Design and Linkage Optimization of Ursane-Thalidomide-Based PROTACs and Identification of Their Targeted-Degradation Properties to MDM2 Protein

2021 ◽  
pp. 104901
Author(s):  
Zhiwen Qi ◽  
Guliang Yang ◽  
Tao Deng ◽  
Jianmin Wang ◽  
Hao Zhou ◽  
...  
1996 ◽  
Vol 444 ◽  
Author(s):  
Hyeon-Seag Kim ◽  
D. L. Polla ◽  
S. A. Campbell

AbstractThe electrical reliability properties of PZT (54/46) thin films have been measured for the purpose of integrating this material with silicon-based microelectromechanical systems. Ferroelectric thin films of PZT were prepared by metal organic decomposition. The charge trapping and degradation properties of these thin films were studied through device characteristics such as hysteresis loop, leakage current, fatigue, dielectric constant, capacitancevoltage, and loss factor measurements. Several unique experimental results have been found. Different degradation processes were verified through fatigue (bipolar stress), low and high charge injection (unipolar stress), and high field stressing (unipolar stress).


2019 ◽  
Author(s):  
Francesco D’Elia ◽  
Philipp Hiester ◽  
Carlo Zimmermann ◽  
Igor Schestakow ◽  
Jelena Horky ◽  
...  

2019 ◽  
Vol 20 (11) ◽  
pp. 1091-1111 ◽  
Author(s):  
Maryam Zanjirband ◽  
Soheila Rahgozar

MDM2 protein is the core negative regulator of p53 that maintains the cellular levels of p53 at a low level in normal cells. Mutation of the TP53 gene accounts for 50% of all human cancers. In the remaining malignancies with wild-type TP53, p53 function is inhibited through other mechanisms. Recently, synthetic small molecule inhibitors have been developed which target a small hydrophobic pocket on MDM2 to which p53 normally binds. Given that MDM2-p53 antagonists have been undergoing clinical trials for different types of cancer, this review illustrates different aspects of these new cancer targeted therapeutic agents with the focus on the major advances in the field. It emphasizes on the p53 function, regulation of p53, targeting of the p53-MDM2 interaction for cancer therapy, and p53-dependent and -independent effects of inhibition of p53-MDM2 interaction. Then, representatives of small molecule MDM2-p53 binding antagonists are introduced with a focus on those entered into clinical trials. Furthermore, the review discusses the gene signatures in order to predict sensitivity to MDM2 antagonists, potential side effects and the reasons for the observed hematotoxicity, mechanisms of resistance to these drugs, their evaluation as monotherapy or in combination with conventional chemotherapy or with other targeted therapeutic agents. Finally, it highlights the certainly intriguing questions and challenges which would be addressed in future studies.


2021 ◽  
Vol 12 (1) ◽  
pp. 20
Author(s):  
Rabia Nazir ◽  
Arne Bruyneel ◽  
Carolyn Carr ◽  
Jan Czernuszka

In addition to biocompatibility, an ideal scaffold for the regeneration of valvular tissue should also replicate the natural heart valve extracellular matrix (ECM) in terms of biomechanical properties and structural stability. In our previous paper, we demonstrated the development of collagen type I and hyaluronic acid (HA)-based scaffolds with interlaced microstructure. Such hybrid scaffolds were found to be compatible with cardiosphere-derived cells (CDCs) to potentially regenerate the diseased aortic heart valve. This paper focused on the quantification of the effect of crosslinking density on the mechanical properties under dry and wet conditions as well as degradation resistance. Elastic moduli increased with increasing crosslinking densities, in the dry and wet state, for parent networks, whereas those of interlaced scaffolds were higher than either network alone. Compressive and storage moduli ranged from 35 ± 5 to 95 ± 5 kPa and 16 ± 2 kPa to 113 ± 6 kPa, respectively, in the dry state. Storage moduli, in the dry state, matched and exceeded those of human aortic valve leaflets (HAVL). Similarly, degradation resistance increased with increasing the crosslinking densities for collagen-only and HA-only scaffolds. Interlaced scaffolds showed partial degradation in the presence of either collagenase or hyaluronidase as compared to when exposed to both enzymes together. These results agree with our previous findings that interlaced scaffolds were composed of independent collagen and HA networks without crosslinking between them. Thus, collagen/HA interlaced scaffolds have the potential to fill in the niche for designing an ideal tissue engineered heart valve (TEHV).


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mary Beth Wandel ◽  
Craig A. Bell ◽  
Jiayi Yu ◽  
Maria C. Arno ◽  
Nathan Z. Dreger ◽  
...  

AbstractComplex biological tissues are highly viscoelastic and dynamic. Efforts to repair or replace cartilage, tendon, muscle, and vasculature using materials that facilitate repair and regeneration have been ongoing for decades. However, materials that possess the mechanical, chemical, and resorption characteristics necessary to recapitulate these tissues have been difficult to mimic using synthetic resorbable biomaterials. Herein, we report a series of resorbable elastomer-like materials that are compositionally identical and possess varying ratios of cis:trans double bonds in the backbone. These features afford concomitant control over the mechanical and surface eroding degradation properties of these materials. We show the materials can be functionalized post-polymerization with bioactive species and enhance cell adhesion. Furthermore, an in vivo rat model demonstrates that degradation and resorption are dependent on succinate stoichiometry in the elastomers and the results show limited inflammation highlighting their potential for use in soft tissue regeneration and drug delivery.


Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 2008
Author(s):  
Samsul Rizal ◽  
N. I. Saharudin ◽  
N. G. Olaiya ◽  
H. P. S. Abdul Khalil ◽  
M. K. Mohamad Haafiz ◽  
...  

The degradation and mechanical properties of potential polymeric materials used for green manufacturing are significant determinants. In this study, cellulose nanofibre was prepared from Schizostachyum brachycladum bamboo and used as reinforcement in the PLA/chitosan matrix using melt extrusion and compression moulding method. The cellulose nanofibre(CNF) was isolated using supercritical carbon dioxide and high-pressure homogenisation. The isolated CNF was characterised with transmission electron microscopy (TEM), FT-IR, zeta potential and particle size analysis. The mechanical, physical, and degradation properties of the resulting biocomposite were studied with moisture content, density, thickness swelling, tensile, flexural, scanning electron microscopy, thermogravimetry, and biodegradability analysis. The TEM, FT-IR, and particle size results showed successful isolation of cellulose nanofibre using this method. The result showed that the physical, mechanical, and degradation properties of PLA/chitosan/CNF biocomposite were significantly enhanced with cellulose nanofibre. The density, thickness swelling, and moisture content increased with the addition of CNF. Also, tensile strength and modulus; flexural strength and modulus increased; while the elongation reduced. The carbon residue from the thermal degradation and the glass transition temperature of the PLA/chitosan/CNF biocomposite was observed to increase with the addition of CNF. The result showed that the biocomposite has potential for green and sustainable industrial application.


2020 ◽  
Vol 6 (1) ◽  
pp. 34-49
Author(s):  
Abul Arafat ◽  
Sabrin A. Samad ◽  
Jeremy J. Titman ◽  
Andrew L. Lewis ◽  
Emma R. Barney ◽  
...  

AbstractThis study investigates the role of yttrium in phosphate-based glasses in the system 45(P2O5)–25(CaO)– (30-x)(Na2O)–x(Y2O3) (0≤x≤5) prepared via melt quenching and focuses on their structural characterisation and degradation properties. The structural analyses were performed using a combination of solid-state nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). 31P NMR analysis showed that depolymerisation of the phosphate network occurred which increased with Y2O3 content as metaphosphate units (Q2) decreased with subsequent increase in pyrophosphate species (Q1). The NMR results correlated well with structural changes observed via FTIR and XPS analyses. XRD analysis of crystallised glass samples revealed the presence of calcium pyrophosphate (Ca2P2O7) and sodium metaphosphate (NaPO3) phases for all the glass formulations explored. Yttrium-containing phases were found for the formulations containing 3 and 5 mol% Y2O3. Degradation analyses performed in Phosphate buffer saline (PBS) and Milli-Q water revealed significantly reduced rates with addition of Y2O3 content. This decrease was attributed to the formation of Y-O-P bonds where the octahedral structure of yttrium (YO6) cross-linked phosphate chains, subsequently leading to an increase in chemical durability of the glasses. The ion release studies also showed good correlation with the degradation profiles.


RSC Advances ◽  
2020 ◽  
Vol 10 (73) ◽  
pp. 44815-44823
Author(s):  
Peng Yin ◽  
Chunhao Chen ◽  
Hongpeng Ma ◽  
Huijuan Gan ◽  
Bin Guo ◽  
...  

Here, we report a method to improve the properties of thermoplastic starch (TPS) by surface ultraviolet (UV) cross-linking.


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