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1.
Biol Pharm Bull ; 47(6): 1224-1230, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38925923

RESUMO

We prepared a supramolecular hydrogel composed of decanoic acid and arginine (C10/Arg gel) and evaluated its application to a transdermal formulation. C10/Arg gel adjusted to pH 7 with 1 M NaOH aq or 1 M HCl aq provided a translucent hydrogel with a lamellar liquid crystal structure in the concentration region of decanoic acid ≥12% and arginine ≤9%. Rheological measurements showed that C10/Arg gel is a viscoelastic material with both solid and liquid properties, with elasticity being dominant over viscosity in the low shear stress region. The skin permeability of hydrocortisone (HC) and indomethacin (IM) from C10/Arg gels was investigated in vitro using hairless mouse skin and compared to control formulation drug suspensions (IM or HC) in water. The cumulative permeation amount of HC and IM from the C10/Arg gel at 10 h after application was approximately 16 and 11 times higher than that of the control, respectively. On the other hand, the flux of IM decreased with increasing arginine concentration, likely due to the acid-base interaction between Arg and IM in C10/Arg gel. Adequate drug skin permeation enhancement by C10/Arg gel requires optimizing the gel composition for each specific drug.


Assuntos
Administração Cutânea , Arginina , Ácidos Decanoicos , Hidrocortisona , Hidrogéis , Indometacina , Camundongos Pelados , Absorção Cutânea , Pele , Animais , Arginina/química , Arginina/administração & dosagem , Hidrogéis/química , Absorção Cutânea/efeitos dos fármacos , Pele/metabolismo , Pele/efeitos dos fármacos , Indometacina/administração & dosagem , Indometacina/química , Indometacina/farmacocinética , Ácidos Decanoicos/química , Ácidos Decanoicos/administração & dosagem , Hidrocortisona/administração & dosagem , Hidrocortisona/química , Hidrocortisona/farmacocinética , Camundongos , Reologia , Permeabilidade , Masculino
2.
Biol Pharm Bull ; 47(5): 997-999, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38777759

RESUMO

Patch tests are often used in safety evaluations to identify the substance causing skin irritation, but the same substance can sometimes give positive or negative results depending on the test conditions. Here, we investigated differences in the skin penetration of two test compounds under different application conditions. We studied the effects of the anionic surfactant sodium dodecyl sulfate (SDS) and the nonionic surfactant polysorbate 80 (PS) on skin penetration of the preservatives methylisothiazolinone (MT) and methylchloroisothiazolinone (MCT), which are used in cosmetics such as shampoos. The skin permeation of MT was enhanced by SDS but was unchanged by PS. Skin impedance decreased in the presence of SDS whereas PS had the same effect as the control aqueous solution, suggesting that SDS reduction of the barrier function of skin affects the permeation of MT, a hydrophilic drug. Application of a mixture of MCT and MT in the presence of SDS did not affect the skin permeation of MCT whereas the permeation of MT was enhanced by SDS, indicating that the skin permeation of MCT is less affected by SDS than is MT. Thus, attention should be paid to the possible effect of co-solutes, especially hydrophilic drugs.


Assuntos
Polissorbatos , Absorção Cutânea , Pele , Dodecilsulfato de Sódio , Tensoativos , Tiazóis , Tiazóis/farmacocinética , Tensoativos/farmacologia , Absorção Cutânea/efeitos dos fármacos , Polissorbatos/farmacologia , Pele/metabolismo , Pele/efeitos dos fármacos , Animais , Conservantes Farmacêuticos , Suínos , Cosméticos/farmacocinética , Impedância Elétrica , Permeabilidade/efeitos dos fármacos
3.
In Vitro Cell Dev Biol Anim ; 60(5): 563-568, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38472720

RESUMO

Human pluripotent stem cells, such as human embryonic stem cells and human induced pluripotent stem cells, are used in basic research and various applied fields, including drug discovery and regenerative medicine. Stem cell technologies have developed rapidly in recent years, and the supply of culture materials has improved. This has facilitated the culture of human pluripotent stem cells and has enabled an increasing number of researchers and bioengineers to access this technology. At the same time, it is a challenge to share the basic concepts and techniques of this technology among researchers and technicians to ensure the reproducibility of research results. Human pluripotent stem cells differ from conventional somatic cells in many aspects, and many points need to be considered in their handling, even for those experienced in cell culture. Therefore, we have prepared this proposal, "Points of Consideration for Pluripotent Stem Cell Culture," to promote the effective use of human pluripotent stem cells. This proposal includes seven items to be considered and practices to be confirmed before using human pluripotent stem cells. These are laws/guidelines and consent/material transfer agreements, diversity of pluripotent stem cells, culture materials, thawing procedure, media exchange and cell passaging, freezing procedure, and culture management. We aim for the concept of these points of consideration to be shared by researchers and technicians involved in the cell culture of pluripotent stem cells. In this way, we hope the reliability of research using pluripotent stem cells can be improved, and cell culture technology will advance.


Assuntos
Técnicas de Cultura de Células , Células-Tronco Pluripotentes , Humanos , Técnicas de Cultura de Células/métodos , Células-Tronco Pluripotentes/citologia , Criopreservação/métodos , Meios de Cultura/química
4.
Yakugaku Zasshi ; 144(1): 87-97, 2024.
Artigo em Japonês | MEDLINE | ID: mdl-38171800

RESUMO

I have been studying the improvement of drug solubility using solid dispersion and skin-applied formulations. When preparing solid dispersions using phosphatidylcoline (PC) as a carrier, drug with hydrogen-donating groups interacts with PC to produce amorphous solid dispersions with high drug content; this overcomes improves drug absorption. The drug was solubilized and supersaturated in the oil-based gel formed with hyadrogenated lecithin; this facilitates drug permeation through the skin. The promoting effect differs with the nature of the oil used because of the skin penetration of the oil itself and the accompanying increase in drug solubility and diffusion coefficient in the skin. At actual application volumes of 10 µL/cm2 or less, the skin penetration of poorly-absorbable drugs depends on the molecular weight and surface tension of the oil. The penetration of the oil vehicle into the upper stratum corneum influences the reach of the drug into the stratum corneum; a high drug concentration near the 7th layer of the stratum corneum promotes migration through the skin by increasing the linear concentration gradient in deeper layers. In addition, we performed a risk assessment, in collaboration with toxicologists, for dermal safety that included the toxicity potential of substances and the parts related to skin transfer.


Assuntos
Lecitinas , Pele , Lecitinas/metabolismo , Lecitinas/farmacologia , Pele/metabolismo , Absorção Cutânea , Epiderme , Solubilidade
5.
Biol Pharm Bull ; 47(1): 245-252, 2024 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-38092382

RESUMO

We investigated the effect of the rheological properties and composition of lecithin reverse wormlike micelles (LRWs) on the skin permeation of a model of a hydrophilic drug to determine whether LRWs support uniform hydrophilic drug/oil-based formulations and good drug penetrate into skin. Here, we prepared LRWs with D (-)-ribose (RI) or glycerol (GL) as polar compounds, liquid paraffin (LP) or isopropyl myristate (IPM) as oils, and 6-carboxyfluorescein (CF) as a model for a hydrophilic drug, and evaluated the rheological properties and skin penetration characteristics of the preparations. The LRWs showed moderate viscosity at 25 °C, a typical storage temperature, but decreasing viscosity at 32 °C, the surface temperature of human skin, suggesting that the LRWs would penetrate the microstructure of skin (e.g., wrinkles and hair follicles). The highest skin permeability of CF was observed when IPM was used as the oil, suggesting that both the stratum corneum and hair follicle routes are involved in drug permeation. The penetration of CF into hair follicles is influenced not only by the rheology of the formulation but also by the interaction between IPM and sebum in the hair follicles.


Assuntos
Lecitinas , Micelas , Humanos , Lecitinas/química , Lecitinas/metabolismo , Pele/metabolismo , Absorção Cutânea , Óleos/química , Reologia
6.
BMC Cancer ; 22(1): 984, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36109807

RESUMO

BACKGROUND: Malignant mesothelioma (MM) is an aggressive mesothelial cell cancer type linked mainly to asbestos inhalation. MM characterizes by rapid progression and resistance to standard therapeutic modalities such as surgery, chemotherapy, and radiotherapy. Our previous studies have suggested that tumor cell-derived connective tissue growth factor (CTGF) regulates the proliferation of MM cells as well as the tumor growth in mouse xenograft models. METHODS: In this study, we knock downed the bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) and CTGF in MM cells and investigated the relationship between both and their impact on the cell cycle and cell proliferation. RESULTS: The knockdown of CTGF or BAMBI reduced MM cell proliferation. In contrast to CTGF knockdown which decreased BAMBI, knockdown of BAMBI increased CTGF levels. Knockdown of either BAMBI or CTGF reduced expression of the cell cycle regulators; cyclin D3, cyclin-dependent kinase (CDK)2, and CDK4. Further, in silico analysis revealed that higher BAMBI expression was associated with shorter overall survival rates among MM patients. CONCLUSIONS: Our findings suggest that BAMBI is regulated by CTGF promoting mesothelioma growth by driving cell cycle progression. Therefore, the crosstalk between BAMBI and CTGF may be an effective therapeutic target for MM treatment.


Assuntos
Fator de Crescimento do Tecido Conjuntivo , Proteínas de Membrana , Mesotelioma Maligno , Ativinas , Animais , Proliferação de Células/genética , Fator de Crescimento do Tecido Conjuntivo/genética , Ciclina D3 , Quinases Ciclina-Dependentes , Humanos , Proteínas de Membrana/genética , Camundongos
7.
Chem Pharm Bull (Tokyo) ; 70(1): 52-56, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34980734

RESUMO

Lecithin reverse wormlike micelles (LRWs) have been studied recently for dermal application dosage use but the effects of the physicochemical properties of oils on the formation and rheological properties of LRWs have not been investigated. We studied the effect of oil on the formation of LRWs using 5 types of liquid paraffin (LP) with kinematic viscosities ranging from 4.00 to 88.0 mm2/s. Partial phase diagrams of lecithin/water/LP systems indicated that LPs with low molecular weights could form LRWs with only a small amount of water, but LPs with high molecular weights could not form LRWs, regardless of the water concentration. The solubility of lecithin in LPs was higher for low molecular weight LPs, thus possibly affecting the formation of LRWs. The zero-shear viscosity and relaxation time of LRWs initially increased with increasing water concentration, and then decreased. The water concentration providing the maximum value was dependent on the molecular weight of the LP, whereas the maximum amount and length of the LRWs were independent of the water concentration. Our results indicate that the molecular weight of LP affects the ease of formation and the viscoelasticity of LRWs.


Assuntos
Lecitinas/química , Parafina/química , Físico-Química , Micelas , Reologia
8.
Chem Pharm Bull (Tokyo) ; 69(11): 1083-1087, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34719590

RESUMO

Our aim was to determine the surface free energy (SFE) of semi-solid dosage forms (SSDFs) by establishing a reproducible method for measuring the contact angle of liquids to SSDFs. Four SSDFs were used: petrolatum, an oil/water (O/W) and a water/oil (W/O) cream, and an alcohol-based gel. The SSDFs were evenly spread on a glass slide, and the change in contact angle over time was measured by dropping water, glycerol, diiodomethane and n-hexadecane as the test liquids. Depending on the combination of test liquid and SSDF, the contact angle was either constant or decreased in an exponential manner. Contact angles may have decreased in an exponential manner because the reaction between the test liquid and the SSDF altered the interfacial tension between the two phases and changed the surface tension of the test liquid and the SFE of the SSDF. The contact angle of the test liquid to the SSDF could be determined reproducibly using the initial contact angle immediately after dropping the liquid on the SSDF as the contact angle before reaction. Using the obtained contact angles and the Owens-Wendt-Rabel-Kaelble equation, we calculated the SFE and its component for the SSDFs tested and found that the results reflect the physicochemical properties of SSDFs. Furthermore, the work of adhesion (WA) of the SSDF to Yucatan micropig skin was calculated using the SFE for the SSDFs. Interestingly, the WA values for all SSDFs tested were comparable.


Assuntos
Vaselina/química , Administração Tópica , Animais , Composição de Medicamentos , Glicerol/química , Humanos , Vaselina/administração & dosagem , Transição de Fase , Pele , Tensão Superficial , Suínos , Termodinâmica , Molhabilidade
9.
J Clin Periodontol ; 48(10): 1367-1378, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34250613

RESUMO

AIM: Non-alcoholic steatohepatitis (NASH) is a critical liver disease showing potential progression to liver cirrhosis/cancer. Previously, we had reported that odontogenic infection of Porphyromonas gingivalis (P. gingivalis), a major periodontal pathogen, exacerbates fibrosis in NASH through the production of fibrosis mediators such as transforming growth factor-ß1 (TGF-ß1) and galectin-3. In this study, we determined the effects of therapeutic interventions using antibiotics on NASH progression induced by P. gingivalis odontogenic infection. MATERIALS AND METHODS: To eliminate P. gingivalis infection, the macrolide antibiotic [azithromycin (AZM)] was applied locally and/or systemically to a high-fat-diet-induced NASH mouse model with P. gingivalis odontogenic infection. After treatment with AZM, liver and periodontal tissues were analysed with focus on inflammation markers such as tumour necrosis factor-α (TNF-α)/Tnf-α and interleukin-1ß (IL-1ß)/Il-1ß, and fibrosis markers such as galectin-3, phosphorylated Smad2 (pSmad2; key signalling molecule of TGF-ß1), and the number of hepatic crown-like structures (hCLSs). Further, Non-alcoholic Fatty Liver Disease Activity Score (NAS), a common histological scoring system, and fibrosis area were evaluated. RESULTS: P. gingivalis odontogenic infection significantly increased the expression of Tnf-α, Il-1ß, galectin-3, and pSmad2, the number of hCLSs, and NAS score, whereas the elimination of P. gingivalis odontogenic infection, especially local with or without systemic application, significantly inhibited them. CONCLUSION: This study suggests that elimination of P. gingivalis odontogenic infection inhibited NASH progression induced by the infection.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Inflamação , Cirrose Hepática , Camundongos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Porphyromonas gingivalis
10.
J Gen Virol ; 102(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33843575

RESUMO

Human adenoviruses (Ads), common pathogens that cause upper respiratory and gastrointestinal infections, are blocked by neutralizing antibodies (nAbs). However, Ads are not fully eliminated even in hosts with nAbs. In this study, we assessed the infectivity of progeny Ad serotype 5 (Ad5) in the presence of nAb. The infectivity of Ad5 was evaluated according to the expression of the Ad genome and reporter gene. Infection by wild-type Ad5 and Ad5 vector continued to increase until 3 days after infection even in the presence of nAb. We established an assay for determining the infection levels of progeny Ad5 using a sorting system with magnetic beads and observed little difference in progeny Ad5 counts in the presence and absence of nAb 1 day after infection. Moreover, progeny Ad5 in the presence of nAb more effectively infected coxsackievirus and adenovirus receptor (CAR)-positive cells than CAR-negative cells. We investigated the function of fiber proteins, which are the binding partners of CAR, during secondary infection, observing that fibre proteins spread from infected cells to adjacent cells in a CAR-dependent manner. In conclusion, this study revealed that progeny Ad5 could infect cells even in the presence of nAb, differing from the common features of the Ad5 infection cycle. Our findings may be useful for developing new therapeutic agents against Ad infection.


Assuntos
Infecções por Adenovirus Humanos/virologia , Adenovírus Humanos/patogenicidade , Anticorpos Neutralizantes/imunologia , Virulência/imunologia , Genes Reporter , Vetores Genéticos , Células HEK293 , Humanos
11.
Chem Pharm Bull (Tokyo) ; 68(12): 1178-1183, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33268650

RESUMO

Hydrophobically modified hydroxypropyl methylcellulose (HM-HPMC), a polymer in which a small amount of HPMC is stearoxyl substituted, was used as an emulsifier of emulsion-type lotion. A high-pressure homogenizer (microfluidizer) was used. The viscosity of the 1% HM-HPMC aqueous gel decreased after passing through the microfluidizer from 5.5 to 2.7 Pa·s. When liquid paraffin (LP) was used as the oil phase, a stable emulsion was obtained with an LP ratio of 1-40%. The apparent viscosity decreased with LP ratios up to 20%, and then increased with increasing LP concentration. The emulsions with an LP ratio <20% presented a pseudo-viscous flow, similar to that of the diluted polymer solution. HM-HPMC likely adsorbed onto the oil with a stearoxyl group; thus, the interaction between the stearoxyl group, which explained the high viscosity of HM-HPMC, decreased, reducing the viscosity of the emulsion. The LP ratio was 40%, and the emulsion presented a plastic flow, which is typical of concentrated emulsions. The size of the droplet in the emulsion was approximately 1 µm regardless of the LP ratio. When low-viscosity LPs or monoester-type oils such as isopropyl myristate were used, some of the emulsions presented creaming. An emulsion using HM-HPMC as an emulsifier and an appropriate oil homogenized with a microfluidizer is stable, has low viscosity, and can be easily spread on skin.


Assuntos
Emulsificantes/química , Derivados da Hipromelose/química , Interações Hidrofóbicas e Hidrofílicas , Óleo Mineral/química , Estrutura Molecular , Tamanho da Partícula , Pressão , Propriedades de Superfície , Viscosidade
12.
Yakugaku Zasshi ; 140(3): 435-441, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32115566

RESUMO

Hydrophobically-modified hydroxypropylmethylcellulose (HM-HPMC) is a thickener with a long hydrophobic alkyl side chain. In this study, we investigated the gelation ability and rheological properties of a liposome/HM-HPMC mixed solution. The liposome suspension and the HM-HPMC aqueous solution each had low viscosities, but the viscosity increased rapidly when they were mixed. This is thought to be due to the formation of a 3D network structure caused by the hydrophobic group of HM-HPMC penetrating into the liposomal bilayer membrane, crosslinking the liposomes together. This hypothesis was supported by the fact that gelation did not occur when hydroxypropylmethylcellulose without a hydrophobic group was used. The viscosity of the liposome/HM-HPMC mixed solution decreased rapidly when a shear was applied, but immediately returned to the original gel state when the shear was removed, indicating a reversible reaction. When a strong shear is applied, the hydrophobic group of HM-HPMC detaches from the liposome. When the shear is removed, the liposome is again cross-linked by HM-HPMC. From these results, it was revealed that liposome cross-linked gels can be prepared when HM-HPMC is used.


Assuntos
Interações Hidrofóbicas e Hidrofílicas , Derivados da Hipromelose/química , Lipossomos/química , Reologia , Hidrogéis
13.
Sci Rep ; 10(1): 4134, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32139740

RESUMO

Odontogenic infection of Porphyromonas gingivalis (P.g.), a major periodontal pathogen, exacerbates pathological progression of non-alcoholic steatohepatitis (NASH). In this study, we aimed to clarify the detailed mechanism in which P.g. induced hepatic stellate cells (HSCs; key effector cells in liver fibrosis) activation. In the liver of high fat diet-induced NASH mouse model with P.g. odontogenic infection, immunolocalization of P.g. was detected. The number of hepatic crown-like structure, which was macrophage aggregation and related to liver fibrosis, was drastically increased and fibrosis area was also increased through upregulating immunoexpression of Phosphorylated Smad2 (key signaling molecule of TGF-ß1) and Galectin-3. P.g.-secreted trypsin-like enzyme [gingipain; an activator of protease-activated receptor 2 (PAR2)] stimulated HSC proliferation and differentiation through Smad and ERK signaling induced by TGF-ß1 produced from HSCs with P.g.-infection. Further, Galectin-3 produced from HSCs with P.g. infection and P.g.-derived LPS/lipoprotein stimulation stabilized TGFß-receptor II resulting in increasing sensitivity for TGF-ß1, finally leading to HSC differentiation via activating Smad and ERK signaling. In addition to them, hepatocytes (main component cells of liver) contributed to HSC activation through TGF-ß1 and Galectin-3 production in paracrine manner. Collectively, P.g.-odontogenic infection exacerbates fibrosis of NASH by HSC activation through TGF-ß1 and Gal-3 production from HSCs and hepatocytes.


Assuntos
Cirrose Hepática/microbiologia , Cirrose Hepática/patologia , Hepatopatia Gordurosa não Alcoólica/microbiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Porphyromonas gingivalis/patogenicidade , Animais , Western Blotting , Diferenciação Celular/fisiologia , Linhagem Celular , Proliferação de Células/fisiologia , Ensaio de Imunoadsorção Enzimática , Granuloma/metabolismo , Granuloma/microbiologia , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/microbiologia , Hepatócitos/metabolismo , Imuno-Histoquímica , Cirrose Hepática/metabolismo , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
14.
Yakugaku Zasshi ; 139(4): 635-640, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-30930399

RESUMO

In this study, we propose a new technique for evaluating wetting and adhesion of lotions to skin using surface tension measurements, contact angle measurements and calculations based on the Owens-Wendt-Rabel-Kaelble (OWRK) method. Three prescription lotions (Napageln® Lotion 3%, Sumilu® Lotion 3% and Felbinac Lotion 3% ï½¢Rakool」) and two over-the-counter lotions (Feitas® Lotion and Salomethyl® FB Lotion α) were used. Based on the dispersive and polar components of the surface free energy of Yucatan micro pig (YMP) skin, isograms of contact angle (wetting envelope) and adhesion work of the YMP skin surface were constructed. Plotting the surface tension and its polar component of lotions on this isogram revealed that it is possible to predict the wettability and adhesion of lotions to YMP skin. Such diagrams can be easily constructed even using the surface free energy of other types of skin, such as that of humans and hairless mice. This evaluation method may be applicable to other external use medicines.


Assuntos
Adesividade , Química Farmacêutica/métodos , Físico-Química/métodos , Creme para a Pele , Molhabilidade , Animais , Feminino , Previsões , Humanos , Camundongos , Camundongos Pelados , Tensão Superficial , Suínos , Porco Miniatura
15.
J Biol Chem ; 294(13): 4966-4980, 2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30718277

RESUMO

Transforming growth factor (TGF)-ß signaling in humans is stringently regulated to prevent excessive TGF-ß signaling. In tumors, TGF-ß signaling can both negatively and positively regulate tumorigenesis dependent on tumor type, but the reason for these opposite effects is unclear. TGF-ß signaling is mainly mediated via the Smad-dependent pathway, and herein we found that PDZK1-interacting protein 1 (PDZK1IP1) interacts with Smad4. PDZK1IP1 inhibited both the TGF-ß and the bone morphogenetic protein (BMP) pathways without affecting receptor-regulated Smad (R-Smad) phosphorylation. Rather than targeting R-Smad phosphorylation, PDZK1IP1 could interfere with TGF-ß- and BMP-induced R-Smad/Smad4 complex formation. Of note, PDZK1IP1 retained Smad4 in the cytoplasm of TGF-ß-stimulated cells. To pinpoint PDZK1IP1's functional domain, we created several PDZK1IP1 variants and found that its middle region, from Phe40 to Ala49, plays a key role in its Smad4-regulating activity. PDZK1IP1 knockdown enhanced the expression of the TGF-ß target genes Smad7 and prostate transmembrane protein androgen-induced (TMEPAI) upon TGF-ß stimulation. In contrast, PDZK1IP1 overexpression suppressed TGF-ß-induced reporter activities, cell migration, and cell growth inhibition. In a xenograft tumor model in which TGF-ß was previously shown to elicit tumor-promoting effects, PDZK1IP1 gain of function decreased tumor size and increased survival rates. Taken together, these findings indicate that PDZK1IP1 interacts with Smad4 and thereby suppresses the TGF-ß signaling pathway.


Assuntos
Proteínas de Membrana/metabolismo , Neoplasias/metabolismo , Mapas de Interação de Proteínas , Transdução de Sinais , Proteína Smad4/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Humanos , Masculino , Camundongos Endogâmicos BALB C , Fosforilação
16.
Biol Pharm Bull ; 42(2): 295-298, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30504641

RESUMO

Surface free energy (SFE) is an important factor for evaluation of wettability or adhesion. Thus, the SFE of a Yucatan micropig (YMP) skin and a hairless mouse (HM) skin, which are commonly used in skin permeation studies instead of human skin, were compared with the human skin. Contact angles of water and 1-bromo naphthalene to skin were measured and the SFE was calculated using the Owens-Wendt equation. The SFE of the human abdominal skin was 40 mN/m and its polar component σsp was as low as 2 mN/m, which was similar to that of the low sebum skin reported previously. In the case of the YMP skin, σsp was high on the surface but similar to that obtained after the skin was tape-stripped twice. The HM skin showed similar SFE as that of the human skin. When the surfactant was applied on the skin, wiped, and dried, the remaining surfactant increased the SFE in σsp; however, the original SFE was obtained after rinsing with water. The YMP skin and HM skin is similar to the human abdominal skin with a low sebum level. Thus, they are also good skin models for studying wettability or adhesion of a substance.


Assuntos
Fenômenos Fisiológicos da Pele , Pele/metabolismo , Adulto , Fatores Etários , Animais , Feminino , Humanos , Camundongos , Camundongos Pelados , Pessoa de Meia-Idade , Pele/efeitos dos fármacos , Tensão Superficial , Tensoativos/farmacologia , Suínos , Porco Miniatura , Molhabilidade
17.
Biol Pharm Bull ; 42(1): 116-122, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30369530

RESUMO

The emulsion prepared with ß-cyclodextrin as an emulsifier (ßCDE) is considered to be a Pickering emulsion. We examined the characteristics of ßCDEs using captopril (CP) as a model drug, and studied the in vitro skin permeation of CP from ßCDEs through hairless mouse skin. The stability of ßCDE was increased with increasing ßCD concentration and conversely decreased with increasing CP concentration. The yield stress value from the rheological measurement results was suggested to be one of the factors determining the stability of the ßCDE, and ßCDEs with higher yield stress values were more stable. We found that the skin permeability of CP could be improved by using ßCDE with isopropyl myristate as the oil phase and that the flux of CP depended on the free CP concentration in the water phase of ßCDE.


Assuntos
Ciclodextrinas/administração & dosagem , Ciclodextrinas/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Emulsificantes/administração & dosagem , Emulsificantes/metabolismo , Absorção Cutânea/efeitos dos fármacos , Administração Cutânea , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Animais , Captopril/administração & dosagem , Captopril/metabolismo , Camundongos , Camundongos Pelados , Técnicas de Cultura de Órgãos , Absorção Cutânea/fisiologia
18.
Oncotarget ; 9(59): 31516-31530, 2018 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-30140387

RESUMO

N-cadherin is a neural cell adhesion molecule that aberrantly occurs in head and neck cancers to promote cancer cell growth. However, the underlying mechanisms remain unclear. Here we report that N-cadherin increases cancer cell growth by inhibiting apoptosis. Apoptosis eliminates old, unnecessary, and unhealthy cells. However, tumor cells have the ability of avoiding apoptosis that increases cancer cell growth. Recent studies have found that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in tumor cells by reacting with four distinct cell surface receptors: TRAIL-R1 (DR-4), TRAIL-R2 (DR-5), TRAIL-R3 (DcR-1), and TRAIL-R4 (DcR-2). Among these TRAIL receptors, the death receptors DR-4 and DR-5 transmit apoptotic signals owing to the death domain in the intracellular portion. Conversely, the decoy receptors DcR-1 and DcR-2 lack a complete intracellular portion, so neither can transmit apoptotic signals. DcR-1 or DcR-2 overexpression suppresses TRAIL-induced apoptosis. In this study, N-cadherin overexpression increased DcR-2 expression and decreased DR-5 expression. In contrast, knockdown of N-cadherin expression upregulated DR-5 expression and downregulated DcR-2 expression. A significantly positive relationship between N-cadherin and DcR-2 expression was also found in HNSCC specimens. Those specimens with a lower apoptotic index showed a higher expression of N-cadherin and/or DcR-2. In addition, we demonstrated that N-cadherin interacts directly with DcR-2. Notably, DcR-2 induces cancer cell survival through the cleavage of caspases and PARP by activating MAPK/ERK pathway and suppressing NF-kB/ p65 phosphorylation, which has a very important role in resistance to chemotherapy.

19.
Eur J Pharm Sci ; 109: 280-287, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-28821439

RESUMO

We studied the effect that three alcohols, ethanol (EA), propanol (PA), and isopropanol (IPA), have on the skin permeation of p-hydroxy benzoic acid methyl ester (HBM), a model ester-type prodrug. HBM was applied to Yucatan micropig skin in a saturated phosphate buffered solution with or without 10% alcohol, and HBM and related materials in receptor fluid and skin were determined with HPLC. In the absence of alcohol, p-hydroxy benzoic acid (HBA), a metabolite of HBM, permeated the skin the most. The three alcohols enhanced the penetration of HBM at almost the same extent. The addition of 10% EA or PA to the HBM solution led to trans-esterification into the ethyl ester or propyl ester of HBA, and these esters permeated skin as well as HBA and HBM did. In contrast, the addition of 10% IPA promoted very little trans-esterification. Both hydrolysis and trans-esterification in the skin S9 fraction were inhibited by BNPP, an inhibitor of carboxylesterase (CES). Western blot and native PAGE showed the abundant expression of CES in micropig skin. Both hydrolysis and trans-esterification was simultaneously catalyzed by CES during skin permeation. Our data indicate that the alcohol used in dermal drug preparations should be selected not only for its ability to enhance the solubility and permeation of the drug, but also for the effect on metabolism of the drug in the skin.


Assuntos
Álcoois/farmacologia , Parabenos/farmacocinética , Pró-Fármacos/farmacocinética , Absorção Cutânea/efeitos dos fármacos , Pele/efeitos dos fármacos , Animais , Pele/metabolismo , Suínos
20.
J Oleo Sci ; 66(9): 997-1007, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28794316

RESUMO

We report new lecithin reverse wormlike micelles with high viscoelasticity formed using lecithin/polyglycerol fatty acid monoester (PGLFA)/oil systems. In this study, the influence of the amphiphilicity (i.e., hydrophile-lipophile balance, HLB) of PGLFA on the phase behavior and rheological properties of reverse wormlike micelles was investigated in detail. PGLFAs with degrees of polymerization of polyglycerol varying between 6-40 and constituent fatty acids with chains between 6-18 carbon atoms long were used. Partial phase diagrams of the lecithin/PGLFA/n-decane systems indicated that the appropriate PGLFA could change the lecithin/oil solution into a highly viscoelastic solution comprising reverse wormlike micelles. Rheological measurements showed that all systems that formed reverse wormlike micelles exhibited an unusual phenomenon called "shear-thickening". Furthermore, reverse wormlike micelles grew as the PGLFA concentration increased and the zero-shear viscosity (η0) of the solution rapidly increased. Our results indicate that the magnitude of the maximum η0 depends on the degree of polymerization of the constituent polyglycerol in the PGLFA, while the size of the reverse micellar region and the highly viscous region in the phase diagram depends on the HLB value of the PGLFA.


Assuntos
Ésteres/química , Ácidos Graxos/química , Glicerol/química , Lecitinas/química , Óleos/química , Polímeros/química , Fenômenos Químicos , Elasticidade , Interações Hidrofóbicas e Hidrofílicas , Micelas , Polimerização , Reologia , Espalhamento a Baixo Ângulo , Soluções , Viscosidade , Raios X
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