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PubMed1995

[Morphometric study on the cerebral cortex of partial status epilepticus rats induced by coriaria lactone].

Twenty adult male Wistar rats, divided into two groups were studied. Experimental rats were embedded with a particle containing Coriaria Lactone into the fore limb's representative area of cerebral motor cortex to induce epilepsy. Control rats were embedded with a particle containing distilled water. After 6 h motor cortex was cut and the structure was compared morphologically with control rats. Some pale neurons, dark shrunken neurons and severe sponginess of neuropil were observed in layers I-V of the epileptic rat under LM. Under EM, the mitochondria became swollen and other organelles migrated and close associated with the nucleus in pale neurons, and in dark neurons both cytoplasm and karyoplasm showed highly electron dense. The spongiform neuropil was mainly occupied by swollen glial processes. The number of neuron and neuroglia were counted from photos under LM. The number of synaptic terminal was counted directly and the areal fraction of the constituents in the neuropil was measured stereologically in the EM photos. The number of neuron and neueroglia decreased significantly. Both the number of synaptic terminal in neuropil and the areal fraction of synaptic terminal decreased significantly. These changes were most prominent in the focus area of epileptic rats and in the parafocus area, too. This may indicate that the decrease of areal fraction of synaptic terminal results from the decrease of the number of synaptic terminal.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Modulation of the activity of a human granulocyte-macrophage colony-stimulating factor/interleukin-3 fusion protein (pIXY 321) by the macrocyclic lactone protein kinase C activator bryostatin 1.

We have examined the effect of the macrocyclic lactone protein kinase C (PK-C) activator bryostatin 1 on the proliferative capacity and lineage commitment of CD34+ human bone marrow cells exposed to the granulocyte-macrophage colony-stimulating factor/interleukin-3 (GM-CSF/IL-3) fusion protein pIXY 321. pIXY 321 administered at a dose of 10 ng/mL was as effective as the combination of plateau concentrations of recombinant (r) IL-3 and rGM-CSF (e.g., 50 ng/mL) in stimulating the growth of day-14 committed myeloid progenitors (colony-forming units granulocyte/macrophage [CFU-GM]). In the large majority of samples tested, coadministration of 0.5 to 100 nM bryostatin 1 with either pIXY 321 or the combination of rIL-3 plus rGM-CSF led to modest but significant increases (e.g., 30 to 75%) in the number of CFU-GM, compared to administration of growth factors alone. The degree of bryostatin 1-induced potentiation, however, was considerably less than that previously observed in the case of cells exposed to either rIL-3 or rGM-CSF, where increases of 100 to 150% were regularly noted. While at least 50% of day-14 CFU-GM stimulated by either pIXY 321 or the combination of rIL-3 plus rGM-CSF were of the pure or mixed eosinophilic variety, coadministration of bryostatin 1 resulted in a dramatic inhibition of eosinophilic colonies and a corresponding increase in pure and mixed neutrophil and macrophage colonies. Although coadministration of recombinant granulocyte colony-stimulating factor (rG-CSF) or recombinant colony-stimulating factor-1 (rCSF-1) mimicked the capacity of bryostatin 1 to increase the total number of pIXY 321-induced day-14 CFU-GM, these growth factors, unlike bryostatin 1, were not capable of inhibiting eosinophilic colony formation. Furthermore, whereas addition of neutralizing antibodies to G-CSF or CSF-1 blocked the capacity of these growth factors to potentiate colony formation in the presence of pIXY 321, it did not abrogate the effect of bryostatin 1 on progenitor cell growth or lineage commitment. Finally, in contrast to its effects on committed myeloid progenitors, bryostatin 1 did not increase the growth of erythroid (burst-forming units-erythroid [BFU-E]) and multipotent (multipotent colony-forming units [CFU-GEMM]) progenitors stimulated by pIXY 321, but instead inhibited colony formation at higher concentrations (e.g., 10 to 100 nM).(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies↗
PubMed1994

[Morphometric study of motor cortex in acute focal epilepsy rat induced by coriaria lactone].

Twenty adult male Wistar rats were divided randomly into two groups (10 rats for LM, 10 rats for EM). The experimental rats were injected with convulsive dosage 3.8 microliters (19 micrograms) of coriaria lactone (CL) in the left cerebral motor cortex of the fore limb to induce acute focal epilepsy. The control rats were injected with normal saline of the same volume and at the same location. Motor cortex was cut coronally 2 hours after seizure and the layer V was studied morphometrically. Under x400 and x7000, take photos of focus, parafocus areas respectively for morphometric study. The number of neurons and neuroglias of layer V was counted in the LM photos. The number of presynaptic terminals of the neuropil was counted in the x7000 EM photos and the area fraction of each constitute in the neuropil was measured. The positive results demonstrated that the number of neurons and neuroglias in the focus and parafocus areas of the experimental animals was significantly lower than that in the control group, the side injected was lower than the other side and it was the lowest in the focus. The number and area fraction of the presynaptic terminals of the experimental rats at the focus neuropil decreased significantly, but the area fraction of neuroglial components increased significantly. The authors suggest that the convulsive dosage of CL may have toxic effect on some neurons and neuroglias and therefore to decrease the number of both types of cells and the number and area fraction of presynaptic terminals in the neuropil.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1993

[The sesquiterpene lactone "azerin" has memory enhancing properties].

The memory property of Sesquiterpene Lactone Azerin, isolated from the plant species Ferula compared with placebo (PCO) and clinical well known drug Nootropyl/Piracetam (NOO) were studied on rats. The experiments showed that Azerin in 7-8 times improved the ability of rats to keep the signs of Passive Avoidance Response (PAR), when NOO only in 3-4 times. The learning and transcorneally amnesic electro-shock leaded to 100% PCO, 63% NOO and only 20% Azerin rats retrograde amnesia syndrome. Thus, the mechanisms of amnestic and antiamnestic properties of Azerin have been studied.

Amnesia↗
PubMed1994

The macrocyclic lactone protein kinase C activator, bryostatin 1, either alone, or in conjunction with recombinant murine granulocyte-macrophage colony-stimulating factor, protects Balb/c and C3H/HeN mice from the lethal in vivo effects of ionizing radiation.

We have examined the in vivo radioprotective effects of the macrocyclic lactone protein kinase C (PK-C) activator, bryostatin 1, administered either alone or in conjunction with recombinant murine granulocyte-macrophage colony-stimulating factor (rmGM-CSF), in Balb/c and C3H/HeN mice subjected to lethal total body irradiation (TBI). When administered alone on a divided dose schedule (24 hours and 30 minutes before TBI), rmGM-CSF (20 micrograms/kg) was ineffective in increasing survival in either strain. However, in Balb/c mice, bryostatin 1 alone (1 microgram) permitted the long-term survival (60 days) of 70% of the animals following TBI, and 80% when administered in conjunction with rmGM-CSF. Bryostatin 1 administered alone according to this schedule exerted minimal radioprotective effects in C3H/HeN mice, but, when combined with a subeffective dose of rmGM-CSF, allowed 50% of the animals to survive. Treatment of Balb/c mice with bryostatin 1 administered as a single dose 4 hours before TBI resulted in a 20% survival rate, and 45% when administered with rmGM-CSF; corresponding values for the C3H/HeN strain were 60% and 40%, respectively. Lastly, the survival rates of Balb/c mice treated with bryostatin 1 administered as a single dose 4 hours following TBI was 20%, and 25% with rmGM-CSF; corresponding values were 50% and 25% for C3H/HeN mice. These findings indicate that the PK-C activator bryostatin 1 exhibits intrinsic in vivo radioprotective effects in lethally irradiated Balb/c and C3H/HeN mice, and may, under some circumstances, augment the radioprotective capacity of rmGM-CSF. They also underscore the critical role that strain differences and scheduling considerations play in determining the in vivo radioprotective capacity of bryostatin 1, as well as its interactions with rmGM-CSF.

Animals↗
PubMed1996

[A morphometric study on hippocampus of epileptic rats induced by coriaria lactone].

This experiment was carried out with these rats were injected with 3.8 microliters (19 micrograms) convulsive dosage of coriaria lactone (CL) in the left cerebral motor cortex of the forelimb to induce acute focal epilepsy, while the other 5 rats as controls (no seizure) received normal saline solution of the same volume and at the same location. The brains were taken after seizuring for 60 min. The volume (water displacement method) and weight of the brain were measured. The brain was cut coronally and the structures of hippocampus were compared morphologically with those of the pair-matched control. The area of hippocampal formation was measured with paraffin section by test grid under 40x. The mean size (Feret's diameter) of pyramidal neurons in CA1 region was measured with semithin section by ocular micrometer under 1000x. The areal fraction of several organelles of the CA1 pyramidal cells was measured with EM negative film by magnifier. Under conditions of the consistent reference space, especially the size of CA1 pyramidal cells, the areal fraction of rough endoplasmic reticulum, lysosome and mitochondria increased significantly (P < 0.05) in epileptic rats. It indicated that their volume increased. The results show that certain ultrastructural changes have taken place after seizuring for 60 min.

Animals↗
PubMed2000

Induction of antibodies against GD3 ganglioside in melanoma patients by vaccination with GD3-lactone-KLH conjugate plus immunological adjuvant QS-21.

The gangliosides GD3, GD2 and GM2 are expressed on the cell surface of malignant melanomas, GD3 being the most abundant. We have shown that immunization of melanoma patients with GM2 adherent to Bacillus Calmette-Guerin (GM2/BCG) induced an IgM antibody response. Vaccines containing GM2-keyhole limpet hemocyanin (KLH) conjugate and the immunological adjuvant QS-21 induced a higher titer IgM response and consistent IgG antibodies. Patients with antibodies against GM2 survived longer than patients without antibody. On the other hand, our previous trials with GD3/BCG, GD3 derivatives including GD3-lactone (GD3-L)/BCG failed to induce antibodies against GD3. In our continuing efforts to induce antibody against GD3, we have immunized groups of 6 melanoma patients with GD3-KLH or GD3-L-KLH conjugates containing 30 microg of ganglioside plus 100 microg of QS-21 at 0, 1, 2, 3, 7 and 19 weeks. Prior to vaccination, no serological reactivity against GD3 or GD3-L was detected. After immunization, IgM and IgG antibodies were detected against both GD3 and GD3-L in the GD3-L group exclusively. The GD3-L-KLH vaccine induced IgM titers against GD3-L of 1:40-1/1,280 in all patients and IgG titers of 1/160-1/1,280 in 4 patients. These antibodies also strongly cross-reacted with GD3. ELISA reactivity was confirmed by immune thin-layer chromatography on GD3 and melanoma extracts. Sera obtained from 4 of these 6 patients showed cell surface reactivity by FACS and from 2 showed strong cell surface reactivity by immune adherence (IA) assay and complement lysis against the GD3 positive cell line SK-Mel-28.

Adjuvants, Immunologic↗
PubMed2002

Homoleptic lanthanide complexes of chelating bis(phosphanyl)amides: synthesis, structure, and ring-opening polymerization of lactones.

Treatment of the bis(phosphanyl)amide (Ph2P)2NH with KH in boiling THF followed by crystallization from THF/n-pentane leads to [K(thf)n][N(PPh2)2] (n = 1.25, 1.5). Reaction of [K(thf)n][N(PPh2)2] with anhydrous yttrium or lanthanide trichlorides in a 3:1 molar ratio afforded homoleptic bis(phosphanyl)amide complexes [Ln[N(PPh2)2]3] (Ln = Y, Er) as large crystals in good yields. [Ln[N(PPh2)2]3] can also be obtained by reaction of the homoleptic bis(trimethylsilyl)amides of Group 3 metals and lanthanides [Ln[N(SiMe3)2]3] (Ln = Y, La, Nd) with three equivalents of (Ph2P)2NH in boiling toluene. The single-crystal X-ray structures of these complexes always show eta 2 coordination of the ligand. Dynamic behavior of the ligand is observed in solution and is caused by rapid exchange of the two different phosphorus atoms. [Ln[N(PPh2)2]3] was used as catalyst for the polymerization of epsilon-caprolactone. Significant differences in terms of correlation of theoretical and experimental molecular weights as well as polydispersities were observed depending on the nature of Ln. On the basis of the crystal structure of the heteroleptic complex [Lu[N(PPh2)2]3(thf)], we suggest that in the initiation step of epsilon-caprolactone polymerization the lactone adds to the lanthanide atom to form a sevenfold coordination sphere around the central atom.

Journal Article↗
PubMed2002

The anti-inflammatory sesquiterpene lactone parthenolide suppresses IL-4 gene expression in peripheral blood T.

Sesquiterpene lactones (SL) derived from Mexican India medicinal plants and parthenolide, the major SL from European feverfew, have raised considerable interest because of their anti-inflammatory and complex pharmacological action. Interleukin-4 (IL-4) is a key cytokine that influences the development of T helper 2 cells and plays an important role in the pathogenesis of allergic diseases. We show here that the anti-inflammatory parthenolide suppresses IL-4 expression at the mRNA and the protein levels in a dose-dependent manner. We demonstrate that parthenolide blocks NF-kappaB binding to two important IL-4 promoter regulatory elements and suppresses promoter activity upon T cell activation. Differences regarding the effects of parthenolide on expression levels of IL-4, IL-2 and IFN-gamma were observed. Parthenolide (2.5 microM) could completely suppress IL-4 protein levels secreted in anti-CD3/CD28-stimulated peripheral blood T cells from allergic and normal donors. Complete inhibition of IL-2 and IFN-gamma requires higher doses of parthenolide. So far, drugs directed against IL-4 expression have not been described. This finding raises the potential to develop parthenolide to treat IL-4-mediated allergic-like inflammation.

Adult↗
PubMed2006

Microbial synthesis of triacetic acid lactone.

Native g2ps1-encoded 2-pyrone synthase (2-PS) from Gerbera hybrida, a mutant Brevibacterium ammoniagenes fatty acid synthase B (FAS-B) and two different mutants of Penicillium patulum 6-methylsalycilic acid synthase (6-MSAS) are examined to identify the best enzyme to recruit for the microbial synthesis of triacetic acid lactone (TAL). To identify the best microbial host for these evaluations, the native TAL-synthesizing activity of g2ps1-encoded 2-PS is expressed in recombinant Escherichia coli and Saccharomyces cerevisiae constructs. Five-fold higher expression levels of 2-PS are observed in S. cerevisiae. Consequently, microbial synthesis of TAL focuses on S. cerevisiae constructs. Comparison of different promoters for the expression of g2ps1 in S. cerevisiae indicates that the alcohol dehydrogenase II promoter (P(ADH2)) affords the highest expression levels of 2-PS. As a result, the genes encoding the various TAL-synthesizing enzyme activities are expressed in S. cerevisiae from a P(ADH2) promoter. To extend TAL-synthesizing activity beyond g2ps1-encoded 2-PS, the ketoreductase domains of fasB-encoded FAS-B and 6-MSAS-encoded 6-MSAS are modified using a single mutation. Modification of the nicotinamide cofactor-binding site of 6-MSAS with a triple mutation is also examined. Separate S. cerevisiae constructs expressing native g2ps1, mutant Y2226F fasB, mutant Y1572F 6-MSAS, and mutant G1419A-G1421P-G1424A 6-MSAS are cultured under the same fermentor-controlled conditions. The highest concentration (1.8 g/L) and yield (6%) of TAL are synthesized from glucose by S. cerevisiae expressing the Y1572F mutant of 6-MSAS.

Acyltransferases↗
PubMed2003

Analysis of N-acyl-L-homoserine lactones produced by Burkholderia cepacia with partial filling micellar electrokinetic chromatography--electrospray ionization-ion trap mass spectrometry.

A method for the analysis of N-acyl-L-homoserine lactones (AHLs) with micellar electrokinetic chromatography coupled to electrospray ionization-ion trap mass spectrometry, combining the flexibility of capillary electrophoresis with the unmatched structural information provided by mass spectrometry is presented. Different surfactants were evaluated, with sodium dodecyl sulfate (SDS) yielding the best results considering sensitivity and flexibility. We examined the interaction of AHLs with the SDS micelles at different analysis conditions and applied the optimized method to the analysis of a real bacterial sample. Two AHLs from Burkholderia cepacia colonizing the rhizosphere of traditional Indian rice cultivars could be unambiguously determined in an ethyl acetate extract with high resolution flexibility.

4-Butyrolactone↗
PubMed2005

Triple quadrupole tandem mass spectrometry of sesquiterpene lactones: a study of goyazensolide and its congeners.

Electrospray ionization tandem mass spectrometry (ESI-MS/MS) was used to investigate the fragmentation pattern of ten sesquiterpene lactones of the goyazensolide type under low-energy collision-induced dissociation (CID) using a triple quadrupole mass spectrometer. The analysis revealed that loss of CO(2)[M + H - 44](+) is the predominant process for compounds that exhibit a hydroxyl at C-8. In contrast, compounds with different acyloxy groups at C-8 fragment by means of elimination of the corresponding carboxylic acids [M + H - (R(2)CO(2)H)](+) and consecutive losses of CO and H(2)O. Our results also demonstrate the influence of both the stereochemistry of the acyloxy group at C-8 on the relative abundances of product ions and the hydroxyl at C-15, which creates an additional pathway, resulting in highly diagnostic product ions. This work clearly demonstrates the utility of tandem quadrupole low-resolution mass spectrometry for studies on the rationalization of the fragmentation of a series of compounds with a highly conserved core structure, but differing in substituent groups.

Asteraceae↗
PubMed2002

Mevastatin induces degeneration and decreases viability of cAMP-induced differentiated neuroblastoma cells in culture by inhibiting proteasome activity, and mevalonic acid lactone prevents these effects.

Statins with a closed-ring structure (mevastatin, lovastatin, and simvastatin) and with an open-ring structure (pravastatin and fluvastatin) are widely used in the human population to manage hypercholesterolemia. These statins may have neuroprotective or neurotoxic effects, but these effects remain controversial. We have utilized adenosine 3',5'-cyclic monophosphate-induced terminally differentiated murine neuroblastoma (NB) cells in culture as an experimental model to study the effect of statins. Results showed that mevastatin induced degenerative changes and reduced the viability of differentiated NB cells by inhibiting proteasome activity. Lactacystin, an established inhibitor of proteasome, also produced similar degenerative changes in these cells. In contrast, pravastatin neither affected the degeneration and viability of differentiated NB cells nor the proteasome activity. High-performance liquid chromatography (HPLC) analysis of the extract obtained from mevastatin-treated growth medium and differentiated cells revealed that about 50% of mevastatin is converted to an open-ring structure in the growth medium; however, differentiated cells did not convert any portion of mevastatin into an open-ring structure and accumulated only mevastatin with a closed-ring structure. Mevalonic acid lactone by itself did not affect the viability of differentiated NB cells or the proteasome activity, but it completely prevented mevastatin-induced degeneration and decreased viability by reducing the uptake of mevastatin and by blocking its action on proteasome activity. Mevalonic acid failed to prevent lactacystin-induced degeneration and inhibition of proteasome activity. Our results suggest that mevastatin could act as a neurotoxic agent or neuroprotective agent, depending upon the extent of its hydrolysis to an open-ring structure and the level of mevalonic acid.

Animals↗
PubMed1980

Antihyperlipidemic activity of sesquiterpene lactones and related compounds.

Some naturally occurring pseudoguaianolides and germacranolides as well as synthetic related compounds were observed to be antihyperlipidemic agents in mice. Several of these compounds at a dose of 20 mg/kg/day resulted in lowering of serum cholesterol by approximately 30% and of serum triglycerides by approximately 25%. Thiol-bearing enzymes of lipid synthesis, i.e., acetyl-CoA, citrate-lyase, acetyl-CoA synthetase, and beta-hydroxy-beta-methylglutaryl-CoA reductase, were inhibited by these agents in vitro, supporting the premise that these agents alkylate thiol nucleophiles by a Michael-type addition. The alpha-methylene-gamma-lactone moiety, the beta-unsubstituted cyclopentenone ring, and the alpha-epoxycyclopentanone system of these compounds appeared to be responsible for the lowering of serum lipids.

Animals↗
PubMedDate not supplied

Superheated water chromatography-nuclear magnetic resonance spectroscopy of kava lactones.

Three kava lactone constituents of Piper methysticum, namely, kawain, methysticin and desmethoxyyangonin, have been separated and identified by reversed-phase HPLC using superheated deuterium oxide as the mobile phase and on-line 1H-NMR detection. The method avoids the use of organic solvents in the mobile phase and hence interferences in the NMR analysis are minimised.

Chromatography, High Pressure Liquid↗
PubMed2004

Direct analysis of selected N-acyl-L-homoserine lactones by gas chromatography/mass spectrometry.

A rapid, simple and selective method involving direct separation by gas chromatography (GC) with electron ionization mass spectrometry (EI-MS) was employed to determine some N-acylhomoserine lactones (AHLs). Using GC/EI-MS, simultaneous separation and characterization of AHLs were possible without prior derivatization. Informative fragmentation patterns were obtained to identify the structures of N-acyl chains of AHLs. Electron ionization resulted in a common fragmentation pattern with the most abundant ion at m/z 143 and other minor peaks at m/z 71, 57, and 43. The presence of AHLs in extracts of Burkholderia cepacia strains was achieved in selected ion monitoring mode by using the prominent fragment at m/z 143.

4-Butyrolactone↗
PubMed1995

The refined X-ray structure of muconate lactonizing enzyme from Pseudomonas putida PRS2000 at 1.85 A resolution.

We report here the refined X-ray crystal structure of muconate lactonizing enzyme (MLE) from Pseudomonas putida PRS2000 at a resolution of 1.85 A with an R-factor of 16.8%. An enzyme from the beta-ketoadipate pathway, MLE catalyses the conversion of cis,cis-muconate to muconolactone. It is a homo-octamer, one monomer consisting of 373 amino acid residues. MLE has two large domains and a C-terminal subdomain: an alpha + beta domain, an alpha beta-barrel domain and a C-terminal meandering subdomain. The alpha beta-barrel domain is highly irregular. Its structure is (beta/alpha)7 beta, with the structural role of the last alpha-helix being replaced by both the C-terminal subdomain and part of the N-terminal domain. The fifth, seventh and eighth barrel strands are unusual because they have left-handed twist about their axes. The strand crossing angles also vary enormously, from +9 degrees to -69 degrees; the first and last strands, which close the barrel, cross at an angle of -69 degrees, making extensive strand-strand hydrogen bonding impossible. The first barrel strand is also unusual because it starts in the N-terminal domain and forms hydrogen bonds to the C-terminal subdomain beta-sheet as well as to its neighbouring strands in the barrel. It thus cements the whole protein together. As in other alpha beta-barrel proteins, the active site of MLE, present in each subunit is at the C-terminal ends of the barrel beta-strands. The active site cleft contains an essential manganese ion, is lined with charged and other polar residues, and contains many of the crystallographic water molecules. The manganese ion is octahedrally co-ordinated to three side-chain carboxylate groups and three water molecules, and is at the centre of a radiating web of ionic and hydrogen-bonding interactions. Additionally, two water molecules are buried in the centre of the barrel and two hydrophilic side-chains (Lys167 and Arg196) make both hydrophobic and hydrophilic packing interactions with much of the barrel interior. The barrel interior is thus also unusual because it is so hydrophilic; the dominating force appears to be the need to solvate the metal ion effectively. This might account for the irregularity of the barrel. The catalytic mechanism has been investigated by docking both substrate and product in the active site with the C-COO- of muconolactone superimposed on the corresponding atoms of cis,cis-muconate. In agreement with earlier kinetic and spectroscopic results, the manganese ion does not interact directly with substrate or product.(ABSTRACT TRUNCATED AT 400 WORDS)

Crystallization↗