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31.
Koch MA Wittenberg LO Basu S Jeyaraj DA Gourzoulidou E Reinecke K Odermatt A Waldmann H 《Proceedings of the National Academy of Sciences of the United States of America》2004,101(48):16721-16726
To identify biologically relevant and drug-like protein ligands for medicinal chemistry and chemical biology research the grouping of proteins according to evolutionary relationships and conservation of molecular recognition is an established method. We propose to employ structure similarity clustering of the ligand-sensing cores of protein domains (PSSC) in conjunction with natural product guided compound library development as a synergistic approach for the identification of biologically prevalidated ligands with high fidelity. This is supported by the concepts that (i) in nature spatial structure is more conserved than amino acid sequence, (ii) the number of fold types characteristic for all protein domains is limited, and (iii) the underlying frameworks of natural product classes with multiple biological activities provide evolutionarily selected starting points in structural space. On the basis of domain core similarity considerations and irrespective of sequence similarity, Cdc25A phosphatase, acetylcholinesterase, and 11beta-hydroxysteroid dehydrogenases type 1 and type 2 were grouped into a similarity cluster. A 147-member compound collection derived from the naturally occurring Cdc25A inhibitor dysidiolide yielded potent and selective inhibitors of the other members of the similarity cluster with a hit rate of 2-3%. Protein structure similarity clustering may provide an experimental opportunity to identify supersites in proteins. 相似文献
32.
Eleni Maria Varypataki Koen van der Maaden Joke Bouwstra Ferry Ossendorp Wim Jiskoot 《The AAPS journal》2015,17(1):216-226
For effective cancer immunotherapy by vaccination, co-delivery of tumour antigens and adjuvants to dendritic cells and subsequent activation of antigen-specific cytotoxic T cells (CTLs) is crucial. In this study, a synthetic long peptide (SLP) harbouring the model CTL epitope SIINFEKL was encapsulated with the TLR3 ligand poly(inosinic-polycytidylic acid) (poly(I:C)) in cationic liposomes consisting of DOTAP and DOPC. The obtained particles were down-sized to about 140 nm (measured by dynamic light scattering) and had a positive zeta-potential of about 26 mV (according to laser Doppler electrophoresis). SLP loading efficiency was about 40% as determined by HPLC. Poly(I:C) loading efficiency was about 50%, as assessed from the fluorescence intensity of fluorescently labelled poly(I:C). Immunogenicity of the liposomal SLP vaccine was evaluated in vitro by its capacity to activate dendritic cells (DCs) and present the processed SLP to SIINFEKL-specific T cells. The effectiveness of the vaccine to activate CD8+ T cells was analysed in vivo after intradermal and subcutaneous immunisation in mice, by measuring antigen-specific T cells in blood and spleens and assessing their functionality by cytokine production and in vivo cytotoxicity. The liposomal formulation efficiently delivered the SLP to DCs in vitro and induced a functional CD8+ T cell immune response in vivo to the CTL epitope present in the SLP. The SLP-specific CD8+ T cell frequency induced by the poly(I:C)-adjuvanted liposomal SLP formulation showed an at least 25 fold increase over the T cell frequency induced by the poly(I:C)-adjuvanted soluble SLP. In conclusion, cationic liposomes loaded with SLP and poly(I:C) have potential as a powerful therapeutic cancer vaccine formulation.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-014-9686-4) contains supplementary material, which is available to authorized users.KEY WORDS: cancer immunotherapy, cationic liposomes, CTL epitope, peptide antigen, Poly(I:C) 相似文献33.
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36.
Anna Theodorou-Kanakari Spyridon Karampitianis Vasiliki Karageorgou Eleni Kampourelli Efstathios Kapasakis Panagiotis Theodossiadis Irini Chatziralli 《Advances in therapy》2018,35(10):1510-1518
Introduction
The purpose of this review is to present the current and emerging treatment alternatives for Leber’s hereditary optic neuropathy (LHON), emphasizing the most recent use of idebenone and stem cells or gene therapy.Methods
A comprehensive literature review was performed at the PubMed database regarding the various treatment modalities for LHON.Results
Treatment modalities for LHON include nutritional supplements, activators of mitochondrial biogenesis, brimonidine, and symptomatic and supportive treatment, but nowadays attention is being paid to idebenone and gene therapy or stem cells.Conclusion
The treatment of LHON remains challenging, given the nature of the disease and its prognosis.37.
38.
Aikaterini Nanou Chrisavgi Toumpeki Pavlos Fanis Nicoletta Bianchi Lucia Carmela Cosenza Cristina Zuccato George Sentis Giorgos Giagkas Coralea Stephanou Marios Phylactides Soteroula Christou Michalis Hadjigavriel Maria Sitarou Carsten W. Lederer Roberto Gambari Marina Kleanthous Eleni Katsantoni 《Haematologica》2021,106(4):1207
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40.
Ghrelin secretion in humans is sexually dimorphic,suppressed by somatostatin,and not affected by the ambient growth hormone levels 总被引:11,自引:0,他引:11
Barkan AL Dimaraki EV Jessup SK Symons KV Ermolenko M Jaffe CA 《The Journal of clinical endocrinology and metabolism》2003,88(5):2180-2184
We studied plasma ghrelin and GH concentrations over a 24-h period in young healthy men and women and in patients with acromegaly. Healthy subjects were restudied after administration of GH-lowering agents, octreotide or GHRH antagonist. Ghrelin concentrations in women studied during the late follicular stage of the cycle were about 3-fold higher than in men. Suppression of GH secretion by GHRH antagonist did not alter ghrelin concentration profiles. In the presence of high GH levels (acromegaly), ghrelin levels were similar to those found in healthy men. Administration of somatostatin analog octreotide suppressed both GH and ghrelin concentration profiles. We conclude that: 1) ghrelin secretion is sexually dimorphic in humans, with women in the late follicular stage having higher levels than men; 2) ghrelin secretion is suppressed by somatostatin; and 3) GH has no influence over ghrelin secretion. 相似文献