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1.
ACS Biomater Sci Eng ; 10(5): 3086-3096, 2024 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-38588325

RESUMO

The timely administration of glucagon is a standard clinical practice for the treatment of severe hypoglycemia. However, the process involves cumbersome steps, including the reconstitution of labile glucagon and filling of the syringe, which cause considerable delays in emergency situations. Moreover, multiple dosages are often required to prevent the recurrence of the hypoglycemic episode because of the short half-life of glucagon in plasma. Herein, we develop a glucagon-loaded long-dissolving microneedle (GLMN) patch that exhibits the properties of fast onset and sustained activity for the effective treatment of severe hypoglycemia. Three types of MN patches were fabricated with different dimensions (long, medium, and short). The longer MN patch packaged a higher dosage of glucagon and exhibited supreme mechanical strength compared to the shorter one. Additionally, the longer MN patch could insert more deeply into the skin, resulting in higher permeability of glucagon across the skin tissue and more rapid systemic absorption as compared with the shorter MN patch. The GLMN patch was observed to reverse the effects of hypoglycemia within 15 min of application in animal models (specifically, rat and rhesus monkey models) and maintained long-term glycemic control, owing to highly efficient drug permeation and the drug reservoir effect of the MN base. The current study presents a promising strategy for the rapid reversal of severe hypoglycemia that exhibits the desirable properties of easy use, high efficiency, and sustained action.


Assuntos
Glucagon , Hipoglicemia , Macaca mulatta , Agulhas , Animais , Glucagon/administração & dosagem , Glucagon/farmacocinética , Hipoglicemia/tratamento farmacológico , Hipoglicemia/sangue , Ratos , Masculino , Ratos Sprague-Dawley , Adesivo Transdérmico , Administração Cutânea , Sistemas de Liberação de Medicamentos/instrumentação , Glicemia/análise , Glicemia/efeitos dos fármacos
2.
Angew Chem Int Ed Engl ; 62(10): e202216060, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36640110

RESUMO

Constructing the backbones of polymers with metal atoms is an attractive strategy to develop new functional polymeric materials, but it has yet to be studied due to synthetic challenges. Here, metal atoms are interconnected as the backbones of polymers to yield metal-backboned polymers (MBPs). Rational design of multidentate ligands synthesized via an efficient iterative approach leads to the successful construction of a series of nickel-backboned polymers (NBPs) with well-defined lengths and up to 21 nickel atoms, whose structures are systematically confirmed. These NBPs exhibit strong and length-depended absorption with narrow band gaps, offering promising applications in optoelectronic devices and semiconductors. We also demonstrate the high thermal stability and solution processsability of such nickel-backboned polymers. Our results represent a new opportunity to design and synthesize a variety of new metal-backboned polymers for promising applications in the future.

3.
Food Funct ; 11(6): 5513-5524, 2020 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-32514515

RESUMO

Obesity is related to osteoarthritis (OA). Aberrant lipid metabolism results in increased levels of free fatty acids, such as palmitate (PA), leading to inflammatory responses and excess catabolism of chondrocytes. Asiatic acid (AA), a plant anti-inflammatory compound, has been reported to exert protective effects for several diseases, but its effect on obesity-related OA is still unclear. The aim of this study is to evaluate the chondro-protective effect of AA on PA-induced human chondrocytes and a high fat diet (HFD)-fed mouse cartilage degeneration model. In vitro, the levels of the inflammatory and extracellular matrix (ECM) markers of chondrocytes after being treated with PA (500 µM) and AA (2.5-10 µM) were determined using western blotting and immunofluorescence enzyme-linked immunosorbent assay (ELISA). In vivo, after the oral administration of HFD and AA, X-ray examination, safranin O staining, and ELISA assay were conducted to evaluate cartilage calcification and degeneration and cytokine and adipokine levels in the serum of mice. AA treatment eliminated the inflammation caused by PA and extracellular matrix degradation. Mechanistically, AA blocked the stimulation of the NF-κB pathway. Analysis with co-immunoprecipitation and molecular docking indicated that the MD-2/TLR4 complex was a target of AA. In vivo, AA treatment not only prevented HFD-induced OA changes but also reduced proinflammatory cytokine and adipokine production in obese mice. AA exerted a chondroprotective effect by inhibiting the TLR4/MD-2 axis, thus showing promise for treating obesity-related OA.


Assuntos
Antígeno 96 de Linfócito/antagonistas & inibidores , Osteoartrite/tratamento farmacológico , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/farmacologia , Triterpenos Pentacíclicos/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Cartilagem , Sobrevivência Celular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Citocinas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Matriz Extracelular/metabolismo , Humanos , Inflamação/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Obesidade/metabolismo , Palmitatos/farmacologia
4.
Biomaterials ; 255: 120138, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32521330

RESUMO

Great efforts have been made to develop suitable bioactive constructs that release growth factors (GFs) in a controlled manner for tissue-regeneration applications. Platelet lysates (PLs) are an affordable source of multiple GFs and other proteins, and show great potential in the wound-healing process. Herein, poly-l-lysine (PLL) and hyaluronic acid (HA) were applied to build free-standing polyelectrolyte multilayer films (PEMs) using the PH-amplified layer-by-layer self-assembly method. Molecular simulations were performed, which showed that in the end layer of PEMs, HA was more attractive to PLs than was PLL. The HA/PLL films constructed with or without 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide hydrochloride (EDC) cross-linking both absorbed PLs successfully, exhibiting high hydrophilicity and GF absorptivity. The release profile of the EDC30 film lasted up to 2 weeks, and PL-loaded films supported cell proliferation, adhesion, migration, and angiogenesis in vitro. Moreover, due to sustained delivery of PLs, the membranes (especially the crosslinked film) helped to promote granulation-tissue formation, collagen deposition, and neovascularization in the region of the defect, resulting in rapid re-epithelialization and regeneration of skin. Mechanistically, the beneficial effects of a PL-loaded PEM coating might be related to activation of the hypoxia-inducible factor-1(Hif-1α)/vascular endothelial growth factor (VEGF) axis. As an off-the-shelf and cell-free treatment option, these biomimetic multilayers have great potential for use in the fabrication of devices that allow stable incorporation of PLs, thereby exerting synergistic effects for efficient wound healing.


Assuntos
Bandagens , Fator A de Crescimento do Endotélio Vascular , Ácido Hialurônico , Pele , Cicatrização
5.
J Cell Mol Med ; 24(7): 4183-4193, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32090454

RESUMO

Osteoarthritis (OA), which is principally featured by progressive joint metabolic imbalance and subsequent degeneration of articular cartilage, is a common chronic joint disease. Arctigenin (ATG), a dietary phyto-oestrogen, has been described to have potent anti-inflammatory effects. Nevertheless, its protective effects on OA have not been clearly established. The target of our following study is to evaluate the protective effects of ATG on IL-1ß-induced human OA chondrocytes and mouse OA model. Our results revealed that the ATG pre-treatment effectively decreases the level of pro-inflammatory mediators, such as prostaglandin E2 (PGE2), nitrous oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), IL-6 and tumour necrosis factor alpha (TNF-α) in IL-1ß-induced human chondrocytes. In addition, ATG protects against the degradation of extracellular matrix (ECM) under the stimulation of IL-1ß and the possible mechanism might be connected with the inactivation of phosphatidylinositol-3-kinase (PI3K)/Akt/nuclear factor-kappa B (NF-κB) axis. Furthermore, a powerful binding capacity between ATG and PI3K was also uncovered in our molecular docking research. Meanwhile, ATG may act as a protector on the mouse OA model. Collectively, all these findings suggest that ATG could be utilized as a promising therapeutic agent for the treatment of OA.


Assuntos
Furanos/farmacologia , Inflamação/tratamento farmacológico , Interleucina-1beta/genética , Lignanas/farmacologia , Osteoartrite/tratamento farmacológico , Animais , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/crescimento & desenvolvimento , Condrócitos/efeitos dos fármacos , Dinoprostona/genética , Modelos Animais de Doenças , Progressão da Doença , Humanos , Inflamação/genética , Inflamação/patologia , Interleucina-6/genética , Camundongos , Simulação de Acoplamento Molecular , NF-kappa B/genética , Óxido Nítrico Sintase Tipo II/genética , Óxido Nitroso/metabolismo , Osteoartrite/genética , Osteoartrite/patologia , Fosfatidilinositol 3-Quinases/genética , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos
6.
Food Funct ; 9(11): 5641-5652, 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30299441

RESUMO

Osteoarthritis (OA) is a major cause of joint pain and disability, resulting in large socioeconomic costs worldwide. Isofraxidin (ISO), a bioactive coumarin compound isolated from the functional foods Siberian ginseng and Apium graveolens, exerts anti-inflammatory effects in a variety of diseases. However, no studies have reported the protective effects of ISO against OA development. Accordingly, this study aimed to assess the therapeutic effect of ISO in human OA chondrocytes, and in a mouse model of OA induced by destabilisation of the medial meniscus (DMM). In vitro, lipopolysaccharide (LPS)-induced overproduction of nitric oxide (NO), prostaglandin E2 (PGE2), tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) was decreased by ISO pre-treatment. Furthermore, ISO attenuated the increased expression of inflammatory enzymes, including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), in response to LPS stimulation. Meanwhile, LPS-induced extracellular matrix (ECM) degradation was also reversed by ISO treatment. Mechanistically, ISO competitively inhibited Toll-like receptor 4 (TLR4)/myeloid differentiation protein-2 (MD-2) complex formation, and thus TLR4/nuclear factor kappa B (NF-κB) signalling cascades. In vivo, ISO treatment not only prevented the calcification and erosion of cartilage, as well as the thickening of subchondral bone, but also reduced the serum levels of inflammatory cytokines in the mouse OA model. Taken together, these data suggest that ISO has potential in the treatment of OA.


Assuntos
Cumarínicos/farmacologia , Antígeno 96 de Linfócito/metabolismo , Osteoartrite/tratamento farmacológico , Receptor 4 Toll-Like/metabolismo , Idoso , Animais , Cartilagem/efeitos dos fármacos , Cartilagem/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/genética , Dinoprostona/metabolismo , Modelos Animais de Doenças , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Feminino , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolissacarídeos/toxicidade , Antígeno 96 de Linfócito/genética , Masculino , Camundongos , Pessoa de Meia-Idade , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Osteoartrite/genética , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
7.
Food Funct ; 9(3): 1701-1712, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29484338

RESUMO

Osteoarthritis (OA), which is characterized by progressive degradation of the articular cartilage, is the most prevalent form of human arthritis. Accumulating evidence has shown that polydatin (PD) exerts special biological functions in a variety of diseases. However, whether it protects against OA development has remained unknown. Here, we investigated the anti-inflammatory and chondroprotective effects of PD on interleukin (IL)-1ß-induced human osteoarthritic chondrocytes and in the surgical destabilization of medial meniscus mouse (DMM) OA models. In vitro, PD treatment completely suppressed the over-production of pro-inflammatory mediators, including prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), nitric oxide (NO), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and IL-6 in IL-1ß-induced human OA chondrocytes. Moreover, PD exerted a suppressive effect on the expression of matrix-degrading proteases, including matrix metalloproteinase 13 (MMP13) and thrombospondin motifs 5 (ADAMTS-5), which leads to the degradation of the extracellular matrix (ECM). Meanwhile, specific inhibition of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) level by short-interfering RNA (siRNA) strongly reversed the anti-inflammatory and chondroprotective effects of PD in human OA chondrocytes. The protective effects of PD were also observed in vivo. In conclusion, our studies demonstrate that PD holds novel therapeutic potential for the development of OA.


Assuntos
Anti-Inflamatórios/administração & dosagem , Condrócitos/efeitos dos fármacos , Glucosídeos/administração & dosagem , Interleucina-1beta/imunologia , Fator 2 Relacionado a NF-E2/imunologia , Osteoartrite/tratamento farmacológico , Osteoartrite/imunologia , Estilbenos/administração & dosagem , Animais , Condrócitos/imunologia , Humanos , Interleucina-1beta/genética , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , NF-kappa B/imunologia , Óxido Nítrico/imunologia , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Osteoartrite/genética , Transdução de Sinais/efeitos dos fármacos
8.
Int J Pharm ; 359(1-2): 63-9, 2008 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-18455893

RESUMO

The purpose of this study was to evaluate the potential of microspheres for taste masking when incorporated into orally disintegrating tablets. The microspheres were produced by spray drying a mixture of the model compound (famotidine) with taste masking material. The spray process was optimized using a central composite design for two variables to obtain microspheres with desirable characteristics. Then the microspheres were mixed with other excipients to form orally disintegrating tablets. The optimal spray-drying process parameters were 34mg/ml for solid concentration and 7ml/min for feed rate. The drug encapsulation efficiency of the spray-dried microspheres ranges from of 37.59 to 61.56%, with a mean diameter of less than 10microm size and low moisture content (less than 4%). Results from an evaluation by a panel of six human volunteers demonstrated that the orally disintegrating tablets with taste masking microspheres improved the taste significantly. Furthermore, an in vivo study in rats showed that the microspheres neither decrease the bioavailability nor retard the release of famotidine significantly. In conclusion, spray-dried microspheres can effectively mask the bitter taste of the active pharmaceutical ingredients in combination with the orally disintegrating tablets.


Assuntos
Famotidina/química , Antagonistas dos Receptores H2 da Histamina/química , Microesferas , Paladar , Administração Oral , Animais , Disponibilidade Biológica , Química Farmacêutica , Famotidina/farmacocinética , Antagonistas dos Receptores H2 da Histamina/farmacocinética , Humanos , Masculino , Tamanho da Partícula , Ratos , Ratos Wistar , Método Simples-Cego , Solubilidade , Comprimidos
9.
Zhongguo Zhong Yao Za Zhi ; 29(2): 101-3, 2004 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-15719670

RESUMO

As a drug additive, polyvinyl alcohol(PVA) has merits of solubility, easy forming, strong conglutination, high thermal stability, low toxicity and no irritation. In these years, PVA has been applied wider and wider in medicine industry. In the study of modem preparations of TCM PVA, as film material of membrane and pellicles, is very promising owing to its easy forming and excellent toughness. PVA is good polymer matrix for suppositories and gel, because it can not only carry drug but also improve the properties of preparations on application and technology. It can be said that PVA is an excellent carrier. At the present, PVA is mainly applied in vitro preparations of TCM, but its applications will be spread with further research. The prospective applications of PVA in osmotic pump controlled release preparations, drug carried microspheres and swelling controlled release system are foreseen.


Assuntos
Sistemas de Liberação de Medicamentos , Medicamentos de Ervas Chinesas/administração & dosagem , Plantas Medicinais , Álcool de Polivinil , Preparações de Ação Retardada , Portadores de Fármacos , Medicamentos de Ervas Chinesas/isolamento & purificação , Plantas Medicinais/química
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