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At least 1,675 records · Page 93Linked to original sources
PubMed2006

Sphingosylphosphorylcholine-induced ERK activation inhibits melanin synthesis in human melanocytes.

Sphingosylphosphorylcholine (SPC) is emerging as a potent signaling-lipid mediator. In this study, we investigated the effects of SPC on melanogenesis using cultured human melanocytes. Our results show that SPC significantly inhibits melanin synthesis in a concentration-dependent manner, and further that it reduces the activity of tyrosinase, the rate-limiting melanogenic enzyme. SPC treatment was also found to induce short-thick dendrites in human melanocytes, but not to reduce tyrosinase activity in a cell-free system, whereas kojic acid directly inhibited tyrosinase. These results suggest that SPC reduces pigmentation by indirectly regulating tyrosinase. In further experiments, SPC was found to downregulate microphthalmia-associated transcription factor (MITF) and tyrosinase, and Western blotting showed that SPC induces the activations of extracellular signal-regulated kinase (ERK) and 90 kDa ribosomal S6 kinase (RSK-1). Moreover, the specific ERK pathway inhibitor, PD98059, blocked the hypopigmentation effect of SPC, and abrogated the SPC-mediated downregulation of MITF. These results suggest that the ERK pathway is involved in the melanogenic signaling cascade, and that ERK activation by SPC reduces melanin synthesis via MITF downregulation.

Antioxidants↗
PubMed1993

Increased biliary transferrin excretion following parenteral aluminium administration to rats.

Aluminium accumulates in the livers of patients receiving either parenteral nutrition or haemodialysis. When given parenterally to rats, aluminium causes cholestasis. However, the mechanism of hepatic aluminium uptake and the fate of aluminum in the liver are poorly understood. We examined the effect of parenteral aluminium administration on biliary excretion of transferrin, the major circulating aluminum-binding protein. Male Wistar rats were given parenterally aluminum 5 mg/kg/day for 1-14 days. Bile was collected for 3 hr at the end of the study period. Biliary total protein concentration and IgA/total protein were unaffected by up to 14 days of parenteral aluminium administration. However, biliary transferrin excretion increased with duration of aluminum administration up to five-fold by day 14. Biliary transferrin concentration and transferrin/total protein was higher in aluminum treated rats than controls after 7 and 14 days of study. Hepatic aluminum concentration reached a maximum after 4 days of parenteral aluminum administration, at which time serum bile acid and alanine amino transferase values were not different from controls. Since biliary transferrin is normally derived from the serum, it is likely that aluminum promotes hepatocellular uptake of transferrin and that aluminum enters the hepatocyte bound to transferrin. We postulate that transferrin may direct aluminum to intracellular sites where its toxic effects would be minimized.

Alanine Transaminase↗
PubMed2005

Induction of leukemia cell apoptosis by cheliensisin A involves down-regulation of Bcl-2 expression.

AIM: To investigate the apoptosis-inducing effect of cheliensisin A (GC-51), a novel styryl-lactone isolated from Goniothalamus cheliensis, on human promyelocytic leukemia HL-60 cells and the mechanism of action involved. METHODS: Apoptotic cell death was determined by morphological examination and DNA agarose gel electrophoresis. The activity of caspase-3 was assessed using Western blotting and the expression of Bcl-2 and Bax genes was analyzed using the reverse transcription-polymerase chain reaction (RT-PCR) method. RESULTS: GC-51 significantly inhibited the proliferation of HL-60 cells with an IC50 of 2.4+/-0.2 micromol/L and effectively induced apoptosis in HL-60 cells. Exposure of HL-60 cells to 10 micromol/L GC-51 for 8 h resulted in approximately 53% of the cells undergoing apoptosis. Caspase-3 was activated in GC-51-treated cells, which was manifested by the appearance of the 17 kDa active form of caspase-3 and the cleavage of poly(ADP-ribose) polymerase (PARP). Meanwhile, GC-51 markedly reduced the expression of the anti-apoptotic gene Bcl-2 and increased the expression of the pro-apoptotic gene Bax. The apoptosis-inducing effect of GC-51 was cAMP-dependent protein kinase (PKA) dependent because PKA, but not the protein kinase C, specific inhibitor H-89, blocked the induction of apoptosis by GC-51 in HL-60 cells. CONCLUSION: The results demonstrate that GC-51 effectively induces apoptosis in HL-60 cells and that this effect is PKA-dependent and involves the downregulation of Bcl-2 expression and the activation of caspase-3.

Annonaceae↗
PubMed1993

Immunosuppression by discodermolide.

In summary, discodermolide, a novel, marine-derived compound, is a potent in vitro and in vivo immunosuppressive agent. Discodermolide blocks cellular proliferation in lymphoid and nonlymphoid cells. This blocking action is not due to cytotoxicity. Blockage of cell proliferation by discodermolide appears to occur at the G2/M interface of the cell cycle, similar to that observed with other types of antiproliferative drugs (i.e., doxorubicin). The cell cycle block appears to be reversible, as cells recover normal cycling patterns within 48 h after removal of the compound. Additional work with this compound is targeted towards determining the exact nature of discodermolide's mitotic block and is currently under way.

Alkanes↗
PubMed2005

Synergistic cytotoxicity of acidity and 3,4-Dideoxyglucosone-3-ene under the existence of lactate in peritoneal dialysis fluid.

Of the non-physiological compounds in glucose-rich peritoneal dialysis fluid, we investigated the synergistic cytotoxicity of acidity and 3,4-Dideoxyglucosone-3-ene(3,4-DGE) under the existence of lactate using human peritoneal mesothelial cells (HPMC). The effect of pH on cell viability at various levels of pH (5.5, 6.7, 7.15), with or without lactate was examined by adding 1N-HCl to phosphate buffer solution. We also examined the cytotoxic effects of 3,4-DGE and pH (5.5, 6.7 or 7.15). Additionally, we compared the cytotoxic effects of 3,4-DGE and pH (5.5, 6.7 or 7.15) under existence of lactate (40 meq/L) or absence of lactate. The cells were exposed to these solutions for 2 or 4 h. Cell viability was determined by MTT (3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenylterazolium bromide) assay. 3,4-DGE or acidic solution alone had no significant effects on MTT viability under the absence of lactate. However, acidic solutions containing 3,4-DGE significantly decreased MTT viability under the existence of lactate. The MTT viability of HPMC was not decreased by 3,4-DGE or acidity alone under the absence of lactate. However, the combination of acidity and 3,4-DGE markedly decreased MTT viability under the existence of lactate, strongly suggesting the synergistic cytotoxicity of 3,4-DGE and acidity under the existence of lactate.

Cell Survival↗
PubMed1990

Lipid peroxidation effects of a novel iron compound, ferric maltol. A comparison with ferrous sulphate.

Lipid peroxidation effects of ferric maltol have been compared with those of ferrous sulphate both in lecithin liposomes and in brush border and mitochondrial membranes prepared from rat small intestine. Ferrous sulphate, but not ferric maltol, initiated peroxidation in liposomes as measured by conjugated diene production, but, with 500 microM ascorbic acid present, both caused intense peroxidation which was inhibitable by N2, tocopherol, maltol and ferrous chelators, but not by OH or H2O2 scavengers. The rate of peroxidation increased with ferrous sulphate concentration up to 100 microM but was independent of ferric maltol concentration between 5-500 microM. Material eluted from rat small intestine contained a reducing factor, similar in size to ascorbic acid, capable of generating ferrous ions from ferric maltol and initiating peroxidation. Peroxidation in mitochondrial membranes appeared unaffected by addition of iron whilst that in brush border membranes was detectable only in the presence of iron. At iron concentrations of 100 microM and above ferric maltol produced less liposomal peroxidation than ferrous sulphate. Maltol itself may delay recycling of Fe3+ to Fe2+. Thus ferric maltol could provide a less toxic alternative to ferrous salts in the oral treatment of iron-deficiency.

Animals↗
PubMed1990

The importance of reductive mechanisms for intestinal uptake of iron from ferric maltol and ferric nitrilotriacetic acid (NTA).

Intestinal iron absorption is thought to proceed with iron mainly in the ferrous form, yet the novel iron complex, ferric maltol is an effective oral preparation. Although possessing a high oil: water partition coefficient, ferric maltol does not diffuse across the intestine but donates its iron to the endogenous uptake system. Reduction of the ferric iron in the gut lumen appears to precede iron uptake both from ferric maltol and from ferric nitrilotriacetic acid (NTA) which is a non-penetrating iron ligand. Uptake of radiolabelled iron (59Fe) into isolated fragments of rat small intestine was inhibited by the ferrous chelator, bathophenanthroline sulphonate (BPS) and enhanced at low concentrations by the reducing agent ascorbic acid. Spectrophotometric evidence was obtained that ferrous ions are generated from these ferric complexes in the presence of ascorbic acid and other reducing agents. The rate of ferrous ion formation was independent of ferric maltol concentration at low ascorbic acid levels and decreased with increasing ferric maltol concentration at higher levels of ascorbate. Maltol has a high affinity for ferric ions and may delay reduction at higher concentrations. By contrast, a higher rate of ferrous ion generation was seen with ferric NTA and this increased with iron ligand concentration. Washings from the intestinal lumen also brought about ferrous ion formation from these ferric ligands. Gel filtration revealed these reducing factors to be of low molecular weight. The washings, however, interfered with 59Fe uptake into the isolated fragments, but when reducing fractions only from the filtered washings were used, enhanced iron uptake was seen.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗
PubMed1994

Kojic acid, a cosmetic skin whitening agent, is a slow-binding inhibitor of catecholase activity of tyrosinase.

It was found that kojic acid, which is used in cosmetics for its excellent whitening effect, inhibits catecholase activity of tyrosinase in a non-classical manner. A decrease in the initial velocity to a steady-state inhibited velocity can be observed over a few minutes. This time-dependence, which is unaltered by prior incubation of the enzyme with the inhibitor, is consistent with a first-order transition. The kinetic data obtained correspond to those for a postulated mechanism that involves the rapid formation of an enzyme inhibitor complex that subsequently undergoes a relatively slow reversible reaction. Kinetic parameters characterizing this type of inhibition were evaluated by means of nonlinear regression of product accumulation curves.

Animals↗
PubMed1998

Nepetalactone: a new opioid analgesic from Nepeta caesarea Boiss.

The essential oils of Nepeta species including Nepeta phyllochlamys P. H. Davis, N. nuda L. ssp. nuda, and N. caesarea Boiss. have been screened by use of the tail-flick and tail immersion (52.5 degrees C) methods. Of the species studied, only N. caesarea showed significant analgesic activity, besides marked sedation, which was also blocked by naloxone, indicating involvement of opioid receptors. Moreover, it was only active on mechanical, not thermal, algesic response which suggests specificity for specific opioid receptor subtypes, excluding mu-opioid receptors. Because 4a alpha,7alpha,7a alpha-nepetalactone is the main component of the essential oil of N. caesarea, and is present at very high levels (92-95%), it is concluded that 4a alpha,7alpha,7a alpha-nepetalactone is the active principle and has a specific opioid receptor subtype agonistic activity.

Analgesia↗
PubMed2005

Pharmacokinetics and disposition of the kavalactone kawain: interaction with kava extract and kavalactones in vivo and in vitro.

Reported adverse drug interactions with the popular herb kava have spurred investigation of the mechanisms by which kava could mediate these effects. In vivo and in vitro experiments were conducted to examine the effects of kava extract and individual kavalactones on cytochrome P450 (P450) and P-glycoprotein activity. The oral pharmacokinetics of the kavalactone, kawain (100 mg/kg), were determined in rats with and without coadministration of kava extract (256 mg/kg) to study the effect of the extract on drug disposition. Kawain was well absorbed, with >90% of the dose eliminated within 72 h, chiefly in urine. Compared with kawain alone, coadministration with kava extract caused a tripling of kawain AUC(0-8 h) and a doubling of C(max). However, a 7-day pretreatment with kava extract (256 mg /kg/day) had no effect on the pharmacokinetics of kawain administered on day 8. The 7-day pretreatment with kava extract only modestly induced hepatic P450 activities. The human hepatic microsomal P450s most strongly inhibited by kava extract (CYP2C9, CYP2C19, CYP2D6, CYP3A4) were inhibited to the same degree by a "composite" kava formulation composed of the six major kavalactones contained in the extract. K(i) values for the inhibition of CYP2C9 and CYP2C19 activities by methysticin, dihydromethysticin, and desmethoxyyangonin ranged from 5 to 10 microM. Kava extract and kavalactones (< or =9 microM) modestly stimulated P-glycoprotein ATPase activities. Taken together, the data indicate that kava can cause adverse drug reactions via inhibition of drug metabolism.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Extracts and kavalactones of Piper methysticum G. Forst (kava-kava) inhibit P-glycoprotein in vitro.

Root extracts from kava-kava (Piper methysticum G. Forst) are clinically used for the treatment of anxiety and restlessness. Due to reported cases of liver toxicity, kava-kava extracts were withdrawn from the market in several countries in 2002. Because the efflux transporter P-glycoprotein (P-gp) is involved in the absorption, distribution, and excretion of many drugs and often participates in drug-drug interactions, we studied the effect of a crude kava extract and the main kavalactones kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin on the P-gp-mediated efflux of calcein-acetoxymethylester in the P-gp-overexpressing cell line P388/dx and the corresponding cell line P388. The crude extract and the kavalactones showed a moderate to potent inhibitory activity with f2) (concentration needed to double baseline fluorescence) values of 170 microg/ml and 17 to 90 microM, respectively. The f2 value of yangonin could not be determined due to its higher lipophilicity. In conclusion, our results for the first time demonstrate P-gp-inhibitory activity of kava-kava and its components in vitro.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Inhibition of human cytochrome P450 activities by kava extract and kavalactones.

The herb kava has recently been associated with numerous drug interactions, but its interaction with cytochrome P450 (P450) enzymes has not been investigated. In the present work the inhibition of P450 enzymes by kava extract and individual kavalactones in human liver microsomes (HLMs) was investigated. Whole kava extract (normalized to 100 microM total kavalactones) caused concentration-dependent decreases in P450 activities, with significant inhibition of the activities of CYP1A2 (56% inhibition), 2C9 (92%), 2C19 (86%), 2D6 (73%), 3A4 (78%), and 4A9/11 (65%) following preincubation for 15 min with HLMs and NADPH; CYP2A6, 2C8, and 2E1 activities were unaffected. The activities of CYP2C9, 2C19, 2D6, and 3A4 were also measured after incubation of HLMs with the major kavalactones kawain (K), desmethoxyyangonin (DMY), methysticin (M), dihydromethysticin (DHM) (each at 10 microM), and NADPH. Whereas K did not inhibit these enzymes, there was significant inhibition of CYP2C9 by DMY (42%), M (58%), and DHM (69%); of 2C19 by DHM (76%); of 2D6 by M (44%); and of 3A4 by DMY (40%), M (27%), and DHM (54%). Consistent with their potency as inhibitors, the two major kavalactones bearing a methylenedioxyphenyl moiety (M and DHM) formed "455 nm" metabolic intermediate complexes after incubation with HLMs and NADPH, but K and DMY did not. These data indicate that kava has a high potential for causing drug interactions through inhibition of P450 enzymes responsible for the majority of the metabolism of pharmaceutical agents.

Cytochrome P-450 Enzyme Inhibitors↗
PubMed2004

The tyrosine phosphatase inhibitor bis(maltolato)oxovanadium attenuates myocardial reperfusion injury by opening ATP-sensitive potassium channels.

Vanadate has been shown to inhibit tyrosine phosphatase, leading to an increased tyrosine phosphorylation state. The latter has been demonstrated to be involved in the signal transduction pathway of ischemic preconditioning, the most potent endogenous mechanism to limit myocardial infarct size. Furthermore, there is evidence that phosphatase inhibition may be cardioprotective when given late after the onset of ischemia, but the mechanism of protection is unknown. We tested the hypothesis that the organic vanadate compound bis(maltolato)oxovanadium (BMOV) limits myocardial infarct size by attenuating reperfusion injury and investigated the underlying mechanism. Myocardial infarction was produced in 112 anesthetized rats by a 60-min coronary artery occlusion, and infarct size was determined histochemically after 180 min of reperfusion. Intravenous infusion of BMOV in doses of 3.3, 7.5, and 15 mg/kg i.v. decreased infarct size dose-dependently from 70 +/- 2% of the area at risk in vehicle-treated rats down to 41 +/- 5% (P < 0.05 versus control), when administered before occlusion. Administration of the low dose just before reperfusion was ineffective, but administration of the higher doses was equally cardioprotective as compared with administration before occlusion. The cardioprotection by BMOV was abolished by the tyrosine kinase inhibitor genistein and by the ATP-sensitive potassium (K(+)(ATP)) channel blocker glibenclamide but was not affected by the ganglion blocker hexamethonium. We conclude that BMOV afforded significant cardioprotection principally by limiting reperfusion injury. The mode of action appears to be by opening of cardiac K(+)(ATP) channels via increased tyrosine phosphorylation.

Adenosine Triphosphate↗