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1.
Nature ; 582(7813): 511-514, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32581381

RESUMEN

Decrease in processing speed due to increased resistance and capacitance delay is a major obstacle for the down-scaling of electronics1-3. Minimizing the dimensions of interconnects (metal wires that connect different electronic components on a chip) is crucial for the miniaturization of devices. Interconnects are isolated from each other by non-conducting (dielectric) layers. So far, research has mostly focused on decreasing the resistance of scaled interconnects because integration of dielectrics using low-temperature deposition processes compatible with complementary metal-oxide-semiconductors is technically challenging. Interconnect isolation materials must have low relative dielectric constants (κ values), serve as diffusion barriers against the migration of metal into semiconductors, and be thermally, chemically and mechanically stable. Specifically, the International Roadmap for Devices and Systems recommends4 the development of dielectrics with κ values of less than 2 by 2028. Existing low-κ materials (such as silicon oxide derivatives, organic compounds and aerogels) have κ values greater than 2 and poor thermo-mechanical properties5. Here we report three-nanometre-thick amorphous boron nitride films with ultralow κ values of 1.78 and 1.16 (close to that of air, κ = 1) at operation frequencies of 100 kilohertz and 1 megahertz, respectively. The films are mechanically and electrically robust, with a breakdown strength of 7.3 megavolts per centimetre, which exceeds requirements. Cross-sectional imaging reveals that amorphous boron nitride prevents the diffusion of cobalt atoms into silicon under very harsh conditions, in contrast to reference barriers. Our results demonstrate that amorphous boron nitride has excellent low-κ dielectric characteristics for high-performance electronics.

2.
Small ; 20(7): e2308176, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37803430

RESUMEN

The structure of graphene grown in chemical vapor deposition (CVD) is sensitive to the growth condition, particularly the substrate. The conventional growth of high-quality graphene via the Cu-catalyzed cracking of hydrocarbon species has been extensively studied; however, the direct growth on noncatalytic substrates, for practical applications of graphene such as current Si technologies, remains unexplored. In this study, nanocrystalline graphene (nc-G) spirals are produced on noncatalytic substrates by inductively coupled plasma CVD. The enhanced out-of-plane electrical conductivity is achieved by a spiral-driven continuous current pathway from bottom to top layer. Furthermore, some neighboring nc-G spirals exhibit a homogeneous electrical conductance, which is not common for stacked graphene structure. Klein-edge structure developed at the edge of nc-Gs, which can easily form covalent bonding, is thought to be responsible for the uniform conductance of nc-G aggregates. These results have important implications for practical applications of graphene with vertical conductivity realized through spiral structure.

3.
Mar Drugs ; 22(2)2024 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-38393043

RESUMEN

Although melanin protects against ultraviolet radiation, its overproduction causes freckles and senile lentigines. Recently, various biological effects of metabolites derived from marine microorganisms have been highlighted due to their potential for biological and pharmacological applications. In this study, we discovered the anti-melanogenic effect of Bacillus sp. APmarine135 and verified the skin-whitening effect. Fractions of APmarine135 showed the melanin synthesis inhibition effect in B16 melanoma cells, and 2,4,6-triphenyl-1-hexene was identified as an active compound. The melanogenic capacity of 2,4,6-triphenyl-1-hexene (1) was investigated by assessing the intracellular melanin content in B16 cells. Treatment with 5 ppm of 2,4,6-triphenyl-1-hexene (1) for 72 h suppressed the α-melanocyte-stimulating hormone (α-MSH)-induced intracellular melanin increase to the same level as in the untreated control group. Additionally, 2,4,6-triphenyl-1-hexene (1) treatment suppressed the activity of tyrosinase, the rate-limiting enzyme for melanogenesis. Moreover, 2,4,6-triphenyl-1-hexene (1) treatment downregulated tyrosinase, Tyrp-1, and Tyrp-2 expression by inhibiting the microphthalmia-associated transcription factor (MITF). Furthermore, 2,4,6-triphenyl-1-hexene (1) treatment decreased the melanin content in the three-dimensional (3D) human-pigmented epidermis model MelanoDerm and exerted skin-whitening effects. Mechanistically, 2,4,6-triphenyl-1-hexene (1) exerted anti-melanogenic effects by suppressing tyrosinase, Tyrp-1, and Tyrp-2 expression and activities via inhibition of the MITF. Collectively, these findings suggest that 2,4,6-triphenyl-1-hexene (1) is a promising anti-melanogenic agent in the cosmetic industry.


Asunto(s)
Alquenos , Bacillus , Melaninas , Compuestos de Terfenilo , Humanos , Monofenol Monooxigenasa/metabolismo , Bacillus/metabolismo , Rayos Ultravioleta/efectos adversos , Línea Celular Tumoral , Factor de Transcripción Asociado a Microftalmía/metabolismo , alfa-MSH/farmacología
4.
FASEB J ; 35(5): e21349, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33786938

RESUMEN

Mice with a mutation (D244G, DG) in calsequestrin 1 (CASQ1), analogous to a human mutation in CASQ1 associated with a delayed onset human myopathy (vacuolar aggregate myopathy), display a progressive myopathy characterized by decreased activity, decreased ability of fast twitch muscles to generate force and low body weight after one year of age. The DG mutation causes CASQ1 to partially dissociate from the junctional sarcoplasmic reticulum (SR) and accumulate in the endoplasmic reticulum (ER). Decreased junctional CASQ1 reduces SR Ca2+ release. Muscles from older DG mice display ER stress, ER expansion, increased mTOR signaling, inadequate clearance of aggregated proteins by the proteasomes, and elevation of protein aggregates and lysosomes. This study suggests that the myopathy associated with the D244G mutation in CASQ1 is driven by CASQ1 mislocalization, reduced SR Ca2+ release, CASQ1 misfolding/aggregation and ER stress. The subsequent maladaptive increase in protein synthesis and decreased protein aggregate clearance are likely to contribute to disease progression.


Asunto(s)
Proteínas de Unión al Calcio/genética , Calcio/metabolismo , Estrés del Retículo Endoplásmico , Enfermedades por Almacenamiento Lisosomal/patología , Músculo Esquelético/patología , Enfermedades Musculares/patología , Mutación , Retículo Sarcoplasmático/patología , Animales , Calsecuestrina , Enfermedades por Almacenamiento Lisosomal/etiología , Enfermedades por Almacenamiento Lisosomal/metabolismo , Masculino , Ratones , Músculo Esquelético/metabolismo , Enfermedades Musculares/etiología , Enfermedades Musculares/metabolismo , Retículo Sarcoplasmático/metabolismo
6.
Int J Mol Sci ; 23(23)2022 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-36499251

RESUMEN

Excess melanin in skin is known to be the main cause of hyper-pigmentary skin diseases such as freckles and lentigo. This study aimed to evaluate the depigmenting efficacy of an extract from the marine microorganism strain, Streptomyces sp. SNA077. To determine the anti-melanogenic efficacy of SNA077, we assessed the melanin contents of SNA077-treated B16, Melan-a, and MNT-1 cells. We observed the expression of key enzymes in melanogenesis via qRT-PCR and Western blot analyses. We further estimated the skin-whitening effect of SNA077 using a skin-equivalent model. SNA077 dramatically decreased the melanin production of B16 cells, Melan-a, and MNT-1 cells. In B16 cells treated with SNA077, the activity of cellular tyrosinase was clearly inhibited. In addition, the mRNA and protein expression levels of melanogenic genes were suppressed by SNA077 treatment in B16 and MNT-1 cells. Upstream of tyrosinase, the expression levels of phospho-CREB, phospho-p38, PKA activity, cyclic AMP production, and MC1R gene expression were inhibited by SNA077. Finally, SNA077 clearly showed a skin-brightening effect with a reduced melanin content in the skin tissue model. Collectively, our results suggest for the first time that an extract of marine Streptomyces sp. SNA077 could be a novel anti-melanogenic material for skin whitening.


Asunto(s)
Melanoma Experimental , Streptomyces , Animales , Melaninas , Streptomyces/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Línea Celular Tumoral , Monofenol Monooxigenasa/metabolismo , Factor de Transcripción Asociado a Microftalmía/genética , Factor de Transcripción Asociado a Microftalmía/metabolismo , Extractos Vegetales/farmacología , Melanoma Experimental/metabolismo
7.
Mar Drugs ; 19(11)2021 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-34822483

RESUMEN

An ubiquinone derivative, pseudoalteromone A (1), has been isolated from two marine-derived Pseudoalteromonas spp., APmarine002 and ROA-050, and its anti-melanogenesis activity was investigated. The anti-melanogenic capacity of pseudoalteromone A was demonstrated by assessing the intracellular and extracellular melanin content and cellular tyrosinase activity in the B16 cell line, Melan-a mouse melanocyte cell line, and MNT-1 human malignant melanoma cell line. Treatment with pseudoalteromone A (40 µg/mL) for 72 h reduced α-melanocyte-stimulating hormone (α-MSH)-induced intracellular melanin production by up to 44.68% in B16 cells and 38.24% in MNT-1 cells. Notably, pseudoalteromone A induced a concentration-dependent reduction in cellular tyrosinase activity in B16 cell, and Western blot analyses showed that this inhibitory activity was associated with a significant decrease in protein levels of tyrosinase and tyrosinase-related protein 1 (Tyrp-1), suggesting that pseudoalteromone A exerts its anti-melanogenesis activity through effects on melanogenic genes. We further evaluated the skin-whitening effect of pseudoalteromone A in the three-dimensional (3D) pigmented-epidermis model, MelanoDerm, and visualized the 3D distribution of melanin by two-photon excited fluorescence imaging in this human skin equivalent. Collectively, our findings suggest that pseudoalteromone A inhibits tyrosinase activity and expression and that this accounts for its anti-melanogenic effects in melanocytes.


Asunto(s)
Antineoplásicos , Melanocitos , Pseudoalteromonas , Ubiquinona , Animales , Humanos , Antineoplásicos/química , Antineoplásicos/farmacología , Organismos Acuáticos , Línea Celular Tumoral/efectos de los fármacos , Melanocitos/efectos de los fármacos , Monofenol Monooxigenasa/metabolismo , Ubiquinona/química , Ubiquinona/farmacología
8.
J Biol Chem ; 294(1): 379-388, 2019 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-30425097

RESUMEN

Perilipin 2 (PLIN2) is a major lipid droplet (LD)-associated protein that regulates intracellular lipid homeostasis and LD formation. Under lipid-deprived conditions, the LD-unbound (free) form of PLIN2 is eliminated in the cytosol by an as yet unknown ubiquitin (Ub)-proteasome pathway that is associated with the N-terminal or near N-terminal residues of the protein. Here, using HeLa, HEK293T, and HepG2 human cell lines, cycloheximide chase, in vivo ubiquitylation, split-Ub yeast two-hybrid, and chemical cross-linking-based reciprocal co-immunoprecipitation assays, we found that TEB4 (MARCH6), an E3 Ub ligase and recognition component of the Ac/N-end rule pathway, directly targets the N-terminal acetyl moiety of Nα-terminally acetylated PLIN2 for its polyubiquitylation and degradation by the 26S proteasome. We also show that the TEB4-mediated Ac/N-end rule pathway reduces intracellular LD accumulation by degrading PLIN2. Collectively, these findings identify PLIN2 as a substrate of the Ac/N-end rule pathway and indicate a previously unappreciated role of the Ac/N-end rule pathway in LD metabolism.


Asunto(s)
Gotas Lipídicas/metabolismo , Perilipina-2/metabolismo , Proteolisis , Ubiquitinación , Acetilación , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Perilipina-2/genética , Complejo de la Endopetidasa Proteasomal/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Dominios Proteicos , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo
9.
Int J Biometeorol ; 64(4): 571-584, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31907654

RESUMEN

Impacts of climate change (e.g., abnormal growth in plants, early flowering, and shifting vegetation zones) are being detected throughout the world. Urban land use and its resulting microclimates work in conjunction with the impacts of climate change. Among the principal environmental signals that modulate bud flush, only temperature has changed significantly in recent years. Throughout South Korea, abnormal shoots (usually known as lammas shoots) in Korean red pine (Pinus densiflora), which were once a rare phenomenon, have become notably more common in recent years. The phenomenon is prominent in urban site of each local area. These abnormal shoots appear at a higher frequency and grow to longer lengths in Seoul's hotter urban center than in suburban sites and showed a close positive correlation with urban density and a close negative correlation with vegetation cover expressed as NDVI. Differences in temperature among the urban center, urban edge, and suburban greenbelt were significantly correlated with land-use intensity. Korean red pines planted in urban parks at sites in urban centers showed a lower frequency of abnormal shoots, and the length of the shoots was shorter, compared with those at the other urban sites. Furthermore, the phenology of Korean red pines in an urban park with a fountain showed a spatial difference, depending upon the distance from the fountain: pine trees close to the fountain did not produce abnormal shoots, but abnormal shoot growth increased with the distance from the fountain. These results are noteworthy because they are related to the cooling effects of evapotranspiration from vegetated landscapes and evaporation from a water body. From the results of this study, we could confirm that microclimate change due to urbanization accelerates the impacts of climate change on plant phenology. Furthermore, we identified the possibility that judicious land-use planning could contribute to minimizing the adverse effects of climate change.


Asunto(s)
Pinus , Urbanización , Microclima , República de Corea , Seúl
10.
Int J Mol Sci ; 21(5)2020 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-32138354

RESUMEN

Sugars are ubiquitous in organisms and well-known cosmetic ingredients for moisturizing skin with minimal side-effects. Glucose, a simple sugar used as an energy source by living cells, is often used in skin care products. Several reports have demonstrated that sugar and sugar-related compounds have anti-melanogenic effects on melanocytes. However, the underlying molecular mechanism by which glucose inhibits melanin synthesis is unknown, even though glucose is used as a whitening as well as moisturizing ingredient in cosmetics. Herein, we found that glucose significantly reduced the melanin content of α-melanocyte-stimulating hormone (MSH)-stimulated B16 cells and darkly pigmented normal human melanocytes with no signs of cytotoxicity. Furthermore, topical treatment of glucose clearly demonstrated its whitening efficacy through photography, Fontana-Masson (F&M) staining, and multi-photon microscopy in a pigmented 3D human skin model, MelanoDerm. However, glucose did not alter the gene expression or protein levels of major melanogenic proteins in melanocytes. While glucose potently decreased intracellular tyrosinase activity in melanocytes, it did not reduce mushroom tyrosinase activity in a cell-free experimental system. However, glucose was metabolized into lactic acid, which can powerfully suppress tyrosinase activity. Thus, we concluded that glucose indirectly inhibits tyrosinase activity through conversion into lactic acid, explaining its anti-melanogenic effects in melanocytes.


Asunto(s)
Glucosa/farmacología , Melanocitos/metabolismo , Monofenol Monooxigenasa/metabolismo , Animales , Western Blotting , Línea Celular Tumoral , Humanos , Melaninas/metabolismo , Melanocitos/efectos de los fármacos , Ratones , Piel/citología , Piel/metabolismo , alfa-MSH/farmacología
11.
Int J Mol Sci ; 21(9)2020 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-32366052

RESUMEN

The outer epidermal skin is a primary barrier that protects the body from extrinsic factors, such as ultraviolet (UV) radiation, chemicals and pollutants. The complete epithelialization of a wound by keratinocytes is essential for restoring the barrier function of the skin. However, age-related alterations predispose the elderly to impaired wound healing. Therefore, wound-healing efficacy could be also considered as a potent function of an anti-aging reagent. Here, we examine the epidermal wound-healing efficacy of the fourth-generation retinoid, seletinoid G, using HaCaT keratinocytes and skin tissues. We found that seletinoid G promoted the proliferation and migration of keratinocytes in scratch assays and time-lapse imaging. It also increased the gene expression levels of several keratinocyte proliferation-regulating factors. In human skin equivalents, seletinoid G accelerated epidermal wound closure, as assessed using optical coherence tomography (OCT) imaging. Moreover, second harmonic generation (SHG) imaging revealed that seletinoid G recovered the reduced dermal collagen deposition seen in ultraviolet B (UVB)-irradiated human skin equivalents. Taken together, these results indicate that seletinoid G protects the skin barrier by accelerating wound healing in the epidermis and by repairing collagen deficiency in the dermis. Thus, seletinoid G could be a potent anti-aging agent for protecting the skin barrier.


Asunto(s)
Dioxolanos/farmacología , Piranos/farmacología , Línea Celular , Movimiento Celular/efectos de los fármacos , Movimiento Celular/efectos de la radiación , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Dioxolanos/síntesis química , Epidermis/efectos de los fármacos , Epidermis/metabolismo , Epidermis/efectos de la radiación , Humanos , Queratinocitos/efectos de los fármacos , Queratinocitos/efectos de la radiación , Piranos/síntesis química , Piel/efectos de los fármacos , Piel/metabolismo , Tomografía de Coherencia Óptica , Rayos Ultravioleta , Cicatrización de Heridas/efectos de los fármacos , Cicatrización de Heridas/efectos de la radiación
12.
Exp Dermatol ; 28(6): 738-741, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30408247

RESUMEN

Hyperpigmentation is caused by excessive production of melanin in melanocytes. Mannosylerythritol lipids (MELs) are glycolipid biosurfactants that are abundantly produced by yeasts and used commercially in cosmetics. However, the potential depigmenting efficacy of MELs has not been evaluated. In this study, the depigmentary effect of MELs was tested in primary normal human melanocytes (NHMs), α-melanocyte-stimulating hormone (MSH)-stimulated B16 cells (murine melanoma cells) and a human skin equivalent (MelanoDerm) using photography, Fontana-Masson (F&M) staining and two-photon microscopy. Mannosylerythritol lipids significantly decreased the melanin contents in NHMs and α-MSH-stimulated B16 cells. Consistent with these findings, MELs treatment had a clear whitening effect in a human skin equivalent, brightening the tissue colour and reducing the melanin content. The molecular mechanism underlying the anti-melanogenic effect of MELs treatment was examined by real-time PCR and Western blotting. Mechanistically, MELs clearly suppressed the gene expression levels of representative melanogenic enzymes, including tyrosinase, Tyrp-1 and Tyrp-2, by inhibiting the ERK/CREB/MiTF signalling pathway in NHMs. This work demonstrates for the first time that MELs exert whitening effects on human melanocytes and skin equivalent. Thus, we suggest that MELs could be developed as a potent anti-melanogenic agent for effective whitening, beyond their use as a biosurfactant in cosmetics.


Asunto(s)
Glucolípidos/farmacología , Hiperpigmentación/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Melanocitos/efectos de los fármacos , Animales , Línea Celular , Evaluación Preclínica de Medicamentos , Glucolípidos/uso terapéutico , Humanos , Melaninas/biosíntesis , Melanocitos/metabolismo , Ratones , Cultivo Primario de Células
13.
Int J Mol Sci ; 20(22)2019 Nov 12.
Artículo en Inglés | MEDLINE | ID: mdl-31726751

RESUMEN

Rhododenol (RD), a whitening cosmetic ingredient, was withdrawn from the market due to RD-induced leukoderma (RIL). While many attempts have been made to clarify the mechanism underlying RIL, RIL has not been fully understood yet. Indeed, affected subjects showed uneven skin pigmentation, but the features are different from vitiligo, a skin hypopigmentary disorder, alluding to events more complex than simple melanocyte cytotoxicity. Here, we discovered that rhododenol treatment reduced the number of melanocytes in a pigmented 3D human skin model, Melanoderm™, confirming the melanocyte toxicity of RD. Of note, melanocytes that survived in the RD treated tissues exhibited altered morphology, such as extended dendrites and increased cell sizes. Consistently with this, sub-cytotoxic level of RD increased cell size and elongated dendrites in B16 melanoma cells. Morphological changes of B16 cells were further confirmed in the immunocytochemistry of treated cells for actin and tubulin. Even more provoking, RD up-regulated the expression of tyrosinase and TRP1 in the survived B16 cells. Evaluation of mRNA expression of cytoskeletal proteins suggests that RD altered the cytoskeletal dynamic favoring cell size expansion and melanosome maturation. Collectively, these results suggest that RD not only induces cytotoxicity in melanocytes but also can lead to a profound perturbation of melanocyte integrity even at sub-cytotoxic levels.


Asunto(s)
Butanoles/farmacología , Melanocitos , Modelos Biológicos , Vitíligo , Animales , Línea Celular Tumoral , Proteínas del Citoesqueleto/biosíntesis , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica , Humanos , Melanocitos/metabolismo , Melanocitos/patología , Ratones , Monofenol Monooxigenasa/biosíntesis , Tripsina/biosíntesis , Vitíligo/tratamiento farmacológico , Vitíligo/metabolismo , Vitíligo/patología
14.
Korean J Physiol Pharmacol ; 23(2): 113-120, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30820155

RESUMEN

Mannosylerythritol lipids (MELs) are glycolipids and have several pharmacological efficacies. MELs also show skin-moisturizing efficacy through a yet-unknown underlying mechanism. Aquaporin-3 (AQP3) is a membrane protein that contributes to the water homeostasis of the epidermis, and decreased AQP3 expression following ultraviolet (UV)-irradiation of the skin is associated with reduced skin moisture. No previous study has examined whether the skin-moisturizing effect of MELs might act through the modulation of AQP3 expression. Here, we report for the first time that MELs ameliorate the UVA-induced downregulation of AQP3 in cultured human epidermal keratinocytes (HaCaT keratinocytes). Our results revealed that UVA irradiation decreases AQP3 expression at the protein and messenger RNA (mRNA) levels, but that MEL treatment significantly ameliorated these effects. Our mitogen-activated protein kinase inhibitor analysis revealed that phosphorylation of c-Jun N-terminal kinase (JNK), but not extracellular signal-regulated kinase or p38, mediates UVA-induced AQP3 downregulation, and that MEL treatment significantly suppressed the UVA-induced phosphorylation of JNK. To explore a possible mechanism, we tested whether MELs could regulate the expression of peroxidase proliferator-activated receptor gamma (PPAR-γ), which acts as a potent transcription factor for AQP3 expression. Interestingly, UVA irradiation significantly inhibited the mRNA expression of PPAR-γ in HaCaT keratinocytes, whereas a JNK inhibitor and MELs significantly rescued this effect. Taken together, these findings suggest that MELs ameliorate UVA-induced AQP3 downregulation in HaCaT keratinocytes by suppressing JNK activation to block the decrease of PPAR-γ. Collectively, our findings suggest that MELs can be used as a potential ingredient that modulates AQP3 expression to improve skin moisturization following UVA irradiation-induced damage.

15.
Hum Mol Genet ; 25(14): 3042-3054, 2016 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-27270415

RESUMEN

We report an individual who presented with severe neurodevelopmental delay and an intractable infantile-onset seizure disorder. Exome sequencing identified a homozygous single nucleotide change that abolishes a splice donor site in the ARV1 gene (c.294 + 1G > A homozygous). This variant completely prevented splicing in minigene assays, and resulted in exon skipping and an in-frame deletion of 40 amino acids in primary human fibroblasts (NP_073623.1: p.(Lys59_Asn98del). The p.(Lys59_Asn98del) and previously reported p.(Gly189Arg) ARV1 variants were evaluated for protein expression and function. The p.(Gly189Arg) variant partially rescued the temperature-dependent growth defect in arv1Δ yeast, while p.(Lys59-Asn98del) completely failed to rescue at restrictive temperature. In contrast to wild type human ARV1, neither variant expressed detectable levels of protein in mammalian cells. Mice with a neuronal deletion of Arv1 recapitulated the human phenotype, exhibiting seizures and a severe survival defect in adulthood. Our data support ARV1 deficiency as a cause of autosomal recessive epileptic encephalopathy.


Asunto(s)
Proteínas Portadoras/genética , Predisposición Genética a la Enfermedad , Proteínas de la Membrana/genética , Espasmos Infantiles/genética , Exones/genética , Femenino , Genotipo , Humanos , Lactante , Mutación , Linaje , Fenotipo , Sitios de Empalme de ARN/genética , Espasmos Infantiles/fisiopatología
16.
Cell Biol Toxicol ; 34(2): 143-162, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-28815372

RESUMEN

A recent hypothesis suggesting that the pharmacological target TRPV1 (transient receptor potential vanilloid subfamily, member 1) may function as a tumour suppressor, which potentially impacts the development of TRPV1 antagonist therapeutics for a range of conditions. However, little is known about the long-term physiologic effects of TRPV1 blockade in the skin. In vitro and in vivo studies suggested that the potent TRPV1 competitive antagonist AMG-9810 promoted proliferation in N/TERT1 cells (telomerase-immortalised primary human keratinocytes 1) and tumour development in mouse skin that was mediated through EGFR/Akt/mTOR signalling. We attempted to reproduce the reported in vitro and in vivo findings to further explore this hypothesis to understand the underlying mechanism and the risk associated with TRPV1 antagonism in the skin. In vitro proliferation studies using multiple methods and topical application with AMG-9810 and structurally similar TRPV1 antagonists such as SB-705498 and PAC-14028 were performed. Although we confirmed expression of TRPV1 in primary human epidermal keratinocytes (HEKn) and spontaneously immortalised human keratinocytes (HaCaT), we were unable to demonstrate cell proliferation in either cell type or any clear evidence of increased expression of proteins in the EGFR/Akt/mTOR signalling pathway with these molecules. We were also unable to demonstrate skin tumour promotion or underlying molecular mechanisms involved in the EGFR/Akt/mTOR signalling pathway in a single-dose and two-stage carcinogenesis mouse study treated with TRPV1 antagonists. In conclusion, our data suggest that inhibiting the pharmacological function of TRPV1 in skin by specific antagonists has not been considered to be indicative of skin tumour development.


Asunto(s)
Proliferación Celular/efectos de los fármacos , Queratinocitos/efectos de los fármacos , Neoplasias Cutáneas/metabolismo , Canales Catiónicos TRPV/antagonistas & inhibidores , Acrilamidas/toxicidad , Animales , Antracenos/toxicidad , Compuestos Bicíclicos Heterocíclicos con Puentes/toxicidad , Capsaicina/análogos & derivados , Capsaicina/toxicidad , Línea Celular , Supervivencia Celular/efectos de los fármacos , Cocarcinogénesis , Femenino , Humanos , Queratinocitos/metabolismo , Queratinocitos/patología , Ratones , Ratones Pelados , Piperidinas/toxicidad , Cultivo Primario de Células , Piridinas/toxicidad , Pirrolidinas/toxicidad , Riesgo , Neoplasias Cutáneas/patología , Canales Catiónicos TRPV/genética , Urea/análogos & derivados , Urea/toxicidad
17.
Phys Chem Chem Phys ; 20(4): 2914, 2018 01 24.
Artículo en Inglés | MEDLINE | ID: mdl-29303525

RESUMEN

Correction for 'Direct characterization of graphene doping state by in situ photoemission spectroscopy with Ar gas cluster ion beam sputtering' by Dong-Jin Yun et al., Phys. Chem. Chem. Phys., 2018, 20, 615-622.

18.
Phys Chem Chem Phys ; 20(1): 615-622, 2017 12 20.
Artículo en Inglés | MEDLINE | ID: mdl-29227482

RESUMEN

On the basis of an in situ photoemission spectroscopy (PES) system, we propose a novel, direct diagnosis method for the characterization of graphene (Gr) doping states at organic semiconductor (OSC)/electrode interfaces. Our in situ PES system enables ultraviolet/X-ray photoelectron spectroscopy (UPS/XPS) measurements during the OSC growth or removal process. We directly deposit C60 films on three different p-type dopants-gold chloride (AuCl3), (trifluoromethyl-sulfonyl)imide (TFSI), and nitric acid (HNO3). We periodically characterize the chemical/electronic state changes of the C60/Gr structures during their aging processes under ambient conditions. Depositing the OSC on the p-type doped Gr also prevents severe degradation of the electrical properties, with almost negligible transition over one month, while the p-type doped Gr without an OSC changes a lot following one month of aging. Our results indicate that the chemical/electronic structures of the Gr layer are completely reflected in the energy level alignments at the C60/Gr interfaces. Therefore, we strongly believe that the variation of energy level alignments at the OSC/graphene interface is a key standard for determining the doping state of graphene after a certain period of aging.

19.
Biol Pharm Bull ; 40(4): 535-539, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28381809

RESUMEN

Pigmentation reflects skin darkening caused by melanin production, but excessive melanin synthesis may cause problems, such as melasma, solar lentigo, dark spots, and freckles. Considerable effort has been devoted to alleviating these undesired symptoms through the development of safe and effective depigmenting agents. Coumestrol, a plant-derived natural isoflavone with an estrogen-like structure and actions, is known to have anti-aging ability, but its potential depigmenting efficacy has not been evaluated. In the present study, we investigated the effects of coumestrol on melanin synthesis in normal melan-a murine melanocytes. Coumestrol significantly reduced melanin synthesis in a concentration-dependent manner up to a concentration of 25 µM without causing cytotoxicity. It also brightened tissue in an artificial skin model (MelanoDerm) that incorporates both human keratinocytes and melanocytes. Interestingly, although coumestrol did not inhibit tyrosinase activity or transcript level in melan-a cells, it clearly decreased the expression level of tyrosinase protein at a concentration of 25 µM. This coumestrol-induced reduction in tyrosinase protein levels was prevented by pretreatment with the proteasome inhibitor MG-132 or the lysosomal proteolysis inhibitor chloroquine. Collectively, our findings indicate that coumestrol exerts an inhibitory effect on melanin synthesis in melan-a cells, at least in part, through degradation of tyrosinase. These findings suggest that coumestrol is a good candidate for use in depigmentary reagents from a cosmetic and clinical perspective.


Asunto(s)
Cumestrol/farmacología , Regulación hacia Abajo/efectos de los fármacos , Melaninas/antagonistas & inhibidores , Melanocitos/efectos de los fármacos , Monofenol Monooxigenasa/metabolismo , Animales , Línea Celular Transformada , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Inhibidores de Cisteína Proteinasa/farmacología , Regulación hacia Abajo/fisiología , Leupeptinas/farmacología , Melaninas/biosíntesis , Melanocitos/metabolismo , Ratones , Ratones Endogámicos C57BL , Fitoestrógenos/farmacología
20.
Mol Cell ; 35(6): 806-17, 2009 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-19782030

RESUMEN

To unravel the roles of LXRs in inflammation and immunity, we examined the function of LXRs in development of IFN-gamma-mediated inflammation using cultured rat brain astrocytes. LXR ligands inhibit neither STAT1 phosphorylation nor STAT1 translocation to the nucleus but, rather, inhibit STAT1 binding to promoters and the expression of IRF1, TNFalpha, and IL-6, downstream effectors of STAT1 action. Immunoprecipitation data revealed that LXRbeta formed a trimer with PIAS1-pSTAT1, whereas LXRalpha formed a trimer with HDAC4-pSTAT1, mediated by direct ligand binding to the LXR proteins. In line with the fact that both PIAS1 and HDAC4 belong to the SUMO E3 ligase family, LXRbeta and LXRalpha were SUMO-conjugated by PIAS1 or HDAC4, respectively, and SUMOylation was blocked by transient transfection of appropriate individual siRNAs, reversing LXR-induced suppression of IRF1 and TNFalpha expression. Together, our data show that SUMOylation is required for the suppression of STAT1-dependent inflammatory responses by LXRs in IFN-gamma-stimulated brain astrocytes.


Asunto(s)
Astrocitos/metabolismo , Proteínas de Unión al ADN/metabolismo , Mediadores de Inflamación/metabolismo , Inflamación/metabolismo , Interferón gamma/metabolismo , Procesamiento Proteico-Postraduccional , Receptores Citoplasmáticos y Nucleares/metabolismo , Factor de Transcripción STAT1/metabolismo , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/metabolismo , Transporte Activo de Núcleo Celular , Animales , Animales Recién Nacidos , Sitios de Unión , Células Cultivadas , Proteínas de Unión al ADN/genética , Histona Desacetilasas/metabolismo , Inflamación/genética , Inflamación/prevención & control , Factor 1 Regulador del Interferón/metabolismo , Interleucina-6/metabolismo , Ligandos , Receptores X del Hígado , Receptores Nucleares Huérfanos , Fosforilación , Regiones Promotoras Genéticas , Proteínas Inhibidoras de STAT Activados/metabolismo , Interferencia de ARN , Ratas , Ratas Sprague-Dawley , Receptores Citoplasmáticos y Nucleares/genética , Factor de Transcripción STAT1/genética , Transducción de Señal , Transfección , Factor de Necrosis Tumoral alfa/metabolismo
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