched nonpsychiatric subjects were compared for reelin (RELN) mRNA and reelin (RELN) protein content. In all of the brain areas studied, RELN and its mRNA were significantly reduced (approximately 50%) in patients with schizophrenia; this decrease was similar in patients affected by undifferentiated or paranoid schizophrenia. To exclude possible artifacts caused by postmortem mRNA degradation, we measured the mRNAs in the same PFC extracts from gamma-aminobutyric acid (GABA)A receptors alpha1 and alpha5 and nicotinic acetylcholine receptor alpha7 subunits. Whereas the expression of the alpha7 nicotinic acetylcholine receptor subunit was normal, that of the alpha1 and alpha5 receptor subunits of GABAA was increased when schizophrenia was present. RELN mRNA was preferentially expressed in GABAergic interneurons of PFC, temporal cortex, hippocampus, and glutamatergic granule cells of cerebellum. A protein putatively functioning as an intracellular target for the signal-transduction cascade triggered by RELN protein released into the extracellular matrix is termed mouse disabled-1 (DAB1) and is expressed at comparable levels in the neuroplasm of the PFC and hippocampal pyramidal neurons, cerebellar Purkinje neurons of schizophrenia patients, and nonpsychiatric subjects; these three types of neurons do not express RELN protein. In the same samples of temporal cortex, we found a decrease in RELN protein of approximately 50% but no changes in DAB1 protein expression. We also observed a large (up to 70%) decrease of GAD67 but only a small decrease of GAD65 protein content. These findings are interpreted within a neurodevelopmental/vulnerability "two-hit" model for the etiology of schizophrenia.
Age of Onset↗
Pretreatment plasma homovanillic acid in schizophrenia and schizoaffective disorder: the influence of demographic variables and the inpatient drug-free period.
BACKGROUND: The relationship between plasma homovanillic acid (pHVA) and schizophrenic symptoms has not been conclusively determined. We reexamine pHVA levels in a new sample of patients with emphasis on demographic variables and the drug-free period. METHODS: Plasma HVA levels were studied in 54 schizophrenic and schizoaffective-disordered, drug-free inpatients suffering from a psychotic exacerbation. RESULTS: A significant correlation was observed between pHVA levels and the number of inpatient drug-free days in the total sample, as well as the schizophrenic patient subsample. Further, pHVA was significantly and positively correlated with the duration of illness in the schizophrenic patient subsample. Plasma HVA correlations with behavior, as measured by Brief Psychiatric Rating Scale factors (anxiety/depression and hostility/suspiciousness), emerged only when considering schizophrenic patients drug-free for more than 2 weeks. No correlation was found between pHVA and the age of illness onset or the duration of the delay of treatment of the first psychotic episode. CONCLUSIONS: The effects of antipsychotic withdrawal on levels of pHVA in clinical populations may have to be examined and controlled for in future studies attempting to study the relationship between this metabolite and behavior in acutely ill, drug-free schizophrenic patients.
Adult↗
Hydrophobic mismatch and the incorporation of peptides into lipid bilayers: a possible mechanism for retention in the Golgi.
Preferential interaction of trans-membrane alpha-helices whose hydrophobic length matches the hydrophobic thickness of the lipid bilayer could be a mechanism of retention in the Golgi apparatus. We have used fluorescence methods to study the interaction of peptides Ac-K2-G-Lm-W-Ln-K2-A-amide (Pm+n) with bilayers of phosphatidylcholines with chain lengths between C14 and C24. The peptide P22 (m = 10, n = 12) incorporates into all bilayers, but P16 (m = 7, n = 9) does not incorporate into bilayers when the fatty acyl chain length is C24 and only partly incorporates into bilayers where the chain length is C22. The strongest binding is seen when the hydrophobic length of the peptide matches the calculated hydrophobic thickness of the bilayer. It is suggested that a too-thin bilayer can match to a too-long peptide both by stretching of the lipid and by tilting of the peptide. However, a too-thick bilayer can only match a too-thin peptide by compression of the lipid, which becomes energetically unfavorable when the difference between the bilayer thickness and the peptide length exceeds about 10 A. The presence of cholesterol in the bilayer leads to a marked reduction in the incorporation of P16 into bilayers where the chain length is C18. Hydrophobic mismatch could explain retention of proteins with short trans-membrane alpha-helical domains in the Golgi, the effect following largely from the low concentration of cholesterol in the Golgi membrane compared to that in the plasma membrane.
Cell Compartmentation↗
Early fumonisin B1 toxicity in relation to disrupted sphingolipid metabolism in male BALB/c mice.
Fumonisin B1 is a mycotoxin produced by Fusarium moniliforme, a common fungus in corn. It is known to cause a variety of diseases, including hepatic and renal degeneration in many species of laboratory and domestic animals. The known biochemical events in fumonisin B1 toxicity involve inhibition of ceramide synthase leading to disruption of sphingolipid metabolism. The effect of fumonisin B1 on ceramide and more complex sphingolipids in mice is not known. Groups of five male BALB/c mice each were injected with fumonisin B1 subcutaneously at doses of 0, 0.25, 0.75, 2.25, and 6.75 mg/kg body weight daily for 5 days. This protocol has been shown to produce a dose-dependent increase in apoptosis in liver and kidney of these animals. In the present study, liver, kidney, and brain were sampled and analyzed for free sphingoid bases and complex sphingolipids one day after the last treatment. A dose-related accumulation of free sphinganine and sphingosine was observed in liver and kidney, but not brain. The maximal increase in free sphinganine in kidney was 10-fold greater than in liver. Total phospholipids increased only in liver, whereas ceramide levels were not consistently altered in liver, kidney, or brain. In liver and kidney, fumonisin B1 treatment increased the sphinganine-containing complex sphingolipids, but no effect was observed on sphingosine-containing complex sphingolipids. No changes in complex sphingolipids were observed in brain. In liver, there was a close correlation between the extent of free sphinganine accumulation, and apoptosis and hepatopathy. This correlation was also evident in kidney but to a lessor extent. Nonetheless, the apoptosis and nephropathy occurred with little or no change in the levels of ceramide or more complex sphingolipids.
Animals↗
The effect of FMRF-amide-like peptides on electrical activity in isolated mammalian spinal cord.
FMRFamide and seven FMRFamide-like peptides were manually synthesized on solid phase and their effects tested upon the amplitude of the dorsal root-ventral root monosynaptic reflex (MSR) and dorsal horn field potentials (FP) in an isolated preparation of rat spinal cord. FLFQPQRFamide (NPFF) and AGEGLSSPFWSLAAPQRFamide (NPAF) both depressed a fast component of the FP with similar potencies. FMRFamide also inhibited the FP but its potency was much lower. NPFF and NPAF potentiated the amplitude of the MSR while FMRFamide had no effect. PQRFamide, PFRFamide, FFRFamide, DPQRFamide and Fmoc-FLFQPQRFamide were also examined on the MSR. PQRFamide and PFRFamide potentiated the MSR whereas FFRFamide and DPQRFamide caused a small depression at high concentrations. The increase in amplitude of the MSR induced by NPFF was completely abolished when the N-terminal was left protected with an Fmoc-group. The results suggest that PFRFamide and PQRFamide may act as agonists of NPFF and NPAF whereas the other peptides did not show such activity.
Amino Acid Sequence↗
Fumonisin B1-induced increases in neurotransmitter metabolite levels in different brain regions of BALB/c mice.
Fumonisin B1, a toxin produced by Fusarium moniliforme, causes a variety of diseases in animals, including those involving the central nervous system, such as equine leukoencephalomalacia (ELEM). The changes of biogenic amines may reflect fumonisin B1 neurotoxicity. It was previously reported that consumption of feed contaminated with Fusarium moniliforme cultures produced an elevation of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of 5-hydroxytryptamine (5-HT), in whole rat brains. In a subsequent study from the same laboratory, rats given fumonisin B1 orally for 4 weeks showed no changes in neurotransmitter levels of the whole brain. In the current study, groups of five male BALB/c mice were injected with fumonisin B1 subcutaneously at doses of 0, 0.25, 0.75, 2.25, 6.75 mg kg-1 body weight daily for 5 days. One day after the last treatment, their brains were dissected into cerebrum, cerebellum, medulla oblongata, midbrain, corpus striatum and hypothalamus. Levels of norepinephrine (NE), dopamine (DA), DA metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and 5-HT and 5-HIAA were determined. A significant elevation of HVA was observed in mice treated with high doses of fumonisin B1 in most brain regions. In striatum, a decrease of 5-HT was observed by the fumonisin B1 treatment. Ratios of neurotransmitters to metabolites such as HVA/DA and 5-HIAA/5-HT were elevated in several brain regions of the treated groups. An accumulation of neurotransmitter metabolites is suggestive of increased neuronal activity or interference with their efflux from cells.
3,4-Dihydroxyphenylacetic Acid↗
Lipid-protein interactions in the membrane: studies with model peptides.
We have used fluorescence quenching of tryptophan-containing trans-membrane peptides by bromine-containing phospholipids to study the specificity of peptide-lipid interactions. We have synthesized peptides Ac-K2GLm WLnK2A-amide where m = 7 and n = 9 (L16) and m = 10 and n = 12 (L22). Binding constants of L22 for dioleoylphosphatidylserine [di(C18 : 1)PS] or dioleoylphosphatidic acid [di(C18 : 1)PA] relative to dieoleoylphosphatidylcholine [di(C18 : 1)PC] were close to 1. However, for L16, whilst the bulk of the di(C18 : 1)PA molecules bound with a binding constant relative to di(C18 : 1)PC close to 1, a small number of di(C18 : 1)PA molecules bound much more strongly. Assuming just one high affinity binding site on L16 for anionic lipid, the affinity of the site for di(C18 : 1)PS was calculated to be ca. 8 times that for di (C18 : 1)PC. The relative binding constant was little affected by ionic strength and close contact between the anionic headgroup of di(C18 : 1)PS and a lysine residue on the peptide was suggested. The relative binding constant for di(C18 : 1)PS at this high affinity site was less than for di(C18 : 1)PA. Cholesterol interacts with L22 with an affinity about 0.7 of that of di(C18 : 1)PC. The structure of the peptide itself is important. The peptide Ac-KKGYL6WL8YKKA-amide (Y2L14) incorporated into bilayers of dinervonylphosphatidylcholine [di(C24 : 1)PC] whereas L16 did not incorporate into this lipid. It is suggested that thinning of a lipid bilayer around a peptide to give optimal hydrophobic matching is less energetically unfavourable when a Tyr residue is located in the lipid/water interfacial region.
Cell Membrane↗
Transmembrane alpha-helices in phospholipid bilayers.
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Amino Acid Sequence↗
Verapamil for the treatment of acute mania: a double-blind, placebo-controlled trial.
OBJECTIVE: This study investigated the efficacy of verapamil in acute mania. METHOD: The study was a 3-week double-blind, random-assignment, parallel-group, placebo-controlled inpatient trial of verapamil for patients with acute mania. Of the 32 study patients, 15 were given placebo and 17 were given verapamil. RESULTS: Mean absolute change scores on the Mania Rating Scale at endpoint, with baseline scores as the covariates, did not differ between the verapamil and placebo groups. There were no significant differences between the two groups in age, sex, and presence of psychosis. CONCLUSIONS: The investigators found no benefit of verapamil over placebo in treating acute mania.
Acute Disease↗
Tumor necrosis factor-alpha as a contributor in fumonisin B1 toxicity.
Fumonisin B1 is a toxic product of Fusarium moniliforme, which inhibits ceramide synthase, leading to accumulation of free sphingoid bases. Despite its known biochemical action, the mechanism of toxicity is not fully understood. Male BALB/c mice were injected subcutaneously with 0 to 6.75 mg/kg/day of fumonisin B1 for 5 days. One day after the last treatment, spleens were collected, and peritoneal macrophages were obtained from separate groups after an intraperitoneal injection of thioglycolate broth. Peripheral leukocyte counts were increased and kidney weights were decreased by fumonisin B1 treatment. Presence of apoptotic cells in the liver and kidney of treated mice was confirmed by enzymatic immunoassay. Macrophages cultured with lipopolysaccharide indicated an increased secretion of tumor necrosis factor-alpha (TNF-alpha) but not of interleukin-1alpha. No effect was seen on interferon-gamma production when splenocytes were incubated with concanavalin A. Elevation of leukocyte and reticulocyte counts was abrogated by pretreatment with anti-TNF-alpha antibody before a single dose of fumonisin B1 (25 mg/kg), supporting the hypothesis that the fumonisin B1 toxicity involves TNF-alpha. Cultures of J774A.1 cells, when treated with fumonisin B1, produced TNF-alpha in vitro. Results indicate that fumonisin B1 toxicity may involve secretion of TNF-alpha by TNF-alpha-producing cells without altering interleukin-1alpha or interferon-gamma. The influence on TNF-alpha-production may be a contributing factor to fumonisin B1-induced apoptosis and other observed toxic effects in animals.
Animals↗
Demonstration of in-situ apoptosis in mouse liver and kidney after short-term repeated exposure to fumonisin B1.
Fumonisin B1, a mycotoxin produced by Fusarium moniliforme, inhibits the activity of ceramide synthetase, the key enzyme in sphingolipid biosynthesis, leading to accumulation ofsphinganine and sphingosine. Ceramide and other sphingolipid pathways have been implicated in signal-induced apoptosis in cells. Groups of male BALB/c mice received subcutaneous injections (0, 0.25, 0.75, 2.25 or 6.25 mg/kg) of fumonisin B1 daily for 5 days and the liver and kidneys were sampled 1 day after the last injection. A decrease in kidney weight was observed after fumonisin treatment. A "blind" random evaluation of stained sections revealed dose-dependent fumonisin B1-associated hepatic and renal lesions in all groups. Terminal uridine triphosphate (UTP) nick-end labelling (TUNEL) in liver and kidney sections confirmed the presence of dose-related apoptotic cells at all treatment levels. Thus fumonisin B1 produced apoptosis after a brief exposure to relatively low doses. The toxicity of fumonisin B1 was greater than that previously found in studies on oral toxicity.
Animals↗
A two-phase, double-blind randomized study of three haloperidol plasma levels for acute psychosis with reassignment of initial non-responders.
To clarify the plasma level/therapeutic response relationship of haloperidol (HPDL) we used a prospective double-blind design in 95 acutely psychotic patients. After drug washout, patients were randomly assigned to a low, middle or high plasma level range for 2 weeks (phase A), and then 50% of the initial non-responders were randomly reassigned into the putative therapeutic range for an additional 2 weeks (phase B). There were no significant differences in clinical outcome between the three plasma level ranges in phase A. However, in phase B initial non-responders displayed greater improvement in the middle range than in the low or the high ranges. No further benefit was observed when plasma levels were raised to or maintained in the high range.
Acute Disease↗
Acute dietary tryptophan depletion: effects on schizophrenic positive and negative symptoms.
Because brain serotonin levels depend directly on the amounts of exogenous tryptophan (TRP) available for its synthesis, amounts of TRP in the diet may be manipulated to alter the corresponding levels of serotonin. This technique has been used for probing the role of serotonin in mediating various forms of pyschopathology. In this study, 16 patients meeting DSM III-R criteria for schizophrenia (n = 14) or schizoaffective disorder (n = 2) were assessed for the effects of acute dietary TRP depletion under controlled conditions. The hypothesis was that lowering of serotonin would result in a diminution of 'positive' and/or 'negative' symptoms of psychotic disorders. No clinically or statistically significant improvement compared to baseline occurred when TRP depletion was imposed. Indeed, there was a statistically significant deterioration on measures of negative symptoms. The results are discussed in the context of the methodological issues.
Adult↗