Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.10.3.1 (tyrosinase)
9,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our laboratory has synthesized two new phenolic thioether amines, N-propionyl-4-S-cysteaminylphenol (N-Pr-4-S-CAP) and N[2-[(4-propionyloxyphenyl)thio]ethyl] propionamide (N,O-diPr-4-S-CAP). These compounds, along with the previously described phenolic thioether amine N-acetyl-4-S-cysteaminylphenol (N-Ac-4-S-CAP) and its acetyl form (N,O-diAc-4-S-CAP), are tyrosine-amine derivative analogues. The cytotoxicity of these compounds is thought to be tyrosinase dependent, which may make them suitable for targeted anti-melanoma therapy since only melanocytes and their malignant counterparts contain this active enzyme. To further investigate this hypothesis, we performed MTT [3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide] assays to determine the cytotoxicity of these compounds in 10 different cell lines. Specifically, we examined to what extent cytotoxicity is related to tyrosinase and tyrosine hydroxylase activity using melanoma and neuroblastoma cells, which have a common metabolic pathway using tyrosinase and tyrosine hydroxylase, respectively. The most sensitive cell line was the highly pigmented SK-MEL-23 melanoma cell line, which shows a very high tyrosinase activity with the highest melanin pigmentation. KAN and SK-NSH (two neuroblastoma cell lines), which have no tyrosinase activity but high tyrosine hydroxylase, were also sensitive. However, C32 (a non-pigmented melanoma with a lower tyrosinase activity) was also sensitive, and MeWo (a moderately pigmented melanoma with a high tyrosinase activity) was less sensitive. This in vitro study may indicate that there is a non-tyrosinase-mediated mechanism of cytotoxicity for phenolic thioether amines in addition to the tyrosinase-mediated one described previously.
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PMID:Comparison of in vitro cytotoxicity of N-acetyl and N-propionyl derivatives of phenolic thioether amines in melanoma and neuroblastoma cells and the relationship to tyrosinase and tyrosine hydroxylase enzyme activity. 1071 35

Ceramide is implicated in the regulation of various signaling pathways leading to proliferation, differentiation or apoptotic cell death, but there have been few investigations about the effects of ceramide on the cell growth and the melanogenesis of melanocytes. In the present study, we investigated the effects of cell-permeable ceramide on Malme-3M human melanoma cell line. MTT proliferation assay showed that C2-ceramide inhibited the growth of Malme-3M cells in a dose-dependent manner. Cell cycle analysis confirmed the inhibition of DNA synthesis by a reduction in the S phase and an increase in the G0/G1 phase. Flow cytometric analysis for apoptotic cells and morphological observations indicated that the antiproliferative effect of C2-ceramide was not due to apoptosis. We next investigated the effects of C2-ceramide on the pigmentation of Malme-3M melanoma cells. The results showed that C2-ceramide induced only a slight decrease of tyrosinase activity and melanin synthesis. To investigate the ceramide signaling pathway, we studied the influence of C2-ceramide on extracellular signal-regulated kinase (ERK) and Akt activation by Western blot. We demonstrated that the amount of phosphorylated Akt was decreased by C2-ceramide, whereas ERK was activated transiently. Because of a well-known involvement of ceramide in apoptosis, we further investigated the level of caspase-3 and HSP70 after treatment of C2-ceramide. We found that the caspase-3 was not activated and the expression of HSP70 increased moderately. In conclusion, C2-ceramide inhibited the cell growth of Malme-3M cells without the induction of apoptosis. We suggest that increased HSP70 may be related to the resistance against apoptosis.
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PMID:Effects of C2-ceramide on the Malme-3M melanoma cell line. 1235 15

Several studies on mitochondrial functions following brief exposure (5-15 min) to dopamine (DA) in vitro have produced extremely variable results. In contrast, this study demonstrates that a prolonged exposure (up to 2 h) of disrupted or lysed mitochondria to DA (0.1-0.4 mM) causes a remarkable and dose-dependent inhibition of complex I and complex IV activities. The inhibition of complex I and complex IV activities is not prevented by the antioxidant enzyme catalase (0.05 mg/ml) or the metal-chelator diethylenetriaminepentaacetic acid (0.1 mM) or the hydroxyl radical scavengers like mannitol (20 mM) and dimethyl sulphoxide (20 mM) indicating the non-involvement of *OH radicals and Fenton's chemistry in this process. However, reduced glutathione (5 mM), a quinone scavenger, almost completely abolishes the DA effect on mitochondrial complex I and complex IV activities, while tyrosinase (250 units/ml) which catalyses the conversion of DA to quinone products dramatically enhances the former effect. The results suggest the predominant involvement of quinone products instead of reactive oxygen radicals in long-term DA-mediated inactivation of complex I and complex IV. This is further indicated from the fact that significant amount of quinones and quinoprotein adducts (covalent adducts of reactive quinones with protein thiols) are formed during incubation of mitochondria with DA. Monoamine oxidase A (MAO-A) inhibitor clorgyline also provides variable but significant protection against DA induced inactivation of complex I and complex IV activities, presumably again through inhibition of quinoprotein formation. Mitochondrial ability to reduce tetrazolium dye 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) in presence of a respiratory substrate like succinate (10 mM) is also reduced by nearly 85% following 2 h incubation with 0.4 mM DA. This effect of DA on mitochondrial function is also dose-dependent and presumably mediated by quinone products of DA oxidation. The mitochondrial dysfunction induced by dopamine during extended periods of incubation as reported here have important implications in the context of dopaminergic neuronal death in Parkinson's disease (PD).
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PMID:Inhibition of rat brain mitochondrial electron transport chain activity by dopamine oxidation products during extended in vitro incubation: implications for Parkinson's disease. 1592 94

The inhibitory effects of nobiletin and hesperidin from citrus peel crude extracts on tyrosinase diphenolase activity are evaluated. IC50 of nobiletin and hesperidin is 1.49 mM and 16.08mM, respectively and their inhibition mechanism is competitive type with Ki = 2.82 mM and noncompetitive with Ki = 9.16 mM, respectively. Crude extracts from citrus peel (C. unshiu Marc.) were extracted with 95% ethanol and fractionated by petroleum ether (PCPE). The ethanol phase (ECPE) was further desorbed from macroporous adsorption resin (FGRE). Their IC50 values were 8.09 mg/mL, 7.53 mg/mL and 4.80 mg/mL, respectively. Their inhibition on melanogenesis in B16 mouse melanoma cells was also evaluated. FGRE showed a significant inhibition (42.5% at 31.25 microg/mL, p < 0.01) while hesperidin showed almost no inhibition. Nobiletin and PCPE give efficacious antiproliferation effects on B16 mouse melanoma cell with IC50 values 88.6 microM and 62.96 microg/mL, respectively, by the MTT test. Hesperidin and other crude extracts showed very low cytotoxity to the B16 cell.
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PMID:Tyrosinase inhibitory effects and inhibition mechanisms of nobiletin and hesperidin from citrus peel crude extracts. 1737 52

The inhibitory effects of nobiletin and hesperidin from citrus peel crude extracts on tyrosinase diphenolase activity have been evaluated. IC50 of nobiletin and hesperidin were 1.49 mM and 16.08 mM, respectively and their inhibition mechanisms are competitive type with inhibition constant (Ki) 2.82 mM and noncompetitive type with Ki 9.16 mM, respectively. Crude extracts from citrus peel (C. unshiu Marc.) were extracted with 95% ethanol and fractionated by petroleum ether (PCPE). The ethanol phase (ECPE) was further desorbed from macroporous adsorption resin (FGRE). Their IC50 values were 8.09 mg/mL, 7.53 mg/mL and 4.80 mg/mL, respectively. Their inhibition of melanogenesis in B16 mouse melanoma cells was also evaluated. FGRE showed a significant inhibition (42.48% at 31.25 microg/mL, p < 0.01) while hesperidin showed almost no inhibition. Nobiletin and PCPE gave efficacious antiproliferation effects on the B16 mouse melanoma cell with IC50 values 88.6 microM and 62.96 microg/mL, respectively, through the MTT test. Hesperidin and other crude extracts showed very low cytotoxity to the B16 cell.
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PMID:Tyrosinase inhibitory effects and inhibition mechanisms of nobiletin and hesperidin from citrus peel crude extracts. 1737 53

Melagenine, extracted from human placenta, has been shown to be effective in treating patients with vitiligo, yet the mechanisms of melagenine in inducing the repigmentation of vitiligo patients have not been fully investigated. Recent studies have suggested that melagenine stimulates melanocyte proliferation and melanogenesis. In this study, we utilized the NCCmelb4M5 melanoblast cell line to investigate the effects of melagenine on proliferation and differentiation of immature melanocytes or melanoblasts. NCCmelb4M5 cells were treated with different concentrations of melagenine (50-400 microg/ml), and MTT assay was performed to evaluate the effects of melagenine on proliferation of melanoblasts. RT-PCR and Western blotting were used to determine the expression of c-KIT and tyrosinase (TYR). Our results show that melagenine stimulates proliferation of NCCmelb4M5 cells in a dose-dependent manner with an optimal concentration of 100 microg/ml. Multipolar and highly branched dendritic network, as well as cluster-like growing cell assembly were visible in melagenine-treated NCCmelb4M5 cells. Melagenine induced expression of c-KIT, TYR and MITF. Our results provide insights into the molecular mechanism of the beneficial effect of melagenine in the treatment of vitiligo.
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PMID:Melagenine modulates proliferation and differentiation of melanoblasts. 1863 73

High mortality rate for metastatic melanoma is related to its resistant to the current methods of therapy. Melanogenesis is a metabolic pathway characteristic for normal and malignant melanocytes that can affect the behavior of melanoma cells or its surrounding environment. Human melanoma cells in which production of melanin pigment is dependent on tyrosine levels in medium were used for experiments. Peripheral blood mononuclear cells were derived from the buffy coats purchased from Lifeblood Biological Services. Cell pigmentation was evaluated macroscopically, and tyrosinase activity was measured spectrophotometrically. Cell proliferation and viability were measured using lactate dehydrogenase release MTT, [(3)H]-thymidine incorporation and DNA content analyses, and gene expression was measured by real time RT-PCR. Pigmented melanoma cells were significantly less sensitive to cyclophosphamide and to killing action of IL-2-activated peripheral blood lymphocytes. The inhibition of melanogenesis by either blocking tyrosinase catalytic site or chelating copper ions sensitized melanoma cells towards cytotoxic action of cyclophosphamide, and amplified immunotoxic activities of IL-2 activated lymphocytes. Exogenous L-DOPA inhibited lymphocyte proliferation producing the cell cycle arrest in G1/0 and dramatically inhibited the production of IL-1beta, TNF-alpha, IL-6 and IL-10. Thus, the active melanogenesis could not only impair the cytotoxic action of cyclophosphamid but also has potent immunosuppressive properties. This resistance to a chemotherapeutic agent or immunotoxic activity of lymphocytes could be reverted by the action of tyrosinase inhibitors. Thus, the inhibition of melanogenesis might represent a valid therapeutic target for the management of advanced melanotic melanomas.
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PMID:Inhibitors of melanogenesis increase toxicity of cyclophosphamide and lymphocytes against melanoma cells. 1908 34

In the present study, three kinds of phlorotannins, marine algal polyphenol, were isolated from a brown alga Ecklonia cava, and their inhibitory effect on melanogenesis as well as the protective effect against photo-oxidative stress induced by UV-B radiation was investigated. The effect on melanogenesis was evaluated via the inhibitory effects of tyrosinase and melanin synthesis. Among the phlorotannins, dieckol showed higher effect than that of the other phlorotannins in the both assays; especially the value of dieckol in the tyrosinase inhibition assay was relatively higher than that of a commercial tyrosinase inhibitor (kojic acid). The UV-B protection effect was evaluated via DCFH-DA, MTT, comet assays, and morphological changes in fibroblast. Intracellular ROS induced by UV-B radiation was reduced by the addition of phlorotannins and cell viability was dose-dependently increased. Moreover, dieckol demonstrated strong protective properties against UV-B radiation-induced DNA damage via damaged tail intensity and morphological changes in fibroblast. Hence, these results indicated that dieckol isolated from E. cava has potential whitening effects and prominent protective effects on UV-B radiation-induced cell damages, which might be used in pharmaceutical and cosmeceutical industries.
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PMID:Effect of phlorotannins isolated from Ecklonia cava on melanogenesis and their protective effect against photo-oxidative stress induced by UV-B radiation. 1949 Sep 39

Premelanosomes are presumed to be essential for melanogenesis in melanocytes and pre-natal retinal pigment epithelium (RPE) cells. We analysed melanin synthesis in adenoviral-transduced tyrosinase-gene-expressing amelanotic RPE (ARPE) 19 cells to determine whether premelanosome formation is needed for post-natal melanogenesis. The synthesis of melanogenic proteins and melanin granules was investigated by immunocytochemistry and light and electron microscopy. The occurrence of tyrosinase was analysed ultrastructurally by dihydroxyphenylalanine histochemistry. The viability of transduced cell cultures was examined via MTT assay. We found active tyrosinase in small granule-like vesicles throughout the cytoplasm and in the endoplasmic reticulum and nuclear membrane. Tyrosinase was also associated with multi-vesicular and multi-lamellar organelles. Typical premelanosomes, structural protein PMEL17, tyrosinase-related protein 1 and classic melanosomal stages I-IV were not detected. Instead, melanogenesis took place inside multi-vesicular and multi-lamellar bodies of unknown origin. Viability was not affected up to 10 days after transduction. We thus demonstrate a pathway of melanin formation lacking typical hallmarks of melanogenesis.
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PMID:The classical pathway of melanogenesis is not essential for melanin synthesis in the adult retinal pigment epithelium. 2014 Apr 56

Melanogenesis is a well-known physiological response of human skin that may occur because of exposure to ultraviolet light, for genetic reasons, or due to other causes. In our efforts to find new skin lightening agents, palmitoleic acid was investigated for its ability to inhibit melanogenesis. In this study, palmitoleic acid's effect on melanin formation was assessed. Results indicated that palmitoleic acid was shown to down-regulate melanin content in a dose-dependent pattern. To clarify the target of palmitoleic acid action in melanogenesis, we performed Western blotting for tyrosinase, tyrosinase-related protein-1 (TRP-1), TRP-2, and microphthalmia-associated transcription factor (MITF), which are key melanogenic enzymes. Palmitoleic acid inhibited tyrosinase, TRP-2, and MITF expressions in a dose-dependent manner. However, it did not inhibit TRP-1 expression. In order to assess its usefulness in future cosmetic product applications, the cytotoxic effects of the palmitoleic acid were also determined by colourimetric MTT assays using human keratinocyte HaCaT cells. Palmitoleic acid exhibited no cytotoxicity at 500 muM in a human cell line. Therefore, this study suggests that palmitoleic acid is a candidate anti-melanogenic agent, and it might be effective in hyperpigmentation disorders.
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PMID:Effect of palmitoleic acid on melanogenic protein expression in murine b16 melanoma. 2048 37


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