Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 39
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Molecules ; 26(21)2021 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-34770799

RESUMO

Biofilm formation is an important virulence factor for the opportunistic microorganisms that elicit skin infections. The recalcitrant feature of biofilms and their antibiotic tolerance impose a great challenge on the use of conventional therapies. Most antibacterial agents have difficulty penetrating the matrix produced by a biofilm. One novel approach to address these concerns is to prevent or inhibit the formation of biofilms using nanoparticles. The advantages of using nanosystems for antibiofilm applications include high drug loading efficiency, sustained or prolonged drug release, increased drug stability, improved bioavailability, close contact with bacteria, and enhanced accumulation or targeting to biomasses. Topically applied nanoparticles can act as a strategy for enhancing antibiotic delivery into the skin. Various types of nanoparticles, including metal oxide nanoparticles, polymeric nanoparticles, liposomes, and lipid-based nanoparticles, have been employed for topical delivery to treat biofilm infections on the skin. Moreover, nanoparticles can be designed to combine with external stimuli to produce magnetic, photothermal, or photodynamic effects to ablate the biofilm matrix. This study focuses on advanced antibiofilm approaches based on nanomedicine for treating skin infections. We provide in-depth descriptions on how the nanoparticles could effectively eliminate biofilms and any pathogens inside them. We then describe cases of using nanoparticles for antibiofilm treatment of the skin. Most of the studies included in this review were supported by in vivo animal infection models. This article offers an overview of the benefits of nanosystems for treating biofilms grown on the skin.

2.
Biomolecules ; 11(7)2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34356649

RESUMO

Curcumin is a known anti-adipogenic agent for alleviating obesity and related disorders. Comprehensive comparisons of the anti-adipogenic activity of curcumin with other curcuminoids is minimal. This study compared adipogenesis inhibition with curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC), and their underlying mechanisms. We differentiated 3T3-L1 cells in the presence of curcuminoids, to determine lipid accumulation and triglyceride (TG) production. The expression of adipogenic transcription factors and lipogenic proteins was analyzed by Western blot. A significant reduction in Oil red O (ORO) staining was observed in the cells treated with curcuminoids at 20 µM. Inhibition was increased in the order of curcumin < DMC < BDMC. A similar trend was observed in the detection of intracellular TG. Curcuminoids suppressed differentiation by downregulating the expression of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), leading to the downregulation of the lipogenic enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). AMP-activated protein kinase α (AMPKα) phosphorylation was also activated by BDMC. Curcuminoids reduced the release of proinflammatory cytokines and leptin in 3T3-L1 cells in a dose-dependent manner, with BDMC showing the greatest potency. BDMC at 20 µM significantly decreased leptin by 72% compared with differentiated controls. Molecular docking computation indicated that curcuminoids, despite having structural similarity, had different interaction positions to PPARγ, C/EBPα, and ACC. The docking profiles suggested a possible interaction of curcuminoids with C/EBPα and ACC, to directly inhibit their expression.


Assuntos
Adipogenia/efeitos dos fármacos , Diarileptanoides/química , Diarileptanoides/farmacologia , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipogenia/fisiologia , Adipocinas/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcuma/química , Curcumina/análise , Curcumina/farmacologia , Enzimas/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , PPAR gama/química , PPAR gama/metabolismo , Extratos Vegetais/análise , Extratos Vegetais/farmacologia , Triglicerídeos/metabolismo
3.
Molecules ; 25(23)2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33287318

RESUMO

Diabetes mellitus is a well-known chronic metabolic disease that poses a long-term threat to human health and is characterized by a relative or absolute lack of insulin, resulting in hyperglycemia. Type 2 diabetes mellitus (T2DM) typically affects many metabolic pathways, resulting in ß-cell dysfunction, insulin resistance, abnormal blood glucose levels, inflammatory processes, excessive oxidative reactions, and impaired lipid metabolism. It also leads to diabetes-related complications in many organ systems. Antidiabetic drugs have been approved for the treatment of hyperglycemia in T2DM; these are beneficial for glucose metabolism and promote weight loss, but have the risk of side effects, such as nausea or an upset stomach. A wide range of active components, derived from medicinal plants, such as alkaloids, flavonoids, polyphenol, quinones, and terpenoids may act as alternative sources of antidiabetic agents. They are usually attributed to improvements in pancreatic function by increasing insulin secretions or by reducing the intestinal absorption of glucose. Ease of availability, low cost, least undesirable side effects, and powerful pharmacological actions make plant-based preparations the key player of all available treatments. Based on the study of therapeutic reagents in the pathogenesis of humans, we use the appropriate animal models of T2DM to evaluate medicinal plant treatments. Many of the rat models have characteristics similar to those in humans and have the advantages of ease of genetic manipulation, a short breeding span, and access to physiological and invasive testing. In this review, we summarize the pathophysiological status of T2DM rat models and focus on several bioactive compounds from herbal medicine with different functional groups that exhibit therapeutic potential in the T2DM rat models, in turn, may guide future approach in treating diabetes with natural drugs.


Assuntos
Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Animais , Modelos Animais de Doenças , Humanos , Hiperglicemia/tratamento farmacológico , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Plantas Medicinais/química , Ratos
4.
Elife ; 92020 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-33044169

RESUMO

Tissue resident mesenchymal stem/stromal cells (MSCs) occupy perivascular spaces. Profiling human adipose perivascular mesenchyme with antibody arrays identified 16 novel surface antigens, including endolysosomal protein CD107a. Surface CD107a expression segregates MSCs into functionally distinct subsets. In culture, CD107alow cells demonstrate high colony formation, osteoprogenitor cell frequency, and osteogenic potential. Conversely, CD107ahigh cells include almost exclusively adipocyte progenitor cells. Accordingly, human CD107alow cells drove dramatic bone formation after intramuscular transplantation in mice, and induced spine fusion in rats, whereas CD107ahigh cells did not. CD107a protein trafficking to the cell surface is associated with exocytosis during early adipogenic differentiation. RNA sequencing also suggested that CD107alow cells are precursors of CD107ahigh cells. These results document the molecular and functional diversity of perivascular regenerative cells, and show that relocation to cell surface of a lysosomal protein marks the transition from osteo- to adipogenic potential in native human MSCs, a population of substantial therapeutic interest.


Assuntos
Adipogenia/genética , Diferenciação Celular/genética , Proteína 1 de Membrana Associada ao Lisossomo/genética , Células-Tronco Mesenquimais/metabolismo , Osteogênese/genética , Adipócitos/metabolismo , Animais , Humanos , Proteína 1 de Membrana Associada ao Lisossomo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Ratos , Ratos Nus , Células-Tronco/metabolismo
5.
Am J Pathol ; 190(9): 1909-1920, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32533926

RESUMO

Perivascular mural cells surround capillaries and microvessels and have diverse regenerative or fibrotic functions after tissue injury. Subsynovial fibrosis is a well-known pathologic feature of osteoarthritis, yet transgenic animals for use in visualizing perivascular cell contribution to fibrosis during arthritic changes have not been developed. Here, inducible Pdgfra-CreERT2 reporter mice were subjected to joint-destabilization surgery to induce arthritic changes, and cell lineage was traced over an 8-week period with a focus on the joint-associated fat pad. Results showed that, at baseline, inducible Pdgfra reporter activity highlighted adventitial and, to a lesser extent, pericytic cells within the infrapatellar fat pad. Joint-destabilization surgery was associated with marked fibrosis of the infrapatellar fat pad, accompanied by an expansion of perivascular Pdgfra-expressing cellular descendants, many of which adopted α-smooth muscle actin expression. Gene expression analysis of microdissected infrapatellar fat pad confirmed enrichment in membrane-bound green fluorescent protein/Pdgfra-expressing cells, along with a gene signature that corresponded with injury-associated fibro-adipogenic progenitors. Our results highlight dynamic changes in joint-associated perivascular fibro-adipogenic progenitors during osteoarthritis.


Assuntos
Adipócitos/patologia , Fibroblastos/patologia , Osteoartrite/patologia , Tecido Adiposo/patologia , Animais , Linhagem da Célula , Articulação do Joelho/patologia , Camundongos , Camundongos Transgênicos , Células-Tronco
6.
Bone Res ; 8(1): 22, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32509378

RESUMO

Human osteogenic progenitors are not precisely defined, being primarily studied as heterogeneous multipotent cell populations and termed mesenchymal stem cells (MSCs). Notably, select human pericytes can develop into bone-forming osteoblasts. Here, we sought to define the differentiation potential of CD146+ human pericytes from skeletal and soft tissue sources, with the underlying goal of defining cell surface markers that typify an osteoblastogenic pericyte. CD146+CD31-CD45- pericytes were derived by fluorescence-activated cell sorting from human periosteum, adipose, or dermal tissue. Periosteal CD146+CD31-CD45- cells retained canonical features of pericytes/MSC. Periosteal pericytes demonstrated a striking tendency to undergo osteoblastogenesis in vitro and skeletogenesis in vivo, while soft tissue pericytes did not readily. Transcriptome analysis revealed higher CXCR4 signaling among periosteal pericytes in comparison to their soft tissue counterparts, and CXCR4 chemical inhibition abrogated ectopic ossification by periosteal pericytes. Conversely, enrichment of CXCR4+ pericytes or stromal cells identified an osteoblastic/non-adipocytic precursor cell. In sum, human skeletal and soft tissue pericytes differ in their basal abilities to form bone. Diversity exists in soft tissue pericytes, however, and CXCR4+ pericytes represent an osteoblastogenic, non-adipocytic cell precursor. Indeed, enrichment for CXCR4-expressing stromal cells is a potential new tactic for skeletal tissue engineering.

7.
Stem Cells Dev ; 29(15): 1007-1015, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32460636

RESUMO

Adipose-derived stem/stromal cells (ASCs) have been previously used for bone repair. However, significant cell heterogeneity exists within the ASC population, which has the potential to result in unreliable bone tissue formation and/or low efficacy. Although the use of cell sorting to lower cell heterogeneity is one method to improve bone formation, this is a technically sophisticated and costly process. In this study, we tried to find a simpler and more deployable solution-blocking antiosteogenic molecule Dickkopf-1 (DKK1) to improve osteogenic differentiation. Human adipose-derived stem cells were derived from = 5 samples of human lipoaspirate. In vitro, anti-DKK1 treatment, but not anti-sclerostin (SOST), promoted ASC osteogenic differentiation, assessed by alizarin red staining and real-time polymerase chain reaction (qPCR). Increased canonical Wnt signaling was confirmed after anti-DKK1 treatment. Expression levels of DKK1 peaked during early osteogenic differentiation (day 3). Concordantly, anti-DKK1 supplemented early (day 3 or before), but not later (day 7) during osteogenic differentiation positively regulated osteoblast formation. Finally, anti-DKK1 led to increased transcript abundance of the Wnt inhibitor SOST, potentially representing a compensatory cellular mechanism. In sum, DKK1 represents a targetable "molecular brake" on the osteogenic differentiation of human ASC. Moreover, release of this brake by neutralizing anti-DKK1 antibody treatment at least partially rescues the poor bone-forming efficacy of ASC.


Assuntos
Diferenciação Celular , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Células-Tronco Mesenquimais/citologia , Osteogênese , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Regulação da Expressão Gênica , Humanos , Testes de Neutralização , Fatores de Tempo , Via de Sinalização Wnt/genética
8.
Cells ; 9(5)2020 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-32397494

RESUMO

Microbial proteins have recently been found to have more benefits in clinical disease treatment because of their better-developed strategy and properties than traditional medicine. In this study, we investigated the effectiveness of a truncated peptide synthesized from the C-terminal sequence of pneumolysin, i.e., C70PLY4, in Streptococcus pneumoniae, in treating chronic inflammatory conditions. It has been shown that C70PLY4 significantly blocks the transendothelial migration of neutrophils and attenuates the formation of atherosclerotic plaque and the secretion of soluble forms of the intercellular adhesion molecule-1 (ICAM-1), the vascular cell adhesion molecule 1 (VCAM-1), and E-selectin in high-fat-diet/streptozotocin-induced inflammatory rats. The mechanism and the docking simulation analysis further indicated that C70PLY4 might serve as a Toll-like receptor 4 (TLR4) antagonist by competing for the binding site of MD2, an indispensable protein for lipopolysaccharide (LPS)-TLR4 interaction signaling, on the TLR4 structure. Moreover, compared to the full-length PLY, C70PLY4 seems to have no cytotoxicity in human vascular endothelial cells. Our study elucidated a possible therapeutic efficacy of C70PLY4 in reducing chronic inflammatory conditions and clarified the underlying mechanism. Thus, our findings identify a new drug candidate that, by blocking TLR4 activity, could be an effective treatment for patients with chronic inflammatory diseases.


Assuntos
Inflamação/tratamento farmacológico , Proteínas Mutantes/farmacologia , Proteínas Mutantes/uso terapêutico , Streptococcus pneumoniae/metabolismo , Estreptolisinas/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Apoptose/efeitos dos fármacos , Proteínas de Bactérias/química , Proteínas de Bactérias/farmacologia , Sítios de Ligação , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Dieta Hiperlipídica , Selectina E/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Lipopolissacarídeos , Camundongos , Simulação de Acoplamento Molecular , Proteínas Mutantes/química , NF-kappa B/metabolismo , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Solubilidade , Estreptolisinas/química , Estreptozocina , Receptor 4 Toll-Like/metabolismo , Migração Transendotelial e Transepitelial/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/metabolismo
9.
J Orthop Res ; 38(11): 2484-2494, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32134140

RESUMO

Pericytes ubiquitously surround capillaries and microvessels within vascularized tissues and have diverse functions after tissue injury. In addition to regulation of angiogenesis and tissue regeneration after injury, pericytes also contribute to organ fibrosis. Destabilization of the medial meniscus (DMM) phenocopies post-traumatic osteoarthritis, yet little is known regarding the impact of DMM surgery on knee joint-associated pericytes and their cellular descendants. Here, inducible platelet-derived growth factor receptor-ß (PDGFRß)-CreERT2 reporter mice were subjected to DMM surgery, and lineage tracing studies performed over an 8-week period. Results showed that at baseline PDGFRß reporter activity highlights abluminal perivascular cells within synovial and infrapatellar fat pad (IFP) tissues. DMM induces a temporospatially patterned increase in vascular density within synovial and subsynovial tissues. Marked vasculogenesis within IFP was accompanied by expansion of PDGFRß reporter+ perivascular cell numbers, detachment of mGFP+ descendants from vessel walls, and aberrant adoption of myofibroblastic markers among mGFP+ cells including α-SMA, ED-A, and TGF-ß1. At later timepoints, fibrotic changes and vascular maturation occurred within subsynovial tissues, with the redistribution of PDGFRß+ cellular descendants back to their perivascular niche. In sum, PDGFRß lineage tracing allows for tracing of perivascular cell fate within the diarthrodial joint. Further, destabilization of the joint induces vascular and fibrogenic changes of the IFP accompanied by perivascular to myofibroblast transdifferentiation.


Assuntos
Artrite Experimental/patologia , Transdiferenciação Celular , Articulações/patologia , Miofibroblastos/citologia , Osteoartrite/patologia , Pericitos/fisiologia , Animais , Linhagem da Célula , Feminino , Fibrose , Genes Reporter , Articulações/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo
10.
Bone Res ; 7: 36, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31840004

RESUMO

Heterotopic ossification (HO) is a debilitating condition characterized by the pathologic formation of ectopic bone. HO occurs commonly following orthopedic surgeries, burns, and neurologic injuries. While surgical excision may provide palliation, the procedure is often burdened with significant intra-operative blood loss due to a more robust contribution of blood supply to the pathologic bone than to native bone. Based on these clinical observations, we set out to examine the role of vascular signaling in HO. Vascular endothelial growth factor A (VEGFA) has previously been shown to be a crucial pro-angiogenic and pro-osteogenic cue during normal bone development and homeostasis. Our findings, using a validated mouse model of HO, demonstrate that HO lesions are highly vascular, and that VEGFA is critical to ectopic bone formation, despite lacking a contribution of endothelial cells within the developing anlagen.

11.
Elife ; 82019 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-31482845

RESUMO

The vascular wall is a source of progenitor cells that are able to induce skeletal repair, primarily by paracrine mechanisms. Here, the paracrine role of extracellular vesicles (EVs) in bone healing was investigated. First, purified human perivascular stem cells (PSCs) were observed to induce mitogenic, pro-migratory, and pro-osteogenic effects on osteoprogenitor cells while in non-contact co-culture via elaboration of EVs. PSC-derived EVs shared mitogenic, pro-migratory, and pro-osteogenic properties of their parent cell. PSC-EV effects were dependent on surface-associated tetraspanins, as demonstrated by EV trypsinization, or neutralizing antibodies for CD9 or CD81. Moreover, shRNA knockdown in recipient cells demonstrated requirement for the CD9/CD81 binding partners IGSF8 and PTGFRN for EV bioactivity. Finally, PSC-EVs stimulated bone repair, and did so via stimulation of skeletal cell proliferation, migration, and osteodifferentiation. In sum, PSC-EVs mediate the same tissue repair effects of perivascular stem cells, and represent an 'off-the-shelf' alternative for bone tissue regeneration.


Assuntos
Vasos Sanguíneos/citologia , Vesículas Extracelulares/metabolismo , Osteócitos/efeitos dos fármacos , Osteócitos/fisiologia , Osteogênese , Células-Tronco/metabolismo , Células Cultivadas , Técnicas de Cocultura , Humanos
12.
Future Med Chem ; 11(16): 2131-2150, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31538520

RESUMO

Prodrug entrapment into nanocarriers for tumor delivery is a strategy to achieve a valid therapy with high efficiency. The prodrug contains anticancer agents conjugating with functional moieties or ligands so that the active component is released after metabolism in the body or tumor. The advantages of nanosystems for loading prodrugs include high loading, increased prodrug stability, improved bioavailability and enhanced targeting to tumor cells. In the present article, we introduce the prodrug delivery approaches according to nanomedicine and the recent advances in prodrug-loaded nanocarriers. First, we discuss the conceptional design of combined prodrugs and nanocarriers in response to the obstruction in anticancer therapy. Then we describe the cases of prodrug-loaded nanoparticles for cancer treatment during the past 5 years.


Assuntos
Antineoplásicos/administração & dosagem , Portadores de Fármacos/química , Nanopartículas/química , Neoplasias/tratamento farmacológico , Pró-Fármacos/administração & dosagem , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Humanos , Nanoconjugados/química , Nanomedicina/métodos , Nanotecnologia/métodos , Neoplasias/metabolismo , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Resultado do Tratamento
13.
Stem Cells Dev ; 28(18): 1214-1223, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31264500

RESUMO

Human perivascular progenitor cells, including pericytes, are well-described multipotent mesenchymal cells giving rise to mesenchymal stem cells in culture. Despite the unique location of pericytes, specific antigens to distinguish human pericytes from other cell types are few. Here, we employed a human tissue microarray (Human Protein Atlas) to identify proteins that are strongly and specifically expressed in a pericytic location within human adipose tissue. Next, these results were cross-referenced with RNA sequencing data from human adipose tissue pericytes, as defined as a fluorescence activated cell sorting (FACS) purified CD146+CD34-CD31-CD45- cell population. Results showed that from 105,532 core biopsies of soft tissue, 229 proteins showed strong and specific perivascular immunoreactivity, the majority of which (155) were present in the tunica intima. Next, cross-referencing with the transcriptome of FACS-derived CD146+ pericytes yielded 25 consistently expressed genes/proteins, including 18 novel antigens. A majority of these transcripts showed maintained expression after culture propagation (56% of genes). Interestingly, many novel antigens within pericytes are regulators of osteogenic differentiation. In sum, our study demonstrates the existence of novel pericyte markers, some of which are conserved in culture that may be useful for future efforts to typify, isolate, and characterize human pericytes.


Assuntos
Antígenos CD/genética , Pericitos/metabolismo , Transcriptoma , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Antígenos CD/metabolismo , Células Cultivadas , Citometria de Fluxo/métodos , Perfilação da Expressão Gênica/métodos , Humanos , Proteoma/genética , Proteoma/metabolismo , Software , Análise Serial de Tecidos/métodos
14.
Acta Biomater ; 90: 350-361, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30951898

RESUMO

Both phosphodiesterase (PDE4) inhibitors and omega-9 fatty acids show anti-inflammatory activity for treating inflamed skin diseases, but their efficacy remains low. Combinatorial agents are anticipated to offer an advanced strategy for efficient therapy. We prepared cilomilast-loaded oleic acid (OA) nanocarriers to test the inhibitory capability against human neutrophil stimulation and a murine psoriasis model. OA played dual roles in the nanocarriers as both the active ingredient and lipid matrix in the nanoparticulate core. OA nanoparticles but not free OA could restrain calcium mobilization in activated neutrophils. The inhibition level of superoxide anion and elastase by cilomilast-loaded OA nanocarriers approximated that of free forms. In the mouse model, the intradermal nanosystems reduced imiquimod-induced epidermal thickening from 230.4 to 63.1 µm. Transepidermal water loss was decreased from 30.2 to 11.3 g/m2/h by integrated nanocarriers. The nanosystems mitigated neutrophil infiltration and hyperproliferation in the psoriasiform lesion via decreased expression of cytokines and chemokines. STATEMENT OF SIGNIFICANCE: The long-term therapy for psoriasis is unsatisfactory due to the possible adverse effects and inefficiency after prolonged use. Both phosphodiesterase (PDE4) inhibitors and omega-9 fatty acids such as oleic acid (OA) show anti-inflammatory activity for treating inflamed skin diseases. Combinatorial agents are anticipated to offer an advanced strategy for efficient therapy. OA is also ideal for incorporation into nanoparticles to enhance particulate emulsification, drug entrapment, and biocompatibility. We prepared cilomilast-loaded oleic acid (OA) nanocarriers to test the inhibitory capability against human neutrophil stimulation and a murine psoriasis lesion. OA nanocarriers are indigenous to prevent neutrophil activation and the deterioration of psoriatic lesion. Cilomilast incorporation in OA nanocarriers could further mitigate the clinical score and suppressing proinflammatory mediators.


Assuntos
Ácidos Cicloexanocarboxílicos , Portadores de Fármacos , Nanopartículas , Ativação de Neutrófilo/efeitos dos fármacos , Neutrófilos/metabolismo , Nitrilas , Ácido Oleico , Inibidores da Fosfodiesterase 4 , Psoríase , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Ácidos Cicloexanocarboxílicos/química , Ácidos Cicloexanocarboxílicos/farmacocinética , Ácidos Cicloexanocarboxílicos/farmacologia , Modelos Animais de Doenças , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/uso terapêutico , Neutrófilos/patologia , Nitrilas/química , Nitrilas/farmacocinética , Nitrilas/farmacologia , Ácido Oleico/química , Ácido Oleico/farmacocinética , Ácido Oleico/farmacologia , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacocinética , Inibidores da Fosfodiesterase 4/farmacologia , Psoríase/tratamento farmacológico , Psoríase/metabolismo , Psoríase/patologia
15.
Nutrients ; 11(1)2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30609658

RESUMO

The chemical environment and enzymes in the gastrointestinal (GI) membrane limit the oral absorption of some vitamins. The GI epithelium also contributes to the poor permeability of numerous antioxidant agents. Thus, lipophilic vitamins do not readily dissolve in the GI tract, and therefore they have low bioavailability. Nanomedicine has the potential to improve the delivery efficiency of oral vitamins. In particular, the use of lipid nanocarriers for certain vitamins that are administered orally can provide improved solubility, chemical stability, epithelium permeability and bioavailability, half-life, nidus targeting, and fewer adverse effects. These lipid nanocarriers include self-emulsifying drug delivery systems (SEDDSs), nanoemulsions, microemulsions, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs). The use of nontoxic excipients and sophisticated material engineering of lipid nanosystems allows for control of the physicochemical properties of the nanoparticles and improved GI permeation via mucosal or lymphatic transport. In this review, we highlight recent progress in the development of lipid nanocarriers for vitamin delivery. In addition, the same lipid nanocarriers used for vitamins may also be effective as carriers of vitamin derivatives, and therefore enhance their oral bioavailability. One example is the incorporation of d-α-tocopheryl polyethylene glycol succinate (TPGS) as the emulsifier in lipid nanocarriers to increase the solubility and inhibit P-glycoprotein (P-gp) efflux. We also survey the concepts and discuss the mechanisms of nanomedical techniques that are used to develop vitamin-loaded nanocarriers.


Assuntos
Nanopartículas , Vitaminas/administração & dosagem , Administração Oral , Disponibilidade Biológica , Portadores de Fármacos , Humanos , Lipídeos/química
16.
Bone Res ; 7(1): 36, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33293508

RESUMO

Heterotopic ossification (HO) is a debilitating condition characterized by the pathologic formation of ectopic bone. HO occurs commonly following orthopedic surgeries, burns, and neurologic injuries. While surgical excision may provide palliation, the procedure is often burdened with significant intra-operative blood loss due to a more robust contribution of blood supply to the pathologic bone than to native bone. Based on these clinical observations, we set out to examine the role of vascular signaling in HO. Vascular endothelial growth factor A (VEGFA) has previously been shown to be a crucial pro-angiogenic and pro-osteogenic cue during normal bone development and homeostasis. Our findings, using a validated mouse model of HO, demonstrate that HO lesions are highly vascular, and that VEGFA is critical to ectopic bone formation, despite lacking a contribution of endothelial cells within the developing anlagen.

17.
J Mol Diagn ; 20(6): 738-742, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30309763

RESUMO

Previously, we detected circulating tumor DNA that contained two EGFR mutations (p.L858R and exon19 del) in plasma of patients with late-stage non-small-cell lung carcinoma (NSCLC) using the electric field-induced release and measurement (EFIRM) platform. Our aim was to determine whether EFIRM technology can detect these mutations in patients with early-stage NSCLC. Prospectively, 248 patients with radiographically determined pulmonary nodules were recruited. Plasma was collected before biopsy and histologic examination of the nodule. Inclusion criteria were histologic diagnosis of benign nodule (control) and stage I or II adenocarcinoma harboring either p.L858R or exon19 delEGFR mutations. Plasma samples were available from 44 patients: 23 with biopsy-proven benign pulmonary nodules and 21 with stage I or II adenocarcinoma (12 p.L858R and 9 exon19 delEGFR variants). Samples were analyzed for the EGFR mutations using the EFIRM platform. Assay sensitivity was 92% for p.L858R (11 of 12 samples positive) and 77% for exon19 del (7 of 9 samples positive). Specificity was 91% with two false-positive results in 23 patients with EGFR-positive nodules and 95% for the entire 44-patient series. Concordance was 100% with identical mutations discovered in plasma and nodule biopsy. The EFIRM platform is able to noninvasively detect two EGFR mutations in individuals with early-stage NSCLC.


Assuntos
Detecção Precoce de Câncer/métodos , Eletricidade , Biópsia Líquida/métodos , Neoplasias Pulmonares/diagnóstico , Feminino , Humanos , Masculino
18.
Menopause ; 25(7): 772-782, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29533366

RESUMO

OBJECTIVE: This study examined the effects of dietary and exercise interventions on weight loss and body composition in overweight/obese peri- and postmenopausal women. METHODS: Medline, Central, Embase, and Google Scholar databases were searched for relevant trials conducted until December 31, 2016. Randomized controlled trials (RCTs) and prospective studies of overweight/obese peri- or postmenopausal women that examined the effects of dietary or exercise interventions, alone or combined, on weight loss were included. The primary outcome was percentage reduction in body weight. RESULTS: From 292 studies initially identified, 11 studies with 12 sets of participants were included. Both dietary and exercise intervention groups had significantly greater weight loss than control groups (diet vs control: difference in means = -6.55, 95% CI, -9.51 to -3.59, P < 0.001; exercise vs control: difference in means = -3.49, 95% CI, -6.96 to -0.02, P = 0.049). Combined dietary and exercise interventions resulted in greater weight loss than dietary interventions alone (diet plus exercise vs diet: difference in means = -1.22, 95% CI, -2.14 to -0.29, P = 0.010). Diet plus exercise resulted in greater fat loss (difference in means = -0.44, 95% CI, -0.67 to -0.20, P < 0.001) and greater lean mass loss (difference in means = -0.84, 95% CI, -1.13 to -0.55, P < 0.001) than diet alone. CONCLUSIONS: Dietary interventions reduced body weight and body composition profile parameters in peri- and postmenopausal women more than exercise alone. The addition of exercise reinforced the effect of dietary interventions on changing body weight and composition.


Assuntos
Composição Corporal/fisiologia , Manejo da Obesidade/métodos , Obesidade/terapia , Pós-Menopausa , Perda de Peso/fisiologia , Idoso , Dieta Redutora/métodos , Terapia por Exercício/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Obesidade/fisiopatologia , Resultado do Tratamento
19.
Nanomedicine ; 14(2): 215-225, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29128664

RESUMO

The aim of this study was to develop PEGylated phosphatidylcholine (PC)-rich nanovesicles (phosphatiosomes) carrying ciprofloxacin (CIPX) for lung targeting to eradicate extracellular and intracellular methicillin-resistant Staphylococcus aureus (MRSA). Soyaethyl morphonium ethosulfate (SME) was intercalated in the nanovesicle surface with the dual goals of achieving strengthened bactericidal activity of CIPX-loaded phosphatiosomes and delivery to the lungs. The isothermal titration calorimetry (ITC) results proved the strong association of SME phosphatiosomes with pulmonary surfactant. We demonstrated a superior anti-MRSA activity of SME phosphatiosomes compared to plain phosphatiosomes and to free CIPX. A synergistic effect of CIPX and SME nanocarriers was found in the biofilm eradication. SME phosphatiosomes were readily engulfed by the macrophages, restricting the intracellular MRSA count by 1-2 log units. SME phosphatiosomes efficiently accumulated in the lungs after intravenous injection. In a rat model of lung infection, the MRSA burden in the lungs could be decreased by 8-fold after SME nanosystem application.


Assuntos
Antibacterianos/farmacologia , Ciprofloxacina/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Nanopartículas/administração & dosagem , Pneumonia/tratamento farmacológico , Surfactantes Pulmonares/metabolismo , Infecções Estafilocócicas/tratamento farmacológico , Administração Intravenosa , Animais , Antibacterianos/administração & dosagem , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Ciprofloxacina/administração & dosagem , Masculino , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Modelos Animais , Nanopartículas/química , Fosfatidilcolinas/química , Pneumonia/microbiologia , Polietilenoglicóis/química , Ratos , Ratos Sprague-Dawley , Infecções Estafilocócicas/microbiologia
20.
Int J Nanomedicine ; 12: 8227-8238, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29184410

RESUMO

Pathogens usually invade hair follicles when skin infection occurs. The accumulated bacteria in follicles are difficult to eradicate. The present study aimed to assess the cutaneous and follicular delivery of chloramphenicol (Cm)-loaded liposomes and the antibacterial activity of these liposomes against methicillin-resistant Staphylococcus aureus (MRSA). Skin permeation was conducted by in vitro Franz diffusion cell. The anti-MRSA potential was checked using minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), a well diffusion test, and intracellular MRSA killing. The classic, dimyristoylphosphatidylcholine (DMPC), and deoxycholic acid (DA) liposomes had a vesicle size of 98, 132, and 239 nm, respectively. The incorporation of DMPC or DA into the liposomes increased the bilayer fluidity. The malleable vesicles containing DMPC and DA showed increased follicular Cm uptake over the control solution by 1.5- and 2-fold, respectively. The MIC and MBC of DA liposomes loaded with Cm were 62.5 and 62.5-125 µg/mL, comparable to free Cm. An inhibition zone about 2-fold higher was achieved by DA liposomes as compared to the free control at a Cm dose of 0.5 mg/mL. DA liposomes also augmented antibacterial activity on keratinocyte-infected MRSA. The deformable liposomes had good biocompatibility against keratinocytes and neutrophils (viability >80%). In vivo administration demonstrated that DA liposomes caused negligible toxicity on the skin, based on physiological examination and histology. These data suggest the potential application of malleable liposomes for follicular targeting and the treatment of MRSA-infected dermatologic conditions.


Assuntos
Antibacterianos/administração & dosagem , Cloranfenicol/administração & dosagem , Folículo Piloso/efeitos dos fármacos , Lipossomos/administração & dosagem , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Administração Cutânea , Animais , Cloranfenicol/farmacologia , Ácido Desoxicólico/química , Dimiristoilfosfatidilcolina/química , Sistemas de Liberação de Medicamentos/métodos , Feminino , Folículo Piloso/microbiologia , Queratinócitos/microbiologia , Lipossomos/química , Lipossomos/farmacologia , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Camundongos Nus , Testes de Sensibilidade Microbiana , Absorção Cutânea/efeitos dos fármacos , Infecções Cutâneas Estafilocócicas/tratamento farmacológico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...