http://chineseinput.net/에서 pinyin(병음)방식으로 중국어를 변환할 수 있습니다.
변환된 중국어를 복사하여 사용하시면 됩니다.
In silico evaluation of acetylation mimics in the 27 lysine residues of human tau protein
Kim, Yong-Chan,Jeong, Byung-Hoon Bentham Science 2019 Current Alzheimer research Vol.16 No.5
<B>Background:</B><P>Various neurodegenerative diseases, including Alzheimer’s disease (AD), are related to abnormal hyper-phosphorylated microtubule-associated protein tau accumulation in brain lesions. Recent studies have focused on toxicity caused by another post-translational modification (PTM), acetylation of the lysine (K) residues of tau protein. Because there are numerous acetylation sites, several studies have introduced mimics of tau acetylation using amino acid substitutions from lysine to glutamine (Q). However, human tau protein contains over 20 acetylation sites; thus, investigation of the effects of acetylated tau is difficult.</P><B>Objectives:</B><P>Here, we in silico evaluated acetylation effects using SIFT, PolyPhen-2 and PROVEAN which can estimate the effects of amino acid substitutions based on the sequence homology or protein structure in tau isoforms. In addition, we also investigated 27 acetylation effects on amyloid formation of tau protein using Waltz.</P><B>Methods:</B><P>15 acetylation mimics were estimated to be most detrimental, which indicates that there may be novel pathogenic acetylation sites in human tau protein. Interestingly, deleterious effect of acetylation mimics was different according to type of isoforms. Furthermore, all acetylation mimics were predicted to be region of amyloid formation at the codons 274-279 of human tau protein. Notably, acetylation mimic of codon 311 (K311Q) induced formation of additional amyloid region located on codons 306-311 of human tau protein.</P><B>Results:</B><P> Serum exosomes were increased in transgenic mice compared to wild types as determined by increased levels of the exosome markers flotillin and alix. High levels of neuronal markers were found in exosomes, without difference between the 2 groups. Markers for endothelial-derived exosomes were decreased in the transgenic model, while astrocytic-derived exosomes were increased. Exosome characterization showed increased levels of oligomeric Aβ and oligomeric and monomeric forms tau on the transgenic animals. Levels of amyloid precursor protein were also increased. In addition, pathological and phosphorylated forms of tau were detected, but no difference was observed between groups.</P><B>Conclusion:</B><P>To the best of our knowledge, this is the first simultaneous in-silico evaluation of the acetylation state of 27 human tau protein residues</P>
Nanoparticle-Based Combination Therapy for Cancer Treatment.
Yhee, Ji Young,Son, Sejin,Lee, Hyukjin,Kim, Kwangmeyung Bentham Science Publishers 2015 CURRENT PHARMACEUTICAL DESIGN Vol.21 No.22
<P>In recent years, combination of different types of therapies using nanoparticles has emerged as an advanced strategy for cancer treatment. Most of all, combination of chemotherapeutic drug and siRNA in nanoformulation has shown a great potential, because siRNA-mediated specific gene silencing can compensate for the incomplete anti-cancer actions of chemotherapy. In this article, nanoparticle-based combination therapy for cancer treatment is introduced to be focused on the therapeutic chemical and siRNA combination. It is classified into 3 groups: 1) general chemotherapy combined with siRNA carrying nanoparticle, 2) co-delivery of chemical and siRNA therapeutics within a single nanoparticle, and 3) Use of multiple nanoparticles for chemical and siRNA therapeutics. The purpose of the combination and the mechanisms of anti-cancer action was described according to the categories. Examples of some recent developments of nanotechnology-based chemo- and siRNA- therapeutics combination therapy are summarized for better understanding of its practical application.</P>
Gadhe, Changdev G,Balupuri, Anand,Balasubramanian, Pavithra K,Cho, Seung Joo Bentham Science Publishers 2014 ANTICANCER AGENTS IN MEDICINAL CHEMISTRY Vol.14 No.7
<P>Multidrug resistance (MDR) is a phenomenon whereby cancer cells experience intrinsic or acquired resistance to a broad spectrum of structurally and functionally distinct chemotherapeutic agents. Permeability glycoprotein (P-gp) is the key protein responsible for the development of MDR in cancer cells, as it exports chemotherapeutic agents from cells. In the present study, comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and hologram quantitative structure activity relationship (HQSAR) techniques were used to derive predictive models for phenylsulfonylfuroxan derivatives as P-gp inhibitors. Cross-validated correlation coefficients (q(2)) of 0.811, 0.855, and 0.907 and non-cross-validated correlation coefficients (r(2)) of 0.87, 0.985, and 0.973 were obtained for CoMFA, CoMSIA, and HQSAR derived models, respectively. The predictive power of the models were assessed using an external test set of five compounds and showed reasonable external predictabilities (r(2) pred) of 0.704, 0.517, and 0.713, respectively. Contour and atomic contribution maps were generated to investigate physicochemical requirements of ligands for better receptor binding affinity. 3D Contour maps suggested molecular interactions such as steric and electrostatic effects and hydrogen bond formation. However, atomic contribution maps indicated that ortho and para positions of the R(1) phenylsulfonyl ring are the most desirable regions to modulate P-gp antagonism. The 3(rd) and 4(th) positions of the central five-membered ring were also found to be important. Our results are in line with previous reports. Information obtained from the contour and atomic contribution maps were utilized to design more potent compounds containing different R(1) fragments. In addition, the activities of these more potent compounds were predicted using derived models.</P>