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1.
Sci Rep ; 10(1): 4967, 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32188912

RESUMO

Aging is associated with increased prevalence of skeletal and cardiac muscle disorders, such as sarcopenia and cardiac infarction. In this study, we constructed a compendium of purified ginsenoside compounds from Panax ginseng C.A. Meyer, which is a traditional Korean medicinal plant used to treat for muscle weakness. Skeletal muscle progenitor cell-based screening identified three compounds that enhance cell viability, of which 20(R)-ginsenoside Rh2 showed the most robust response. 20(R)-ginsenoside Rh2 increased viability in myoblasts and cardiomyocytes, but not fibroblasts or disease-related cells. The cellular mechanism was identified as downregulation of cyclin-dependent kinase inhibitor 1B (p27Kip1) via upregulation of Akt1/PKB phosphorylation at serine 473, with the orientation of the 20 carbon epimer being crucially important for biological activity. In zebrafish and mammalian models, 20(R)-ginsenoside Rh2 enhanced muscle cell proliferation and accelerated recovery from degeneration. Thus, we have identified 20(R)-ginsenoside Rh2 as a p27Kip1 inhibitor that may be developed as a natural therapeutic for muscle degeneration.

2.
Elife ; 92020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32014112

RESUMO

Cyclic AMP (cAMP) is involved in many biological processes but little is known regarding its role in shaping immunity. Here we show that cAMP-PKA-CREB signaling (a pattern recognition receptor [PRR]-independent mechanism) regulates conventional type-2 Dendritic Cells (cDC2s) in mice and reprograms their Th17-inducing properties via repression of IRF4 and KLF4, transcription factors essential for cDC2-mediated Th2 induction. In mice, genetic loss of IRF4 phenocopies the effects of cAMP on Th17 induction and restoration of IRF4 prevents the cAMP effect. Moreover, curdlan, a PRR-dependent microbial product, activates CREB and represses IRF4 and KLF4, resulting in a pro-Th17 phenotype of cDC2s. These in vitro and in vivo results define a novel signaling pathway by which cDC2s display plasticity and provide a new molecular basis for the classification of novel cDC2 and cDC17 subsets. The findings also reveal that repressing IRF4 and KLF4 pathway can be harnessed for immuno-regulation.

3.
PLoS One ; 14(8): e0221721, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31449546

RESUMO

BACKGROUND: A20 protein has ubiquitin-editing activities and acts as a key regulator of inflammation and immunity. Previously, our group showed that A20 promotes tumor metastasis through multi-monoubiquitylation of SNAIL1 in basal-like breast cancer. Here, we investigated survival outcomes in patients with breast cancer according to A20 expression. PATIENTS AND METHODS: We retrospectively collected tumor samples from patients with breast cancer. Immunohistochemistry (IHC) with an A20-specific antibody was performed, and survival outcomes were analyzed. RESULTS: A20 expression was evaluated in 442 patients. High A20 expression was associated with advanced anatomical stage and young age. High A20 expression showed significantly inferior recurrence-free-survival and overall-survival (P<0.001 and P<0.001, respectively). Multivariate analysis showed that A20 was an independent prognostic marker for RFS (HRs: 2.324, 95% CIs: 1.446-3.736) and OS (HRs: 2.629, 95% CIs: 1.585-4.361). In human epidermal growth factor receptor 2 (HER2)-positive and triple negative breast cancer (TNBC) subtypes, high A20 levels were associated with poor OS. CONCLUSION: We found that A20 expression is a poor prognostic marker in breast cancer. The prognostic impact of A20 was pronounced in aggressive tumors, such as HER2-positive and TNBC subtypes. Our findings suggested that A20 may be a valuable target in patients with aggressive breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalos de Confiança , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/patologia , Prognóstico , Modelos de Riscos Proporcionais , Análise de Sobrevida , Adulto Jovem
4.
ACS Appl Mater Interfaces ; 11(33): 30154-30162, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31353888

RESUMO

Here, we propose a simple approach for the design of highly porous multicomponent heterostructures by infiltration of block-co-polymer templates with inorganic precursors in swelling solvents followed by gas-phase sequential infiltration synthesis and thermal annealing. This approach can prepare conformal coatings, free-standing membranes, and powders consisting of uniformly sized metal or metal oxide nanoparticles (NPs) well dispersed in a porous oxide matrix. We employed this new, versatile synthetic concept to synthesize catalytically active heterostructures of uniformly dispersed ∼4.3 nm PdO nanoparticles accessible through three-dimensional pore networks of the alumina support. Importantly, such materials reveal high resistance against sintering at 800 °C, even at relatively high loadings of NPs (∼10 wt %). At the same time, such heterostructures enable high mass transport due to highly interconnected nature of the pores. The surface of synthesized nanoparticles in the porous matrix is highly accessible, which enables their good catalytic performance in methane and carbon monoxide oxidation. In addition, we demonstrate that this approach can be utilized to synthesize heterostructures consisting of different types of NPs on a highly porous support. Our results show that swelling-based infiltration provides a promising route toward the robust and scalable synthesis of multicomponent structures.

5.
ACS Appl Mater Interfaces ; 11(32): 28699-28719, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31339695

RESUMO

A rapid increase in the number of antibiotic-resistant bacteria urgently requires the development of new more effective yet safe materials to fight infection. Herein, we uncovered the contribution of different metal nanoparticles (NPs) (Pt, Fe, and their combination) homogeneously distributed over the surface of nanostructured TiCaPCON films in the total antibacterial activity toward eight types of clinically isolated bacterial strains (Escherichia coli K261, Klebsiella pneumoniae B1079k/17-3, Acinetobacter baumannii B1280A/17, Staphylococcus aureus no. 839, Staphylococcus epidermidis i5189-1, Enterococcus faecium Ya-235: VanA, E. faecium I-237: VanA, and E. coli U20) taking into account various factors that can affect bacterial mechanisms: surface chemistry and phase composition, wettability, ion release, generation of reactive oxygen species (ROS), potential difference and polarity change between NPs and the surrounding matrix, formation of microgalvanic couples on the sample surfaces, and contribution of a passive oxide layer, formed on the surface of films, to general kinetics of the NP dissolution. The results indicated that metal ion implantation and subsequent annealing significantly changed the chemistry of the TiCaPCON film surface. This, in turn, greatly affected the shedding of ions, ROS formation, potential difference between film components, and antibacterial activity. The presence of NPs was critical for ROS generation under UV or daylight irradiation. By eliminating the potential contribution of ions and ROS, we have shown that bacteria can be killed using direct microgalvanic interactions. The possibility of charge redistribution at the interfaces between Pt NPs and TiO2 (anatase and rutile), TiC, TiN, and TiCN components was demonstrated using density functional theory calculations. The TiCaPCON-supported Pt and Fe NPs were not toxic for lymphocytes and had no effect on the ability of lymphocytes to activate in response to a mitogen. This study provides new insights into understanding and designing of antibacterial yet biologically safe surfaces.


Assuntos
Antibacterianos , Bactérias/crescimento & desenvolvimento , Ferro , Nanopartículas Metálicas/química , Platina , Antibacterianos/química , Antibacterianos/farmacologia , Humanos , Ferro/química , Ferro/farmacologia , Linfócitos/metabolismo , Teste de Materiais , Platina/química , Platina/farmacologia
6.
Artif Intell Med ; 94: 110-116, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30871677

RESUMO

INTRODUCTION: Visual field testing via standard automated perimetry (SAP) is a commonly used glaucoma diagnosis method. Applying machine learning techniques to the visual field test results, a valid clinical diagnosis of glaucoma solely based on the SAP data is provided. In order to reflect structural-functional patterns of glaucoma on the automated diagnostic models, we propose composite variables derived from anatomically grouped visual field clusters to improve the prediction performance. A set of machine learning-based diagnostic models are designed that implement different input data manipulation, dimensionality reduction, and classification methods. METHODS: Visual field testing data of 375 healthy and 257 glaucomatous eyes were used to build the diagnostic models. Three kinds of composite variables derived from the Garway-Heath map and the glaucoma hemifield test (GHT) sector map were included in the input variables in addition to the 52 SAP visual filed locations. Dimensionality reduction was conducted to select important variables so as to alleviate high-dimensionality problems. To validate the proposed methods, we applied four classifiers-linear discriminant analysis, naïve Bayes classifier, support vector machines, and artificial neural networks-and four dimensionality reduction methods-Pearson correlation coefficient-based variable selection, Markov blanket variable selection, the minimum redundancy maximum relevance algorithm, and principal component analysis- and compared their classification performances. RESULTS: For all tested combinations, the classification performance improved when the proposed composite variables and dimensionality reduction techniques were implemented. The combination of total deviation values, the GHT sector map, support vector machines, and Markov blanket variable selection obtains the best performance: an area under the receiver operating characteristic curve (AUC) of 0.912. CONCLUSION: A glaucoma diagnosis model giving an AUC of 0.912 was constructed by applying machine learning techniques to SAP data. The results show that dimensionality reduction not only reduces dimensions of the input space but also enhances the classification performance. The variable selection results show that the proposed composite variables from visual field clustering play a key role in the diagnosis model.


Assuntos
Glaucoma/diagnóstico , Aprendizado de Máquina , Testes de Campo Visual , Adulto , Automação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
7.
Sci Rep ; 9(1): 493, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30679508

RESUMO

Obesity is a medical condition that impacts on all levels of society and causes numerous comorbidities, such as diabetes, cardiovascular disease, and cancer. We assessed the suitability of targeting enolase, a glycolysis pathway enzyme with multiple, secondary functions in cells, to treat obesity. Treating adipocytes with ENOblock, a novel modulator of these secondary 'moonlighting' functions of enolase, suppressed the adipogenic program and induced mitochondrial uncoupling. Obese animals treated with ENOblock showed a reduction in body weight and increased core body temperature. Metabolic and inflammatory parameters were improved in the liver, adipose tissue and hippocampus. The mechanism of ENOblock was identified as transcriptional repression of master regulators of lipid homeostasis (Srebp-1a and Srebp-1c), gluconeogenesis (Pck-1) and inflammation (Tnf-α and Il-6). ENOblock treatment also reduced body weight gain, lowered cumulative food intake and increased fecal lipid content in mice fed a high fat diet. Our results support the further drug development of ENOblock as a therapeutic for obesity and suggest enolase as a new target for this disorder.

8.
Langmuir ; 35(3): 796-803, 2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30614710

RESUMO

Infiltration of the polymer templates with inorganic precursors using the selective vapor-phase infiltration approach, or sequential infiltration synthesis (SIS), allows the design of materials with advanced properties. Swelling of the block co-polymer (BCP) templates enables the additional control of the structure, porosity, and thickness of the composite or inorganic materials. Here, we use the highly precise quartz crystal microbalance (QCM) technique to investigate quantitatively the effect of the micelle opening by swelling and inorganic precursor infiltrating on the evolution of porosity in amphiphilic BCPs. We show that swelling of the polystyrene- block-poly-4-vinyl pyridine (PS- b-P4VP) BCP in ethanol at 75 °C occurs rapidly and results in a stable polymer structure in 30 min. By using an alumina model system, we found that swelling enables access to all available polar domains of the PS- b-P4VP film leading to an increase in the SIS-infiltrated alumina mass as compared to the nonswelled BCP layer. Our results demonstrate that swelling of the 110 nm thick BCP template results in the formation of 192 nm thick alumina films with 2 times larger alumina mass and 4 times larger effective pore volume than in case of the nonswelled sample. In the case of the thicker polymer template, the difference due to swelling becomes even more substantial because the fraction of accessible polymer is increased much more than in thin films. Our findings provide important insights into the mechanism of the infiltration of the inorganic precursors into swelled and nonswelled, spin-coated BCP templates enabling the design of highly porous thick ceramic films by SIS.

9.
Stem Cells ; 37(3): 368-381, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30444564

RESUMO

Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into mature cells of various cell types. Although the differentiation process of MSCs requires lineage-specific transcription factors, the exact molecular mechanism that determines MSCs differentiation is not clearly addressed. Here, we demonstrate a Smad4-Taz axis as a new intrinsic regulator for adipo-osteogenic differentiation of MSCs and show that this function of Smad4 is independent of the transforming growth factor-ß signal. Smad4 directly bound to the Taz protein and facilitated nuclear localization of Taz through its nuclear localization signal. Nuclear retention of Taz by direct binding to Smad4 increased expression of osteogenic genes through enhancing Taz-runt-related transcription factor 2 (Runx2) interactions in the C3H10T1/2 MSC cell line and preosteoblastic MC3T3-E1 cells, whereas it suppressed expression of adipogenic genes through promoting Taz-peroxisome proliferator-activated receptor-γ (PPARγ) interaction in C3H10T1/2 and preadipogenic 3T3-L1 cells. A reciprocal role of the Smad4 in osteogenic and adipogenic differentiation was also observed in human adipose tissue-derived stem cells (hASCs). Consequently, Smad4 depletion in C3H10T1/2 and hASCs reduced nuclear retention of Taz and thus caused the decreased interaction with Runx2 or PPARγ, resulting in delayed osteogenesis or enhanced adipogenesis of the MSC. Therefore, these findings provide insight into a novel function of Smad4 to regulate the balance of MSC lineage commitment through reciprocal targeting of the Taz protein in osteogenic and adipogenic differentiation pathways. Stem Cells 2019;37:368-381.


Assuntos
Adipogenia , Células-Tronco Mesenquimais/metabolismo , Osteogênese , Transdução de Sinais , Proteína Smad4/metabolismo , Transativadores/metabolismo , Animais , Diferenciação Celular , Linhagem Celular , Humanos , Células-Tronco Mesenquimais/citologia , Camundongos , Proteína Smad4/genética , Transativadores/genética
10.
Micromachines (Basel) ; 9(4)2018 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-30424102

RESUMO

Recent advances in graphene and other two-dimensional (2D) material synthesis and characterization have led to their use in emerging technologies, including flexible electronics. However, a major challenge is electrical contact stability, especially under mechanical straining or dynamic loading, which can be important for 2D material use in microelectromechanical systems. In this letter, we investigate the stability of dynamic electrical contacts at a graphene/metal interface using atomic force microscopy (AFM), under static conditions with variable normal loads and under sliding conditions with variable speeds. Our results demonstrate that contact resistance depends on the nature of the graphene support, specifically whether the graphene is free-standing or supported by a substrate, as well as on the contact load and sliding velocity. The results of the dynamic AFM experiments are corroborated by simulations, which show that the presence of a stiff substrate, increased load, and reduced sliding velocity lead to a more stable low-resistance contact.

11.
Nanotechnology ; 29(49): 495703, 2018 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-30211698

RESUMO

Inorganic nanoporous materials with highly accessible pores are of great interest for the design of efficient catalytic, purification and detection systems. Limited access to the pores is a common problem associated with traditional approaches for the synthesis of porous materials, affecting the functionality of the low-density structure. Recently, infiltration of a nanoporous polymer template with inorganic precursors followed by oxidative annealing was proposed as a new and efficient approach to creating porous inorganic structures with controlled thickness, composition and pore sizes. Here, we report an ultra-high accessibility of the pores in porous films prepared via polymer-swelling-assisted sequential infiltration synthesis (SIS). Using a quartz crystal microbalance technique, we show the increased solvent adsorbing capabilities of highly porous alumina films as a result of high interconnectivity of the pores in such structures. The directionality and highly interconnected nature of the pores are demonstrated in experiments with the partial blocking of pore access by the deposition of a single-layer graphene that is not transparent to solvent. 60% of the pores remain accessible when only 20% of the surface is exposed to solvent. Using humidity detection as an example, we also show that highly porous alumina produced by polymer-swelling-assisted SIS is a promising candidate for sensing applications.

12.
EMBO Rep ; 19(4)2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29487085

RESUMO

Autophagy begins with the formation of autophagosomes, a process that depends on the activity of the serine/threonine kinase ULK1 (hATG1). Although earlier studies indicated that ULK1 activity is regulated by dynamic polyubiquitination, the deubiquitinase involved in the regulation of ULK1 remained unknown. In this study, we demonstrate that ubiquitin-specific protease 20 (USP20) acts as a positive regulator of autophagy initiation through stabilizing ULK1. At basal state, USP20 binds to and stabilizes ULK1 by removing the ubiquitin moiety, thereby interfering with the lysosomal degradation of ULK1. The stabilization of basal ULK1 protein levels is required for the initiation of starvation-induced autophagy, since the depletion of USP20 by RNA interference inhibits LC3 puncta formation, a marker of autophagic flux. At later stages of autophagy, USP20 dissociates from ULK1, resulting in enhanced ULK1 degradation and apoptosis. Taken together, our findings provide the first evidence that USP20 plays a crucial role in autophagy initiation by maintaining the basal expression level of ULK1.


Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Autofagia , Ubiquitina Tiolesterase/metabolismo , Animais , Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Linhagem Celular , Sobrevivência Celular , Expressão Gênica , Células HEK293 , Humanos , Lisossomos/metabolismo , Camundongos , Ligação Proteica , Estabilidade Proteica , Proteólise , Interferência de RNA , RNA Interferente Pequeno/genética , Ubiquitina Tiolesterase/genética , Ubiquitinação
13.
Expert Opin Drug Discov ; 13(4): 307-326, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29421943

RESUMO

INTRODUCTION: Degenerative diseases, such as Alzheimer's disease, heart disease and arthritis cause great suffering and are major socioeconomic burdens. An attractive treatment approach is stem cell transplantation to regenerate damaged or destroyed tissues. However, this can be problematic. For example, donor cells may not functionally integrate into the host tissue. An alternative methodology is to deliver bioactive agents, such as small molecules, directly into the diseased tissue to enhance the regenerative potential of endogenous stem cells. Areas covered: In this review, the authors discuss the necessity of developing these small molecules to treat degenerative diseases and survey progress in their application as therapeutics. They describe both the successes and caveats of developing small molecules that target endogenous stem cells to induce tissue regeneration. This article is based on literature searches which encompass databases for biomedical research and clinical trials. These small molecules are also categorized per their target disease and mechanism of action. Expert opinion: The development of small molecules targeting endogenous stem cells is a high-profile research area. Some compounds have made the successful transition to the clinic. Novel approaches, such as modulating the stem cell niche or targeted delivery to disease sites, should increase the likelihood of future successes in this field.


Assuntos
Regeneração/fisiologia , Transplante de Células-Tronco/métodos , Células-Tronco/citologia , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/terapia , Animais , Artrite/fisiopatologia , Artrite/terapia , Desenho de Fármacos , Cardiopatias/fisiopatologia , Cardiopatias/terapia , Humanos
14.
Elife ; 62017 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-28968219

RESUMO

Rab GTPases, which are involved in intracellular trafficking pathways, have recently been reported to be ubiquitinated. However, the functions of ubiquitinated Rab proteins remain unexplored. Here we show that Rab5 is monoubiquitinated on K116, K140, and K165. Upon co-transfection with ubiquitin, Rab5 exhibited abnormalities in endosomal localization and EGF-induced EGF receptor degradation. Rab5 K140R and K165R mutants restored these abnormalities, whereas K116R did not. We derived structural models of individual monoubiquitinated Rab5 proteins (mUbRab5s) by solution scattering and observed different conformational flexibilities in a site-specific manner. Structural analysis combined with biochemical data revealed that interactions with downstream effectors were impeded in mUbRab5K140, whereas GDP release and GTP loading activities were altered in mUbRab5K165. By contrast, mUbRab5K116 apparently had no effect. We propose a regulatory mechanism of Rab5 where monoubiquitination downregulates effector recruitment and GDP/GTP conversion in a site-specific manner.


Assuntos
Regulação para Baixo , Nucleotídeos de Guanina/metabolismo , Ubiquitinação , Proteínas rab5 de Ligação ao GTP/metabolismo , Linhagem Celular , Análise Mutacional de DNA , Humanos , Hidrólise , Ligação Proteica , Conformação Proteica , Espalhamento a Baixo Ângulo , Proteínas rab5 de Ligação ao GTP/química , Proteínas rab5 de Ligação ao GTP/genética
15.
Materials (Basel) ; 10(9)2017 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-28930189

RESUMO

For optimum production of ultra-high performance concrete (UHPC), the material and microstructural properties of UHPC cured under various heat treatment (HT) conditions are studied. The effects of HT temperature and duration on the hydration reaction, microstructure, and mechanical properties of UHPC are investigated. Increasing HT temperature accelerates both cement hydration and pozzolanic reaction, but the latter is more significantly affected. This accelerated pozzolanic reaction in UHPC clearly enhances compressive strength. However, strength after the HT becomes stable as most of the hydration finishes during the HT period. Particularly, it was concluded that the mechanical benefit of the increased temperature and duration on the 28 day-strength is not noticeable when the HT temperature is above 60 °C (with a 48 h duration) or the HT duration is longer than 12 h (with 90 °C temperature). On the other hand, even with a minimal HT condition such as 1 day at 60 °C or 12 h at 90 °C, outstanding compressive strength of 179 MPa and flexural tensile strength of 49 MPa are achieved at 28 days. Microstructural investigation conducted herein suggests that portlandite content can be a good indicator for the mechanical performance of UHPC regardless of its HT curing conditions. These findings can contribute to reducing manufacturing energy consumption, cost, and environmental impact in the production of UHPC and be helpful for practitioners to better understand the effect of HT on UHPC and optimize its production.

16.
Nat Cell Biol ; 19(10): 1260-1273, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28892081

RESUMO

Although the ubiquitin-editing enzyme A20 is a key player in inflammation and autoimmunity, its role in cancer metastasis remains unknown. Here we show that A20 monoubiquitylates Snail1 at three lysine residues and thereby promotes metastasis of aggressive basal-like breast cancers. A20 is significantly upregulated in human basal-like breast cancers and its expression level is inversely correlated with metastasis-free patient survival. A20 facilitates TGF-ß1-induced epithelial-mesenchymal transition (EMT) of breast cancer cells through multi-monoubiquitylation of Snail1. Monoubiquitylated Snail1 has reduced affinity for glycogen synthase kinase 3ß (GSK3ß), and is thus stabilized in the nucleus through decreased phosphorylation. Knockdown of A20 or overexpression of Snail1 with mutation of the monoubiquitylated lysine residues into arginine abolishes lung metastasis in mouse xenograft and orthotopic breast cancer models, indicating that A20 and monoubiquitylated Snail1 are required for metastasis. Our findings uncover an essential role of the A20-Snail1 axis in TGF-ß1-induced EMT and metastasis of basal-like breast cancers.


Assuntos
Neoplasias da Mama/enzimologia , Movimento Celular , Neoplasias Pulmonares/enzimologia , Fatores de Transcrição da Família Snail/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo , Ubiquitinação , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Movimento Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/metabolismo , Células HEK293 , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/prevenção & controle , Lisina , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/enzimologia , Células-Tronco Neoplásicas/patologia , Fosforilação , Estabilidade Proteica , Interferência de RNA , Transdução de Sinais , Fatores de Transcrição da Família Snail/genética , Fatores de Tempo , Transfecção , Fator de Crescimento Transformador beta1/farmacologia , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/farmacologia , Ubiquitinação/efeitos dos fármacos
17.
Artigo em Inglês | MEDLINE | ID: mdl-28626485

RESUMO

Abnormalities in skin pigmentation can produce disorders such as albinism or melasma. There is a research need to discover novel compounds that safely and effectively regulate pigmentation. To identify novel modulators of pigmentation, we attempted to purify compounds from a bioactive fraction of the Korean medicinal plant Artemisia capillaris Thunberg. The novel compound isofraxidin 7-O-(6'-O-p-coumaroyl)-ß-glucopyranoside (compound 1) was isolated and its pigmentation activity was characterized in mammalian melanocytes. Compound 1 stimulated melanin accumulation and increased tyrosinase activity, which regulates melanin synthesis. Moreover, compound 1 increased the expression of tyrosinase and the key melanogenesis regulator microphthalmia-associated transcription factor (MITF) in melanocytes. Compared to the parent compound, isofraxidin, compound 1 produced greater effects on these pigmentation parameters. To validate compound 1 as a novel hyperpigmentation agent in vivo, we utilized the zebrafish vertebrate model. Zebrafish treated with compound 1 showed higher melanogenesis and increased tyrosinase activity. Compound 1 treated embryos had no developmental defects and displayed normal cardiac function, indicating that this compound enhanced pigmentation without producing toxicity. In summary, our results describe the characterization of novel natural product compound 1 and its bioactivity as a pigmentation enhancer, demonstrating its potential as a therapeutic to treat hypopigmentation disorders.

18.
Int J Technol Assess Health Care ; 33(1): 69-75, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28434410

RESUMO

OBJECTIVES: We conducted a meta-analysis of recently published randomized controlled trials (RCTs) to identify the most effective and safe etanercept dosing regimen and duration of therapy for the treatment of patients with ankylosing spondylitis (AS). METHODS: We systematically reviewed PubMed, Embase, Cochrane Library, and Web of Science databases for RCTs. The proportion of patients attaining 20 percent improvement (according to the Spondyloarthritis International Society response criteria [ASAS 20]) was evaluated as a primary outcome. Secondary outcomes included 50 percent increase in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI 50) used for evaluating efficacy, as well as the BASDAI/Bath Ankylosing Spondylitis Functional Index (BASFI) scores and adverse events. RESULTS: ASAS 20 indicated that the efficacy of etanercept did not differ amongst dosing regimens (25 mg twice-weekly versus 50 mg once-weekly: relative risk [RR], 2.18, 95 percent confidence interval [CI], 1.78-2.67 versus RR, 2.00, 95 percent CI, 1.70-2.37). The ASAS 20 reported subgroup differences among treatment durations of less than 12 weeks (RR, 2.70; 95 percent CI, 2.09-3.49); 12 weeks (RR, 1.74; 95 percent CI, 1.37-2.22); and more than 12 weeks (RR, 2.56; 95 percent CI, 1.88-3.48). Other outcomes included BASDAI, BASDAI 50, and BASFI. Drug safety differed according to the treatment regimen and duration. CONCLUSION: Our meta-analysis found that there was no significant efficacy difference between 50 mg once-weekly and 25 mg twice-weekly dosing for the treatment of AS, and a dosing duration of less than 12 weeks was more effective for treating AS patients.


Assuntos
Antirreumáticos/administração & dosagem , Etanercepte/administração & dosagem , Espondilite Anquilosante/tratamento farmacológico , Humanos , Resultado do Tratamento
19.
Hepatology ; 66(3): 758-771, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28329914

RESUMO

Hepatitis C virus (HCV) alters mitochondrial dynamics associated with persistent viral infection and suppression of innate immunity. Mitochondrial dysfunction is also a pathologic feature of direct-acting antiviral (DAA) treatment. Despite the high efficacy of DAAs, their use in treating patients with chronic hepatitis C in interferon-sparing regimens occasionally produces undesirable side effects such as fatigue, migraine, and other conditions, which may be linked to mitochondrial dysfunction. Here, we show that clinically prescribed DAAs, including sofosbuvir, affect mitochondrial dynamics. To counter these adverse effects, we examined HCV-induced and DAA-induced aberrant mitochondrial dynamics modulated by ginsenoside, which is known to support healthy mitochondrial physiology and the innate immune system. We screened several ginsenoside compounds showing antiviral activity using a robust HCV cell culture system. We investigated the role of ginsenosides in antiviral efficacy, alteration of mitochondrial transmembrane potential, abnormal mitochondrial fission, its upstream signaling, and mitophagic process caused by HCV infection or DAA treatment. Only one of the compounds, ginsenoside Rg3 (G-Rg3), exhibited notable and promising anti-HCV potential. Treatment of HCV-infected cells with G-Rg3 increased HCV core protein-mediated reduction in the expression level of cytosolic p21, required for increasing cyclin-dependent kinase 1 activity, which catalyzes Ser616 phosphorylation of dynamin-related protein 1. The HCV-induced mitophagy, which follows mitochondrial fission, was also rescued by G-Rg3 treatment. CONCLUSION: G-Rg3 inhibits HCV propagation. Its antiviral mechanism involves restoring the HCV-induced dynamin-related protein 1-mediated aberrant mitochondrial fission process, thereby resulting in suppression of persistent HCV infection. (Hepatology 2017;66:758-771).


Assuntos
Ginsenosídeos/farmacologia , Hepacivirus/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Biópsia por Agulha , Western Blotting , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Imunofluorescência , Hepacivirus/fisiologia , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/patologia , Humanos , Imunidade Inata/efeitos dos fármacos , Imuno-Histoquímica , Dinâmica Mitocondrial/fisiologia , Reação em Cadeia da Polimerase em Tempo Real/métodos , Amostragem
20.
Sci Rep ; 7: 44186, 2017 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-28272459

RESUMO

Type 2 diabetes mellitus (T2DM) significantly impacts on human health and patient numbers are predicted to rise. Discovering novel drugs and targets for treating T2DM is a research priority. In this study, we investigated targeting of the glycolysis enzyme, enolase, using the small molecule ENOblock, which binds enolase and modulates its non-glycolytic 'moonlighting' functions. In insulin-responsive cells ENOblock induced enolase nuclear translocation, where this enzyme acts as a transcriptional repressor. In a mammalian model of T2DM, ENOblock treatment reduced hyperglycemia and hyperlipidemia. Liver and kidney tissue of ENOblock-treated mice showed down-regulation of known enolase target genes and reduced enolase enzyme activity. Indicators of secondary diabetic complications, such as tissue apoptosis, inflammatory markers and fibrosis were inhibited by ENOblock treatment. Compared to the well-characterized anti-diabetes drug, rosiglitazone, ENOblock produced greater beneficial effects on lipid homeostasis, fibrosis, inflammatory markers, nephrotoxicity and cardiac hypertrophy. ENOblock treatment was associated with the down-regulation of phosphoenolpyruvate carboxykinase and sterol regulatory element-binding protein-1, which are known to produce anti-diabetic effects. In summary, these findings indicate that ENOblock has potential for therapeutic development to treat T2DM. Previously considered as a 'boring' housekeeping gene, these results also implicate enolase as a novel drug target for T2DM.


Assuntos
Benzamidas/farmacologia , Núcleo Celular/enzimologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fosfopiruvato Hidratase/antagonistas & inibidores , Triazinas/farmacologia , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Núcleo Celular/patologia , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/patologia , Masculino , Camundongos , Células NIH 3T3 , Fosfopiruvato Hidratase/metabolismo
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