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1.
Membranes (Basel) ; 12(5)2022 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-35629779

RESUMO

Common methods for fabricating membrane-based scaffolds for tissue engineering with (hydrophobic) polymers include thermal or liquid-phase inversion, sintering, particle leaching, electrospinning and stereolithography. However, these methods have limitations, such as low resolution and pore interconnectivity and may often require the application of high temperatures and/or toxic porogens, additives or solvents. In this work, we aim to overcome some of these limitations and propose a one-step method to produce large porous membrane-based scaffolds formed by air-water interfacial phase separation using water as a pore-forming agent and casting substrate. Here, we provide proof of concept using poly (trimethylene carbonate), a flexible and biocompatible hydrophobic polymer. Membrane-based scaffolds were prepared by dropwise addition of the polymer solution to water. Upon contact, rapid solvent-non-solvent phase separation took place on the air-water interface, after which the scaffold was cured by UV irradiation. We can tune and control the morphology of these scaffolds, including pore size and porosity, by changing various parameters, including polymer concentration, solvent type and temperature. Importantly, human hepatic stellate cells cultured on these membrane-based scaffolds remained viable and showed no signs of pro-inflammatory stress. These results indicate that the proposed air-water interfacial phase separation represents a versatile method for creating porous membrane-based scaffolds for tissue engineering applications.

2.
Adv Healthc Mater ; 11(13): e2102697, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35362224

RESUMO

Oxygen releasing biomaterials can facilitate the survival of living implants by creating environments with a viable oxygen level. Hydrophobic oxygen generating microparticles (HOGMPs) encapsulated calcium peroxide (CPO) have recently been used in tissue engineering to release physiologically relevant amounts of oxygen for several weeks. However, generating oxygen using CPO is mediated via the generation of toxic levels of hydrogen peroxide (H2 O2 ). The incorporation of antioxidants, such as catalases, can potentially reduce H2 O2 levels. However, the formulation in which catalases can most effectively scavenge H2 O2 within oxygen generating biomaterials has remained unexplored. In this study, three distinct catalase incorporation methods are compared based on their ability to decrease H2 O2 levels. Specifically, catalase is incorporated within HOGMPs, or absorbed onto HOGMPs, or freely laden into the hydrogel entrapping HOGMPs and compared with control without catalase. Supplementation of free catalase in an HOGMP-laden hydrogel significantly decreases H2 O2 levels reflecting a higher cellular viability and metabolic activity of all the groups. An HOGMP/catalase-laden hydrogel precursor solution containing cells is used as an oxygenating bioink allowing improved viability of printed constructs under severe hypoxic conditions. The combination of HOGMPs with a catalase-laden hydrogel has the potential to decrease peroxide toxicity of oxygen generating tissues.


Assuntos
Materiais Biocompatíveis , Bioimpressão , Materiais Biocompatíveis/toxicidade , Bioimpressão/métodos , Catalase , Hidrogéis , Peróxido de Hidrogênio , Oxigênio , Engenharia Tecidual
3.
Trends Biotechnol ; 39(11): 1144-1159, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33602609

RESUMO

Oxygen is essential for the survival, function, and fate of mammalian cells. Oxygen tension controls cellular behaviour via metabolic programming, which in turn controls tissue regeneration, stem cell differentiation, drug metabolism, and numerous pathologies. Thus, oxygen-releasing biomaterials represent a novel and unique strategy to gain control over a variety of in vivo processes. Consequently, numerous oxygen-generating or carrying materials have been developed in recent years, which offer innovative solutions in the field of drug efficiency, regenerative medicine, and engineered living systems. In this review, we discuss the latest trends, highlight current challenges and solutions, and provide a future perspective on the field of oxygen-releasing materials.


Assuntos
Oxigênio , Engenharia Tecidual , Animais , Materiais Biocompatíveis , Diferenciação Celular , Mamíferos , Oxigênio/metabolismo , Medicina Regenerativa
4.
Membranes (Basel) ; 10(10)2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33022962

RESUMO

Despite the increased expenditure of the pharmaceutical industry on research and development, the number of drugs for cardiovascular diseases that reaches the market is decreasing. A major issue is the limited ability of the current in vitro and experimental animal models to accurately mimic human heart disease, which hampers testing of the efficacy of potential cardiac drugs. Moreover, many non-heart-related drugs have severe adverse cardiac effects, which is a major cause of drugs' retraction after approval. A main hurdle of current in vitro models is their inability to mimic the stiffness of in vivo cardiac tissue. For instance, poly(styrene) petri dishes, which are often used in these models, have a Young's modulus in the order of GPa, while the stiffness of healthy human heart tissue is <50 kPa. In pathological conditions, such as scarring and fibrosis, the stiffness of heart tissue is in the >100 kPa range. In this study, we focus on developing new membranes, with a set of properties for mimicry of cardiac tissue stiffness in vitro, based on methacrylate-functionalized macromers and triblock-copolymers of poly(trimethylene carbonate) and poly(ethylene glycol). The new membranes have Young's moduli in the hydrated state ranging from 18 kPa (healthy tissue) to 2.5 MPa (pathological tissue), and are suitable for cell contraction studies using human pluripotent stem-cell-derived cardiomyocytes. The membranes with higher hydrophilicity have low drug adsorption and low Young's moduli and could be suitable for drug screening applications.

5.
Curr Med Chem ; 26(24): 4506-4536, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31119997

RESUMO

Traditionally, natural medicines have been administered as plant extracts, which are composed of a mixture of molecules. The individual molecular species in this mixture may or may not contribute to the overall medicinal effects and some may even oppose the beneficial activity of others. To better control therapeutic effects, studies that characterized specific molecules and describe their individual activity that have been performed over the past decades. These studies appear to underline that natural products are particularly effective as antioxidants and anti-inflammatory agents. In this systematic review we aimed to identify potent anti-inflammatory natural products and relate their efficacy to their chemical structure and physicochemical properties. To identify these compounds, we performed a comprehensive literature search to find those studies, in which a dose-response description and a positive control reference compound was used to benchmark the observed activity. Of the analyzed papers, 7% of initially selected studies met these requirements and were subjected to further analysis. This analysis revealed that most selected natural products indeed appeared to possess anti-inflammatory activities, in particular anti-oxidative properties. In addition, 14% of the natural products outperformed the remaining natural products in all tested assays and are attractive candidates as new anti-inflammatory agents.


Assuntos
Anti-Inflamatórios/química , Produtos Biológicos/química , Animais , Anti-Inflamatórios/uso terapêutico , Produtos Biológicos/uso terapêutico , Cumarínicos/química , Cumarínicos/uso terapêutico , Edema/tratamento farmacológico , Edema/patologia , Plantas Medicinais/química , Plantas Medicinais/metabolismo , Porfirinas/química , Porfirinas/uso terapêutico , Relação Estrutura-Atividade
6.
PLoS One ; 13(6): e0199095, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29902284

RESUMO

Low amounts of human pharmaceuticals in the aquatic environment can affect bacteria, animals and ultimately humans. Here, the environmental consequences of a shift in prescription behavior from prednisolone to berberine was modeled using an environmental decision support system based on four consecutive steps: emission, fate, exposure and effect. This model estimates the relative aquatic and human health impacts of alternative pharmaceutical prescriptions throughout Europe. Since a Defined Daily Dose (DDD) of berberine has yet to be formulated, the environmental impacts of berberine and prednisolone were compared under the assumption of equal DDDs. Subsequently, the relative impact ratio indicates the extent to which the actual DDD of berberine might be higher to still be environmentally preferable over prednisolone. In fact, berberine can be administered at a six times higher dose throughout Europe before its impact on the aquatic environment exceeds that of one prescription of prednisolone. On average, the results for impacts on human health are similar, with the median impact ratio ranging between 5.87 and 22.8 depending on the level of drinking water purification. However, for some regions in Spain, Austria, Baltic States and Finland, berberine can only be considered an environmentally better alternative if it is administered at a lower dose than prednisolone. We conclude that for most regions in Europe it is, up until a certain dose of berberine, beneficial for the aquatic environment and therefore human health to prefer prescription of berberine over prednisolone.


Assuntos
Berberina/toxicidade , Produtos Biológicos/toxicidade , Meio Ambiente , Glucocorticoides/toxicidade , Prednisolona/toxicidade , Organismos Aquáticos/efeitos dos fármacos , Exposição Ambiental/efeitos adversos , Saúde , Humanos
7.
J Neuropathol Exp Neurol ; 76(10): 908-916, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28922850

RESUMO

Insight into processes leading to rupture of intracranial aneurysms (IAs) may identify biomarkers for rupture or lead to management strategies reducing the risk of rupture. We characterized and quantified (ultra)structural differences between unruptured and ruptured aneurysmal walls. Six unruptured and 6 ruptured IA fundi were resected after microsurgical clipping and analyzed by correlative light microscopy for quantitative analysis (proportion of the vessel wall area) and transmission electron microscopy for qualitative ultrastructural analysis. Quantitative analysis revealed extensive internal elastic lamina (IEL) thickening in ruptured IA (36.3% ± 15%), while thin and fragmented IEL were common in unruptured IA (5.6% ± 7.1%). Macrophages were increased in ruptured IA (28.3 ± 24%) versus unruptured IA (2.7% ± 5.5%), as were leukocytes (12.85% ± 10% vs 0%). Vasa vasorum in ruptured but not in unruptured IA contained vast numbers of inflammatory cells and extravasation of these cells into the vessel wall. In conclusion, detection of thickened IEL, leaky vasa vasorum, and heavy inflammation as seen in ruptured IA in comparison to unruptured IA may identify aneurysms at risk of rupture, and management strategies preventing development of vasa vasorum or inflammation may reduce the risk of aneurysmal rupture.


Assuntos
Aneurisma Roto/patologia , Vasos Sanguíneos/patologia , Vasos Sanguíneos/ultraestrutura , Aneurisma Intracraniano/patologia , Técnicas Estereotáxicas , Adulto , Idoso , Endotélio/patologia , Endotélio/ultraestrutura , Feminino , Humanos , Masculino , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Músculo Liso/patologia , Músculo Liso/ultraestrutura , Plasmócitos/patologia , Plasmócitos/ultraestrutura , Adulto Jovem
8.
J Control Release ; 247: 127-133, 2017 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-28065862

RESUMO

Inflammation is a known mediator of adverse ventricular remodeling after myocardial infarction (MI) that may lead to reduction of ejection fraction and subsequent heart failure. Berberine is a isoquinoline quarternary alkaloid from plants that has been associated with anti-inflammatory, anti-oxidative, and cardioprotective properties. Its poor solubility in aqueous buffers and its short half-life in the circulation upon injection, however, have been hampering the extensive usage of this natural product. We hypothesized that encapsulation of berberine into long circulating liposomes could improve its therapeutic availability and efficacy by protecting cardiac function against MI in vivo. Berberine-loaded liposomes were prepared by ethanol injection and characterized. They contained 0.3mg/mL of the drug and were 0.11µm in diameter. Subsequently they were tested for IL-6 secretion inhibition in RAW 264.7 macrophages and for cardiac function protection against adverse remodeling after MI in C57BL/6J mice. In vitro, free berberine significantly inhibited IL-6 secretion (IC50=10.4µM), whereas encapsulated berberine did not as it was not released from the formulation in the time frame of the in vitro study. In vivo, berberine-loaded liposomes significantly preserved the cardiac ejection fraction at day 28 after MI by 64% as compared to control liposomes and free berberine. In conclusion, liposomal encapsulation enhanced the solubility of berberine in buffer and preserves ejection fraction after MI. This shows that delivery of berberine-loaded liposomes significantly improves its therapeutic availability and identifies berberine-loaded liposomes as potential treatment of adverse remodeling after MI.


Assuntos
Anti-Inflamatórios/administração & dosagem , Berberina/administração & dosagem , Cardiotônicos/administração & dosagem , Coração/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Animais , Anti-Inflamatórios/uso terapêutico , Berberina/uso terapêutico , Cardiotônicos/uso terapêutico , Coração/fisiopatologia , Interleucina-6/análise , Lipossomos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/fisiopatologia , Células RAW 264.7 , Remodelação Ventricular/efeitos dos fármacos
9.
Int J Pharm ; 506(1-2): 407-13, 2016 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-27139142

RESUMO

Curcumin, originally used in traditional medicine and as a spice, is one of the most studied and most popular natural products of the past decade. It has been described to be an effective anti-inflammatory and anti-cancer drug and protects against chronic diseases such as rheumatoid arthritis and atherosclerosis. Despite these promising pharmacological properties, curcumin is also very lipophilic, which makes its formulation challenging. Ideally the nanocarrier should additionally also retain the encapsulated curcumin to provide target tissue accumulation. In this study we aimed to tackle this aqueous solubility and carrier retention challenge of curcumin by encapsulating curcumin in different nanoparticles. We successfully loaded LDL (30nm), polymeric micelles (80nm), liposomes (180nm) and Intralipid (280nm) with curcumin. The relative loading capacity was inversely related to the size of the particle. The stability for all formulations was determined in fetal bovine serum over a course of 24h. Although all curcumin-nanoparticles were stable in buffer solution, all leaked more than 70% of curcumin under physiological conditions. Altogether, tested nanoparticles do solve the aqueous insolubility problem of curcumin, however, because of their leaky nature, the challenge of carrier retention remains.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Curcumina/administração & dosagem , Portadores de Fármacos/química , Nanopartículas , Anti-Inflamatórios não Esteroides/química , Química Farmacêutica/métodos , Curcumina/química , Estabilidade de Medicamentos , Emulsões/química , Lipoproteínas LDL/química , Lipossomos , Micelas , Tamanho da Partícula , Fosfolipídeos/química , Polímeros/química , Solubilidade , Óleo de Soja/química
10.
PLoS One ; 11(5): e0155325, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27163931

RESUMO

Inflammation is an important therapeutic target. Due to their potency, steroidal drugs dominate the current treatment of inflammatory disorders. However, steroidal drugs can also exert a broad range of side effects and appear not always effective. This calls for the development of alternative drugs with a different mechanism of action, which are likely to be found in the field of natural products (NPs). For many NPs strong anti-inflammatory effects have been described, but usually investigating a single compound in a single assay. In this study, eight promising NPs were selected and tested against the strong anti-inflammatory drug prednisolone. For this head-to-head comparison, in vitro assays were used which represent different pathways of the inflammatory response: TNF-α and IL-6 expression by macrophages, IL-8 expression by colon epithelial cells, ROS production in polymorphonuclear leukocytes and platelet activation in whole blood. Performance profiles were established which allowed us to identify curcumin, berberine chloride and epigallocatechin gallate as potential alternatives for prednisolone or other glucocorticoids in inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Berberina/farmacologia , Produtos Biológicos/farmacologia , Catequina/análogos & derivados , Curcumina/farmacologia , Neutrófilos/efeitos dos fármacos , Acetofenonas/farmacologia , Animais , Plaquetas/citologia , Plaquetas/efeitos dos fármacos , Plaquetas/imunologia , Células CACO-2 , Catequina/farmacologia , Linhagem Celular , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/biossíntese , Interleucina-6/imunologia , Interleucina-8/antagonistas & inibidores , Interleucina-8/biossíntese , Interleucina-8/imunologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Neutrófilos/citologia , Neutrófilos/imunologia , Ativação Plaquetária/efeitos dos fármacos , Pravastatina/farmacologia , Prednisolona/farmacologia , Cultura Primária de Células , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Estilbenos/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/imunologia
11.
Biotechnol Lett ; 38(6): 969-74, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26879082

RESUMO

OBJECTIVES: To evaluate the potential of adaptive evolution as a tool in generating strains with an improved production of plant biomass degrading enzymes. RESULTS: An Aspergillus niger cellulase mutant was obtained by adaptive evolution. Physiological properties of this mutant revealed a five times higher cellulose production than the parental strain. Transcriptomic analysis revealed that the expression of noxR, encoding the regulatory subunit of the NADPH oxidase complex, was reduced in the mutant compared to the parental strain. Subsequent analysis of a noxR knockout strain showed the same phenotypic effect as observed for the evolution mutant, confirming the role of NoxR in cellulose degradation. CONCLUSIONS: Adaptive evolution is an efficient approach to modify a strain and activate genes involved in polysaccharide degradation.


Assuntos
Aspergillus niger/genética , Celulase/metabolismo , Engenharia Genética/métodos , Adaptação Fisiológica , Aspergillus niger/enzimologia , Celulase/genética , Celulose/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Perfilação da Expressão Gênica , Regulação Fúngica da Expressão Gênica , Técnicas de Inativação de Genes , Microbiologia Industrial/métodos , Mutação , Engenharia de Proteínas/métodos
12.
ACS Nano ; 7(11): 9761-70, 2013 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-24127782

RESUMO

Low-density lipoprotein (LDL) plays a critical role in cholesterol transport and is closely linked to the progression of several diseases. This motivates the development of methods to study LDL behavior from the microscopic to whole-body level. We have developed an approach to efficiently load LDL with a range of diagnostically active nanocrystals or hydrophobic agents. We performed focused experiments on LDL labeled with gold nanocrystals (Au-LDL). The labeling procedure had minimal effect on LDL size, morphology, or composition. Biological function was found to be maintained from both in vitro and in vivo experiments. Tumor-bearing mice were injected intravenously with LDL, DiR-LDL, Au-LDL, or a gold-loaded nanoemulsion. LDL accumulation in the tumors was detected with whole-body imaging methods, such as computed tomography (CT), spectral CT, and fluorescence imaging. Cellular localization was studied with transmission electron microscopy and fluorescence techniques. This LDL labeling procedure should permit the study of lipoprotein biointeractions in unprecedented detail.


Assuntos
Ouro/química , Lipoproteínas LDL/química , Nanopartículas Metálicas/química , Nanopartículas/química , Animais , Carbocianinas/química , Colesterol/química , Feminino , Citometria de Fluxo , Células Hep G2 , Humanos , Melanoma Experimental , Camundongos , Camundongos Knockout , Camundongos Nus , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Transplante de Neoplasias , Fosfolipídeos/química , Tomografia Computadorizada por Raios X
13.
Nat Biotechnol ; 29(10): 922-7, 2011 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-21964414

RESUMO

Thermostable enzymes and thermophilic cell factories may afford economic advantages in the production of many chemicals and biomass-based fuels. Here we describe and compare the genomes of two thermophilic fungi, Myceliophthora thermophila and Thielavia terrestris. To our knowledge, these genomes are the first described for thermophilic eukaryotes and the first complete telomere-to-telomere genomes for filamentous fungi. Genome analyses and experimental data suggest that both thermophiles are capable of hydrolyzing all major polysaccharides found in biomass. Examination of transcriptome data and secreted proteins suggests that the two fungi use shared approaches in the hydrolysis of cellulose and xylan but distinct mechanisms in pectin degradation. Characterization of the biomass-hydrolyzing activity of recombinant enzymes suggests that these organisms are highly efficient in biomass decomposition at both moderate and high temperatures. Furthermore, we present evidence suggesting that aside from representing a potential reservoir of thermostable enzymes, thermophilic fungi are amenable to manipulation using classical and molecular genetics.


Assuntos
Ascomicetos/genética , Biomassa , Genoma Fúngico/genética , Genômica/métodos , Temperatura , Ascomicetos/enzimologia , Ascomicetos/crescimento & desenvolvimento , Biodegradação Ambiental , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Regulação Fúngica da Expressão Gênica , Hidrólise , Medicago sativa/metabolismo , Modelos Genéticos , Dados de Sequência Molecular , Filogenia , Polissacarídeos/metabolismo , Proteoma/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcrição Gênica
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