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https://www.readbyqxmd.com/read/29220790/2-alkoxycarbonyl-3-arylamino-5-substituted-thiophenes-as-a-novel-class-of-antimicrotubule-agents-design-synthesis-cell-growth-and-tubulin-polymerization-inhibition
#1
Romeo Romagnoli, Maria Kimatrai Salvador, Santiago Schiaffino Ortega, Pier Giovanni Baraldi, Paola Oliva, Stefania Baraldi, Luisa Carlota Lopez-Cara, Andrea Brancale, Salvatore Ferla, Ernest Hamel, Jan Balzarini, Sandra Liekens, Elena Mattiuzzo, Giuseppe Basso, Giampietro Viola
Microtubules are recognized as crucial components of the mitotic spindle during cell division, and, for this reason, the microtubule system is an attractive target for the development of anticancer agents. Continuing our search strategy for novel tubulin targeting-compounds, a new series of 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)-5-aryl/heteroarylthiophene derivatives was designed, synthesized and demonstrated to act as tubulin polymerization inhibitors at the colchicine site. A structure-activity relationship study on the phenyl at the 5-position of the thiophene ring was performed by introducing a variety of substituents containing electron-releasing and electron-withdrawing groups, with the 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)thiophene scaffold being the minimum structural requirement for activity...
December 5, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29217824/soluble-tau-has-devastating-effects-on-the-structural-plasticity-of-hippocampal-granule-neurons
#2
M Bolós, N Pallas-Bazarra, J Terreros-Roncal, J R Perea, J Jurado-Arjona, J Ávila, M Llorens-Martín
Tau is a neuronal microtubule-associated protein with countless physiological functions. Although the detrimental effects of insoluble aggregated Tau have been widely studied, recent evidence supports the notion that soluble Tau (composed mostly of monomers and dimers) is also toxic for neurons. Here we evaluated the long-term impact of a single stereotaxic injection of human soluble Tau on hippocampal granule neurons in mice. At the ultrastructural level, soluble Tau reduced the number of afferent synapses and caused a dramatic depletion of synaptic vesicles both in afferent and efferent synapses...
December 8, 2017: Translational Psychiatry
https://www.readbyqxmd.com/read/29216630/rapamycin-promotes-the-survival-and-adipogenesis-of-ischemia-challenged-adipose-derived-stem-cells-by-improving-autophagy
#3
Chichi Li, Lechi Ye, Li Yang, Xiaofang Yu, Yucang He, Zhuojie Chen, Liqun Li, Dan Zhang
BACKGROUND/AIMS: Ischemia is one of the main causes of the high rate of absorption of transplanted autologous fat. Autophagy allows cells to survive by providing energy under starvation. Rapamycin has been found to play a role in promoting autophagy. In this study, we investigated whether rapamycin participates in the survival and adipogenesis of ischemia-challenged adipose-derived stem cells (ADSCs) by regulating autophagy. METHODS: Before the cells were exposed to oxygen-glucose deprivation (OGD), a simulated ischemic microenvironment, the level of autophagy was reduced or increased by lentiviral transfection with short hairpin RNA targeting microtubule-associated protein 1-light chain 3 gene (shRNA-LC3) or treatment with rapamycin, respectively...
December 6, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29216315/the-pul37-tegument-protein-guides-alpha-herpesvirus-retrograde-axonal-transport-to-promote-neuroinvasion
#4
Alexsia L Richards, Patricia J Sollars, Jared D Pitts, Austin M Stults, Ekaterina E Heldwein, Gary E Pickard, Gregory A Smith
A hallmark property of the neurotropic alpha-herpesvirinae is the dissemination of infection to sensory and autonomic ganglia of the peripheral nervous system following an initial exposure at mucosal surfaces. The peripheral ganglia serve as the latent virus reservoir and the source of recurrent infections such as cold sores (herpes simplex virus type I) and shingles (varicella zoster virus). However, the means by which these viruses routinely invade the nervous system is not fully understood. We report that an internal virion component, the pUL37 tegument protein, has a surface region that is an essential neuroinvasion effector...
December 7, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/29215295/quantitative-proteomic-study-reveals-up-regulation-of-camp-signaling-pathway-related-proteins-in-mild-traumatic-brain-injury
#5
Hai Song, Shanhua Fang, Jing Gao, Jiaxong Wang, Zhenzhen Cao, Zeyun Guo, Qiongping Huang, Yongqang Qu, Hu Zhou, Jianyun Yu
Traumatic brain injury (TBI), as a neurological injury, becomes a leading cause of disability and mortality due to lacking effective therapy. About 75% of TBI is mild traumatic brain injury (mTBI). However, the complex molecular mechanisms underlying mTBI pathophysiology remains to be elucidated. In this study, iTRAQ-based quantitative proteomic approach was employed to measure temporal-global proteome changes of rat brain tissues from different time points (1 day, 7 day and 6 months) post single mTBI (smTBI) and repetitive mTBI (rmTBI)...
December 7, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/29215079/design-and-synthesis-of-5-aryl-4-4-arylpiperazine-1-carbonyl-2h-1-2-3-triazole-derivatives-as-colchicine-binding-site-inhibitors
#6
Yue Wu, Dongjie Feng, Meiqi Gao, Zhiwei Wang, Peng Yan, Zhenzhen Gu, Qi Guan, Daiying Zuo, Kai Bao, Jun Sun, Yingliang Wu, Weige Zhang
A series of 5-aryl-4-(4-arylpiperazine-1-carbonyl)-2H-1,2,3-triazol derivatives were designed as potential microtubule targeting agents. The regioselective alkylation of 5-aryl-4-(4-arylpiperazine-1-carbonyl)-2H-1,2,3-triazole was predicted by computations and confirmed by an unambiguous synthetic route. The antiproliferative activity of the synthesized compounds was tested in vitro using three human cancer cell lines and some compounds exhibited significant antiproliferative activity, which suggested the reasonability of introduction of the 1,2,3-triazole fragment...
December 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29215007/multivalent-cross-linking-of-actin-filaments-and-microtubules-through-the-microtubule-associated-protein-tau
#7
Yunior Cabrales Fontela, Harindranath Kadavath, Jacek Biernat, Dietmar Riedel, Eckhard Mandelkow, Markus Zweckstetter
Microtubule-associated proteins regulate microtubule dynamics, bundle actin filaments, and cross-link actin filaments with microtubules. In addition, aberrant interaction of the microtubule-associated protein Tau with filamentous actin is connected to synaptic impairment in Alzheimer's disease. Here we provide insight into the nature of interaction between Tau and actin filaments. We show that Tau uses several short helical segments to bind in a dynamic, multivalent process to the hydrophobic pocket between subdomains 1 and 3 of actin...
December 7, 2017: Nature Communications
https://www.readbyqxmd.com/read/29214451/stmn1-is-overexpressed-in-adrenocortical-carcinoma-and-promotes-a-more-aggressive-phenotype-in-vitro
#8
Anna Aronova, Irene M Min, Michael J P Crowley, Suraj J Panjwani, Brendan M Finnerty, Theresa Scognamiglio, Yi-Fang Liu, Timothy G Whitsett, Shipra Garg, Michael J Demeure, Olivier Elemento, Rasa Zarnegar, Thomas J Fahey Iii
BACKGROUND: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis and few therapeutic options. Stathmin1 (STMN1) is a cytosolic protein involved in microtubule dynamics through inhibition of tubulin polymerization and promotion of microtubule depolymerization, which has been implicated in carcinogenesis and aggressive behavior in multiple epithelial malignancies. We aimed to evaluate expression of STMN1 in ACC and to elucidate how this may contribute to its malignant phenotype...
December 6, 2017: Annals of Surgical Oncology
https://www.readbyqxmd.com/read/29213131/phagosomal-transport-depends-strongly-on-phagosome-size
#9
S Keller, K Berghoff, H Kress
Macrophages internalize pathogens for intracellular degradation. An important part of this process is the phagosomal transport from the cell periphery to the perinuclear region. Biochemical factors are known to influence the fate of phagosomes. Here, we show that the size of phagosomes also has a strong influence on their transport. We found that large phagosomes are transported persistently to the nucleus, whereas small phagosomes show strong bidirectional transport. We show that dynein motors play a larger role in the transport of large phagosomes, whereas actin filament-based motility plays a larger role in the transport of small phagosomes...
December 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29213065/modulation-of-microtubule-acetylation-by-the-interplay-of-tppp-p25-sirt2-and-new-anticancer-agents-with-anti-sirt2-potency
#10
Adél Szabó, Judit Oláh, Sándor Szunyogh, Attila Lehotzky, Tibor Szénási, Marianna Csaplár, Matthias Schiedel, Péter Lőw, Manfred Jung, Judit Ovádi
The microtubule network exerts multifarious functions controlled by its decoration with various proteins and post-translational modifications. The disordered microtubule associated Tubulin Polymerization Promoting Protein (TPPP/p25) and the NAD+-dependent tubulin deacetylase sirtuin-2 (SIRT2) play key roles in oligodendrocyte differentiation by acting as dominant factors in the organization of myelin proteome. Herein, we show that SIRT2 impedes the TPPP/p25-promoted microtubule assembly independently of NAD+; however, the TPPP/p25-assembled tubulin ultrastructures were resistant against SIRT2 activity...
December 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29212814/structural-basis-for-assembly-of-the-cbf3-kinetochore-complex
#11
Vera Leber, Andrea Nans, Martin R Singleton
Eukaryotic chromosomes contain a specialised region known as the centromere, which forms the platform for kinetochore assembly and microtubule attachment. The centromere is distinguished by the presence of nucleosomes containing the histone H3 variant, CENP-A. In budding yeast, centromere establishment begins with the recognition of a specific DNA sequence by the CBF3 complex. This in turn facilitates CENP-ACse4 nucleosome deposition and kinetochore assembly. Here, we describe a 3.6 Å single-particle cryo-EM reconstruction of the core CBF3 complex, incorporating the sequence-specific DNA-binding protein Cep3 together with regulatory subunits Ctf13 and Skp1...
December 6, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29212035/comprehensive-characterization-of-the-complex-lola-locus-reveals-a-novel-role-in-the-octopaminergic-pathway-via-tyramine-beta-hydroxylase-regulation
#12
Nadja Dinges, Violeta Morin, Nastasja Kreim, Tony D Southall, Jean-Yves Roignant
Longitudinals lacking (lola) is one of the most complex genes in Drosophila melanogaster, encoding up to 20 protein isoforms that include key transcription factors involved in axonal pathfinding and neural reprogramming. Most previous studies have employed loss-of-function alleles that disrupt lola common exons, making it difficult to delineate isoform-specific functions. To overcome this issue, we have generated isoform-specific mutants for all isoforms using CRISPR/Cas9. This enabled us to study specific isoforms with respect to previously characterized roles for Lola and to demonstrate a specific function for one variant in axon guidance via activation of the microtubule-associated factor Futsch...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29212018/structure-and-function-of-an-actin-based-filter-in-the-proximal-axon
#13
Varuzhan Balasanyan, Kaori Watanabe, William P Dempsey, Tommy L Lewis, Le A Trinh, Don B Arnold
The essential organization of microtubules within neurons has been described; however, less is known about how neuronal actin is arranged and the functional implications of its arrangement. Here, we describe, in live cells, an actin-based structure in the proximal axon that selectively prevents some proteins from entering the axon while allowing the passage of others. Concentrated patches of actin in proximal axons are present shortly after axonal specification in rat and zebrafish neurons imaged live, and they mark positions where anterogradely traveling vesicles carrying dendritic proteins halt and reverse...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29211997/challenges-in-estimating-the-motility-parameters-of-single-processive-motor-proteins
#14
Felix Ruhnow, Linda Kloβ, Stefan Diez
Cytoskeletal motor proteins are essential to the function of a wide range of intracellular mechano-systems. The biophysical characterization of their movement along their filamentous tracks is therefore of large importance. Toward this end, single-molecule, in vitro stepping-motility assays are commonly used to determine motor velocity and run length. However, comparing results from such experiments has proved difficult due to influences from variations in the experimental conditions and the data analysis methods...
December 5, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/29210287/dexmedetomidine-protects-against-oxygen-glucose-deprivation-reoxygenation-injury-induced-apoptosis-via-the-p38-mapk-erk-signalling-pathway
#15
Ke Wang, Yuekun Zhu
Objective To investigate the protective effects of dexmedetomidine (DEX) in oxygen-glucose deprivation/reoxygenation (OGD/R) injury, which is involved in a number of ischaemic diseases. Methods An in vitro OGD/R injury model was generated using mouse Neuro 2A neuroblastoma (N2A) cells. Different concentrations of DEX were administrated to OGD/R cells. CV-65 was used to inhibit p38 microtubule associated protein kinase/extracellular signal-regulated kinases (MAPK/ERK) signalling. Cell proliferation, cell cycle, apoptosis, and the levels of proteins related to p38 MAPK/ERK signalling and apoptosis were evaluated using Cell Counting Kit-8, flow cytometry, TdT-UTP nick end labelling and Western blot analysis, respectively...
January 1, 2017: Journal of International Medical Research
https://www.readbyqxmd.com/read/29209597/meckel-gruber-syndrome-an-update-on-diagnosis-clinical-management-and-research-advances
#16
REVIEW
Verity Hartill, Katarzyna Szymanska, Saghira Malik Sharif, Gabrielle Wheway, Colin A Johnson
Meckel-Gruber syndrome (MKS) is a lethal autosomal recessive congenital anomaly syndrome caused by mutations in genes encoding proteins that are structural or functional components of the primary cilium. Conditions that are caused by mutations in ciliary genes are collectively termed the ciliopathies, and MKS represents the most severe condition in this group of disorders. The primary cilium is a microtubule-based organelle, projecting from the apical surface of vertebrate cells. It acts as an "antenna" that receives and transduces chemosensory and mechanosensory signals, but also regulates diverse signaling pathways, such as Wnt and Shh, that have important roles during embryonic development...
2017: Frontiers in Pediatrics
https://www.readbyqxmd.com/read/29209346/katanin-a-sword-cutting-microtubules-for-cellular-developmental-and-physiological-purposes
#17
REVIEW
Ivan Luptovčiak, George Komis, Tomáš Takáč, Miroslav Ovečka, Jozef Šamaj
KATANIN is a well-studied microtubule severing protein affecting microtubule organization and dynamic properties in higher plants. By regulating mitotic and cytokinetic and cortical microtubule arrays it is involved in the progression of cell division and cell division plane orientation. KATANIN is also involved in cell elongation and morphogenesis during plant growth. In this way KATANIN plays critical roles in diverse plant developmental processes including the development of pollen, embryo, seed, meristem, root, hypocotyl, cotyledon, leaf, shoot, and silique...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/29208703/distag-tbccd1-is-required-for-basal-cell-fate-determination-in-ectocarpus
#18
Olivier Godfroy, Toshiki Uji, Chikako Nagasato, Agnieszka P Lipinska, Delphine Scornet, Akira F Peters, Komlan Avia, Sebastien Colin, Mignerot Laure, Taizo Motomura, J Mark Cock, Susana M Coelho
Brown algae are one of the most developmentally complex groups within the eukaryotes. As in many land plants and animals, their main body axis is established early in development, when the initial cell gives rise to two daughter cells that have apical and basal identities, equivalent to shoot and root identities in land plants, respectively. We show here that mutations in the Ectocarpus DISTAG (DIS) gene lead to loss of basal structures during both the gametophyte and the sporophyte generations. Several abnormalities were observed in the germinating initial cell in dis mutants including increased cell size, disorganisation of the Golgi apparatus, disruption of the microtubule network and aberrant positioning of the nucleus...
December 5, 2017: Plant Cell
https://www.readbyqxmd.com/read/29208373/roles-of-maternal-wnt8a-transcripts-in-axis-formation-in-zebrafish
#19
Hiromu Hino, Akiko Nakanishi, Ryoko Seki, Tsubasa Aoki, Etsuro Yamaha, Atsuo Kawahara, Takashi Shimizu, Masahiko Hibi
In early zebrafish development, the program for dorsal axis formation begins soon after fertilization. Previous studies suggested that dorsal determinants (DDs) localize to the vegetal pole, and are transported to the dorsal blastomeres in a microtubule-dependent manner. The DDs activate the canonical Wnt pathway and induce dorsal-specific genes that are required for dorsal axis formation. Among wnt-family genes, only the wnt8a mRNA is reported to localize to the vegetal pole in oocytes and to induce the dorsal axis, suggesting that Wnt8a is a candidate DD...
December 2, 2017: Developmental Biology
https://www.readbyqxmd.com/read/29207637/wheat-germ-agglutinin-induced-paraptosis-like-cell-death-and-protective-autophagy-is-mediated-by-autophagy-linked-fyve-inhibition
#20
Tsung Lin Tsai, Hao Chen Wang, Chun Hua Hung, Peng Chan Lin, Yi San Lee, Helen H W Chen, Wu Chou Su
Wheat germ agglutinin (WGA) is a lectin that specifically binds cell surface glycoproteins and disrupts nuclear pore complex function through its interaction with POM121. Our data indicate WGA induces paraptosis-like cell death without caspase activation. We observed the main features of paraptosis, including cytoplasmic vacuolation, endoplasmic reticulum dilation and increased ER stress, and the unfolded protein response in WGA-treated cervical carcinoma cells. Conversion of microtubule-associated protein I light chain 3 (LC3-I) into LC3-II and punctuate formation suggestive of autophagy were observed in WGA-treated cells...
October 31, 2017: Oncotarget
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