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1.
Int J Mol Sci ; 22(6)2021 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-33804685

RESUMEN

The skin of an organism is affected by various environmental factors and fights against aging stress via mechanical and biochemical responses. Photoaging induced by ultraviolet B (UVB) irradiation is common and is the most vital factor in the senescence phenotype of skin, and so, suppression of UVB stress-induced damage is critical. To lessen the UVB-induced hyperimmune response and hyperpigmentation, we investigated the ameliorative effects of intense pulsed light (IPL) treatment on the photoaged phenotype of skin cells. Normal human epidermal keratinocytes and human epidermal melanocytes were exposed to 20 mJ/cm2 of UVB. After UVB irradiation, the cells were treated with green (525-530 nm) and yellow (585-592 nm) IPL at various time points prior to the harvest step. Subsequently, various signs of excessive immune response, including expression of proinflammatory and melanogenic genes and proteins, cellular oxidative stress level, and antioxidative enzyme activity, were examined. We found that IPL treatment reduced excessive cutaneous immune reactions by suppressing UVB-induced proinflammatory cytokine expression. IPL treatment prevented hyperpigmentation, and combined treatment with green and yellow IPL synergistically attenuated both processes. IPL treatment may exert protective effects against UVB injury in skin cells by attenuating inflammatory cytokine and melanogenic gene overexpression, possibly by reducing intracellular oxidative stress. IPL treatment also preserves antioxidative enzyme activity under UVB irradiation. This study suggests that IPL treatment is a useful strategy against photoaging, and provides evidence supporting clinical approaches with non-invasive light therapy.


Asunto(s)
Hipersensibilidad/etiología , Hipersensibilidad/terapia , Tratamiento de Luz Pulsada Intensa , Trastornos de la Pigmentación/etiología , Trastornos de la Pigmentación/terapia , Rayos Ultravioleta/efectos adversos , Antioxidantes/metabolismo , Biomarcadores , Células Cultivadas , Citocinas/metabolismo , Dermatitis/etiología , Dermatitis/metabolismo , Dermatitis/patología , Humanos , Hipersensibilidad/patología , Melaninas/biosíntesis , Estrés Oxidativo/efectos de la radiación , Fototerapia , Pigmentación/efectos de la radiación , Trastornos de la Pigmentación/metabolismo , Trastornos de la Pigmentación/patología , Especies Reactivas de Oxígeno/metabolismo , Piel/metabolismo , Piel/patología , Piel/efectos de la radiación , Envejecimiento de la Piel/efectos de la radiación
2.
Sci Rep ; 11(1): 2232, 2021 01 26.
Artículo en Inglés | MEDLINE | ID: mdl-33500561

RESUMEN

Airborne fine dust particles (FDPs) have been identified as major toxins in air pollution that threaten human respiratory health. While searching for an anti-FDP reagent, we found that green tea extract (GTE) and fractions rich in flavonol glycosides (FLGs) and crude tea polysaccharides (CTPs) had protective effects against FDP-stimulated cellular damage in the BEAS-2B airway epithelial cell line. The GTE, FLGs, and CTPs significantly increased viability and lowered oxidative stress levels in FDP-treated cells. Combined treatment with GTE, FLGs, and CTPs also exerted synergistic protective effects on cells and attenuated FDP-induced elevations in inflammatory gene expression. Moreover, the green tea components increased the proportion of ciliated cells and upregulated ciliogenesis in the airway in FDP-stimulated BEAS-2B cells. Our findings provide insights into how natural phytochemicals protect the airway and suggest that green tea could be used to reduce FDP-induced airway damage as an ingredient in pharmaceutical, nutraceutical, and also cosmeceutical products.


Asunto(s)
Catequina/uso terapéutico , Extractos Vegetales/uso terapéutico , Polisacáridos/uso terapéutico , Té/química , Antioxidantes/metabolismo , Supervivencia Celular/efectos de los fármacos , Cilios/efectos de los fármacos , Cilios/metabolismo , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos
3.
Exp Dermatol ; 28(11): 1270-1278, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31461579

RESUMEN

Ageing is characterized by the accumulation of chronic and irreversible oxidative damage, chronic inflammation and organ dysfunction. To attenuate these ageing-related changes, various natural phytochemicals are often applied. Trans-communic acid (TCA), an active component of brown pine leaf extract, has antimicrobial and cancer chemopreventive activity and inhibits ultraviolet B (UVB)-induced MMP-1 expression. To determine whether the phytochemical TCA could affect the lifespan of an ageing model, Caenorhabditis elegans prevent ageing-related phenotypes of the skin. Caenorhabditis elegans (C. elegans) wild-type N2 and mutant strains were used in this study to explore the lifespan extension effect of TCA and its mechanism. We estimated lipofuscin accumulation and melanin levels, which are closely associated with skin senescence. Moreover, we explored the mechanism of action associated with ageing attenuation. We performed oxidative stress resistance and thermotolerance assays in C. elegans and surface plasmon resonance analysis of TCA binding with the forkhead box-O3a (FoxO3a) protein. TCA, which is the active component in Korean red pine (Pinus densiflora), attenuated ageing-related changes in skin cells. TCA lowered lipofuscin accumulation in fibroblasts and decreased melanin levels in melanocytes. These protective effects were mediated by activation of the representative longevity gene FoxO3a, which was induced by direct binding with TCA. Interestingly, TCA extended the lifespan of C. elegans, although it did not affect stress resistance, oxidative stress or thermotolerance. These results strongly suggest that TCA prevents the senescent phenotype of model organisms and exhibits beneficial effects on ageing-related skin phenotypes through direct FoxO3a activation.


Asunto(s)
Proteínas de Caenorhabditis elegans/metabolismo , Diterpenos/farmacología , Factores de Transcripción Forkhead/metabolismo , Longevidad/efectos de los fármacos , Animales , Caenorhabditis elegans , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Estudios de Factibilidad , Fibroblastos/efectos de los fármacos , Humanos , Melanocitos/efectos de los fármacos , Fitoterapia , Pinus
4.
Exp Dermatol ; 22(8): 541-6, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23879813

RESUMEN

Overproduction of melanin can lead to medical disorders such as postinflammatory melanoderma and melasma. Therefore, developing antimelanogenic agents is important for both medical and cosmetic purposes. In this report, we demonstrated for the first time that the antidiabetic drug voglibose is a potent antimelanogenic agent. Voglibose is a representative antidiabetic drug possessing inhibitory activity towards human α-glucosidase; it blocked the proper N-glycan modification of tyrosinase, resulting in a dramatic reduction of the tyrosinase protein level by altering its stability and subsequently decreasing melanin production. Acarbose, another antihyperglycaemic drug that has a lower inhibitory effect on human intracellular α-glucosidase compared with voglibose, did not cause any changes in either the N-glycan modification of tyrosinase or the tyrosinase protein level, indicating that voglibose was the most efficient antimelanogenic agent among the widely used antihyperglycaemic agents. Considering that voglibose was originally selected from the valiolamine derivatives in a screen for an oral antidiabetic drug with a strong inhibitory activity towards intestinal α-glucosidase and low cell permeability, we propose an alternative strategy for screening compounds from valiolamine derivatives that show high inhibitory activity towards human intracellular α-glucosidases and high cell permeability, with the goal of obtaining antimelanogenic agents that are effective inside the cells.


Asunto(s)
Inhibidores Enzimáticos/uso terapéutico , Inositol/análogos & derivados , Melanocitos/citología , Melanocitos/efectos de los fármacos , Acarbosa/química , Línea Celular Tumoral , Proliferación Celular , Inhibidores de Glicósido Hidrolasas , Humanos , Inflamación , Inositol/uso terapéutico , Manosidasas , Melaninas/biosíntesis , Microscopía Electrónica de Transmisión , Monofenol Monooxigenasa/metabolismo , Permeabilidad , Polisacáridos/química , Reacción en Cadena en Tiempo Real de la Polimerasa , Piel/efectos de los fármacos
5.
Pigment Cell Melanoma Res ; 25(6): 765-72, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22863119

RESUMEN

Human skin hyperpigmentation disorders occur when the synthesis and/or distribution of melanin increases. The distribution of melanin in the skin is achieved by melanosome transport and transfer. The transport of melanosomes, the organelles where melanin is made, in a melanocyte precedes the transfer of the melanosomes to a keratinocyte. Therefore, hyperpigmentation can be regulated by decreasing melanosome transport. In this study, we found that an extract of Saururus chinensis Baill (ESCB) and one of its components, manassantin B, inhibited melanosome transport in Melan-a melanocytes and normal human melanocytes (NHMs). Manassantin B disturbed melanosome transport by disrupting the interaction between melanophilin and myosin Va. Manassantin B is neither a direct nor an indirect inhibitor of tyrosinase. The total melanin content was not reduced when melanosome transport was inhibited in a Melan-a melanocyte monoculture by manassantin B. Manassantin B decreased melanin content only when Melan-a melanocytes were co-cultured with SP-1 keratinocytes or stimulated by α-MSH. Therefore, we propose that specific inhibitors of melanosome transport, such as manassantin B, are potential candidate or lead compounds for the development of agents to treat undesirable hyperpigmentation of the skin.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Furanos/farmacología , Melanocitos/metabolismo , Melanosomas/metabolismo , Miosina Tipo V/metabolismo , Animales , Transporte Biológico/efectos de los fármacos , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Técnicas de Cocultivo , Furanos/química , Humanos , Queratinocitos/citología , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Antígeno MART-1/metabolismo , Melaninas/metabolismo , Melanocitos/citología , Melanocitos/efectos de los fármacos , Melanosomas/efectos de los fármacos , Melanosomas/enzimología , Ratones , Ratones Endogámicos C57BL , Monofenol Monooxigenasa/metabolismo , Extractos Vegetales/farmacología , Unión Proteica/efectos de los fármacos , Saururaceae/química
6.
Pigment Cell Res ; 18(6): 439-46, 2005 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16280009

RESUMEN

The development of effective skin-lightening agents is an increasingly important area of research aimed at the treatment of hyperpigmentation induced by UV irradiation or by medical conditions such as melasma, postinflammatory melanoderma and solar lentigo. Although some inhibit tyrosinase, identifying and understanding the mechanisms of action of other agents is an important goal if more effective pigmentation inhibitors are to be developed. We present here that an extract of Lepidium apetalum (ELA) decreased UV-induced skin pigmentation in brown guinea pigs and melanogenesis of HM3KO human melanoma cells. Interestingly, ELA did not reduce melanogenesis in HM3KO cells unless they were co-cultivated in keratinocyte-conditioned medium prepared by culturing keratinocytes with ELA. Under these conditions, ELA decreased tyrosinase mRNA and protein expression as well as melanin content via an ELA-mediated increase in keratinocyte IL-6 production which in turn was shown to decrease in the expression Mitf, a transcription factor implicated in tyrosinase gene expression and melanocyte differentiation. The results reveal that ELA may be an effective inhibitor of hyperpigmentation caused by UV irradiation or by pigmented skin disorders through a mechanism involving IL-6-mediated downregulation of Mitf rather than a direct inhibition of tyrosinase activity.


Asunto(s)
Interleucina-6/metabolismo , Lepidium/química , Extractos Vegetales/farmacología , Pigmentación de la Piel/efectos de los fármacos , Animales , Western Blotting , Diferenciación Celular , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Células Cultivadas , Regulación hacia Abajo , Ensayo de Inmunoadsorción Enzimática , Cobayas , Queratinocitos/citología , Queratinocitos/efectos de los fármacos , Queratinocitos/efectos de la radiación , Melaninas/metabolismo , Melanoma/tratamiento farmacológico , Melanoma/etiología , Factor de Transcripción Asociado a Microftalmía/antagonistas & inhibidores , Factor de Transcripción Asociado a Microftalmía/metabolismo , Monofenol Monooxigenasa/genética , Monofenol Monooxigenasa/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Semillas/química , Transducción de Señal , Pigmentación de la Piel/efectos de la radiación , Rayos Ultravioleta
7.
Biochemistry ; 43(50): 15775-84, 2004 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-15595833

RESUMEN

Hck is a member of the Src protein-tyrosine kinase family and is expressed strongly in macrophages, an important HIV target cell. Previous studies have shown that Nef, an HIV-1 accessory protein essential for AIDS progression, binds and activates Hck through its SH3 domain. Structural analysis suggests that Nef forms oligomers in vivo, which may bring multiple Hck molecules into close proximity and promote autophosphorylation. Using bimolecular GFP fluorescence complementation, we show for the first time that Nef oligomerizes in living cells and that the oligomers localize to the plasma membrane. To test the role of Nef oligomerization in Hck activation, we fused Nef to the hormone-binding domain of the estrogen receptor (Nef-ER), allowing us to control its dimerization with 4-hydroxytamoxifen (4-HT). In Rat-2 fibroblasts co-expressing Nef-ER and Hck, 4-HT treatment induced Nef-ER dimer and tetramer formation, leading to Hck kinase activation and cellular transformation. The number of transformed foci observed with Nef-ER plus Hck in the presence of 4-HT was markedly greater than that observed with wild-type Nef plus Hck, suggesting that enforced oligomerization enhances activation of Hck by Nef in vivo. Enhanced transformation correlated with increased Hck/Nef complex formation at the plasma membrane. In complementary experiments, we observed that a Nef mutant defective for Hck SH3 domain binding (Nef-PA) suppressed Hck kinase activation and transformation by the wild-type Hck/Nef complex. This effect correlated with the formation of a ternary complex between wild-type Nef, Nef-PA, and Hck, suggesting that Nef-PA suppresses Hck activation by blocking wild-type Nef oligomerization. Finally, Nef-ER induced Hck activation in a 4-HT-dependent manner in the macrophage precursor cell line TF-1, suggesting that oligomerization is essential for signaling through Hck in a cell background relevant to HIV infection. Together, these data demonstrate that Nef oligomerization is critical to the activation of Hck in vivo, and suggest that inhibitors of oligomerization may suppress Nef signaling through Hck in HIV-infected macrophages, slowing disease progression.


Asunto(s)
Productos del Gen nef/metabolismo , VIH-1 , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Tamoxifeno/análogos & derivados , Familia-src Quinasas/metabolismo , Animales , Membrana Celular/química , Células Cultivadas , Dimerización , Activación Enzimática/efectos de los fármacos , Fibroblastos/química , Fibroblastos/metabolismo , Productos del Gen nef/análisis , Productos del Gen nef/genética , Proteínas Fluorescentes Verdes/análisis , Proteínas Fluorescentes Verdes/genética , VIH-1/metabolismo , Inmunoprecipitación , Proteínas Proto-Oncogénicas c-hck , Ratas , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Tamoxifeno/metabolismo , Tamoxifeno/farmacología , Productos del Gen nef del Virus de la Inmunodeficiencia Humana
8.
J Mol Biol ; 343(5): 1255-68, 2004 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-15491611

RESUMEN

The Nef protein of the primate lentiviruses human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) is essential for high-titer viral replication and acquired immune deficiency syndrome (AIDS) progression. Nef binds to the macrophage-specific Src family member Hck through its SH3 domain, resulting in constitutive kinase activation capable of transforming rodent fibroblasts. Nef-Hck interaction may be essential for M-tropic HIV replication and AIDS pathogenesis, identifying this virus-host protein complex as a rational target for anti-HIV drug discovery. Here, we investigated whether interaction with Hck is a common feature of Nef alleles from different strains of HIV-1. We compared the ability of four different laboratory HIV-1 Nef alleles (SF2, LAI, ELI, and Consensus) to induce Hck activation and transformation in our Rat-2 fibroblast model. While SF2, LAI, and Consensus Nef all bound and activated Hck, ELI Nef failed to bind to the Hck SH3 domain in vitro and did not cooperate with Hck in fibroblast transformation. Molecular modeling identified three residues in the core region of SF2 Nef (Ala83, His116, and Tyr120) which are substituted in ELI with Glu, Asn, and Ile, respectively. Two of these residues (Ala83 and Tyr120) form part of the hydrophobic pocket that contacts Ile 96 in the RT loop of the Hck SH3 domain in the Nef-SH3 crystal structure. Substitution of SF2 Nef Tyr120 with Ile completely abolished Hck recruitment and activation. In a complementary experiment, substitution of ELI Ile120 with Tyr partly restored ELI Nef-induced Hck activation and transformation in Rat-2 cells. Hck activation increased further by substitution of ELI Glu83 with Ala and Asn116 with His, suggestive of a supportive role for these residues in Hck binding. This study provides the first biological evidence that the HIV-1 Nef hydrophobic pocket is critical to Hck recruitment and activation in vivo. Targeting the Nef hydrophobic pocket with a small molecule may be sufficient to disrupt Nef signaling through Hck in HIV-infected macrophages, slowing disease progression.


Asunto(s)
Productos del Gen nef/genética , VIH-1/genética , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Secuencia de Aminoácidos , Productos del Gen nef/metabolismo , Variación Genética , VIH-1/enzimología , VIH-1/metabolismo , Humanos , Datos de Secuencia Molecular , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-hck , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Alineación de Secuencia , Tirosina/metabolismo , Productos del Gen nef del Virus de la Inmunodeficiencia Humana , Familia-src Quinasas/metabolismo
9.
Planta Med ; 70(4): 378-80, 2004 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15095159

RESUMEN

In this report, we have demonstrated that deoxypodophyllotoxin from Anthriscus sylvestris (L.) Hoffm decreases UV-induced skin pigmentation of brown guinea pigs. Deoxypodophyllotoxin (0.05 % in propylene glycol: ethanol: water = 5 : 3:2) was topically applied twice daily for two weeks to dorsal skin of brown guinea pigs that were exposed to UV irradiation using a solar simulator. Visual inspection and Fontana-Masson staining both demonstrated that deoxypodophyllotoxin reduced skin pigmentation and total epidermal melanin when compared to that of vehicle-treated areas, suggesting that deoxypodophyllotoxin maybe applicable to treat hyperpigmentation.


Asunto(s)
Apiaceae , Fármacos Dermatológicos/farmacología , Fitoterapia , Extractos Vegetales/farmacología , Podofilotoxina/análogos & derivados , Podofilotoxina/farmacología , Pigmentación de la Piel/efectos de los fármacos , Administración Cutánea , Animales , Fármacos Dermatológicos/administración & dosificación , Fármacos Dermatológicos/uso terapéutico , Medicamentos Herbarios Chinos , Cobayas , Extractos Vegetales/administración & dosificación , Extractos Vegetales/uso terapéutico , Raíces de Plantas , Podofilotoxina/administración & dosificación , Podofilotoxina/uso terapéutico , Pigmentación de la Piel/efectos de la radiación , Rayos Ultravioleta
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