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Background: Premenstrual syndrome (PMS) is experienced by many women who suffer from either its psychological or physical symptoms. Current treatment is limited to symptomatic therapy or oral contraceptives. On the other hand, l-theanine, which has a relaxant effect, has been reported to be useful for PMS, but its short half-life when administered orally makes it less effective. Permeability and properties of transdermal gel containing l-theanine were evaluated as a preclinical study of PMS symptoms relief formulation. Materials and Methods: Lyogel composed of stearic acid, stearyl alcohol, and propylene glycol was selected. The ratio of these components and the preparation method were investigated. Permeation of Strat-M membranes was evaluated by using Franz cells (in vitro). Moreover, lyogel was applied to institute of cancer research mice's backs for 10 days to examine the permeability of l-theanine. Results: l-Theanine solution did not permeate the Strat-M membrane at all in the permeation study, but lyogel allowed l-theanine to permeate. When the composition of lyogel was 4.4:11.1:296 (mmol) for stearic acid, stearyl alcohol, and propylene glycol, l-theanine absorption through Strat-M membrane was better. In skin permeation study using mice, l-theanine was detected in the serum, that is, it was proven that l-theanine penetrated the skin. Conclusion: The preparation of transdermal gels contained l-theanine was investigated as a preclinical study. The skin permeability of semisolid formulations of hydrophobic ointments, hydrophilic ointments, oily creams, creams, and lyogel containing theanine was compared and found that lyogel was the best. The composition of lyogel was also studied to obtain a formulation with good application comfort. Although it is suggested that this lyogel could be tested in clinical studies to determine whether it is effective for relief of PMS symptoms, lyogel may be suitable as an easy-to-use l-theanine-containing formulation for women that can relieve PMS symptoms.
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Liposomes have been reported to be useful nanocarrier, however, there are number of challenges to resolve before they can be optimized for drug delivery. Liposomes are taken up by cell in the reticuloendothelial system (RES). Polyethyleneglycol (PEG) modification on the liposomal membrane forms a fixed aqueous layer and thus prevents uptake by the RES. The physicochemical properties of liposomes that are most commonly evaluated particle size and zeta potential are not sufficient indicator of the passive targeting effect by PEG modification. In contrast, the fixed aqueous layer thickness (FALT) around liposomal surface was clear to be regulated to be the utilized action in the body. It was showed that the FALT value of PEG-modified liposomes containing doxorubicin increased with the increase in the molecular weight of PEG. Furthermore, PEG modification with a combination of high- and low- molecular weight PEGs on liposomal membranes showed in optimal results with respect to FALT and a higher antitumor effect. In addition, we designed and synthesized a novel PEG-lipid, different double arms PEG (DDA-PEG), which consisted of two PEG chains of 500 and 2000 in one molecule to develop more useful PEG-modified liposomes. DDA-PEG was found to have superior antitumor activity and was associated with the prevention of tumor metastasis. Furthermore, we sought to (-)-epigallocatechin-3-O-gallate (EGCG) functions as a target ligand of the 67-kDa laminin receptor (67LR), which is expressed on high-grade tumor cells. EGCG-PEG-modified liposome appear to have superior antitumor activity against high 67LR-expressing tumor cells, as the liposomes had dual effects.
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Lipossomos , Polietilenoglicóis , Polietilenoglicóis/química , Sistemas de Liberação de Medicamentos , Doxorrubicina/química , Tamanho da PartículaRESUMO
BACKGROUND: One-dose packaging is frequently used in Japan for elderly patients who are prescribed several medications. It is useful for easy administration and the prevention of misuse or missed medications. Hygroscopic medications are not suitable for one-dose packaging because moisture absorption may alter their properties. Plastic bags with desiccating agents are sometimes used to store hygroscopic medicines in one-dose packaging. However, the relationship between the quantity of desiccating agents and their safety in the storage of hygroscopic medications is poorly understood. Furthermore, older adults might accidentally consume desiccating agents used in food preservation. In this study, we developed a bag that suppresses the moisture absorption of hygroscopic medications without the use of desiccating agents. METHODS: The bag was manufactured using polyethylene terephthalate, polyethylene, and aluminum film on the outside, and unified with a desiccating film on the inside. RESULTS: The relative humidity (RH) in the bag was maintained at approximately 30-40% when the bag was stored at 75% RH and 35 °C. The manufactured bag's moisture suppressing effect was better than that of plastic bags with desiccating agents when the hygroscopic medications, potassium aspartate and sodium valproate tablets, were stored at 75% RH and 35 °C for 4 weeks. CONCLUSIONS: The moisture-suppression bag effectively stored and preserved hygroscopic medications and was more effective in inhibiting moisture absorption than plastic bags with desiccating agents under high temperature and humidity conditions. The moisture-suppression bags are expected to be useful for elderly patients who are prescribed several medications in one-dose packaging.
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The relationship between the chemical structure, physicochemical properties, and mucosal adjuvanticity of sugar-based surfactants (SBSs) has not been sufficiently elucidated. Thus, in the present study, we systematically analyzed 11 SBSs for mucosal adjuvanticity. Ovalbumin (OVA)-specific antibody titers were measured in mice immunized intranasally with OVA plus SBS. We found that four SBSs (trehalose monododecanoate, sucrose monododecanoate, n-dodecyl-α-d-maltopyranoside, and n-dodecyl-ß-d-maltopyranoside) exhibited the most potent adjuvanticity. We identified the following associations between chemical structure and adjuvanticity: 1) OVA-specific antibody titer increased with an increasing number of carbon atoms in the alkyl chain; 2) the adjuvanticity was not affected by the type of sugar or bond between the sugar and alkyl chain; and 3) SBSs with rigid structures exhibited less adjuvanticity. The relationship between physicochemical properties and adjuvanticity was as follows: 1) SBSs exhibited adjuvanticity above the critical micelle concentration and 2) in the SBSs with potent adjuvanticity, the diameter of the SBS-OVA complex was 70-75 nm. Our study indicates evidence for the direct involvement of chemical structure and physicochemical properties in determining adjuvanticity in SBSs.
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Adjuvantes Imunológicos , Açúcares , Camundongos , Animais , Adjuvantes Imunológicos/química , Anticorpos , Mucosa , Ovalbumina , Camundongos Endogâmicos BALB C , Administração IntranasalRESUMO
Olanzapine, a second-generation antipsychotic used in the treatment of schizophrenia, is classified as a multi-acting receptor-targeted antipsychotic. Abnormal weight gain is one of the most common side effects of this drug, along with an increased appetite and food intake. However, weight gain has also been reported in patients taking olanzapine without an increase in appetite. Olanzapine has been reported to be directly associated with enhanced adipogenesis; however, whether olanzapine increases lipid content in adipocytes under weak stimulus conditions, such as low glucose concentrations and weak differentiation and/or maturation conditions, is poorly understood. The present study examined the stimulatory effect of olanzapine during the differentiation and maturation of 3T3-L1 pre-adipocytes under low-glucose and weak stimulation conditions by evaluating the expression levels of PPARγ by western blotting and oil red O staining. Western blotting revealed that olanzapine suppressed perilipin phosphorylation, which is an important lipolysis step in adipocytes. The findings of the present study provide novel insights to explain weight gain in patients taking olanzapine but not presenting with increased food intake.
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Peritoneal dissemination is a disease that is difficult to treat surgically because it is widely scattered and proliferates in the abdominal cavity. It is a challenge that even if the drug is administered directly into the abdominal cavity, it rapidly disappears from the abdominal cavity, and the therapeutic effect is not optimal, as expected. In this study, for a liposomal paclitaxel in temperature-sensitive gel that is a suspension before administration and a gel after intraperitoneal administration, the antitumor effect of this formulation was evaluated. Temperature-sensitive gels were prepared using methylcellulose, sodium citrate, and macrogol 4000 and mixed with liposomal paclitaxel. Liposomal paclitaxel containing temperature-sensitive gel in the body was administered into the peritoneal cavity of a mouse model of peritoneal dissemination; the number of cells was significantly reduced compared to a paclitaxel solution of liposomal paclitaxel. These results showed that the liposome in temperature-sensitive gel inhibited cell proliferation in the abdominal cavity. This formulation can be administered easily at room temperature, and it gels and remains in the abdominal cavity for a long period, resulting in a more substantial effect than the existing drug.
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Patients with dysphagia have difficulty swallowing oral medications. Swallowing aid foods, such as deglutition aid jellies and food thickeners, are often used to help such patients take oral medications. Yogurt is occasionally used to help swallow medications. It is also advantageous as it is nutritious and easy to swallow. However, the influence of yogurt on the pharmacokinetics of oral medications is poorly understood. In this study, we aimed to evaluate yogurt as a potential swallowing aid for the intake of oral tablets, by comparing the physical properties and effects of yogurt on disintegration and dissolution profiles of various oral tablets with deglutition aid jelly and xanthan gum-based food thickener. Yogurt and the food thickener were found to extend the disintegration time of several tablets; however, this increase was unremarkable. Although dissolution of magnesium oxide tablets decreased by 6%, 14%, and 25% after immersion in deglutition aid jelly, food thickener, and yogurt, respectively, at 15 min, this impact on dissolution reduced over time (dissolution rates of all samples at 120 min were over 90%). Rheological measurements showed that yogurt and food thickeners have a weak gel structure and therefore have better fluidity than deglutition aid jelly. The adhesiveness and dynamic viscosity of yogurt were higher than those of the food thickener, which delayed tablet disintegration and reduced the dissolution rate. However, these effects were not substantial. We can thus conclude that yogurt may be a useful swallowing aid for patients with deglutition disorders who take oral medications.
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Deglutição , Iogurte , Aditivos Alimentares/química , Humanos , Solubilidade , Comprimidos/químicaRESUMO
Intranasal immunization with surfactants as vaccine adjuvants enhances protective immunity against invasive mucosal pathogens. However, the effects of surfactants and their adjuvanticity on mucosal immune responses remain unclear. Comparison of the mucosal adjuvanticity of 20 water-soluble surfactants from the four classes based upon the polarity composition of the hydrophilic headgroup revealed that the order of mucosal adjuvanticity was as follows: amphoteric > nonionic > cationic > anionic. Within the same class, each surfactant displayed different adjuvanticity values. Analysis of the diameter and ζ-potential of amphoteric surfactant-OVA complexes and their surface physicochemical properties revealed that the diameter was approximately 100 nm, which is considered suitable for immune induction, and that the ζ-potential of the anionic surfactant-OVA complexes was exceedingly negative. The increase in the number of carbon atoms in the hydrophobic tailgroups of the amphoteric surfactant resulted in an increase in the OVA-specific Ab titers. Our findings demonstrate that amphoteric surfactants exhibit potent mucosal adjuvanticity and highlight the importance of the number of carbon atoms in the tailgroups and the diameter and ζ-potential of the complexes when designing mucosal adjuvants.
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Adjuvantes Imunológicos/administração & dosagem , Imunidade nas Mucosas/efeitos dos fármacos , Mucosa Nasal/imunologia , Tensoativos/administração & dosagem , Vacinação/métodos , Adjuvantes Imunológicos/química , Administração Intranasal , Animais , Feminino , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Modelos Animais , Mucosa Nasal/efeitos dos fármacos , Propriedades de Superfície , Tensoativos/químicaRESUMO
Food thickening agents help patients with dysphagia to eat, drink, and take medications. Taking medications with food thickeners has been reported to cause problems such as reduction of pharmacological effects through the delayed disintegration or non-disintegration of tablets. We previously reported that long immersion periods in food thickeners causes delayed disintegration and non-disintegration, while an immersion time of 1 min prevents these problems. However, in many studies including ours, water was used as the solvent, and patients with dysphagia use various drinks as food thickener solvents. Therefore, in this study, we examined the effects on tablet disintegration of food thickeners dissolved in 12 solvents. The line spread test (LST) and pH of the food thickeners differed among solvents, whereas the disintegration times of tablets immersed in food thickeners for 1 min were similar. Magnesium oxide tablets immersed in food thickeners for 30 min experienced delayed disintegration or non-disintegration in all solvents. These results suggested that the effects of solvents on the disintegration of medications hardly differ. Therefore, patients taking medications with food thickeners may refer to reports in which water was used as the solvent, regardless of their drink of choice.
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Transtornos de Deglutição , Aditivos Alimentares , Humanos , Solubilidade , Solventes , ComprimidosRESUMO
The one-dose package is useful for patients who are prescribed multiple medications. However, the one-dose packaging of hygroscopic medications is difficult because the quality of the medication is reduced by moisture absorption. Cellophane polyethylene laminating paper at 20 µm or 30 µm thickness and glassine papers are widely used for one-dose packaging. The basic characteristics, such as water permeability, of these packaging papers have been demonstrated by companies; however, the quality changes of hygroscopic medications stored in these packaging papers are poorly understood. In this study, we compared the relative humidity in packaging papers and the qualities of the stored hygroscopic medications among 20 µm and 30 µm thick cellophane polyethylene laminating paper and glassine paper. Glucobay® 50 mg, Magmitt® 330 mg, and Phosblock® 250 mg tablets were used as hygroscopic medications to be packaged and the relative humidity, weight change, and hardness of tablets were measured. The relative humidity decreased in the order of glassine paper, 20 µm thick cellophane polyethylene laminating paper, and 30 µm thick cellophane polyethylene laminating paper. Additionally, tablets inside the 30 µm thick cellophane polyethylene laminating paper gained the least weight. Therefore, tablets in a 30 µm thick polyethylene laminating paper absorb less moisture than those in other papers. However, the effect was less pronounced at high temperature, even if the relative humidity remained the same. We expect that the results will be used by hospitals and clinical pharmacies to understand the characteristics of packaging papers and ensure appropriate usage.
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Food thickening agents are used to aid the administration of medicine to elderly patients with dysphagia. Magnesium oxide tablets are sometimes administered with food thickening agents. Non-disintegration and disintegration delay of these tablets in the body are problems associated with food thickening agent use. However, the appropriate usage of food thickening agents for administering tablets is not established. Here, the reasons for the non-disintegration of magnesium oxide tablets administered with food thickeners and appropriate usage of food thickeners were examined using a disintegration test of newly opened and moisture-absorbed magnesium oxide tablets. Immersion of magnesium oxide tablets for 10 and 30 min in xanthan and guar gum-based food thickening agents caused disintegration delay and non-disintegration in the first fluid (pH 1.2). However, tablets immersed for 1 min quickly disintegrated. The disintegration of xanthan gum-based food thickening agents was faster than guar gum-based food thickening agents. Moisture absorption by magnesium oxide tablets caused a significant delay in their disintegration in water. The tablets that absorbed moisture disintegrated within 1 min in the first fluid, even when immersed in food thickening agents for a short time. Overall, a short immersion of magnesium oxide tablets in food thickening agents can avoid non-disintegration.
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Aditivos Alimentares/administração & dosagem , Óxido de Magnésio/administração & dosagem , Administração Oral , Idoso , Transtornos de Deglutição/dietoterapia , Transtornos de Deglutição/tratamento farmacológico , Galactanos/administração & dosagem , Humanos , Técnicas In Vitro , Mananas/administração & dosagem , Gomas Vegetais/administração & dosagem , Polissacarídeos Bacterianos/administração & dosagem , Solubilidade , Comprimidos , ViscosidadeRESUMO
Cancer cells switch from mitochondrial oxidative phosphorylation to glycolysis, even in the presence of normal oxygen concentrations. Inhibition of the glycolytic pathway is therefore a critical strategy in cancer therapy. A non-metabolic glucose analog, 2-deoxy-D-glucose (2-DG), has been the focus of research on glycolytic inhibitors for use in cancer treatment. The current study examined the anti-cancer effects of 2-DG on idarubicin (IDA)-resistant P388 (P388/IDA) leukemia cells. P388/IDA cells were established following continuous exposure of IDA to P388 cells. Characterization of P388/IDA cells revealed increased lactate production and glucose consumption compared with P388 parent cells. The results of a cell viability assay determined that 2-DG induces higher toxicity in P388/IDA cells compared with P388 cells. Although 2-DG also exhibits endoplasmic reticulum (ER) stress-inducing activity, the cytotoxic effect of the ER stress inducer, tunicamycin, on P388/IDA cells was lower than that of P388 cells. A combination of 2-DG and IDA enhanced P388/IDA cell death compared with each agent alone. The results indicated that P388 cells activated glycolysis after acquiring IDA resistance and therefore, inhibition of the glycolytic pathway via 2-DG might be a useful strategy for cancer therapy against IDA- resistant leukemia cells.
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Food thickeners are widely used to aid the oral administration of medications to patients with dysphagia. Powder-type food thickeners are used to modulate the viscosity of therapeutic solutions depending on the swallowing capacity of patients. Food thickeners inhibit or delay the disintegration of some medications, resulting in reduced pharmaceutical effects of the medications and/or their excretion in the stool. A short immersion time (within 1 min) is important to overcome these problems. Although thickened drinks are commercially available, their use as vehicles for medications is not well understood. In this study, we evaluated the effects of thickened drinks on the disintegration time of therapeutic tablets. Furthermore, we compared the thickened drinks with powder-type xanthan gum-based food thickeners. Forty tablets were used, including naked tablets, film-coated tablets, orally disintegrating tablets, enteric-coated tablets, and sugar-coated tablets. For the disintegration test, the tablets were immersed in thickened drinks or food thickeners for 1 min. The changes in the disintegration time of the 40 tablets immersed in the thickened drinks were comparable with those in food thickeners. The disintegration time of several tablets was shorter or unchanged after immersion in the thickened drinks. The disintegration time of rapidly disintegrating tablets tended to increase when immersed in thickened drinks, but it was less than 2 min for the majority of the tablets. These results demonstrate that thickened drinks, similar to food thickeners, could help administer medications to patients. Overall, our study provides valuable information for pharmacists and clinicians to decide the most suitable way to deliver medications to patients with dysphagia.
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Vitamin B6 compounds, including pyridoxine, pyridoxal, pyridoxamine, and their phosphorylated forms, have been investigated with regard to their cancer preventive and therapeutic effects through epidemiological, in vivo, and in vitro studies. In particular, in vitro studies in cancer cells have evaluated the effects of several B6 vitamers such as pyridoxine, pyridoxal, pyridoxamine, and pyridoxal-5'-phosphate, which is a bioactive form of vitamin B6 However, the anticancer activity and concentration required to influence cancer cells vary among B6 vitamers. In this review, the various in vitro effects of vitamin B6 compounds on cancer cells are presented and discussed.
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Antineoplásicos/farmacologia , Vitamina B 6/farmacologia , Vitaminas/farmacologia , Animais , Humanos , Neoplasias/tratamento farmacológicoRESUMO
In solid tumors, cancer cells are exposed to microenvironment stress, including hypoxia and insufficient nutrients. An acidic microenvironment in tumors is facilitated by the increase in synthesis of lactic acid; this is known as Warburg effect. We previously showed that B16F10 melanoma cells were induced autophagic cell death by glucose-deprivation stress, and lactic acid suppressed the cell death through the inhibition of autophagy. In this study, effects of lactic acid on cell death of B16F10 cells under hypoxic and glucose-depleted double stress conditions were investigated. The double stress promoted autophagic cell death earlier than glucose-depleted stress alone. Lactic acid repressed the double stress-induced cell death by inhibiting autophagy. These results suggest that lactic acid serves for cell survival under microenvironmental stress conditions in B16F10 melanoma cells.
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Hipóxia Celular , Sobrevivência Celular/efeitos dos fármacos , Glucose/deficiência , Ácido Láctico/farmacologia , Melanoma Experimental , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Melanoma Experimental/metabolismo , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismoRESUMO
Cyclic lipopeptides such as surfactin and polymyxin have potent mucosal adjuvant properties. Cyclic lipopeptides are tensioactive compounds but the relationship between adjuvanticity and surface activity is unknown. Here, we show that the critical micelle concentration (cmc) of surfactant and particle size of the surfactant-protein complex are important determinants of cyclic lipopeptide adjuvanticity. We found that the diameter of cyclic lipopeptide-ovalbumin (OVA) complex particles was significantly larger than that in the solutions of OVA alone at cyclic lipopeptide concentrations above the cmc. OVA-specific antibody titers in mice immunized intranasally with OVA and a cyclic lipopeptide at concentrations above its cmc were significantly higher than those in mice immunized with OVA plus the same dose of the cyclic lipopeptide but administered with formulations in which cyclic lipopeptide concentration was below the cmc. Thus, the concentration of the cyclic lipopeptide in the formulation at immunization, but not its overall dose, was critical for its adjuvanticity. Furthermore, two types of aggregates, the cyclic lipopeptide simplex micelles and the cyclic lipopeptide-OVA complex micelles, were found in formulations with SF concentrations above its cmc. Degranulation of mast cells exposed to SF simplex micelles was more pronounced when SF concentration was above the cmc. In conclusion, our study showed that surface activity properties, such as the cmc and the size of surfactant-protein complex contribute to the adjuvanticity of cyclic lipopeptides. Our study proposes a novel idea that cmc is a key parameter for tensioactive adjuvants. This article is protected by copyright. All rights reserved.
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ãCancer chemotherapy-induced stomatitis may spread throughout a patient's entire oral cavity and decrease the patient's QOL. The therapy for stomatitis at Iwate Medical University Hospital (IMUH) includes dental treatment before chemotherapy, in addition to oral rinses or cryotherapy as a preventative measure. However, in our survey of doctors and nurses, the responses of patients "satisfied" with the present approach for stomatitis treatment reached only 5.1%. Therefore, we attempted treatment using an indomethacin spray, prepared as a hospital preparation, with pre-approval of the ethics committee and based on a previous report of its positive effect on patients at another hospital. We observed that the indomethacin spray succeeded in decreasing chemotherapy-induced oral pain, and its effect was maintained for 2 h in patients at IMUH. The ratio of female patients who rated indomethacin spray as good was higher than that of males. Comments from some patients included a complaint that the nozzle of the injection tip was too short; thus we increased the length of the nozzle from 2 to 7 cm. At present, indomethacin spray is being used to treat stomatitis patients at IMUH. Indeed, the indomethacin spray has been used since October 2011. It was used on 34 patients in 2016. In this review, we describe the collaboration between IMUH and the basic application of studies in our university laboratory.
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Anti-Inflamatórios não Esteroides/administração & dosagem , Composição de Medicamentos , Indometacina/administração & dosagem , Colaboração Intersetorial , Sprays Orais , Serviço de Farmácia Hospitalar , Estomatite/induzido quimicamente , Estomatite/tratamento farmacológico , Antineoplásicos/efeitos adversos , Embalagem de Medicamentos , Feminino , Hospitais Universitários , Humanos , Laboratórios Hospitalares , Masculino , Satisfação do PacienteRESUMO
B16F10 murine melanoma cells are frequently used for the study of cancer and melanogenesis. The cells are usually cultured in Dulbecco's Modified Eagle Medium, with the addition of 20 µM pyridoxal (PL) or pyridoxine (PN) for vitamin B6. The difference between these vitamin B6 compounds is thought not to affect cell proliferation, whereas their influence on other physiological effects is poorly understood. In the present study, the effects of PL and PN on cell proliferation and melanogenesis in B16F10 cells were compared. At 500 µM PL significantly suppressed cell growth but the growth inhibitory effect of PN was weak. Although neither of the vitamin B6 compounds affected cell growth at 20 µM, melanogenesis was suppressed by 20 µM PL compared with the effect of PN. In addition, the expression levels of tyrosinase, which is the rate-limiting enzyme, correlated with the melanin content. The results of the present study indicate that PL may be more useful for melanoma therapy and suppression of skin pigmentation than PN. The results also signify the importance of medium selection for cell culture.
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This study sought to evaluate the antitumor effects of and elucidate the mechanisms underlying (-)-epigallocatechin-3-O-gallate (EGCG) and polyethyleneglycol (PEG)-modified liposomes. EGCG functions as a target ligand of the 67-kDa laminin receptor (67LR), which is expressed on high-grade tumor cells. An EGCG derivative was synthesized for binding to the end of PEG. Doxorubicin (DOX)-loaded EGCG-PEG-modified liposome (EPL) significantly decreased tumor size in mice bearing high 67LR-high-expressing tumors. Caspase-3 activity, which indicates induction of apoptosis, was also elevated only in the EPL group. The importance of PEG for the antitumor effects of EGCG was noted, as soluble EGCG did not accumulate at a sufficient concentration to exert an apoptotic effect. Moreover, EPL significantly increased caspase-8 activity, suggesting that EPL-induced apoptosis occurred due to caspase-8 activity induced following the binding of EGCG to 67LR as a cell-death ligand. In conclusion, EPL appear to have superior antitumor activity against high 67LR-expressing tumor cells, as the liposomes had dual effects, namely antitumor effects due to the loaded DOX and apoptosis induced by the bound EGCG.