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PubMed2005

Effect of a small molecule inhibitor of nuclear factor-kappaB nuclear translocation in a murine model of arthritis and cultured human synovial cells.

A small cell-permeable compound, dehydroxymethylepoxyquinomicin (DHMEQ), does not inhibit phosphorylation and degradation of IkappaB (inhibitor of nuclear factor-kappaB [NF-kappaB]) but selectively inhibits nuclear translocation of activated NF-kappaB. This study aimed to demonstrate the antiarthritic effect of this novel inhibitor of the NF-kappaB pathway in vivo in a murine arthritis model and in vitro in human synovial cells. Collagen-induced arthritis was induced in mice, and after onset of arthritis the mice were treated with DHMEQ (5 mg/kg body weight per day). Using fibroblast-like synoviocyte (FLS) cell lines established from patients with rheumatoid arthritis (RA), NF-kappaB activity was examined by electrophoretic mobility shift assays. The expression of molecules involved in RA pathogenesis was determined by RT-PCR, ELISA, and flow cytometry. The proliferative activity of the cells was estimated with tritiated thymidine incorporation. After 14 days of treatment with DHMEQ, mice with collagen-induced arthritis exhibited decreased severity of arthritis, based on the degree of paw swelling, the number of swollen joints, and radiographic and histopathologic scores, compared with the control mice treated with vehicle alone. In RA FLS stimulated with tumor necrosis factor-alpha, activities of NF-kappaB components p65 and p50 were inhibited by DHMEQ, leading to suppressed expression of the key inflammatory cytokine IL-6, CC chemokine ligand-2 and -5, matrix metalloproteinase-3, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1. The proliferative activity of the cells was also suppressed. This is the first demonstration of an inhibitor of NF-kappaB nuclear translocation exhibiting a therapeutic effect on established murine arthritis, and suppression of inflammatory mediators in FLS was thought to be among the mechanisms underlying such an effect.

Animals↗
PubMed2006

Kidneys of mice with hereditary tyrosinemia type I are extremely sensitive to cytotoxicity.

Children with hereditary tyrosinemia type 1 (HT1) suffer from liver failure, renal tubular dysfunction, and rickets. The disease is caused by deficiency of fumarylacetoacetate hydrolase (FAH), the last enzyme of tyrosine catabolism, and leads to accumulation of the toxic substrate fumarylacetoacetate (FAA) in hepatocytes and renal proximal tubular cells. Patients are treated with 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3 cyclohexanedione (NTBC), which prevents accumulation of FAA by blocking an enzyme upstream of FAH. Liver transplantation is performed when patients do not respond to NTBC or develop hepatocellular carcinoma. This reduces the tyrosine load for the kidney but does not abolish renal exposure to locally produced FAA. To investigate the pathogenesis of liver and kidney damage induced by tyrosine metabolites, we challenged FAH-deficient mice with various doses of homogentisic acid (HGA), a precursor of FAA. Injecting NTBC-treated Fah-/- mice with low doses of HGA caused renal damage and death of renal tubular cells, as was shown by histologic analyses and deoxynucleotidyl transferase-mediated dUDP nick-end labeling (TUNEL) assay but did not lead to liver damage. In addition, kidney function, but not liver function, was affected after exposure to low doses of HGA. Administration of high doses of HGA led to massive cell death in both the liver and kidneys. Resistance to HGA-induced cell death was seen after withdrawing NTBC from Fah-/- mice. The finding that the kidneys of Fah-/- mice are especially sensitive to damage induced by low doses of HGA underscores the need to perform careful monitoring of the kidney function of tyrosinemia patients undergoing any form of treatment.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1986

Insulin regulates low density lipoprotein metabolism by swine granulosa cells.

Insulin synergistically amplified the stimulatory effect of low density lipoprotein (LDL) on progesterone biosynthesis by primary cultures of swine granulosa cells. The mechanisms subserving this facilitative interaction included the following: 1) insulin's synergism with LDL was profoundly attenuated by covalent modification of arginine residues in LDL by 1,2-cyclohexanedione treatment; 2) insulin increased by 2- to 6-fold the number of specific high affinity LDL receptors on granulosa cells, with no change in apparent binding affinity; 3) insulin augmented rates of [125I]iodo-LDL internalization and degradation without enhancing nonspecific bulk fluid-phase pinocytosis (assessed with [125I]iodo-polyvinylpyrollidone); 4) insulin increased by 2.5- to 3-fold granulosa cell content of free and esterified cholesterol (measured by fluorometry) in response to treatment with unlabeled LDL; 5) insulin stimulated the intracellular accumulation of free [3H]cholesterol and [3H]cholesteryl ester, and amplified [3H]progesterone secretion by granulosa cells exposed to [3H]cholesteryl linoleate-labeled LDL; and 6) insulin action was specific in that it was not mimicked by desoctapeptide insulin, epidermal growth factor, fibroblast growth factor, or relaxin. We conclude that insulin and LDL synergistically enhance progesterone biosynthesis by swine granulosa cells via specific mechanisms that depend upon 1,2,-cyclohexanedione-sensitive residues within LDL apoprotein. Insulin action results in significantly augmented binding, internalization, and degradation of LDL, which is accompanied by increased effectual delivery of cholesterol substrate into cellular sterol pools that participate in enhanced steroidogenesis.

Animals↗
PubMed1994

Characterisation of the second messenger pathway underlying neurite outgrowth stimulated by FGF.

Cerebellar neurons, cultured on monolayers of 3T3 fibroblasts or on a polylysine/laminin-coated substratum, responded to recombinant basic FGF by extending longer neurites. The response was biphasic reaching a maximum at 5 ng/ml FGF, but desensitising at 100-200 ng/ml FGF. The response to FGF could be inhibited by a tyrosine kinase inhibitor (the erbstatin analogue), by a diacylglycerol lipase inhibitor (RHC-80267) and by a combination of N- and L-type calcium channel antagonists or other agents that negate the effects of calcium influx into neurons. The response to FGF could be fully mimicked by arachidonic acid added directly to the cultures, or generated via activation of phospholipase A2 with melittin. The response to melittin, but not to FGF or arachidonic acid, was inhibited by 4-bromophenacyl bromide, a phospholipase A2 inhibitor. The response to arachidonic acid was also biphasic and high concentrations of this agent could cross-desensitise the FGF response and vice versa. The response to arachidonic acid could be fully inhibited by the agents that block or negate the effects of calcium influx into neurons, but was not inhibited by the tyrosine kinase or diacylglycerol lipase inhibitors. These data suggest that FGF stimulates neurite outgrowth by activating a cascade that involves activation of phospholipase C gamma to produce diacylglycerol, conversion of diacylglycerol to arachidonic acid by diacylglycerol lipase and the activation of voltage-gated calcium channels by arachidonic acid.

3T3 Cells↗
PubMed2000

Apical endocytosis of ricin in MDCK cells is regulated by the cyclooxygenase pathway.

Addition of arachidonic acid or stimulation of arachidonic acid production by secretory phospholipase A2 selectively upregulated apical endocytosis of ricin in MDCK cells without affecting basolateral endocytosis. Electron microscopic studies revealed that MDCK cells treated with secretory phospholipase A2 and incubated with horseradish peroxidase had an increased number of normal appearing peroxidase-labeled endosomes and no sign of membrane ruffling. Moreover, inhibition of basal arachidonic acid release, either by decreasing the cytosolic phospholipase A(2) activity or the diacylglycerol lipase activity, reduced the rate of apical endocytosis. Furthermore, indomethacin, an inhibitor of the cyclooxygenase pathway, counteracted the stimulation of endocytosis seen with both secretory phospholipase A2 and arachidonic acid, suggesting that formation of eicosanoids such as prostaglandins could be essential for the regulation. This idea was supported by the finding that prostaglandin E2, the predominant prostaglandin formed in kidney, also upregulated ricin uptake. The regulatory effect of the cyclooxygenase pathway on apical endocytosis of ricin was found to be independent of protein kinases A and C, which are known to selectively control apical clathrin-independent endocytosis in polarized cells.

Animals↗
PubMed1984

Differential effect of arginine modification with 1,2-cyclohexanedione on the capacity of vimentin and desmin to assemble into intermediate filaments and to bind to nucleic acids.

When the intermediate filament proteins vimentin and desmin were reacted for a short period of time with the arginine-specific reagent 1,2-cyclohexanedione, the modification had a severe, inhibitory effect on the assembly of intermediate filaments and on the susceptibility of the basic, amino-terminal polypeptide of both proteins to degradation by the intermediate filament-specific, Ca2+-activated proteinase. However, it had only a slightly inhibitory effect on the binding of vimentin and desmin to ribosomal RNA from Ehrlich ascites tumour cells. Since the Ca2+-activated proteinase is very likely to be a trypsin-like enzyme, with a preference for arginyl and lysyl peptide bonds, the results indicate that the arginine residues of the amino-terminal polypeptide of vimentin and desmin are highly essential for filament assembly but largely dispensable for the binding of both proteins to nucleic acids. This was supported by the observation that two breakdown products of vimentin lacking a 5 X 10(3) Mr and an 8 X 10(3) Mr polypeptide from the amino terminus, respectively, did not assemble into intermediate filaments but were still capable of binding to rRNA. Both polypeptides also bound to single-stranded DNA-cellulose under non-denaturing conditions, but passed the affinity column in the presence of 6 M-urea. Thus, the binding of vimentin to nucleic acids appears to be based on two components: a non-specific electrostatic interaction mediated by the positively charged arginine residues of the amino-terminal polypeptide that is insensitive to denaturation by urea, and a specific interaction that is sensitive to denaturation by urea.

Arginine↗
PubMed1990

Enantioselective synthesis of cyclohexenone derivatives by a chemicoenzymatic approach: stereo- and regioselective route to potential intermediates of compactin (ML 236B) and mevinolin.

As a synthetic application of the chiral monoester 2, prepared by pig liver esterase (PLE)-catalyzed hydrolysis of the corresponding meso diester 1, conversion of 2 into various cyclohexenone derivatives was examined. This paper describes the preparation of the isomeric cyclohexenones 6 and 7, potential intermediates for the synthesis of anti-hypercholesmic compactin (ML 236B) and mevinolin, under stereo- and regioselective control.

Chemical Phenomena↗
PubMed2000

Ichthyotoxic phloroglucinol derivatives from Dryopteris fragrans and their anti-tumor promoting activity.

Two new ichthyotoxic compounds, aspidin PB (8) and dryofragin (9), along with three known phloroglucinol derivatives (1-3) and five terpenoids, were isolated from the whole herbs of Dryopteris fragrans by toxicity-directed fractionation using Oryzias latipes (Japanese name; medaka). The structures of the new compounds were determined by spectroscopic methods including 2D NMR techniques. Amongst the isolates, aspidin PB (8), dryofragin (9), and 1-5 exhibited potent ichthyotoxic activity against medaka with a median tolerance limit (TLm after 24 h) of 1.2-4.3 microg/ml. These compounds which are toxic to fish also had a potent inhibitory effect on the activation of Epstein-Barr virus early-antigen (EBV-EA) induced by tetradecanoyl phorbol 13-acetate, which is an in vitro short-term assay for anti-tumor promoting agents. Aspidin BB (2) and albicanol (4), which exhibited strong inhibitory effects on the EBV-EA activation, significantly suppressed an in vivo two-stage carcinogenesis on mouse skin.

Animals↗
PubMed2001

Medicinal foodstuffs. XXIV. Chemical constituents of the processed leaves of Apocynum venetum L.: absolute stereostructures of apocynosides I and II.

Two new ionone glucosides, named apocynosides I and II, were isolated from the roasted leaves of Apocynum venetum L. together with nine known compounds. The absolute stereostructures of apocynosides I and II were determined by chemical and physicochemical evidence, which included the application of a modified Mosher's method and the circular dichroism helicity rule.

Apocynaceae↗
PubMed2003

Glochidionionosides A-D: megastigmane glucosides from leaves of Glochidion zeylanicum (Gaertn.) A. Juss.

Five megastigmane glucosides were isolated from the leaves of Glochidion zeylanicum. One of them was a known compound, blumenol C O-beta-D-glucopyranoside (1), and the structures of the four new compounds, glochidionionosides A-D (2-5), were mainly elucidated by spectroscopic methods, including a modified Mosher's method. The absolute configurations of the six-membered ring of glochidionionoside D (5) were deduced by beta-D-glucopyranosylation-induced shift trends in the (13)C-NMR spectra and confirmed by X-ray analysis as its p-bromobenzoate (5b), and the axis chirality of C-7 was determined to be R.

Cyclohexanones↗
PubMed2005

Synthesis of new dihydropyrazines with DNA strand-breakage activity.

Treatment of 1,2-cyclohexanedione with 1,2-diamines, e.g. ethylenediamine and cis-(and trans-)1,2-diaminocyclohexane, caused [4+2] cyclocondensation to give the corresponding dihydropyrazine derivatives (compounds 1-6). They exhibited stronger DNA strand-breakage activity than that of dihydropyrazines, which has already been reported in previous papers.

Cyclization↗
PubMed2005

New megastigmane glucosides from Excoecaria cochinchinensis LOUR. var. cochinchinensis.

Two new megastigmane glucosides, called excoecariosides A and B were isolated from the leaves of a medicinal Vietnamese plant, Excoecaria cochinchinensis LOUR. var. cochinchinensis (Euphorbiaceae) together with seven known compounds. Their structures were elucidated by spectroscopic analyses and chemical reactions including the modified Mosher's method.

Chromatography, High Pressure Liquid↗
PubMed2005

Synthesis of optically active vomifoliol and roseoside stereoisomers.

A synthesis of optically active vomifoliol stereoisomers 1-4 and their glucosides, roseoside stereoisomers 5-8, was accomplished via alpha-acetylenic alcohol 11a or 11b effectively prepared by an asymmetric transfer hydrogenation of alpha,beta-acetylenic ketone 10. Simultaneous separation of these stereoisomers by HPLC was also performed.

Cyclohexanones↗