Articles de revues : « Elastin-Like Polypeptides (ELP) »

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Tang, Xin. « Elastin-Like Polypeptides as Thermosensitive Polymer System ». Advanced Materials Research 898 (février 2014) : 296–99. http://dx.doi.org/10.4028/www.scientific.net/amr.898.296.

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Thermo-responsive elastin-like polypeptides (ELPs) were successfully obtained by inverse transition cycling (ITC) and recursive directional ligation (RDL). Six ELPs displayed thermal properties, depending on their sequence and chain length. It was found that the ELP[KV8F-4 and ELP[KV8F-8 were effective as thermosensitive materials at the body temperature with phase transition temperature from 35 to 45oC.

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Lin, Charng-Yu, et Julie C. Liu. « Incorporation of short, charged peptide tags affects the temperature responsiveness of positively-charged elastin-like polypeptides ». Journal of Materials Chemistry B 7, n^o 34 (2019) : 5245–56. http://dx.doi.org/10.1039/c9tb00821g.

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Dai, Michèle, Evangelos Georgilis, Guillaume Goudounet, Bertrand Garbay, Jan Pille, Jan C. M. van Hest, Xavier Schultze, Elisabeth Garanger et Sébastien Lecommandoux. « Refining the Design of Diblock Elastin-Like Polypeptides for Self-Assembly into Nanoparticles ». Polymers 13, n^o 9 (1 mai 2021) : 1470. http://dx.doi.org/10.3390/polym13091470.

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Diblock copolymers based-on elastin-like polypeptide (ELP) have the potential to undergo specific phase transitions when thermally stimulated. This ability is especially suitable to form carriers, micellar structures for instance, for delivering active cargo molecules. Here, we report the design and study of an ELP diblock library based on ELP-[M1V3-i]-[I-j]. First, ELP-[M1V3-i]-[I-j] (i = 20, 40, 60; j = 20, 90) that showed a similar self-assembly propensity (unimer-to-aggregate transition) as their related monoblocks ELP-[M1V3-i] and ELP-[I-j]. By selectively oxidizing methionines of ELP-[M1V3-i] within the different diblocks structures, we have been able to access a thermal phase transition with three distinct regimes (unimers, micelles, aggregates) characteristic of well-defined ELP diblocks.

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Dragojevic, Sonja, Rebecca Mackey et Drazen Raucher. « Evaluation of Elastin-Like Polypeptides for Tumor Targeted Delivery of Doxorubicin to Glioblastoma ». Molecules 24, n^o 18 (6 septembre 2019) : 3242. http://dx.doi.org/10.3390/molecules24183242.

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To increase treatment efficiency for glioblastoma, we have developed a system to selectively deliver chemotherapeutic doxorubicin (Dox) to Glioblastoma (GBM) tumors. This carrier is based on elastin-like polypeptide (ELP), which is soluble at physiological temperatures but undergoes a phase transition and accumulates at tumor sites with externally applied, mild (40–41 °C) hyperthermia. The CPP-ELP-Dox conjugate consists of a cell penetrating peptide (CPP), which facilitates transcytosis through the blood brain barrier and cell entry, and a 6-maleimidocaproyl hydrazone derivative of doxorubicin at the C-terminus of ELP. The acid-sensitive hydrazone linker ensures release of Dox in the lysosomes/endosomes after cellular uptake of the drug conjugate. We have shown that CPP-ELP-Dox effectively inhibits cell proliferation in three GBM cell lines. Both the free drug and CPP-ELP-Dox conjugate exhibited similar in vitro cytotoxicity, although their subcellular localization was considerably different. The Dox conjugate was mainly dispersed in the cytoplasm, while free drug had partial nuclear accumulation in addition to cytoplasmic distribution. The intracellular Dox concentration was increased in the CPP-ELP-Dox cells compared to that in the cells treated with free Dox, which positively correlates with cytotoxic activity. In summary, our findings demonstrate that CPP-ELP-Dox effectively kills GBM cells. Development of such a drug carrier has the potential to greatly improve current therapeutic approaches for GBM by increasing the specificity and efficacy of treatment and reducing cytotoxicity in normal tissues.

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VerHeul, Ross, Craig Sweet et David H. Thompson. « Rapid and simple purification of elastin-like polypeptides directly from whole cells and cell lysates by organic solvent extraction ». Biomaterials Science 6, n^o 4 (2018) : 863–76. http://dx.doi.org/10.1039/c8bm00124c.

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Elastin-like peptide (ELP) constructs are typically hydrophobic in nature. A rapid organic solvent extraction method is reported that affords highly pure ELP with removal of key contaminants such as nucleic acids and LPS.

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Lee, Sujin, Ji-Eun Kim, Hye-Jin Seo et Jun-Hyeog Jang. « Design of fibronectin type III domains fused to an elastin-like polypeptide for the osteogenic differentiation of human mesenchymal stem cells ». Acta Biochimica et Biophysica Sinica 51, n^o 8 (2 juillet 2019) : 856–63. http://dx.doi.org/10.1093/abbs/gmz063.

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Abstract Extracellular matrix (ECM) including fibronectin (FN) and elastin plays a pivotal role in providing a microenvironment to support tissue regeneration in stem cell therapy. To develop a novel biomimetic ECM for stem cell differentiation, we engineered FN type III 9 and 10 domains fused to elastin-like polypeptides (FN-ELPs). The recombinant FN-ELP fusion protein was expressed in Escherichia coli and purified by inverse transition cycling. Human mesenchymal stem cells (hMSCs) cultured on plates coated with FN-ELP had significantly greater adhesion activity and proliferation than cells grown on non-coated plates. FN-ELP induced the osteogenic differentiation by elevating alkaline phosphatase (ALP) and mineralization activity of hMSCs. Furthermore, the osteogenic marker gene expressions of ALP, collagen type I (Col I), osteopontin (OPN), and transcriptional coactivator with a PDZ-binding motif (TAZ) were increased in hMSCs cultured on plates coated with FN-ELP. We reported a novel biomimetic ECM with potential for bone regeneration that promotes the osteogenic differentiation of hMSCs.

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Funtan, Sebastian, Anne Funtan, Reinhard Paschke et Wolfgang H. Binder. « Biomimetic Elastin-Like Polypeptides as Materials for the Activation of Mechanophoric Catalysts ». Organic Materials 02, n^o 02 (avril 2020) : 116–28. http://dx.doi.org/10.1055/s-0040-1702149.

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Elastin-like polypeptides (ELPs) are well known for their elastic and thermoresponsive behaviors. Their elasticity originates from the formation of a β-spiral which is the consequence of stacking type-II β-turns, formed from individual VPGVG pentapeptide units. Here, the synthesis of ELPs of varying chain lengths [VPGVG, (VPGVG)2, and (VPGVG)4] and their coupling to a mechanoresponsive catalyst are reported. The attached ELP chains can act as “molecular springs,” allowing for an efficient uptake and transmission of an applied force to the mechanophoric bond. This leads to stress-induced activation of the mechanophoric catalyst, in turn transforming mechanical energy into a “click” reaction. Secondary structure analysis via IR and CD spectroscopy revealed that the β–spiral formation of the ELP is not affected by the coupling process and the β–spiral is still intact in the mechanocatalyst after the coupling. Mechanochemical activation of the synthesized catalysts by an external applied force, studied via ultrasonication, showed conversions of the copper(I)-catalyzed alkyne-azide “click” reaction (CuAAC) up to 5.6% with an increasing chain length of the peptide, proving the potential to incorporate this chemistry into biomaterial engineering.

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Wang, Wan, Changrim Lee, Martha Pastuszka, Gordon W. Laurie et J. Andrew MacKay. « Thermally-Responsive Loading and Release of Elastin-Like Polypeptides from Contact Lenses ». Pharmaceutics 11, n^o 5 (7 mai 2019) : 221. http://dx.doi.org/10.3390/pharmaceutics11050221.

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Contact lenses are widely prescribed for vision correction, and as such they are an attractive platform for drug delivery to the anterior segment of the eye. This manuscript explores a novel strategy to drive the reversible adsorption of peptide-based therapeutics using commercially available contact lenses. To accomplish this, thermo-sensitive elastin-like polypeptides (ELPs) alone or tagged with a candidate ocular therapeutic were characterized. For the first time, this manuscript demonstrates that Proclear CompatiblesTM contact lenses are a suitable platform for ELP adsorption. Two rhodamine-labelled ELPs, V96 (thermo-sensitive) and S96 (thermo-insensitive), were employed to test temperature-dependent association to the contact lenses. During long-term release into solution, ELP coacervation significantly modulated the release profile whereby more than 80% of loaded V96 retained with a terminal half-life of ~4 months, which was only 1–4 days under solubilizing conditions. A selected ocular therapeutic candidate lacritin-V96 fusion (LV96), either free or lens-bound LV96, was successfully transferred to HCE-T cells. These data suggest that ELPs may be useful to control loading or release from certain formulations of contact lenses and present a potential for this platform to deliver a biologically active peptide to the ocular surface via contact lenses.

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Sugioka, Yusuke, Jin Nakamura, Chikara Ohtsuki et Ayae Sugawara-Narutaki. « Thixotropic Hydrogels Composed of Self-Assembled Nanofibers of Double-Hydrophobic Elastin-Like Block Polypeptides ». International Journal of Molecular Sciences 22, n^o 8 (15 avril 2021) : 4104. http://dx.doi.org/10.3390/ijms22084104.

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Physically crosslinked hydrogels with thixotropic properties attract considerable attention in the biomedical research field because their self-healing nature is useful in cell encapsulation, as injectable gels, and as bioinks for three-dimensional (3D) bioprinting. Here, we report the formation of thixotropic hydrogels containing nanofibers of double-hydrophobic elastin-like polypeptides (ELPs). The hydrogels are obtained with the double-hydrophobic ELPs at 0.5 wt%, the concentration of which is an order of magnitude lower than those for previously reported ELP hydrogels. Although the kinetics of hydrogel formation is slower for the double-hydrophobic ELP with a cell-binding sequence, the storage moduli G′ of mature hydrogels are similar regardless of the presence of a cell-binding sequence. Reversible gel–sol transitions are demonstrated in step-strain rheological measurements. The degree of recovery of the storage modulus G′ after the removal of high shear stress is improved by chemical crosslinking of nanofibers when intermolecular crosslinking is successful. This work would provide deeper insight into the structure–property relationships of the self-assembling polypeptides and a better design strategy for hydrogels with desired viscoelastic properties.

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Cobb, Jared S., Anna S. Rourke, Aiden Creel et Amol V. Janorkar. « Manipulating the solution environment to control the surface roughness of elastin-based polymer coatings ». Journal of Biomaterials Applications 36, n^o 3 (17 avril 2021) : 419–27. http://dx.doi.org/10.1177/08853282211010302.

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Elastin-like polypeptides (ELP) have been used as a genetically-engineered, biocompatible substitute for elastin. Cell culture coatings prepared using ELP conjugated to low molecular weight polyethyleneimine (PEI) entices cells to form three-dimensional cellular aggregates that mimic their in vivo counterparts. This study seeks to control the deposition of the ELP and ELP-PEI molecules to control the roughness of the final coatings. The two polymers were coated onto three different substrates (glass, polystyrene, tissue-culture polystyrene) and the solution environment was altered by changing the polymer concentration (0.5, 1.0, 1.5 mg/mL) and/or salt concentration (None, 0.2 M phosphate buffered saline) for a total of 36 conditions. Atomic force microscopy (AFM) was used to measure the average roughness (Ra) of the samples and found that ELP coated samples had a higher Ra than their ELP-PEI counterparts. The coatings were tested for stability by performing cell culture media changes every three days for 11 days. AFM showed that the average roughness of the tested samples increased with each media change. To address this, the surfaces were crosslinked using hexamethyl diisocyanate, which minimized the change in surface roughness even when subjected to an intense sonication process. This study provides parameters to achieve elastin-based coatings with controlled roughness that can be used to support stable, long-term in vitro cell culture.

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Ryu, Jung Su, Felix Kratz et Drazen Raucher. « Cell-Penetrating Doxorubicin Released from Elastin-Like Polypeptide Kills Doxorubicin-Resistant Cancer Cells in In Vitro Study ». International Journal of Molecular Sciences 22, n^o 3 (23 janvier 2021) : 1126. http://dx.doi.org/10.3390/ijms22031126.

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Elastin-like polypeptides (ELPs) undergo a characteristic phase transition in response to ambient temperature. Therefore, it has been be used as a thermosensitive vector for the delivery of chemotherapy agents since it can be used to target hyperthermic tumors. This novel strategy introduces unprecedented options for treating cancer with fewer concerns about side effects. In this study, the ELP system was further modified with an enzyme-cleavable linker in order to release drugs within tumors. This system consists of an ELP, a matrix metalloproteinase (MMP) substrate, a cell-penetrating peptide (CPP), and a 6-maleimidocaproyl amide derivative of doxorubicin (Dox). This strategy shows up to a 4-fold increase in cell penetration and results in more death in breast cancer cells compared to ELP-Dox. Even in doxorubicin-resistant cells (NCI/ADR and MES-SA/Dx5), ELP-released cell-penetrating doxorubicin demonstrated better membrane penetration, leading to at least twice the killing of resistant cells compared to ELP-Dox and free Dox. MMP-digested CPP-Dox showed better membrane penetration and induced more cancer cell death in vitro. This CPP-complexed Dox released from the ELP killed even Dox-resistant cells more efficiently than both free doxorubicin and non-cleaved ELP-CPP-Dox.

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Le Fer, Gaëlle, Delphine Portes, Guillaume Goudounet, Jean-Michel Guigner, Elisabeth Garanger et Sébastien Lecommandoux. « Design and self-assembly of PBLG-b-ELP hybrid diblock copolymers based on synthetic and elastin-like polypeptides ». Organic & ; Biomolecular Chemistry 15, n^o 47 (2017) : 10095–104. http://dx.doi.org/10.1039/c7ob01945a.

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Shi, Xianggang, Dongfeng Chen, Guodong Liu, Hailing Zhang, Xiaoyan Wang, Zhi Wu, Yan Wu, Feng Yu et Qinggang Xu. « Application of Elastin-Like Polypeptide in Tumor Therapy ». Cancers 14, n^o 15 (28 juillet 2022) : 3683. http://dx.doi.org/10.3390/cancers14153683.

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Elastin-like polypeptides (ELPs) are stimulus-responsive artificially designed proteins synthesized from the core amino acid sequence of human tropoelastin. ELPs have good biocompatibility and biodegradability and do not systemically induce adverse immune responses, making them a suitable module for drug delivery. Design strategies can equip ELPs with the ability to respond to changes in temperature and pH or the capacity to self-assemble into nanoparticles. These unique tunable biophysicochemical properties make ELPs among the most widely studied biopolymers employed in protein purification, drug delivery, tissue engineering and even in tumor therapy. As a module for drug delivery and as a carrier to target tumor cells, the combination of ELPs with therapeutic drugs, antibodies and photo-oxidation molecules has been shown to result in improved pharmacokinetic properties (prolonged half-life, drug targeting, cell penetration and controlled release) while restricting the cytotoxicity of the drug to a confined infected site. In this review, we summarize the latest developments in the application methods of ELP employed in tumor therapy, with a focus on its conjugation with peptide drugs, antibodies and photosensitizers.

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Sugawara-Narutaki, Ayae, Sawako Yasunaga, Yusuke Sugioka, Duc H. T. Le, Issei Kitamura, Jin Nakamura et Chikara Ohtsuki. « Rheology of Dispersions of High-Aspect-Ratio Nanofibers Assembled from Elastin-Like Double-Hydrophobic Polypeptides ». International Journal of Molecular Sciences 20, n^o 24 (12 décembre 2019) : 6262. http://dx.doi.org/10.3390/ijms20246262.

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Elastin-like polypeptides (ELPs) are promising candidates for fabricating tissue-engineering scaffolds that mimic the extracellular environment of elastic tissues. We have developed a “double-hydrophobic” block ELP, GPG, inspired by non-uniform distribution of two different hydrophobic domains in natural elastin. GPG has a block sequence of (VGGVG)5-(VPGXG)25-(VGGVG)5 that self-assembles to form nanofibers in water. Functional derivatives of GPG with appended amino acid motifs can also form nanofibers, a display of the block sequence’s robust self-assembling properties. However, how the block length affects fiber formation has never been clarified. This study focuses on the synthesis and characterization of a novel ELP, GPPG, in which the central sequence (VPGVG)25 is repeated twice by a short linker sequence. The self-assembly behavior and the resultant nanostructures of GPG and GPPG were when compared through circular dichroism spectroscopy, atomic force microscopy, and transmission electron microscopy. Dynamic rheology measurements revealed that the nanofiber dispersions of both GPG and GPPG at an extremely low concentration (0.034 wt%) exhibited solid-like behavior with storage modulus G′ > loss modulus G” over wide range of angular frequencies, which was most probably due to the high aspect ratio of the nanofibers that leads to the flocculation of nanofibers in the dispersion.

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Won, J. I., J. W. Ro et H. Choi. « Phase behavior and physical properties of elastin-like polypeptide (ELP) block co-polypeptides : effects of drug delivery carriers ». New Biotechnology 44 (octobre 2018) : S108. http://dx.doi.org/10.1016/j.nbt.2018.05.1002.

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Pica, Andrea, et Giuseppe Graziano. « A Rationalization of the Effect That TMAO, Glycine, and Betaine Exert on the Collapse of Elastin-like Polypeptides ». Life 12, n^o 2 (18 janvier 2022) : 140. http://dx.doi.org/10.3390/life12020140.

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Elastin-like polypeptides (ELPs) are soluble in water at low temperature, but, on increasing the temperature, they undergo a reversible and cooperative, coil-to-globule collapse transition. It has been shown that the addition to water of either trimethylamine N-oxide (TMAO), glycine, or betaine causes a significant decrease of T(collapse) in the case of a specific ELP. Traditional rationalizations of these phenomena do not work in the present case. We show that an alternative approach, grounded in the magnitude of the solvent-excluded volume effect and its temperature dependence (strictly linked to the translational entropy of solvent and co-solute molecules), is able to rationalize the occurrence of ELP collapse in water on raising the temperature, as well as the T(collapse) lowering caused by the addition to water of either TMAO, glycine, or betaine.

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Bidwell, Gene L., Fakhri Mahdi, Qingmei Shao, Omar C. Logue, Jamarius P. Waller, Caleb Reese et Alejandro R. Chade. « A kidney-selective biopolymer for targeted drug delivery ». American Journal of Physiology-Renal Physiology 312, n^o 1 (1 janvier 2017) : F54—F64. http://dx.doi.org/10.1152/ajprenal.00143.2016.

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Improving drug delivery to the kidney using renal-targeted therapeutics is a promising but underdeveloped area. We aimed to develop a kidney-targeting construct for renal-specific drug delivery. Elastin-like polypeptides (ELPs) are nonimmunogenic protein-based carriers that can stabilize attached small-molecule and peptide therapeutics. We modified ELP at its NH2-terminus with a cyclic, seven-amino acid kidney-targeting peptide (KTP) and at its COOH-terminus with a cysteine residue for tracer conjugation. Comparative in vivo pharmacokinetics and biodistribution in rat and swine models and in vitro cell binding studies using human renal cells were performed. KTP-ELP had a longer plasma half-life than ELP in both animal models and was similarly accumulated in kidneys at levels fivefold higher than untargeted ELP, showing renal levels 15- to over 150-fold higher than in other major organs. Renal fluorescence histology demonstrated high accumulation of KTP-ELP in proximal tubules and vascular endothelium. Furthermore, a 14-day infusion of a high dose of ELP or KTP-ELP did not affect body weight, glomerular filtration rate, or albuminuria, or induce renal tissue damage compared with saline-treated controls. In vitro experiments showed higher binding of KTP-ELP to human podocytes, proximal tubule epithelial, and glomerular microvascular endothelial cells than untargeted ELP. These results show the high renal selectivity of KTP-ELP, support the notion that the construct is not species specific, and demonstrate that it does not induce acute renal toxicity. The plasticity of ELP for attachment of any class of therapeutics unlocks the possibility of applying ELP technology for targeted treatment of renal disease in future studies.

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Mahdi, Fakhri, Alejandro R. Chade et Gene L. Bidwell. « Utilizing a Kidney-Targeting Peptide to Improve Renal Deposition of a Pro-Angiogenic Protein Biopolymer ». Pharmaceutics 11, n^o 10 (18 octobre 2019) : 542. http://dx.doi.org/10.3390/pharmaceutics11100542.

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Elastin-like polypeptides (ELP) are versatile protein biopolymers used in drug delivery due to their modular nature, allowing fusion of therapeutics and targeting agents. We previously developed an ELP fusion with vascular endothelial growth factor (VEGF) and demonstrated its therapeutic efficacy in translational swine models of renovascular disease and chronic kidney disease. The goal of the current work was to refine renal targeting and reduce off-target tissue deposition of ELP–VEGF. The ELP–VEGF fusion protein was modified by adding a kidney-targeting peptide (KTP) to the N-terminus. All control proteins (ELP, KTP–ELP, ELP–VEGF, and KTP–ELP–VEGF) were also produced to thoroughly assess the effects of each domain on in vitro cell binding and activity and in vivo pharmacokinetics and biodistribution. KTP–ELP–VEGF was equipotent to ELP–VEGF and free VEGF in vitro in the stimulation of primary glomerular microvascular endothelial cell proliferation, tube formation, and extracellular matrix invasion. The contribution of each region of the KTP–ELP–VEGF protein to the cell binding specificity was assayed in primary human renal endothelial cells, tubular epithelial cells, and podocytes, demonstrating that the VEGF domain induced binding to endothelial cells and the KTP domain increased binding to all renal cell types. The pharmacokinetics and biodistribution of KTP–ELP–VEGF and all control proteins were determined in SKH-1 Elite hairless mice. The addition of KTP to ELP slowed its in vivo clearance and increased its renal deposition. Furthermore, addition of KTP redirected ELP–VEGF, which was found at high levels in the liver, to the kidney. Intrarenal histology showed similar distribution of all proteins, with high levels in blood vessels and tubules. The VEGF-containing proteins also accumulated in punctate foci in the glomeruli. These studies provide a thorough characterization of the effects of a kidney-targeting peptide and an active cytokine on the biodistribution of these novel biologics. Furthermore, they demonstrate that renal specificity of a proven therapeutic can be improved using a targeting peptide.

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Shamji, Mohammed F., Odelia Ghodsizadeh, Allan H. Friedman, William J. Richardson, Ashutosh Chilkoti et Lori A. Setton. « Development of a thermally responsive peptide for sustained deliver of solyble TNF receptor II to attenuate inflammatory events associated with radiculopathys ». Clinical & ; Investigative Medicine 30, n^o 4 (1 août 2007) : 94. http://dx.doi.org/10.25011/cim.v30i4.2873.

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Background: Tumor necrosis factor alpha (TNFα) is a cytokine that may mediate inflammatory histopathology of the dorsal root ganglion following lumbar disc herniation.1 Soluble TNF receptor II (sTNFRII) competitively binds TNFa with clinical value for painful radiculopathy.2 Bioactive peptides expressed with elastin-like polypeptides (ELP) fusion partners gain a thermally responsive domain, by which they can undergo hydrophobic collapse and separate from solution to aggregate at physiological temperatures.3 Protein release from such a depot may locally sustain drug presence, an effect demonstrated for non-fusion ELP after intra-articular injection.4 Methods: We expressed sTNFRII fused to ELP to demonstrate potential bidomain functionality. Protein Expression. A gene encoding ELP-(VPGVG)60 was subcloned adjacent to the sTNFRII and transformed into E.coli for expression.5 Protein Safety. Endotoxin content of purified fusion protein was evaluated using a limulus amebocyte lysate endpoint assay and compared to non-fusion ELP using a two-tailed Student’s t-test. Thermal Responsiveness. Dynamic light scattering evaluated the inverse thermal phase transition behaviour of ELP-sTNFRII, and absorbance spectrophotometry quantified the in vitro depot release at 37°C. Fusion Domain Function. Anti-TNFα bioactivity was assessed by the in vitro inhibition of TNFα-induced glutamate production by microglia. Single-factor ANOVA analyzed treatment differences for ELP-sTNFRII, commercial sTNFRII (positive control), and non-fusion ELP (negative control). A 44 kDa recombinant fusion protein was expressed from E. coli and purified by inverse transition cycling. Results: Measured endotoxin content for ELP-sTNFRII was comparable to ELP alone (p < 0.01), well below FDA levels for biomedical implants. The fusion protein underwent a thermally-induced phase transition and formed observable aggregates of ~240 nm upon heating to physiological temperatures (Tt = 32°C). Slow release was observed from this depot with a time constant of 21 ± 3 hours. The fusion protein demonstrated anti-TNFα activity in vitro by attenuating TNFα-induced microglial glutamate production, albeit requiring a greater concentration than the free antagonist to achieve the same effect.(p < 0.01). Conclusion: Fusion of a sTNFRII protein to an ELP can serve to generate a thermally-induced drug depot that may sustain anti-cytokine activity of agents delivered locally to a nerve region. Further directions may involve studying in vivo biodistribution after perineural delivery of ELP and in vivo disease modifying activity of this agent.

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Wada, Iori, Parameswaran G. Sreekumar, Christine Spee, Andrew J. MacKay, Michael Ip et Ram Kannan. « Mechanisms of Epithelial-Mesenchymal Transition and Prevention of Dispase-Induced PVR by Delivery of an Antioxidant αB Crystallin Peptide ». Antioxidants 11, n^o 10 (21 octobre 2022) : 2080. http://dx.doi.org/10.3390/antiox11102080.

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Proliferative Vitreoretinopathy (PVR) is a refractory retinal disease whose primary pathogenesis involves the epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells. At present, there is no effective treatment other than surgery for PVR. The purpose of this study was to investigate the effect of αB crystallin peptide (αBC-P) on EMT in PVR. We have previously shown that this peptide is antiapoptotic and regulates RPE redox status. Subconfluent primary human RPE (hRPE) cells were stimulated by TGFβ2 (10 ng/mL) with or without αBC-P (50 or 75 μg/mL) for 48 h and expression of EMT/mesenchymal to epithelial transition (MET) markers was determined. Mitochondrial ROS (mtROS) generation in hRPE cells treated with TGFβ2 was analyzed. The effect of TGFβ2 and αBC-P on oxidative phosphorylation (OXPHOS) and glycolysis in hRPE was studied. RPE cell migration was also assessed. A PVR-like phenotype was induced by intravitreal dispase injection in C57BL/6J mice. PVR progression and potential therapeutic efficiency of αBC-Elastin-like polypeptides (ELP) was studied using fundus photography, OCT imaging, ERG, and histologic analysis of the retina. αSMA, E-cadherin, Vimentin, Fibronectin and, RPE65, and CTGF were analyzed on Day 28. Additionally, the amount of VEGF-A in retinal cell lysates was measured. The EMT-associated αSMA, Vimentin, SNAIL and SLUG showed a significant upregulation with TGFβ2, and their expression was significantly suppressed by cotreatment with αBC-P. The MET-associated markers, E-cadherin and Sirt1, were significantly downregulated by TGFβ2 and were restored by αBC-P. Incubation of hRPE with TGFβ2 for 24 h showed a marked increase in mitochondrial ROS which was noticeably inhibited by αBC-ELP. We also showed that after TGFβ2 treatment, SMAD4 translocated to mitochondria which was blocked by αBC-ELP. Mitochondrial oxygen consumption rate increased with TGFβ2 treatment for 48 h, and αBC-P co-treatment caused a further increase in OCR. Glycolytic functions of RPE were significantly suppressed with αBC-P (75 μg/mL). In addition, αBC-P significantly inhibited the migration from TGFβ2 treatment in hRPE cells. The formation of proliferative membranes was suppressed in the αBC-ELP-treated group, as evidenced by fundus, OCT, and H&E staining in dispase-induced PVR in mice. Furthermore, ERG showed an improvement in c-wave amplitude. In addition, immunostaining showed significant suppression of αSMA and RPE65 expression. It was also observed that αBC-ELP significantly reduced the expression level of vimentin, fibronectin, and CTGF. Our findings suggest that the antioxidant αBC-P may have therapeutic potential in preventing PVR by reversing the phenotype of EMT/MET and improving the mitochondrial function in RPE cells.

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Mills, Carolyn E., Zachary Michaud et Bradley D. Olsen. « Elastin-like Polypeptide (ELP) Charge Influences Self-Assembly of ELP–mCherry Fusion Proteins ». Biomacromolecules 19, n^o 7 (23 mai 2018) : 2517–25. http://dx.doi.org/10.1021/acs.biomac.8b00147.

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Waller, Jamarius P., John Aaron Howell, Hali Peterson, Eric M. George et Gene L. Bidwell. « Elastin-Like Polypeptide : VEGF-B Fusion Protein for Treatment of Preeclampsia ». Hypertension 78, n^o 6 (décembre 2021) : 1888–901. http://dx.doi.org/10.1161/hypertensionaha.121.17713.

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Preeclampsia is characterized by the development of elevated blood pressure during the second and third trimesters of pregnancy that is accompanied by end organ dysfunction. The pathogenesis of preeclampsia is multifactorial but is commonly characterized by endothelial dysfunction and the overproduction of antiangiogenic factors, including the soluble VEGF (vascular endothelial growth factor) receptor sFlt-1 (soluble Fms-like tyrosine kinase receptor 1). Previously, administration of exogenous VEGF-A, bound to a carrier protein called ELP (elastin-like polypeptide), significantly reduced free sFlt-1 levels and attenuated the hypertensive response in a rodent model of preeclampsia. However, VEGF-A administration induces multifactorial effects mediated through its direct activation of the Flk-1 receptor. In response to this, we developed a therapeutic chimera using ELP bound to VEGF-B, a VEGF isoform that binds to sFlt-1 but not to Flk-1. The purpose of this study was to evaluate the in vitro activity and pharmacological properties of ELP-VEGF-B and to test its efficacy in the reduced uterine perfusion pressure rat model of placental ischemia. ELP-VEGF-B was less potent than ELP-VEGF-A in stimulation of endothelial cell proliferation and matrix invasion, indicating that it is a weaker angiogenic driver. However, after repeated subcutaneous administration in pregnant rats, ELP-VEGF-B was maternally sequestered and reduced blood pressure when compared with saline treated animals following induction of placental ischemia (123.38±11.4 versus 139.98±10.56 mm Hg, P =0.0129). Blood pressure reduction was associated with a restoration of the angiogenic capacity of plasma from rats treated with ELP-VEGF-B. ELP-VEGF-B is a nonangiogenic, maternally sequestered protein with potential efficacy for treatment of preeclampsia.

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Dragojevic, Sonja, Lindsay Turner, Pallabi Pal, Amol V. Janorkar et Drazen Raucher. « Elastin-like Polypeptide Hydrogels for Tunable, Sustained Local Chemotherapy in Malignant Glioma ». Pharmaceutics 14, n^o 10 (28 septembre 2022) : 2072. http://dx.doi.org/10.3390/pharmaceutics14102072.

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Glioblastoma (GBM) is a primary brain tumor that carries a dismal prognosis, which is primarily attributed to tumor recurrence after surgery and resistance to chemotherapy. Since the tumor recurrence appears near the site of surgical resection, a concept of immediate and local application of chemotherapeutic after initial tumor removal could lead to improved treatment outcome. With the ultimate goal of developing a locally-applied, injectable drug delivery vehicle for GBM treatment, we created elastin-like polypeptide (ELP) hydrogels. The ELP hydrogels can be engineered to release anti-cancer drugs over an extended period. The purpose of this study was to evaluate the biomechanical properties of ELP hydrogels, to characterize their ability to release doxorubicin over time, and to investigate, in vitro, the anti-proliferative effect of Dox-laden ELP hydrogels on GBM. Here, we present microstructural differences, swelling ratio measurements, drug release characteristics, and in vitro effects of different ELP hydrogel compositions. We found that manipulation of the ELP–collagen ratio allows for tunable drug release, that the released drug is taken up by cells, and that incubation with a small volume of ELP-Dox hydrogel drastically reduced survival and proliferation of GBM cells in vitro. These results underscore the potential of ELP hydrogels as a local delivery strategy to improve prognosis for GBM patients after tumor resection.

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TURNER, PAUL A., GAURAV V. JOSHI, C. ANDREW WEEKS, R. SCOTT WILLIAMSON, AARON D. PUCKETT et AMOL V. JANORKAR. « NANO AND MICRO-STRUCTURES OF ELASTIN-LIKE POLYPEPTIDE-BASED MATERIALS AND THEIR APPLICATIONS : RECENT DEVELOPMENTS ». Nano LIFE 03, n^o 04 (décembre 2013) : 1343002. http://dx.doi.org/10.1142/s1793984413430022.

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Elastin-like polypeptide (ELP) containing materials have spurred significant research interest for biomedical applications exploiting their biocompatible, biodegradable and nonimmunogenic nature while maintaining precise control over their chemical structure and functionality through genetic engineering. Physical, mechanical and biological properties of ELPs could be further manipulated using genetic engineering or through conjugation with a variety of chemical moieties. These chemical and physical modifications also achieve interesting micro- and nanostructured ELP-based materials. Here, we review the recent developments during the past decade in the methods to engineer elastin-like materials, available genetic and chemical modification methods and applications of ELP micro and nanostructures in tissue engineering and drug delivery.

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Huang, Kaizong, Mengyue Gao, Lin Fan, Yueyang Lai, Hongwei Fan et Zichun Hua. « IR820 covalently linked with self-assembled polypeptide for photothermal therapy applications in cancer ». Biomaterials Science 6, n^o 11 (2018) : 2925–31. http://dx.doi.org/10.1039/c8bm00399h.

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Elastin-like polypeptide covalently was linked with IR820 in an aqueous environment, followed by self-assembly into nanoparticles after adding to zinc ions solution. ELP-IR820 nanoparticles significantly accumulated at the tumor site.

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Cai, Lei, Cong B. Dinh et Sarah C. Heilshorn. « One-pot synthesis of elastin-like polypeptide hydrogels with grafted VEGF-mimetic peptides ». Biomater. Sci. 2, n^o 5 (2014) : 757–65. http://dx.doi.org/10.1039/c3bm60293a.

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We present a one-pot, single-step, cell-compatible strategy to tether VEGF-mimetic QK peptides into elastin-like polypeptide (ELP) hydrogels while simultaneously encapsulating endothelial cells to promote their three-dimensional outgrowth.

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Dragojevic, Sonja, Lindsay Turner et Drazen Raucher. « Circumventing Doxorubicin Resistance Using Elastin-like Polypeptide Biopolymer-Mediated Drug Delivery ». International Journal of Molecular Sciences 23, n^o 4 (19 février 2022) : 2301. http://dx.doi.org/10.3390/ijms23042301.

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Although doxorubicin (dox), an anthracycline antibiotic, is widely used and effective in treating cancer, its treatment efficiency is limited by low blood plasma solubility, poor pharmacokinetics, and adverse side effects, including irreversible cardiotoxicity. Moreover, cancer cells often develop drug resistance over time, which decreases the efficacy of anti-cancer drugs, including dox. In this study, we examine a macromolecular drug delivery system for its ability to specifically deliver doxorubicin to cancer cells with and without drug resistance. This drug delivery system consists of a multi-part macromolecule, which includes the following: elastin-like polypeptide (ELP), cell penetrating peptide (CPP), a cleavable linker (releasing at low pH), and a derivative of doxorubicin. ELP is thermally responsive and improves drug solubility, while the CPP mediates cellular uptake of macromolecules. We compared cytotoxicity of two doxorubicin derivatives, where one is cleavable (DOXO) and contains a pH-sensitive linker and releases dox in an acidic environment, and the other is non-cleavable (ncDox) doxorubicin. Cytotoxicity, apoptosis, cell cycle distribution and mechanism of action of these constructs were tested and compared between dox-responsive MCF-7 and dox-resistant NCI/ADR cell lines. Dox delivered by the ELP construct is comparably toxic to both sensitive and drug resistant cell lines, compared to unconjugated doxorubicin, and given the pharmacokinetic and targeting benefits conveyed by conjugation to ELP, these biopolymers have potential to overcome dox resistance in vivo.

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Ingrole, Rohan S., Wenqian Tao, Jatindra N. Tripathy et Harvinder S. Gill. « Synthesis and Immunogenicity Assessment of Elastin-Like Polypeptide-M2e Construct as an Influenza Antigen ». Nano LIFE 04, n^o 02 (juin 2014) : 1450004. http://dx.doi.org/10.1142/s1793984414500044.

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The 23 amino acid-long extracellular domain of the influenza virus transmembrane protein M2 (M2e) has remained highly conserved since the 1918 pandemic, and is thus considered a good candidate for development of a universal influenza A vaccine. However, M2e is poorly immunogenic. In this study we assessed the potential of increasing immunogenicity of M2e by constructing a nanoscale-designed protein polymer containing the M2e sequence and an elastin-like polypeptide (ELP) nanodomain consisting of alanine and tyrosine guest residues (ELP(A2YA2)24). The ELP nanodomain was included to increase antigen size, and to exploit the inherent thermal inverse phase transition behavior of ELPs to purify the protein polymer. The ELP(A2YA2)24 + M2e nanodomained molecule was recombinantly synthesized. Characterization of its inverse phase transition behavior demonstrated that attachment of M2e to ELP(A2YA2)24 increased its transition temperature compared to ELP(A2YA2)24. Using a dot blot test we determined that M2e conjugated to ELP is recognizable by M2e-specific antibodies, suggesting that the conjugation process does not adversely affect the immunogenic property of M2e. Further, upon vaccinating mice with ELP(A2YA2)24 + M2e it was found that indeed the nanodomained protein enhanced M2e-specific antibodies in mouse serum compared to free M2e peptide and ELP(A2YA2)24. The immune serum could also recognize M2 expressed on influenza virions. Overall, this data suggests the potential of using molecules containing M2e-ELP nanodomains to develop a universal influenza vaccine.

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Kim, Hyun-Jung, Donghyun Lee, Seungryong Cho, Ji-Hyun Jang, Sahng Gyoon Kim et Sun-Young Kim. « Improvement of the Bonding Properties of Mineral Trioxide Aggregate by Elastin-Like Polypeptide Supplementation ». Scanning 2019 (19 août 2019) : 1–8. http://dx.doi.org/10.1155/2019/3484396.

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Introduction. Elastin-like polypeptide (ELP) supplementation was previously reported to enhance the physical properties of mineral trioxide aggregate (MTA). The aim of this study was to investigate the effect of ELP supplementation on the bonding properties of MTA to dentin. Methods. Two types of ELPs were synthesized and mixed with MTA in a 0.3 liquid/powder ratio. The push-out bond strength test and interfacial observation with scanning electron microscopy were performed for ELP-supplemented MTA. The porosity of MTA fillings in the cavity was observed with microcomputed tomography. The stickiness, flow rate, and contact angle were additionally measured for potential increased bonding properties. Results. ELP supplementation improved the bond strength of MTA to dentin. MTA supplemented by a specific ELP exhibited a less porous structure, higher stickiness, and higher flow rate. ELPs also decreased the contact angle to dentin. Conclusions. This research data verifies that ELP improves the bonding properties of MTA to a tooth structure. The sticky and highly flowable characteristics of ELP-supplemented MTA may provide intimate contact with dentin and supply a less porous cement structure, which might improve the bonding properties of MTA.

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Mills, Carolyn E., Erika Ding et Bradley Olsen. « Protein Purification by Ethanol-Induced Phase Transitions of the Elastin-like Polypeptide (ELP) ». Industrial & ; Engineering Chemistry Research 58, n^o 27 (19 juin 2019) : 11698–709. http://dx.doi.org/10.1021/acs.iecr.9b00769.

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Ro, Jang-Won, Heelak Choi, Tae-Young Heo, Soo-Hyung Choi et Jong-In Won. « Characterization of Amphiphilic Elastin-like Polypeptide (ELP) Block Copolymers as Drug Delivery Carriers ». Biotechnology and Bioprocess Engineering 23, n^o 6 (novembre 2018) : 627–33. http://dx.doi.org/10.1007/s12257-018-0365-7.

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Sarangthem, Vijaya, Harshita Sharma, Mohini Mendiratta, Ranjit Kumar Sahoo, Rang-Woon Park, Lalit Kumar, Thoudam Debraj Singh et Sujata Mohanty. « Application of Bio-Active Elastin-like Polypeptide on Regulation of Human Mesenchymal Stem Cell Behavior ». Biomedicines 10, n^o 5 (17 mai 2022) : 1151. http://dx.doi.org/10.3390/biomedicines10051151.

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Regenerative medicine using stem cells offers promising strategies for treating a variety of degenerative diseases. Regulation of stem cell behavior and rejuvenate senescence are required for stem cells to be clinically effective. The extracellular matrix (ECM) components have a significant impact on the stem cell’s function and fate mimicking the local environment to maintain cells or generate a distinct phenotype. Here, human elastin-like polypeptide-based ECM-mimic biopolymer was designed by incorporating various cell-adhesion ligands, such as RGD and YIGSR. The significant effects of bioactive fusion ELPs named R-ELP, Y-ELP, and RY-ELP were analyzed for human bone-marrow-derived stem cell adhesion, proliferation, maintenance of stemness properties, and differentiation. Multivalent presentation of variable cell-adhesive ligands on RY-ELP polymers indeed promote efficient cell attachment and proliferation of human fibroblast cells dose-dependently. Similarly, surface modified with RY-ELP promoted strong mesenchymal stem cell (MSCs) attachment with greater focal adhesion (FA) complex formation at 6 h post-incubation. The rate of cell proliferation, migration, population doubling time, and collagen I deposition were significantly enhanced in the presence of RY-ELP compared with other fusion ELPs. Together, the expression of multipotent markers and differentiation capacity of MSCs remained unaffected, clearly demonstrating that stemness properties of MSCs were well preserved when cultured on a RY-ELP-modified surface. Hence, bioactive RY-ELP offers an anchorage support system and effectively induces stimulatory response to support stem cell proliferation.

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Chu, Hun-Su, Kyung-Ho Lee, Ji-Eun Park, Dong-Myung Kim, Byung-Gee Kim et Jong-In Won. « Expression analysis of an elastin-like polypeptide (ELP) in a cell-free protein synthesis system ». Enzyme and Microbial Technology 46, n^o 2 (février 2010) : 87–91. http://dx.doi.org/10.1016/j.enzmictec.2009.10.003.

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Lindeboom, Tom, Binwu Zhao, George Jackson, Carol K. Hall et Amparo Galindo. « On the liquid demixing of water + elastin-like polypeptide mixtures : bimodal re-entrant phase behaviour ». Physical Chemistry Chemical Physics 23, n^o 10 (2021) : 5936–44. http://dx.doi.org/10.1039/d0cp05013j.

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Newman, Kristen, Kendra Clark, Bhuvaneswari Gurumurthy, Pallabi Pal et Amol V. Janorkar. « Elastin-Collagen Based Hydrogels as Model Scaffolds to Induce Three-Dimensional Adipocyte Culture from Adipose Derived Stem Cells ». Bioengineering 7, n^o 3 (12 septembre 2020) : 110. http://dx.doi.org/10.3390/bioengineering7030110.

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This study aimed to probe the effect of formulation of scaffolds prepared using collagen and elastin-like polypeptide (ELP) and their resulting physico-chemical and mechanical properties on the adipogenic differentiation of human adipose derived stem cells (hASCs). Six different ELP-collagen scaffolds were prepared by varying the collagen concentration (2 and 6 mg/mL), ELP addition (6 mg/mL), or crosslinking of the scaffolds. FTIR spectroscopy indicated secondary bonding interactions between collagen and ELP, while scanning electron microscopy revealed a porous structure for all scaffolds. Increased collagen concentration, ELP addition, and presence of crosslinking decreased swelling ratio and increased elastic modulus and compressive strength of the scaffolds. The scaffold characteristics influenced cell morphology, wherein the hASCs seeded in the softer, non-crosslinked scaffolds displayed a spread morphology. We determined that stiffer and/or crosslinked elastin-collagen based scaffolds constricted the spreading of hASCs, leading to a spheroid morphology and yielded an enhanced adipogenic differentiation as indicated by Oil Red O staining. Overall, this study underscored the importance of spheroid morphology in adipogenic differentiation, which will allow researchers to create more physiologically-relevant three-dimensional, in vitro culture models.

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Sarangthem, Vijaya, Harshita Sharma, Ridhima Goel, Sampa Ghose, Rang-Woon Park, Sujata Mohanty, Tapan Kumar Chaudhuri, Amit Kumar Dinda et Thoudam Debraj Singh. « Application of elastin-like polypeptide (ELP) containing extra-cellular matrix (ECM) binding ligands in regenerative medicine ». International Journal of Biological Macromolecules 207 (mai 2022) : 443–53. http://dx.doi.org/10.1016/j.ijbiomac.2022.03.018.

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Widder, Katharina, Sarah R. MacEwan, Elisabeth Garanger, Vanesa Núñez, Sébastien Lecommandoux, Ashutosh Chilkoti et Dariush Hinderberger. « Characterisation of hydration and nanophase separation during the temperature response in hydrophobic/hydrophilic elastin-like polypeptide (ELP) diblock copolymers ». Soft Matter 13, n^o 9 (2017) : 1816–22. http://dx.doi.org/10.1039/c6sm02427k.

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Pozdniakova, Natalia V., Oxana V. Ryabaya, Alevtina S. Semkina, Vsevolod A. Skribitsky et Alexei B. Shevelev. « Using ELP Repeats as a Scaffold for De Novo Construction of Gadolinium-Binding Domains within Multifunctional Recombinant Proteins for Targeted Delivery of Gadolinium to Tumour Cells ». International Journal of Molecular Sciences 23, n^o 6 (18 mars 2022) : 3297. http://dx.doi.org/10.3390/ijms23063297.

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Three artificial proteins that bind the gadolinium ion (Gd3+) with tumour-specific ligands were de novo engineered and tested as candidate drugs for binary radiotherapy (BRT) and contrast agents for magnetic resonance imaging (MRI). Gd3+-binding modules were derived from calmodulin. They were joined with elastin-like polypeptide (ELP) repeats from human elastin to form the four-centre Gd3+-binding domain (4MBS-domain) that further was combined with F3 peptide (a ligand of nucleolin, a tumour marker) to form the F3-W4 block. The F3-W4 block was taken alone (E2-13W4 protein), as two repeats (E1-W8) and as three repeats (E1-W12). Each protein was supplemented with three copies of the RGD motif (a ligand of integrin αvβ3) and green fluorescent protein (GFP). In contrast to Magnevist (a Gd-containing contrast agent), the proteins exhibited three to four times higher accumulation in U87MG glioma and A375 melanoma cell lines than in normal fibroblasts. The proteins remained for >24 h in tumours induced by Ca755 adenocarcinoma in C57BL/6 mice. They exhibited stability towards blood proteases and only accumulated in the liver and kidney. The technological advantages of using the engineered proteins as a basis for developing efficient and non-toxic agents for early diagnosis of tumours by MRI as well as part of BRT were demonstrated.

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Liang, P., W. Zhuoran, G. Weiping et W. Guihuai. « P12.01 Local implantation of thermoresponsive interferon alpha-polypeptide conjugate combined with temozolomide for post-surgical glioblastoma chemoimmunotherapy ». Neuro-Oncology 21, Supplement_3 (août 2019) : iii59. http://dx.doi.org/10.1093/neuonc/noz126.212.

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Abstract BACKGROUND Glioblastoma(GBM) is associated with gloomy prognosis despite maximal safe resection and following chemoradiation. In recent years, significant progress has been made in cancer immunotherapy except for GBM, which is largerly due to its local immunosuppressive microenvironment. Some research has demonstrated that local immunotherapy may be more efficient than systematic administrators. IFNα has been investigated as antitumor agent for some cancers, including glioma. Nevertheless, the short circulating half-life greatly limits its clinical application. Hence, a thermoresponsive IFNα-elastin-like polypeptide (IFNα-ELP) was genetically engineered for the earliest local intervention post-surgery. MATERIAL AND METHODS Firstly, IFNα-ELP(V) was constructed, expressed and purified, then, its physicochemical characterization was verified. The tumor was resected 10 days after U87MG-mCherry-luc cells orthotopic implantation, and IFNα-ELP(V) was injected into the resection cavity. Two days later, temozolomide(TMZ) was intraperitoneally injected. Using in vivo imaging technique, we could monitor the trends in tumor size. The survival time of mice was counted. Biosafety was evaluated by peripheral blood biochemistry analysis and pathology of the organs. RESULTS In this study, the bioconjugate not only in situ deposited in the resection cavity because of the thermoresponsive characteristic, but also showed zero-order release kinetics from the depot and dramatically improved pharmacokinetics and biodistribution of IFNα. Consequently, it showed the inhibition of tumor relapse in GBM orthotopic resection mice models. When followed by TMZ intraperitoneal injection, IFNα-ELP(V) could significantly prevent the tumor recurrence than itself or TMZ alone. Biosafety results indicated that the systemic toxicity of IFNα-ELP(V) in mice can be reduced to safe levels. CONCLUSION The results reveal that local implantation of thermoresponsive IFNα-ELP(V) combined with TMZ exhibits the synergy of post-surgical GBM chemoimmunotherapy.

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Manzari, Mandana T., Grace R. Anderson, Kevin H. Lin, Ryan S. Soderquist, Merve Çakir, Mitchell Zhang, Chandler E. Moore et al. « Genomically informed small-molecule drugs overcome resistance to a sustained-release formulation of an engineered death receptor agonist in patient-derived tumor models ». Science Advances 5, n^o 9 (septembre 2019) : eaaw9162. http://dx.doi.org/10.1126/sciadv.aaw9162.

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Extrinsic pathway agonists have failed repeatedly in the clinic for three core reasons: Inefficient ligand-induced receptor multimerization, poor pharmacokinetic properties, and tumor intrinsic resistance. Here, we address these factors by (i) using a highly potent death receptor agonist (DRA), (ii) developing an injectable depot for sustained DRA delivery, and (iii) leveraging a CRISPR-Cas9 knockout screen in DRA-resistant colorectal cancer (CRC) cells to identify functional drivers of resistance. Pharmacological blockade of XIAP and BCL-XL by targeted small-molecule drugs strongly enhanced the antitumor activity of DRA in CRC cell lines. Recombinant fusion of the DRA to a thermally responsive elastin-like polypeptide (ELP) creates a gel-like depot upon subcutaneous injection that abolishes tumors in DRA-sensitive Colo205 mouse xenografts. Combination of ELPdepot-DRA with BCL-XL and/or XIAP inhibitors led to tumor growth inhibition and extended survival in DRA-resistant patient-derived xenografts. This strategy provides a precision medicine approach to overcome similar challenges with other protein-based cancer therapies.

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Wang, Huiyuan, Lei Cai, Alexandra Paul, Annika Enejder et Sarah C. Heilshorn. « Hybrid Elastin-like Polypeptide–Polyethylene Glycol (ELP-PEG) Hydrogels with Improved Transparency and Independent Control of Matrix Mechanics and Cell Ligand Density ». Biomacromolecules 15, n^o 9 (20 août 2014) : 3421–28. http://dx.doi.org/10.1021/bm500969d.

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Ma, Qun, Lichao Liu, Zeyue Yang et Peng Zheng. « Facile Synthesis of Peptide-Conjugated Gold Nanoclusters with Different Lengths ». Nanomaterials 11, n^o 11 (2 novembre 2021) : 2932. http://dx.doi.org/10.3390/nano11112932.

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The synthesis of ultra-small gold nanoclusters (Au NCs) with sizes down to 2 nm has received increasing interest due to their unique optical and electronic properties. Like many peptide-coated gold nanospheres synthesized before, modified gold nanoclusters with peptide conjugation are potentially significant in biomedical and catalytic fields. Here, we explore whether such small-sized gold nanoclusters can be conjugated with peptides also and characterize them using atomic force microscopy. Using a long and flexible elastin-like polypeptide (ELP)20 as the conjugated peptide, (ELP)20-Au NCs was successfully synthesized via a one-pot synthesis method. The unique optical and electronic properties of gold nanoclusters are still preserved, while a much larger size was obtained as expected due to the peptide conjugation. In addition, a short and rigid peptide (EAAAK)3 was conjugated to the gold nanoclusters. Their Yong’s modulus was characterized using atomic force microscopy (AFM). Moreover, the coated peptide on the nanoclusters was pulled using AFM-based single molecule-force spectroscopy (SMFS), showing expected properties as one of the first force spectroscopy experiments on peptide-coated nanoclusters. Our results pave the way for further modification of nanoclusters based on the conjugated peptides and show a new method to characterize these materials using AFM-SMFS.

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Engel, Jason E., Erika Williams, Maxx L. Williams, Gene L. Bidwell et Alejandro R. Chade. « Targeted VEGF (Vascular Endothelial Growth Factor) Therapy Induces Long-Term Renal Recovery in Chronic Kidney Disease via Macrophage Polarization ». Hypertension 74, n^o 5 (novembre 2019) : 1113–23. http://dx.doi.org/10.1161/hypertensionaha.119.13469.

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Chronic kidney disease (CKD) universally associates with renal microvascular rarefaction and inflammation, but whether a link exists between these 2 processes is unclear. We designed a therapeutic construct of VEGF (vascular endothelial growth factor) fused to an ELP (elastin-like polypeptide) carrier and show that it improves renal function in experimental renovascular disease. We test the hypothesis that ELP-VEGF therapy will improve CKD, and that recovery will be driven by decreasing microvascular rarefaction partly via modulation of macrophage phenotype and inflammation. CKD was induced in 14 pigs, which were observed for 14 weeks. At 6 weeks, renal blood flow and filtration were quantified using multidetector computed tomography, and then pigs received single intrarenal ELP-VEGF or placebo (n=7 each). Renal function was quantified again 4 and 8 weeks later. Pigs were euthanized and renal microvascular density, angiogenic and inflammatory markers, fibrosis, macrophage infiltration, and phenotype were quantified. Loss of renal hemodynamics in CKD was progressively recovered by ELP-VEGF therapy, accompanied by improved renal microvascular density, fibrosis, and expression of inflammatory mediators. Although renal macrophage infiltration was similar in both CKD groups, ELP-VEGF therapy distinctly shifted their phenotype from proinflammatory M1 to VEGF-expressing M2. Our study unravels potential mechanisms and feasibility of a new strategy to offset progression of CKD using drug-delivery technologies. The results indicate that renal recovery after ELP-VEGF therapy was largely driven by modulation of renal macrophages toward VEGF-expressing M2 phenotype, restoring VEGF signaling and sustaining improvement of renal function and microvascular integrity in CKD.

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Guise, Erika, Jason E. Engel, Maxx L. Williams, Fakhri Mahdi, Gene L. Bidwell et Alejandro R. Chade. « Biopolymer-delivered vascular endothelial growth factor improves renal outcomes following revascularization ». American Journal of Physiology-Renal Physiology 316, n^o 5 (1 mai 2019) : F1016—F1025. http://dx.doi.org/10.1152/ajprenal.00607.2018.

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Renal angioplasty and stenting (PTRAs) resolves renal artery stenosis, but inconsistently improves renal function, possibly due to persistent parenchymal damage. We developed a bioengineered fusion of a drug delivery vector (elastin-like polypeptide, ELP) with vascular endothelial growth factor (VEGF), and showed its therapeutic efficacy. We tested the hypothesis that combined ELP-VEGF therapy with PTRAs improves renal recovery more efficiently than PTRAs alone, by protecting the stenotic renal parenchyma. Unilateral renovascular disease (RVD) was induced by renal artery stenosis in 14 pigs. Six weeks later, stenotic kidney blood flow (RBF) and glomerular filtration rate (GFR) were quantified in vivo using multidetector CT. Blood and urine were collected during in vivo studies. All pigs underwent PTRAs and then were randomized into single intrarenal ELP-VEGF administration or placebo ( n = 7 each) groups. Pigs were observed for four additional weeks, in vivo CT studies were repeated, and then pigs were euthanized for ex vivo studies to quantify renal microvascular (MV) density, angiogenic factor expression, and morphometric analysis. Renal hemodynamics were similarly blunted in all RVD pigs. PTRAs resolved stenosis but modestly improved RBF and GFR. However, combined PTRAs+ ELP-VEGF improved RBF, GFR, regional perfusion, plasma creatinine, asymmetric dimethlyarginine (ADMA), and albuminuria compared with PTRAs alone, accompanied by improved angiogenic signaling, MV density, and renal fibrosis. Greater improvement of renal function via coadjuvant ELP-VEGF therapy may be driven by enhanced MV proliferation and repair, which ameliorates MV rarefaction and fibrogenic activity that PTRAs alone cannot offset. Thus, our study supports a novel strategy to boost renal recovery in RVD after PTRAs.

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Clark, Kendra, et Amol Janorkar. « Milieu for Endothelial Differentiation of Human Adipose-Derived Stem Cells ». Bioengineering 5, n^o 4 (3 octobre 2018) : 82. http://dx.doi.org/10.3390/bioengineering5040082.

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Human adipose-derived stem cells (hASCs) have been shown to differentiate down many lineages including endothelial lineage. We hypothesized that hASCs would more efficiently differentiate toward the endothelial lineage when formed as three-dimensional (3D) spheroids and with the addition of vascular endothelial growth factor (VEGF). Three conditions were tested: uncoated tissue culture polystyrene (TCPS) surfaces that induced a 2D monolayer formation; elastin-like polypeptide (ELP)-collagen composite hydrogel scaffolds that induced encapsulated 3D spheroid culture; and ELP-polyethyleneimine-coated TCPS surfaces that induced 3D spheroid formation in scaffold-free condition. Cells were exposed to endothelial differentiation medium containing no additional VEGF or 20 and 50 ng/mL of VEGF for 7 days and assayed for viability and endothelial differentiation markers. While endothelial differentiation media supported endothelial differentiation of hASCs, our 3D spheroid cultures augmented this differentiation and produced more von Willebrand factor than 2D cultures. Likewise, 3D cultures were able to uptake LDL, whereas the 2D cultures were not. Higher concentrations of VEGF further enhanced differentiation. Establishing angiogenesis is a key factor in regenerative medicine. Future studies aim to elucidate how to produce physiological changes such as neoangiogenesis and sprouting of vessels which may enhance the survival of regenerated tissues.

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Wang, Yongjuan, Yanli Guo, Haowei Wang, Zhi Wu, Weiming Hong, Huaichang Sun et Shanyuan Zhu. « Protection of Ducklings from Duck Hepatitis A Virus Infection with ELPylated Duck Interferon-α ». Viruses 14, n^o 3 (18 mars 2022) : 633. http://dx.doi.org/10.3390/v14030633.

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Duck viral hepatitis type I (DVH I) is a lethal disease in ducklings caused by duck hepatitis A virus (DHAV). Although the commercial vaccine is available for vaccination of one-day-old ducklings or breeder ducks, the disease is still prevalent due to the delayed immune response in ducklings and variable maternal antibody levels in breeder duck flocks. To explore the feasibility of duck interferon-α (DuIFN-α) for control of DVH I, DuIFN-α was expressed as an elastin-like polypeptide (ELP) fusion protein (ELP-DuIFN-α) in E. coli and purified by inverse phase transition cycling (ITC). After detection of its cytotoxicity, bioactivity, plasma stability and serum half-life, the protective efficacy of ELP-DuIFN-α against DHAV-1 infection of embryos or ducklings was evaluated using different treatment routes at different infection times. The results show that ELP-DuIFN-α was correctly expressed and purified to more than 90% purity after two cycles of ITC. The purified fusion protein had a specific anti-DHAV-1 activity of 6.0 × 104 IU/mg protein, significantly extended plasma stability and serum half-life without overt cytotoxicity. After allantoic injection with ELP-DuIFN-α pre-infection, co-infection or post-infection with DHAV-1, 5/5, 5/5 or 4/5 embryos survived from the virus challenge. After intramuscular injection or oral administration with ELP-DuIFN-α, 3/5 or 4/5 ducklings survived from co-infection with DHAV-1. After oral administration with ELP-DuIFN-α pre-infection, co-infection or post-infection with DHAV-1, 3/5, 4/5 or 4/5 ducklings survived from the virus challenge, and the relative transcription levels of interferon-stimulated genes were significantly higher than the normal control group and virus challenge control group (p < 0.01). These experimental data suggest that ELP-DuIFN-α can be used as a long-lasting anti-DHAV-1 reagent.

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Chade, Alejandro R., Maxx L. Williams, Jason E. Engel, Erika Williams et Gene L. Bidwell. « Molecular targeting of renal inflammation using drug delivery technology to inhibit NF-κB improves renal recovery in chronic kidney disease ». American Journal of Physiology-Renal Physiology 319, n^o 1 (1 juillet 2020) : F139—F148. http://dx.doi.org/10.1152/ajprenal.00155.2020.

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Inflammation is a major determinant for the progression of chronic kidney disease (CKD). NF-κB is a master transcription factor upregulated in CKD that promotes inflammation and regulates apoptosis and vascular remodeling. We aimed to modulate this pathway for CKD therapy in a swine model of CKD using a peptide inhibitor of the NF-κB p50 subunit (p50i) fused to a protein carrier [elastin-like polypeptide (ELP)] and equipped with a cell-penetrating peptide (SynB1). We hypothesized that intrarenal SynB1-ELP-p50i therapy would inhibit NF-κB-driven inflammation and induce renal recovery. CKD was induced in 14 pigs. After 6 wk, pigs received single intrarenal SynB1-ELP-p50i therapy (10 mg/kg) or placebo ( n = 7 each). Renal hemodynamics were quantified in vivo using multidetector computed tomography before and 8 wk after treatment. Pigs were then euthanized. Ex vivo experiments were performed to quantify renal activation of NF-κB, expression of downstream mediators of NF-κB signaling, renal microvascular density, inflammation, and fibrosis. Fourteen weeks of CKD stimulated NF-κB signaling and downstream mediators (e.g., TNF-α, monocyte chemoattractant protein-1, and IL-6) accompanying loss of renal function, inflammation, fibrosis, and microvascular rarefaction versus controls. All of these were improved after SynB1-ELP-p50i therapy, accompanied by reduced circulating inflammatory cytokines as well, which were evident up to 8 wk after treatment. Current treatments for CKD are largely ineffective. Our study shows the feasibility of a new treatment to induce renal recovery by offsetting inflammation at a molecular level. It also supports the therapeutic potential of targeted inhibition of the NF-κB pathway using novel drug delivery technology in a translational model of CKD.

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Shamji, Mohammed F., Liufang Jing, Jun Chen, Priscilla Hwang, Odelia Ghodsizadeh, Allan H. Friedman, William J. Richardson et Lori A. Setton. « Treatment of neuroinflammation by soluble tumor necrosis factor receptor Type II fused to a thermally responsive carrier ». Journal of Neurosurgery : Spine 9, n^o 2 (août 2008) : 221–28. http://dx.doi.org/10.3171/spi/2008/9/8/221.

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Object Biochemical irritation of the dorsal root ganglion (DRG) after intervertebral disc herniation contributes to radiculopathy through tumor necrosis factor–α (TNFα)–mediated inflammation. Soluble TNF receptor Type II (sTNFRII) sequesters this cytokine, providing clinical benefit. Previous work involving conjugation of sTNFRII with thermally responsive elastin-like polypeptide (ELP) yielded a chimeric protein (ELP–sTNFRII) with in vitro anti-TNFα bioactivity. Furthermore, temperature-triggered ELP aggregation into a “depot” prolongs protein residence time following perineural injection. In this study the authors evaluated the inflammatory phenotype of DRG explants after TNFα stimulation, and assessed the abilities of sTNFRII or ELP–sTNFRII to attenuate these neuro-inflammatory changes. Methods Rat lumbar DRGs (35 animals) were treated in 6 groups, as follows: control; TNFα (25 ng/ml); TNFα with low-(0.2 μg/ml) or high-dose (1 μg/ml) sTNFRII; and TNFα with low-(52.5 μg/ml) or high-dose (262.5 μg/ml) ELP–sTNFRII. After 24 hours, supernatant was evaluated for inflammatory cytokines (interleukin [IL]–1, IL-6, and IL-10); prostaglandin E2; and metabolites (glutamate, lactate, and pyruvate). Single-factor analysis of variance with post hoc Dunn analysis (α = 0.05) was used to assess treatment differences. Results Incubation of explants with TNFα caused metabolic stress reflected by an increased lactate/pyruvate ratio (1.8 ± 0.5–fold) and extracellular glutamate (79 ± 8% increase). Inflammatory activation was observed with heightened IL-6 release (5.2 ± 1.4–fold) and prostaglandin E2 production (14 ± 3–fold). An autoregulatory response occurred with an 11.8 ± 0.6–fold increase in sTNFRI shedding. Treatment with high doses of sTNFRII or ELP–sTNFRII reversed all changes. Values are expressed as the mean ± standard deviation. Conclusions These results demonstrate that TNFα stimulation of DRG explants yields a phenotype of neurotoxic metabolite release and inflammatory mediator expression. Coincubation with either sTNFRII or ELP–sTNFRII antagonizes TNFα activity to abrogate these changes, suggesting potential for therapeutic intervention to treat peripheral nerve inflammatory disease.

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Engel, Jason E., Maxx L. Williams, Erika Williams, Camille Azar, Erin B. Taylor, Gene L. Bidwell et Alejandro R. Chade. « Recovery of Renal Function following Kidney-Specific VEGF Therapy in Experimental Renovascular Disease ». American Journal of Nephrology 51, n^o 11 (2020) : 891–902. http://dx.doi.org/10.1159/000511260.

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Background: Chronic renovascular disease (RVD) can lead to a progressive loss of renal function, and current treatments are inefficient. We designed a fusion of vascular endothelial growth factor (VEGF) conjugated to an elastin-like polypeptide (ELP) carrier protein with an N-terminal kidney-targeting peptide (KTP). We tested the hypothesis that KTP-ELP-VEGF therapy will effectively recover renal function with an improved targeting profile. Further, we aimed to elucidate potential mechanisms driving renal recovery. Methods: Unilateral RVD was induced in 14 pigs. Six weeks later, renal blood flow (RBF) and glomerular filtration rate (GFR) were quantified by multidetector CT imaging. Pigs then received a single intrarenal injection of KTP-ELP-VEGF or vehicle. CT quantification of renal hemodynamics was repeated 4 weeks later, and then pigs were euthanized. Ex vivo renal microvascular (MV) density and media-to-lumen ratio, macrophage infiltration, and fibrosis were quantified. In parallel, THP-1 human monocytes were differentiated into naïve macrophages (M0) or inflammatory macrophages (M1) and incubated with VEGF, KTP-ELP, KTP-ELP-VEGF, or control media. The mRNA expression of macrophage polarization and angiogenic markers was quantified (qPCR). Results: Intrarenal KTP-ELP-VEGF improved RBF, GFR, and MV density and attenuated MV media-to-lumen ratio and renal fibrosis compared to placebo, accompanied by augmented renal M2 macrophages. In vitro, exposure to VEGF/KTP-ELP-VEGF shifted M0 macrophages to a proangiogenic M2 phenotype while M1s were nonresponsive to VEGF treatment. Conclusions: Our results support the efficacy of a new renal-specific biologic construct in recovering renal function and suggest that VEGF may directly influence macrophage phenotype as a possible mechanism to improve MV integrity and function in the stenotic kidney.

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Liao, Yi-Ting, Anthony C. Manson, Michael R. DeLyser, William G. Noid et Paul S. Cremer. « TrimethylamineN-oxide stabilizes proteins via a distinct mechanism compared with betaine and glycine ». Proceedings of the National Academy of Sciences 114, n^o 10 (22 février 2017) : 2479–84. http://dx.doi.org/10.1073/pnas.1614609114.

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We report experimental and computational studies investigating the effects of three osmolytes, trimethylamineN-oxide (TMAO), betaine, and glycine, on the hydrophobic collapse of an elastin-like polypeptide (ELP). All three osmolytes stabilize collapsed conformations of the ELP and reduce the lower critical solution temperature (LSCT) linearly with osmolyte concentration. As expected from conventional preferential solvation arguments, betaine and glycine both increase the surface tension at the air–water interface. TMAO, however, reduces the surface tension. Atomically detailed molecular dynamics (MD) simulations suggest that TMAO also slightly accumulates at the polymer–water interface, whereas glycine and betaine are strongly depleted. To investigate alternative mechanisms for osmolyte effects, we performed FTIR experiments that characterized the impact of each cosolvent on the bulk water structure. These experiments showed that TMAO red-shifts the OH stretch of the IR spectrum via a mechanism that was very sensitive to the protonation state of the NO moiety. Glycine also caused a red shift in the OH stretch region, whereas betaine minimally impacted this region. Thus, the effects of osmolytes on the OH spectrum appear uncorrelated with their effects upon hydrophobic collapse. Similarly, MD simulations suggested that TMAO disrupts the water structure to the least extent, whereas glycine exerts the greatest influence on the water structure. These results suggest that TMAO stabilizes collapsed conformations via a mechanism that is distinct from glycine and betaine. In particular, we propose that TMAO stabilizes proteins by acting as a surfactant for the heterogeneous surfaces of folded proteins.

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