RESUMO
Self-assembled peptide nanostructures have been increasingly exploited as functional materials for applications in biomedicine and energy. The emergent properties of these nanomaterials determine the applications for which they can be exploited. It has recently been appreciated that nanomaterials composed of multicomponent coassembled peptides often display unique emergent properties that have the potential to dramatically expand the functional utility of peptide-based materials. This review presents recent efforts in the development of multicomponent peptide assemblies. The discussion includes multicomponent assemblies derived from short low molecular weight peptides, peptide amphiphiles, coiled coil peptides, collagen, and ß-sheet peptides. The design, structure, emergent properties, and applications for these multicomponent assemblies are presented in order to illustrate the potential of these formulations as sophisticated next-generation bio-inspired materials.
Assuntos
Peptídeos/síntese química , Peso Molecular , Nanoestruturas/química , Peptídeos/química , Conformação ProteicaRESUMO
Fluorenylmethoxycarbonyl-protected phenylalanine (Fmoc-Phe) derivatives are a privileged class of molecule that spontaneously self-assemble into hydrogel fibril networks. Fmoc-Phe-derived hydrogels are typically formed by dilution of the hydrogelator from an organic cosolvent into water, by dissolution of the hydrogelator under basic aqueous conditions followed by adjustment of the pH with acid, or by other external triggering forces, including sonication and heating. These conditions complicate biological applications of these hydrogels. Herein, we report C-terminal cation-modified Fmoc-Phe derivatives that are positively charged across a broad range of pH values and that can self-assemble and form hydrogel networks spontaneously without the need to adjust pH or to use an organic cosolvent. In addition, these cationic Fmoc-Phe derivatives are found to self-assemble into novel sheet-based nanotube structures at higher concentrations. These nanotube structures are unique to C-terminal cationic Fmoc-Phe derivatives; the parent Fmoc-Phe carboxylic acids form only fibril or worm-like micelle structures. Nanotube formation by the cationic Fmoc-Phe molecules is dependent on positive charge at the C-terminus, since at basic pH where the positive charge is reduced only fibrils/worm-like micelles are formed and nanotube formation is suppressed. These studies provide an important example of Fmoc-Phe derivatives that can elicit hydrogelation without organic cosolvent or pH modification and also provide insight into how subtle modification of structure can perturb the self-assembly pathways of Fmoc-Phe derivatives.
RESUMO
Self-assembled peptide-based hydrogels are emerging materials that have been exploited for wound healing, drug delivery, tissue engineering, and other applications. In comparison to synthetic polymer hydrogels, supramolecular peptide-based gels have advantages in biocompatibility, biodegradability, and ease of synthesis and modification. Modification of the emergent viscoelasticity of peptide hydrogels in a stimulus responsive fashion is a longstanding goal in the development of next-generation materials. In an effort to selectively modulate hydrogel viscoelasticity, we report herein a method to enhance the elasticity of ß-sheet peptide hydrogels using specific molecular recognition events between functionalized hydrogel fibrils and biomolecules. Two distinct biomolecular recognition strategies are demonstrated: oligonucleotide Watson-Crick duplex formation between peptide nucleic acid (PNA) modified fibrils with a bridging oligonucleotide and protein-ligand recognition between mannose modified fibrils with concanavalin A. These methods to modulate hydrogel elasticity should be broadly adaptable in the context of these materials to a wide variety of molecular recognition partners.
Assuntos
Materiais Biocompatíveis/química , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Ácidos Nucleicos Peptídicos/química , Peptídeos/química , Materiais Biocompatíveis/síntese química , Sistemas de Liberação de Medicamentos , Elasticidade , Humanos , Hidrogel de Polietilenoglicol-Dimetacrilato/síntese química , Ácidos Nucleicos Peptídicos/síntese química , Peptídeos/síntese química , Polímeros/síntese química , Polímeros/química , Engenharia TecidualRESUMO
The display of functional proteins on self-assembled peptide nanofibrils is challenging since the steric bulk of proteins attached to simple self-assembling peptides often impedes incorporation into nanofibrils. Herein is described a split-protein strategy to tether functional proteins to preassembled peptide nanofibrils. In this strategy, a short affinity motif peptide derived from a split protein system is appended to a self-assembly motif (the amphipathic Ac-(FKFE)2-NH2 peptide) to form an affinity-assembly fusion peptide. The small size of the affinity motif allows the affinity-assembly fusion peptide to be readily incorporated into peptide nanofibrils that display the affinity motif when the affinity-assembly peptide is coassembled with Ac-(FKFE)2-NH2. Introduction of the split-protein that is complementary to the affinity motif to the assembled nanofibrils results in efficient, multivalent attachment of functional proteins to the peptide nanofibrils. This strategy is demonstrated with two split-protein systems, ribonuclease S' (RNase S') and split green fluorescent protein (GFP).
Assuntos
Proteínas de Fluorescência Verde/química , Nanofibras/química , Peptídeos/química , Ribonucleases/química , Substâncias Macromoleculares/síntese química , Substâncias Macromoleculares/química , Modelos Moleculares , Tamanho da Partícula , Peptídeos/síntese químicaRESUMO
BACKGROUND: Obesity is a risk factor for asthma. Studies in mice suggest that the adipokines leptin and adiponectin affect asthmatic responses. The purpose of this study was to determine if adipokines associated with obesity are (1) altered in obese women with asthma compared to controls and (2) associated with increased cytokines and chemokines involved in allergic inflammation. METHODS: We performed a cross-sectional study of asthmatic and non-asthmatic obese premenopausal women. Participants answered questionnaires and performed lung function tests. Serum and peripheral blood mononuclear cells (PBMCs) were collected for analysis of cytokines and adipokines. RESULTS: A total of 22 asthmatic (mean body mass index 40.0 ± 5.1 kg/m(2)) and 20 non-asthmatic women (mean body mass index 41.3 ± 5.6 kg/m(2)) participated. We found no difference in serum adipokine concentrations between asthmatics and non-asthmatics. Serum adiponectin correlated positively with PBMC eotaxin (r(s) = 0.55, p = .0003) and RANTES (regulated upon activation, normal T-cell expressed, and secreted) (r(s) = 0.36, p = .03), whereas serum leptin correlated negatively with PBMC eotaxin (r(s) = -0.34, p = .04). There was a negative correlation between serum adiponectin and PBMC interferon-γ (r(s) = -0.41, p = .01). CONCLUSIONS: Perturbations of adipokines that occur in obesity were correlated with decreased cytokine production typically associated with allergic responses in PBMC of obese premenopausal women. This study suggests that although obese asthmatics may have elements of Th2-mediated inflammation, adipokine derangements in obesity are associated with Th1 rather than Th2 bias. Obesity has complex effects on allergic inflammation and is likely to be important modifier of the pathogenesis of airway disease in asthma.
Assuntos
Adiponectina/imunologia , Asma/imunologia , Leptina/imunologia , Pulmão/fisiopatologia , Obesidade/imunologia , Adiponectina/sangue , Adolescente , Adulto , Asma/sangue , Asma/fisiopatologia , Estudos Transversais , Feminino , Humanos , Leptina/sangue , Leucócitos Mononucleares/imunologia , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/fisiopatologia , Testes de Função Respiratória , Estatísticas não Paramétricas , Células Th1/imunologia , Células Th2/imunologia , Adulto JovemRESUMO
BACKGROUND: Asthma is a chronic inflammatory disease of the airway that is characterized by a Th2-type of immune response with increasing evidence for involvement of Th17 cells. The role of IL-6 in promoting effector T cell subsets suggest that IL-6 may play a functional role in asthma. Classically IL-6 has been viewed as an inflammatory marker, along with TNFalpha and IL-1beta, rather than as regulatory cytokine. OBJECTIVE: To investigate the potential relationship between IL-6 and other proinflammatory cytokines, Th2/Th17 cytokines and lung function in allergic asthma, and thus evaluate the potential role of IL-6 in this disease. METHODS: Cytokine levels in induced sputum and lung function were measured in 16 healthy control and 18 mild-moderate allergic asthmatic subjects. RESULTS: The levels of the proinflammatory biomarkers TNFalpha and IL-1beta were not different between the control and asthmatic group. In contrast, IL-6 levels were specifically elevated in asthmatic subjects compared with healthy controls (p < 0.01). Hierarchical regression analysis in the total study cohort indicates that the relationship between asthma and lung function could be mediated by IL-6. Among Th2 cytokines only IL-13 (p < 0.05) was also elevated in the asthmatic group, and positively correlated with IL-6 levels (rS = 0.53, p < 0.05). CONCLUSIONS: In mild-moderate asthma, IL-6 dissociates from other proinflammatory biomarkers, but correlates with IL-13 levels. Furthermore, IL-6 may contribute to impaired lung function in allergic asthma.
Assuntos
Asma/imunologia , Citocinas/imunologia , Interleucina-6/imunologia , Pulmão/imunologia , Pneumonia/imunologia , Hipersensibilidade Respiratória/imunologia , Adulto , Feminino , Humanos , Masculino , Pneumonia/complicaçõesRESUMO
Supramolecular hydrogels are emerging as next-generation alternatives to synthetic polymers for drug delivery applications. Self-assembling peptides are a promising class of supramolecular gelator for in vivo drug delivery that have been slow to be adopted despite advantages in biocompatibility due to the relatively high cost of producing synthetic peptide hydrogels compared to synthetic polymer gels. Herein we describe the development and use of inexpensive low molecular weight cationic derivatives of phenylalanine (Phe) as injectable hydrogels for in vivo delivery of an anti-inflammatory drug, diclofenac, for pain mitigation in a mouse model. N-Fluorenylmethoxycarbonyl phenylalanine (Fmoc-Phe) derivatives were modified at the carboxylic acid with diaminopropane (DAP) to provide Fmoc-Phe-DAP molecules that spontaneously and rapidly self-assemble in aqueous solutions upon addition of physiologically relevant sodium chloride concentrations to give hydrogels. When self-assembly occurs in the presence of diclofenac, the drug molecule is efficiently encapsulated within the hydrogel network. These hydrogels exhibit robust shear-thinning behavior, mechanical stability, and drug release profiles to enable application as injectable hydrogels for in vivo drug delivery. Delivery of diclofenac in vivo was demonstrated by a localized injection of an Fmoc-F5-Phe-DAP/diclofenac hydrogel into the ankle joint of mice with induced ankle injury and associated inflammation-induced pain. Remediation of pain in the ankle joint was observed immediately after initial injection and was sustained for a period of nearly two weeks while diclofenac controls remediated pain for less than one day. This data demonstrates the promise of these supramolecular hydrogels as inexpensive next-generation materials for sustained and localized drug delivery in vivo.
RESUMO
STUDY OBJECTIVES: The purpose of this study was to determine if asthma with rhinitis and asthma without rhinitis represent distinct forms of disease. DESIGN: We performed a prospective cross-sectional study. PARTICIPANTS: The study included healthy controls, participants with asthma without rhinitis, and participants with both asthma and rhinitis. Interventions We compared lung function and airway inflammation between the three groups of participants. RESULTS: We recruited 32 participants: 12 normals, 8 asthmatics without rhinitis, and 12 with rhinitis. Compared to asthmatics with rhinitis, asthmatics without rhinitis had more severe airflow limitation (FEV(1)/FVC = 60.6% [IQR = 22.8] vs. 74.8% [IQR = 7.8] and fewer induced sputum eosinophils (2.8 [IQR = 5.8] and 9.6 [IQR = 23.8], respectively). Sputum interleukin-6 correlated inversely with lung function measured by postbronchodilator FEV(1) in the study cohort (Spearman correlation coefficient = -0.55, p < 0.01). CONCLUSIONS: Asthmatics without rhinitis tend to have lower lung function and less eosinophilic inflammation in the lung. This small study suggests that asthmatics without rhinitis represent a distinct phenotype of asthma in which low lung function is dissociated from eosinophilic cellular inflammation, and it suggests that larger studies addressing this phenotype are warrented.