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PubMed2005

RKTS-33, an epoxycyclohexenone derivative that specifically inhibits Fas ligand-dependent apoptosis in CTL-mediated cytotoxicity.

Cytotoxic T lymphocytes (CTLs) eliminate virus-infected cells and tumor cells by two distinct killing pathways, mediated by lytic granules containing perforin and by Fas ligand (FasL). ECH [(2R,3R,4S)-2,3-epoxy-4-hydroxy-5-hydroxymethyl-6-(1E)-propenyl-cyclohex-5-en-1-one] has been shown to inhibit FasL-dependent apoptosis or the killing pathway in short-term culture. However, since ECH exhibited cell toxicity in long-term culture, we attempted the synthesis of less toxic epoxycyclohexenone derivatives. In the present study, we found that RKTS-33 [(2R,3R,4S)-2,3-epoxy-4-hydroxy-5-hydroxymethyl-cyclohex-5-en-1-one] has cell toxicity lower than ECH in long-term culture, and further investigated the inhibitory effect of RKTS-33 on CTL-mediated killing pathways. RKTS-33 did not affect cell-surface expression of FasL upon CD3 stimulation, but profoundly inhibited the FasL-dependent killing pathway mediated by CD4+ and CD8+ CTLs, indicating that RKTS-33 specifically blocks target cell apoptosis but not CTL function. By contrast, RKTS-33 did not affect the perforin-dependent killing pathway in CD8+ CTLs. These results indicate that RKTS-33 is a specific inhibitor of the FasL-dependent killing pathway in CTL-mediated cytotoxicity.

Animals↗
PubMed2005

Three oxygenated cyclohexenone derivatives produced by an endophytic fungus.

Three cyclohexenone derivatives, (4S,5S,6S)-5,6-epoxy-4-hydroxy-3-methoxy-5-methyl-cyclohex-2-en-1-one (1), (4R,5R)-4,5-dihydroxy-3-methoxy-5-methyl-cyclohex-2-en-1-one (2), and (4R,5S,6R)-4,5,6-trihydroxy-3-methoxy-5-methyl-cyclohex-2-en-1-one (3), were isolated from unpolished rice fermented with an xylariaceous endophytic fungus (strain YUA-026). The structures of three compounds were established on the basis of spectroscopic analyses and chemical conversion. The minimum inhibitory concentrations of 1 and 3 were 100 microg/ml and 400 microg/ml against Staphylococcus aureus, 100 microg/ml and 200 microg/ml against Pseudomonas aeruginosa, and 200 microg/ml and >400 microg/ml against Candida albicans, respectively. In addition, 1 and 3 exhibited phytotoxic activity against lettuce.

Anti-Infective Agents↗
PubMed2006

Synthetic studies on breviones and structurally related natural products.

Breviones, allelopathic agents that have been isolated from Penicillium sp., are structurally unique diterpenoid derivatives. Breviones have attracted attention due to their bioactivity, because their allelopathic activities may offer agricultural use as environmentally benign herbicides. On the other hand, their structural uniqueness is also remarkable, and construction of their unique structure is a challenge from the viewpoint of organic synthesis. This review summarizes synthetic studies on breviones and structurally related natural products.

Cyclohexanones↗
PubMed2003

4-Hydroxyphenylpyruvate dioxygenase as a drug discovery target.

The molecular mechanism for 4-hydroxyphenylpyruvate dioxygenase (4-HPPD) inhibition by nitisinone, a recently approved new drug for the treatment of hereditary tyrosinemia type I, has been satisfactorily explained by its action as an analogue to the substrate 4-hydroxyphenylpyruvate. In addition, a novel induced conformationally restricted 4-HPPD inhibitor, diketonitrile, which serves as a nonclassical bioisostere for rigid cyclic 1,3-diketone derivatives, has been introduced. Further application of the molecular mode of action of nitisinone in rational design of potential inhibitors for alpha-ketoglutarate-coupled dioxygenases is discussed.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed2006

Blocking NF-kappaB as a potential strategy to treat adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATL), a fatal T-cell leukemia/lymphoma resistant to chemotherapy, is caused by human T-cell leukemia/lymphoma virus type I (HTLV-1), occurring even after 50 years of clinical latency from initial transmission. Constitutively activated nuclear factor kappaB (NF-kappaB) appears to be a molecular basis for the aberrant growth and cytokine gene expression observed in ATL cells, thereby serving as an ideal target in the treatment of ATL. Dehydroxymethylepoxyquinomicin (DHMEQ) is a new NF-kappaB inhibitor that is a 5-dehydroxymethyl derivative of epoxyquinomicin C, having a 4-hydroxy-5,6-epoxycyclohexenone structure similar to panepoxydone. This unique compound acts in the translocation of NF-kappaB into the nucleus. Dehydroxymethylepoxyquinomicin inhibits NF-kappaB activation in ATL cells and induces apoptotic cell death. In addition, DHMEQ selectively targets HTLV-1-infected cells in the peripheral blood of virus carriers in vitro, resulting in a decreased number of infected cells. We have concluded that blocking NF-kappaB is a potential strategy for the treatment and prevention of ATL. As a potent NF-kappaB inhibitor, DHMEQ is a promising compound for translating this strategy into clinical medicine.

Adult↗
PubMed2004

Inhibition of RANKL-induced osteoclastogenesis by (-)-DHMEQ, a novel NF-kappaB inhibitor, through downregulation of NFATc1.

UNLABELLED: (-)-DHMEQ, a newly designed NF-kappaB inhibitor, inhibited RANKL-induced osteoclast differentiation in mouse BMMs through downregulation of the induction of NFATc1, an essential transcription factor of osteoclastogenesis. INTRODUCTION: Bone destruction is often observed in advanced case of rheumatoid arthritis and neoplastic diseases, including multiple myeloma. Effective and nontoxic chemotherapeutic agents are expected for the suppression of these bone destructions. RANKL induces activation of NF-kappaB and osteoclastogenesis in bone marrow-derived monocyte/macrophage precursor cells (BMMs). Targeted disruption or pharmacological suppression of NF-kappaB result in impaired osteoclastogenesis, but how NF-kappaB is involved in the regulation of osteoclastogenesis is not known. MATERIALS AND METHODS: The effect of (-)-dehydroxymethylepoxyquinomicin [(-)-DHMEQ] on osteoclast differentiation was studied using a culture system of mouse BMMs stimulated with RANKL and macrophage colony-stimulating factor. The mechanism of the inhibition was studied by biochemical analysis such as immunoblotting and retroviral transfer experiments. RESULTS: (-)-DHMEQ strongly inhibited RANKL-induced NF-kappaB activation in BMMs and inhibited RANKL-induced formation of TRACP(+) multinucleated cells. Interestingly, (-)-DHMEQ specifically inhibited the RANKL-induced expression of NFATc1 but not the expressions of TRAF6 or c-fos. Inhibition of osteoclast differentiation by (-)-DHMEQ was rescued by overexpression of NFATc1, suggesting that the inhibition is not caused by a toxic effect. Moreover, pit formation assays showed that (-)-DHMEQ also inhibited the bone-resorbing activity of mature osteoclasts. CONCLUSION: The inhibition of NF-kappaB suppresses osteoclastogenesis by downregulation of NFATc1, suggesting that NFATc1 expression is regulated by NF-kappaB in RANKL-induced osteoclastogenesis. Our results also indicate the possibility of (-)-DHMEQ becoming a new therapeutic strategy against bone erosion.

Animals↗
PubMed2006

Etiology-specific endothelin-1 clearance in human precapillary pulmonary hypertension.

STUDY OBJECTIVES: Endothelin (ET)-1 is a mediator of vascular remodeling seen in human pulmonary hypertension (PH), and it is normally cleared via endothelial ET-B receptors. Increased levels of ET-1 are found in precapillary PH, partly from increased synthesis. We hypothesized that the endothelial dysfunction and vascular remodeling seen in human precapillary PH would also reduce ET-1 clearance. DESIGN AND SETTING: Case series from a single institutional PH center. PATIENTS: Thirty-four patients with pulmonary arterial hypertension (PAH; idiopathic [IPAH], n = 19; connective tissue disease [CTD], n = 15) and 11 patients with chronic thromboembolic PH were studied. MEASUREMENTS AND RESULTS: Using indicator dilution methods, the first-pass extraction of radiolabeled ET-1 through the pulmonary circulation, and permeability surface (PS) area, an index of functional microvascular surface available for ET-1 clearance, were determined. Mean extraction for IPAH and thromboembolic PH groups was normal, but it was reduced in PAH from CTD; 69% of all patients studied had normal extraction. The mean PS product was reduced significantly for all three etiologies as compared to normal, but 58% of IPAH patients and 40% of CTD-related PAH patients had normal PS products. CONCLUSIONS: Receptor-mediated ET-1 extraction and functional vascular surface area for clearance vary between etiologies of PAH. However, contrary to our hypothesis, endothelial ET-B receptor-mediated extraction is preserved in many patients. The scientifically significant finding of our study is that high ET-1 levels seen in patients with PAH must be predominantly due to excess synthesis rather than reduced clearance. The finding that endothelial ET-B receptors are still present and functional in PAH may also be of relevance to the choice of selective vs nonselective ET receptor antagonists.

Cyclohexanones↗
PubMed1976

Determination of arginine in the reactive site of proteinase inhibitors by selective and reversible derivatization of the arginine side chain.

Reversible and selective modification of the guanidino group by 1,2-cyclohexanedione or 2,3-butanedione in borate buffer was applied to identify arginine residues in the reactive sites of proteinase inhibitors. The ability of the method to distinguish between arginine and lysine residues was examined. Trypsin inhibitors with arginine at the reactive site were almost completely inactivated within 2 h, e.g. the low-molecular weight inhibitors from soybeans (Kunitz), peanuts and porcine seminal plasma. Inhibitors of the lysine-type were not inactivated by 1,2-cyclohexanedione/borate, e.g. the bovine trypsin/kallikrein inhibitor, the trypsin inhibitors from cow colostrum, porcine pancreas, or snail epidermis (isoinhibitor K from Helix pomatia), and the human alpha1-proteinase inhibitor (alpha1-antitrypsin). However, 2,3-butanedione/borate does not show this high specificity. The method was applied to four high-molecular weight proteinase inhibitors from the albumin gland of the snail (Helix pomatia). All four inhibitors were subject to inactivation by the reagent, indicating an arginine residue at the reactive site. Evidence is given by NMR, UV, and titration data that a complex is formed from 1,2-cyclohexanedione and borate. Due to this complex formation, the amount of free carbonyl component is drastically decreased. Since 1,2-cyclohexanedione without borate lacks the high specificity for arginine residues, the borate complex of the reagent is presumed to be responsible for the high specificity. The new procedure for identification of reactive sites is based on a reversible modification of the guanidium group of the arginine residues.

Arginine↗
PubMed1991

Binding of locust high-density lipophorin to fat body proteins monitored by an enzyme-linked immunosorbant assay.

Binding of locust high-density lipophorin (HDLp) to fat body proteins coated on immunoassay plates was studied using the ELISA method and ligand blotting techniques. HDLp binding proved to be correlated with the amount of fat body protein coated. From the concentration-dependent total HDLp binding an equilibrium dissociation constant could be calculated (Kd = 1.6 x 10(-8) M). Heparin inhibits the HDLp binding, indicating that positively charged groups are involved in the HDLp-fat body interaction. These groups were shown to be arginyl residues, as the arginine-specific treatment of HDLp by 1,2-cyclohexanedione resulted in a approximately 50% decrease in the binding ability of HDLp. HDLp binding is also affected by the pH. A decrease from pH 7.5 to pH 6.5 increases the binding affinity by approximately 250%. A monoclonal antibody specific for apolipophorin-II (apoLp-II) hampered the HDLp binding significantly, whereas a monoclonal anti-apoLp-I had no effect. Locust fat body HDLp binding proteins are highly specific for locust HDLp.

Animals↗
PubMed1997

Mechanism of angiotensin II-induced arachidonic acid metabolite release in aortic smooth muscle cells: involvement of phospholipase D.

In a previous study, we have shown that angiotensin II (Ang II) activates phosphatidylcholine-hydrolyzing phospholipase D due to Ang II-induced Ca2+ influx from extracellular space in subcultured rat aortic smooth muscle cells. In the present study, we have investigated the role of phospholipase D in Ang II-induced arachidonic acid (AA) metabolite release and prostacyclin synthesis in subcultured rat aortic smooth muscle cells. Ang II significantly stimulated AA metabolite release in a concentration-dependent manner in the range between 1 nmol/I and 0.1 mumol/I. D.L.-Propranolol hydrochloride (propranolol), an inhibitor of phosphatidic acid phosphohydrolase, significantly inhibited the Ang II-induced release of AA metabolites. The Ang II-induced AA metabolite release was reduced by chelating extracellular Ca2+ with EGTA. Genistein, an inhibitor of protein tyrosine kinases, significantly suppressed the Ang II-induced AA metabolite release. 1,6-Bis-(cyclohexyloximinocarbonylamino)-hexane (RHC-80267), a potent and selective inhibitor of diacylglycerol lipase, significantly inhibited the Ang II-induced AA metabolite release. Both propranolol and RHC-80267 inhibited the Ang II-induced synthesis of 6-keto-prostaglandin F1 alpha, a stable metabolite of prostacyclin. The synthesis was suppressed by genistein. These results strongly suggest that the AA metabolite release induced by Ang II is mediated, at least in part, through phosphatidylcholine hydrolysis by phospholipase D activation in aortic smooth muscle cells.

Angiotensin II↗
PubMed2002

Effects of RHC-80267, an inhibitor of diacylglycerol lipase, on excitation of circular smooth muscle of the guinea-pig gastric antrum.

In small segments of circular smooth muscle isolated from the guinea-pig gastric antrum, the effects of RHC-80267, an inhibitor of diacylglycerol lipase, were investigated both on regenerative slow potentials (either occurring spontaneously or as the result of a depolarizing intracellular current injection) and on the actions of acetylcholine (ACh). As diacylglycerol is a known activator of protein kinase C (PKC), it would therefore be expected that RHC-80267 would activate PKC indirectly. In circular smooth muscle bundles, spontaneously generating slow potentials recorded simultaneously from two given cells were synchronized, indicating that these two cells were electrically coupled. RHC-80267 (0.3-1 microM) increased the frequency of slow potential generation, with no alteration to the amplitude of either the slow potentials or the resting membrane potential. Synchronous electrical activity in a given pair of cells was also unchanged by RHC-80267, indicating that intercellular electrical coupling was not altered. The input resistance of smooth muscle cells calculated from the amplitude of electrotonic potentials produced by injection of current was not significantly altered by RHC-80267. The refractory period for the generation of slow potentials evoked by depolarizing stimuli was about 8 s, and it was decreased to about 5 s by RHC-80267, with no significant alteration to the amplitude of spontaneous or evoked slow potentials. ACh (0.5 microM) depolarized the membrane by about 5 mV and increased the amplitude and frequency of slow potentials. The actions of ACh on the frequency of slow potentials were enhanced by RHC-80267, with no alteration to the amplitudes of both the ACh-induced depolarization and slow potentials. These results support the idea that PKC is involved in determining the frequency of slow potentials, by shortening the refractory period for excitation of gastric smooth muscle cells.

Acetylcholine↗
PubMed2000

Isolation and initial characterization of 13(2)-hydroxychlorophyll a induced by cyclohexanedione derivatives in tobacco cell suspension cultures.

This paper reports that a new photobleaching compound, 2-(2-chloro-5-propoxycarbonylphenyl)aminomethylidene-5-5-dim ethyl- cyclohexane-1,3-dione (RWH-21), stimulates accumulation of 13(2)-hydroxychlorophyll a in cultured tobacco cells. This was shown based on isolation of 13(2)-hydroxychlorophyll a from pigment extracts of cultured tobacco cells by diode-array HPLC and subsequent fast atom bombardment mass spectrometry analysis. 13(2)-Hydroxychlorophyll a rapidly accumulates in tobacco cells both in the light and dark in the presence of RWH-21 (50 microM). Analysis of 13(2)-hydroxychlorophyll a formation in tobacco cells indicates that 13(2)-hydroxychlorophyll a is rapidly accumulated within 20 h incubation time both in the dark and light. Although the amount of 13(2)-hydroxychlorophyll a is continuously increased in the dark, the amount of 13(2)-hydroxychlorophyll a decreased remarkably in the light after 20 h incubation. Analysis of 13(2)-hydroxychlorophyll a formation and lipid peroxidation by determination malondialdehyde in tobacco cells suggests that RWH-21-induced 13(2)-hydroxychlorophyll a has the potential to cause a photodynamic action in cultured tobacco cells.

Cells, Cultured↗
PubMed2003

Antitumor effect of a novel nuclear factor-kappa B activation inhibitor in bladder cancer cells.

Nuclear factor (NF)-kappaB is a transcription factor that not only induces and controls various genes, including those of inflammatory cytokines, but also activates genes which suppress apoptosis. It has been clearly demonstrated that certain advanced human bladder cancer cells constitutively acquire the ability to activate NF-kappaB, which not only protects cancer cells from apoptotic cell death, but also upregulates the production of various cytokines that may increase the malignant potential of the disease and cause paraneoplastic syndromes. The NF-kappaB inhibitors may therefore be useful as anticancer agents. An NF-kappaB function inhibitor, a dehydroxymethyl derivative of epoxyquinomicin C (DHMEQ), has recently been designed and synthesized. The effectiveness of DHMEQ against advanced human bladder cancer cell line KU-19-19, in which NF-kappaB is constitutively activated, has been investigated. The DNA-binding activity of NF-kappaB was completely inhibited following 2-6-h exposure to 10 microg/ml of DHMEQ. Marked levels of apoptosis were observed 48 h after DHMEQ administration. These results confirmed that NF-kappaB activation maintains the viability of KU-19-19 cells, that DHMEQ inhibited constitutively activated NF-kappaB, and, consequently, apoptosis was induced. However, it was still possible that DHMEQ caused apoptotic cell death through some other mechanism which has not yet been fully investigated. The authors conclude that DHMEQ could represent a new treatment strategy against advanced bladder cancer.

Animals↗
PubMed2006

Fumigant toxicity of plant essential oils to Thrips palmi (Thysanoptera: Thripidae) and Orius strigicollis (Heteroptera: Anthocoridae).

The fumigant toxicity of 92 plant essential oils to adult Thrips palmi Karny (Thysanoptera: Thripidae) and Orius strigicollis Poppius (Heteroptera: Anthocoridae) was examined by using a vapor phase toxicity bioassay and compared with those of dichlorvos, emamectin benzoate, spinosad, and thiamethoxam, four commonly used insecticides. Responses varied according to oil type and insect species. As judged by 24-h LC50 values, pennyroyal oil (2.63 mg/liter air) was the most toxic fumigant and was 23.6-fold more toxic than dichlorvos (62.09 mg/liter air) against adult T. palmi. Potent fumigant toxicity (LC50, 11.03-19.21 mg/liter air) was observed in armoise, basil, cedarleaf, coriander, cypress, howood, hyssop, marjoram, myrtle, niaouli, rosemary, and sage (Dalmatia) oils. Neither emamectin benzoate, spinosad, nor thiamethoxam exhibited fumigant action. Against adult O. strigicollis, dichlorvos (LC50, 6.3 x 10(-6) mg/liter air) was the most toxic fumigant, whereas the LC50 values of the 13 essential oils ranged from 17.29 to 158.22 mg/liter air. O. strigicollis was 1.4-22.1 times less susceptible than T. palmi to the essential oils. The essential oils described merit further study as potential fumigants for the control of T. palmi in greenhouses.

Animals↗
PubMed1996

Production of [3H]choline-labelled metabolites from endogenously 3H-labelled phosphatidylcholine in mouse pancreatic islets.

The involvement of phosphatidylcholine (PC) hydrolysis in the regulation of insulin secretion was studied in mouse pancreatic islets prelabelled with [3H]choline. Phospholipase C (PLC) and phospholipase D (PLD) activities were demonstrated and also that of an enzyme that removes both fatty acids from PC and thus catalyses the production of [3H]glycerophosphorylcholine (GroPCho). After 2 min of incubation with 20 mM glucose a 35% increase in the content of [3H]GroPCho was observed in prelabelled islets, whereas the amount of [3H]lysoPC, [3H]phosphorylcholine (PCho) and [3H]choline was unaffected. After 30 min of incubation with 20 mM glucose, 0.2 mM tolbutamide, 40 mM KC1, 10 mM succinic acid monomethyl ester (SME) or 10 mM NaF, a 25-50% increase in [3H]GroPCho was observed. In the presence of 100 microM diazoxide or 35 microM RHC 80267 the glucose activation was attenuated. PLC was stimulated slightly by tolbutamide and 100 microM isoprenaline (isoproterenol), whereas SME decreased the amount of [3H]PCho by 10%. [3H]Choline content was increased by 25-40% in the presence of 0.16 microM 12-O-tetradecanoylphorbol 13-acetate (TPA), 10 mM NaF or 100 microM carbachol. This effect of fluoride was potentiated in the presence of 20 mM glucose. It is concluded that metabolism of PC to GroPCho may be involved in the regulation of glucose-stimulated insulin secretion, and that PLD may participate in insulin secretion evoked by TPA, carbachol and fluoride.

Animals↗
PubMed2005

Hepatic porphyria induced by the herbicide tralkoxydim in small mammals is species-specific.

Tralkoxydim is the active ingredient in a postemergent herbicide used in cereal crops. During preregistration trials, tralkoxydim was observed to cause hepatic porphyria and cholestasis in laboratory mice. Porphyria was not seen in similarly exposed rats or hamsters, but data were not collected regarding the susceptibility of any wild small mammal species to the tralkoxydim-induced porphyria. To address this data gap, we exposed small mammals to tralkoxydim, to 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC; a known porphyrinogenic chemical), or to sunflower oil alone. We studied small mammal species that might be exposed following agricultural applications of the herbicide, including the white-footed mouse (Peromyscus leucopus), the deer mouse (P. maniculatus), and the meadow vole (Microtus pennsylvanicus). Because of their known susceptibility to both tralkoxydim- and DDC-induced porphyria, commercially supplied Mus musculus (CD-1 Swiss mice) were exposed as positive-control animals. We also exposed offspring of wild-caught M. musculus to compare their responses to those of the commercially supplied animals. Potential hepatotoxicity was determined by assessing the accumulation of liver protoporphyrin. Of the species tested, only M. musculus was susceptible to the porphyrinogenic action of tralkoxydim, and no significant accumulation of protoporphyrin was observed in any of the other species exposed to the herbicide.

Animals↗
PubMed2006

Nitisinone in the treatment of hereditary tyrosinaemia type 1.

Hereditary tyrosinaemia type 1 (HT-1) is a rare genetic disease caused by mutations in the gene for the enzyme fumarylacetoacetase. It usually presents with liver failure but can be manifest as chronic liver disease. Rarely, it may present with nonhepatic manifestations such as renal dysfunction, porphyria-like illness or cardiomyopathy. There is a high lifetime risk of developing hepatocellular carcinoma (HCC). Prior to the development of liver transplantation, most patients died in childhood.The clinical manifestations stem from the cytotoxicity of tyrosine metabolites accumulating proximal to the metabolic defect. Nitisinone acts on tyrosine metabolism upstream of the defect to prevent the production of these metabolites. Nitisinone is used in combination with a tyrosine- and phenylalanine-restricted diet. Nitisinone has transformed the natural history of tyrosinaemia. Liver failure is controlled in 90% of patients, those with chronic liver disease improve and nonhepatic manifestations are abolished. Nitisinone is well tolerated and has few adverse effects other than a predictable rise in plasma tyrosine levels. Nitisinone provides protection against HCC if it is started in infancy, but if commenced after the age of 2 years, a significant risk of HCC remains. Furthermore, where nitisinone is used pre-emptively, liver disease appears to be prevented, suggesting the importance of neonatal screening for tyrosinaemia where possible. Nitisinone is indicated for all children with HT-1, and liver transplantation is only indicated where nitisinone fails, or where the development of HCC is likely or suspected.

Carcinoma, Hepatocellular↗