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991.
Madhura Pradhan Charu Suri Sinjan Choudhary Pradeep Kumar Naik 《Journal of biomolecular structure & dynamics》2018,36(1):195-208
Beta-sitosterol (β-SITO), a phytosterol present in many edible vegetables, has been reported to possess antineoplastic properties and cancer treatment potential. We have shown previously that it binds at a unique site (the ‘SITO-site’) compared to the colchicine binding site at the interface of α- and β-tubulin. In this study, we investigated the anticancer efficacy of β-SITO against invasive breast carcinoma using MCF-7 cells. Since ‘isotypes’ of β-tubulin show tissue-specific expression and many are associated with cancer drug resistance, using computer-assisted docking and atomistic molecular dynamic simulations, we also examined its binding interactions to all known isotypes of β-tubulin in αβ-tubulin dimer. β-SITO inhibited MCF-7 cell viability by up to 50%, compared to vehicle-treated control cells. Indicating its antimetastatic potential, the phytosterol strongly inhibited cell migration. Immunofluorescence imaging of β-SITO-treated MCF-7 cells exhibited disruption of the microtubules and chromosome organization. Far-UV circular dichroism spectra indicated loss of helical stability in tubulin when bound to β-SITO. Docking and MD simulation studies, combined with MM-PBSA and MM-GBSA calculations revealed that β-SITO preferentially binds with specific β-tubulin isotypes (βII and βIII) in the αβ-tubulin dimer. Both these β-tubulin isotypes have been implicated in drug resistance against tubulin-targeted chemotherapeutics. Our data show the tubulin-targeted anticancer potential of β-SITO, and its potential clinical utility against βII and βIII isotype-overexpressing neoplasms. 相似文献
992.
Elisabet Barbero-Camps Vicente Roca-Agujetas Isabel Bartolessis Cristina de Dios Jose C. Fernández-Checa Montserrat Marí 《Autophagy》2018,14(7):1129-1154
Macroautophagy/autophagy failure with the accumulation of autophagosomes is an early neuropathological feature of Alzheimer disease (AD) that directly affects amyloid beta (Aβ) metabolism. Although loss of presenilin 1 function has been reported to impair lysosomal function and prevent autophagy flux, the detailed mechanism leading to autophagy dysfunction in AD remains to be elucidated. The resemblance between pathological hallmarks of AD and Niemann-Pick Type C disease, including endosome-lysosome abnormalities and impaired autophagy, suggests cholesterol accumulation as a common link. Using a mouse model of AD (APP-PSEN1-SREBF2 mice), expressing chimeric mouse-human amyloid precursor protein with the familial Alzheimer Swedish mutation (APP695swe) and mutant presenilin 1 (PSEN1-dE9), together with a dominant-positive, truncated and active form of SREBF2/SREBP2 (sterol regulatory element binding factor 2), we demonstrated that high brain cholesterol enhanced autophagosome formation, but disrupted its fusion with endosomal-lysosomal vesicles. The combination of these alterations resulted in impaired degradation of Aβ and endogenous MAPT (microtubule associated protein tau), and stimulated autophagy-dependent Aβ secretion. Exacerbated Aβ-induced oxidative stress in APP-PSEN1-SREBF2 mice, due to cholesterol-mediated depletion of mitochondrial glutathione/mGSH, is critical for autophagy induction. In agreement, in vivo mitochondrial GSH recovery with GSH ethyl ester, inhibited autophagosome synthesis by preventing the oxidative inhibition of ATG4B deconjugation activity exerted by Aβ. Moreover, cholesterol-enrichment within the endosomes-lysosomes modified the levels and membrane distribution of RAB7A and SNAP receptors (SNAREs), which affected its fusogenic ability. Accordingly, in vivo treatment with 2-hydroxypropyl-β-cyclodextrin completely rescued these alterations, making it a potential therapeutic tool for AD. 相似文献
993.
Abberent expression of NOR1 protein in tumor associated macrophages contributes to the development of DEN‐induced hepatocellular carcinoma 下载免费PDF全文
994.
Dongliang Zhang Wei Hu Jiangang Xie Yuan Zhang Bo Zhou Xueqin Liu Yun Zhang Yingjun Su Boquan Jin Shuzhong Guo Ran Zhuang 《生物化学与生物物理学报:疾病的分子基础》2018,1864(9):3085-3098
Graft-versus-host disease (GVHD) is the most common complication and major limitation of allogeneic hematopoietic stem cell transplantation. The CD226/TIGIT-CD155 signal is critical for the cross-talk between T cells and dendritic cells (DCs). Studies have shown that blockade of the CD226-CD155 interaction, using an anti-CD226 antibody, can significantly ameliorate GVHD. It has also been reported that a TIGIT-Fc fusion protein exerts immunosuppressive effects by binding to CD155 on DCs. Here, we used a mouse allogeneic acute GVHD model to explore the therapeutic potential and mechanism of action of TIGIT-Fc. C57/BL6 and Balb/c mice were used as hematopoietic cell graft donors and recipients, respectively. In the TIGIT-Fc-treated mice, GVHD symptom occurrence and mortality were delayed compared to that in isotype control group mice. Histopathological analyses revealed that following TIGIT-Fc treatment, liver and small intestine tissue damage was reduced with minimal lymphocytic infiltration. The percentage of CD8+IFN-γ+ and CD8+ granzyme B+ cells significantly decreased in the TIGIT-Fc group. Moreover, treatment with TIGIT-Fc, even after the onset of GVHD, ameliorated symptoms and prolonged survival. TIGIT-Fc also inhibited CD8+ T cell activation in vitro; this was dependent on the presence of CD155 on bone marrow-derived dendritic cells (BMDCs) and on IL-10 production. In addition, TIGIT–CD155 ligation triggered both Erk phosphorylation and STAT3 nuclear translocation. These data indicate that TIGIT plays an important role in the development of GVHD and is an ideal molecular target to treat acute GVHD. 相似文献
995.
Toshihiko Tashima 《Bioorganic & medicinal chemistry letters》2018,28(18):3015-3024
Cancer is one of the major causes of death globally. The current treatment options are insufficient, leading to unmet medical needs in cancer treatment. Off-target side effects, multidrug resistance, selective distribution to cancerous tissues, and cell membrane permeation of anti-cancer agents are critical problems to overcome. There is a method to solve these problems by using receptor-mediated endocytosis (RME). It is well known that proteins such as integrin, HER2, EGFR, or other cancer biomarkers are specifically overexpressed on the surface of target cancer cells. By taking advantage of such specific receptors, payloads can be transported into cells through endocytosis using a conjugate composed of the corresponding ligands connected to the payloads by an appropriate linker. After RME, the payloads released by endosomal escape into the cytoplasm can exhibit the cytotoxic activity against cancer cells. Cell-penetrating peptides (CPPs), tumor-homing peptides (THPs), and monoclonal antibodies (mAbs) are utilized as ligands in this system. Antibody drug conjugates (ADCs) based on RME have already been used to cure cancer. In addition to the canonical conjugate method, nanocarriers for spontaneous accumulation in cancer tissue due to enhanced permeability and retention (EPR) effect are extensively used. In this review, I introduce the possibilities and advantages of drug design and development based on RME for the treatment of cancer. 相似文献
996.
The diterpenes, strobol, strobal, manoyl oxide, and cis- and trans-abienols, were isolated as major constituents of the extract of Pinus strobus L. cortex tissue. The known triterpene, 3β-methoxy-14-serraten-21-one, was also found. A polyprenol was isolated from the needle extractives. 相似文献
997.
Molecular-sieve chromatography of an extract from ungerminated rye indicated the presence of enzymes which hydrolysed cellobiose, laminaribiose and the β-glucans cellodextrin, laminarin and barley β-glucan. A purified endo-β-1,3-glucanase was prepared from the extract by ammonium sulphate fractionation and molecular-sieve chromatography on Biogel P60. The substrate specificity and some properties of the enzyme are reported and the in vivo role of the enzyme is discussed. 相似文献
998.
In order to study rabbit mononuclear cell surface receptors, it was necessary to develop a procedure to isolate mononuclear cell preparations that are free of significant contamination by other cell types, especially platelets. Centrifugation of dextran-sedimented, anti-coagulated whole blood through Hypaque (density 1.060) at 600 X g for 5 min at 22 degrees C eliminated greater than 93% of starting platelets. A second 5-min Hypaque centrifugation of Hypaque-Ficoll-isolated mononuclear cells (MNC) (approximately 80% lymphocytes) at 450 X g for 5 min at 22 degrees C reduced platelet contamination to less than one platelet per three MNC, and resulted in the overall removal of greater than 99.5% of starting platelets. These relatively pure MNC which were isolated in less than 2 hr were identified as having beta-adrenergic receptors by radioligand binding techniques using [125I]iodohydroxybenzylpindolol [( 125I]IHYP). Binding of [125I]IHYP to intact rabbit MNC was a saturable, stereospecific, and rapid process with a dissociation constant (KD) of 0.53 +/- 0.18 nM and a binding capacity of 3,461 +/- 235 sites/cell. 相似文献
999.
Ten alkaloids (I-X), five β-phenethylamines, two tetrahydroisoquinolines, and three indole-3-alkylamines, have been isolated from Desmodium tiliaefolium. Chemical transformations, spectral (UV,IR, NMR, MS) evidence, and in most cases comparison with reference materials established their identity as tyramine (I), hordenine (II), 3,4-dimethoxy-β-phenethylamine (III), N,N- dimethyl-3,4-dimethoxyphenethylamine (IV), N-methyl-3,4-dimethoxy-β-hydroxyphenethylamine (V), salsoline (V1), salsolidine (VII), tryptamine (VIII), abrine (IX), and hypahorine (X). Alkaloid (V) is a new naturally occurring compound, while no tetrahydroisoquinoline alkaloid has been encountered before in this genus. This is the first time that three different types of alkaloids have been reported in a single legume species. In addition to the above alkaloids, four quaternary β-phenethylamines and tetrahydroisoquinoline alkaloids have been detected, and choline and betaine have been isolated from the water-soluble alkaloid fraction of the roots. 相似文献
1000.
Sk Moquammel Haque Avijit Chakraborty Biswajit Ghosh 《Journal of Genetic Engineering and Biotechnology》2018,16(2):645-651
Ledebouria revoluta are important ethnomedicinal plant found in India and South Africa. Micropropagation via indirect shoot organogenesis had been established from three types of explant (i.e. scale leaf, leaf lamina and root) of L. revoluta. Scale leaf was found superior as compared to leaf lamina and root explant with respect to their organogenic callus induction potentiality. Murashige and Skoog (1962) [MS] media supplemented with 3.0?mg?L?1 2,4-dichlorophenoxyacetic acid, 0.75?mg?L?1 β-naphthoxyacetic acid were best effective for inducing organogenic callus. Maximum 17.0?±?0.52 bulblets were induced from about 500?mg of callus within 42–46?days sub-culturing on a medium containing 0.75?mg?L?1 kinetin. The bulblets were matured (86.7% success) after one month culture on the same medium composition. The best result of in vitro root induction with 100% response and 8.4?±?0.31 roots per bulb was achieved after 18?days of implantation on MS medium containing 2.0?mg?L?1 indole-3-butyric acid. Plantlets were acclimatized with a 96.0% survival rate. Chromosomal studies revealed cytological stability of callus cells and all regenerants containing 2n?=?30 chromosomes, same as parental plants. Antimicrobial activity of L. revoluta was tested against two Gram-positive bacteria, three Gram-negative bacteria and two fungi. The methanol and ethanol extract proved more effective against bacteria, whereas acetone and chloroform extract shows potential anti-fungal activities. Present protocol can be applied reliably to produce uniform planting materials in large scale. In addition, this efficient indirect regeneration pathway via callus culture opens a way for improvement through genetic transformation. 相似文献