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1.
Biomaterials ; 297: 122105, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37031548

RESUMO

The WNT signaling pathway is a central regulator of bone development and regeneration. Functional alterations of WNT ligands and inhibitors are associated with a variety of bone diseases that affect bone fragility and result in a high medical and socioeconomic burden. Hence, this cellular pathway has emerged as a novel target for bone-protective therapies, e.g. in osteoporosis. Here, we investigated glycosaminoglycan (GAG) recognition by Dickkopf-1 (DKK1), a potent endogenous WNT inhibitor, and the underlying functional implications in order to develop WNT signaling regulators. In a multidisciplinary approach we applied in silico structure-based de novo design strategies and molecular dynamics simulations combined with synthetic chemistry and surface plasmon resonance spectroscopy to Rationally Engineer oligomeric Glycosaminoglycan derivatives (REGAG) with improved neutralizing properties for DKK1. In vitro and in vivo assays show that the GAG modification to obtain REGAG translated into increased WNT pathway activity and improved bone regeneration in a mouse calvaria defect model with critical size bone lesions. Importantly, the developed REGAG outperformed polymeric high-sulfated hyaluronan (sHA3) in enhancing bone healing up to 50% due to their improved DKK1 binding properties. Thus, rationally engineered GAG variants may represent an innovative strategy to develop novel therapeutic approaches for regenerative medicine.


Assuntos
Doenças Ósseas , Regeneração Óssea , Glicosaminoglicanos , Peptídeos e Proteínas de Sinalização Intercelular , Animais , Camundongos , Osso e Ossos/metabolismo , Glicosaminoglicanos/metabolismo , Via de Sinalização Wnt
2.
RSC Adv ; 12(11): 6601, 2022 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-35427078

RESUMO

[This corrects the article DOI: 10.1039/D1RA03390E.].

3.
BMC Med Imaging ; 11: 15, 2011 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-21699694

RESUMO

BACKGROUND: With the development of increasingly sophisticated three-dimensional volumetric imaging methods, tumor volume can serve as a robust and reproducible measurement of drug efficacy. Since the use of molecularly targeted agents in the clinic will almost certainly involve combinations with other therapeutic modalities, the use of volumetric determination can help to identify a dosing schedule of sequential combinations of cytostatic drugs resulting in long term control of tumor growth with minimal toxicity. The aim of this study is to assess high resolution sonography imaging for the in vivo monitoring of efficacy of Infliximab in pancreatic tumor. METHODS: In the first experiment, primary orthotopic pancreatic tumor growth was measured with Infliximab treatment. In the second experiment, orthotopic tumors were resected ten days after inoculation of tumor cells and tumor recurrence was measured following Infliximab treatment. Tumor progression was evaluated using 3D high resolution sonography. RESULTS: Sonography measurement of tumor volume in vivo showed inhibitory effect of Infliximab on primary tumor growth in both non-resected and resected models. Measurement of the dynamics of tumor growth by sonography revealed that in the primary tumor Infliximab is effective against established tumors while in the resection model, Infliximab is more effective at an early stage following tumor resection. Infliximab treatment is also effective in inhibiting tumor growth growth as a result of tumor cell contamination of the surgical field. CONCLUSIONS: Clinical application of Infliximab is feasible in both the neoadjuvant and adjuvant setting. Infliximab is also effective in slowing the growth of tumor growth under the peritoneum and may have application in treating peritoneal carcinomatosis. Finally the study demonstrates that high resolution sonography is a sensitive imaging modality for the measurement of pancreatic tumor growth.


Assuntos
Anticorpos Monoclonais/farmacologia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/tratamento farmacológico , Análise de Variância , Animais , Modelos Animais de Doenças , Feminino , Interpretação de Imagem Assistida por Computador , Imageamento Tridimensional , Infliximab , Camundongos , Camundongos SCID , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Reprodutibilidade dos Testes , Carga Tumoral , Ultrassonografia
4.
RSC Adv ; 11(36): 22221-22229, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-35480817

RESUMO

Compared to the numerous X-ray crystal structures of protein-carbohydrate complexes, the successful elucidation of the crystal structures of complexes between artificial receptors and carbohydrates has been very rarely reported in the literature. In this work, we describe the binding modes of two complexes formed between methyl α-d-glucopyranoside and an artificial receptor belonging to the class of compounds consisting of a 1,3,5-trisubstituted 2,4,6-trialkylbenzene scaffold. It is particularly noteworthy that these two complexes are present in one crystal structure, as was observed by us for the first time in the case of the recently reported three crystal structures of the complexes with methyl ß-d-glucopyranoside, each containing two different receptor-carbohydrate complexes. The noncovalent interactions stabilizing the new complexes are compared with those observed in the aforementioned crystalline complexes with methyl ß-d-glucopyranoside.

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