keyword
https://read.qxmd.com/read/37269004/a-polo-like-kinase-inhibitor-identified-by-computational-repositioning-attenuates-pulmonary-fibrosis
#21
JOURNAL ARTICLE
Takeshi Imakura, Seidai Sato, Kazuya Koyama, Hirohisa Ogawa, Takahiro Niimura, Kojin Murakami, Yuya Yamashita, Keiko Haji, Nobuhito Naito, Kozo Kagawa, Hiroshi Kawano, Yoshito Zamami, Keisuke Ishizawa, Yasuhiko Nishioka
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease with few effective therapeutic options. Recently, drug repositioning, which involves identifying novel therapeutic potentials for existing drugs, has been popularized as a new approach for the development of novel therapeutic reagents. However, this approach has not yet been fully utilized in the field of pulmonary fibrosis. METHODS: The present study identified novel therapeutic options for pulmonary fibrosis using a systematic computational approach for drug repositioning based on integration of public gene expression signatures of drug and diseases (in silico screening approach)...
June 2, 2023: Respiratory Research
https://read.qxmd.com/read/37263374/multiple-pathways-for-reestablishing-par-polarity-in-c-elegans-embryo
#22
JOURNAL ARTICLE
Laurel A Koch, Lesilee S Rose
Asymmetric cell divisions, where cells divide with respect to a polarized axis and give rise to daughter cells with different fates, are critically important for development. In many such divisions, the conserved PAR polarity proteins accumulate in distinct cortical domains in response to a symmetry breaking cue. The one-cell C. elegans embryo is a paradigm for understanding mechanisms of PAR polarization, but much less is known about polarity in subsequent divisions. Here, we investigate the polarization of the P1 cell of the two-cell embryo...
May 30, 2023: Developmental Biology
https://read.qxmd.com/read/37137308/bub-1-bound-plk-1-directs-cdc-20-kinetochore-recruitment-to-ensure-timely-embryonic-mitoses
#23
JOURNAL ARTICLE
Jack Houston, Midori Ohta, J Sebastián Gómez-Cavazos, Amar Deep, Kevin D Corbett, Karen Oegema, Pablo Lara-Gonzalez, Taekyung Kim, Arshad Desai
During mitosis, chromosomes assemble kinetochores to dynamically couple with spindle microtubules.1 , 2 Kinetochores also function as signaling hubs directing mitotic progression by recruiting and controlling the fate of the anaphase promoting complex/cyclosome (APC/C) activator CDC-20.3 , 4 , 5 Kinetochores either incorporate CDC-20 into checkpoint complexes that inhibit the APC/C or dephosphorylate CDC-20, which allows it to interact with and activate the APC/C.4 , 6 The importance of these two CDC-20 fates likely depends on the biological context...
April 28, 2023: Current Biology: CB
https://read.qxmd.com/read/37071125/exposure-to-microbial-products-followed-by-loss-of-tet2-promotes-myelodysplastic-syndrome-via-remodeling-hscs
#24
JOURNAL ARTICLE
Takako Yokomizo-Nakano, Ai Hamashima, Sho Kubota, Jie Bai, Supannika Sorin, Yuqi Sun, Kenta Kikuchi, Mihoko Iimori, Mariko Morii, Akinori Kanai, Atsushi Iwama, Gang Huang, Daisuke Kurotaki, Hitoshi Takizawa, Hirotaka Matsui, Goro Sashida
Aberrant innate immune signaling in myelodysplastic syndrome (MDS) hematopoietic stem/progenitor cells (HSPCs) has been implicated as a driver of the development of MDS. We herein demonstrated that a prior stimulation with bacterial and viral products followed by loss of the Tet2 gene facilitated the development of MDS via up-regulating the target genes of the Elf1 transcription factor and remodeling the epigenome in hematopoietic stem cells (HSCs) in a manner that was dependent on Polo-like kinases (Plk) downstream of Tlr3/4-Trif signaling but did not increase genomic mutations...
July 3, 2023: Journal of Experimental Medicine
https://read.qxmd.com/read/37067150/bub-1-and-cenp-c-recruit-plk-1-to-control-chromosome-alignment-and-segregation-during-meiosis-i-in-c-elegans-oocytes
#25
JOURNAL ARTICLE
Samuel J P Taylor, Laura Bel Borja, Flavie Soubigou, Jack Houston, Dhanya K Cheerambathur, Federico Pelisch
Phosphorylation is a key post-translational modification that is utilised in many biological processes for the rapid and reversible regulation of protein localisation and activity. Polo-like kinase 1 (PLK-1) is essential for both mitotic and meiotic cell divisions, with key functions being conserved in eukaryotes. The roles and regulation of PLK-1 during mitosis have been well characterised. However, the discrete roles and regulation of PLK-1 during meiosis have remained obscure. Here, we used Caenorhabditis elegans (C...
April 17, 2023: ELife
https://read.qxmd.com/read/37049713/development-of-cell-permeable-nanobret-probes-for-the-measurement-of-plk1-target-engagement-in-live-cells
#26
JOURNAL ARTICLE
Xuan Yang, Jeffery L Smith, Michael T Beck, Jennifer M Wilkinson, Ani Michaud, James D Vasta, Matthew B Robers, Timothy M Willson
PLK1 is a protein kinase that regulates mitosis and is both an important oncology drug target and a potential antitarget of drugs for the DNA damage response pathway or anti-infective host kinases. To expand the range of live cell NanoBRET target engagement assays to include PLK1, we developed an energy transfer probe based on the anilino-tetrahydropteridine chemotype found in several selective PLK inhibitors. Probe 11 was used to configure NanoBRET target engagement assays for PLK1, PLK2, and PLK3 and measure the potency of several known PLK inhibitors...
March 25, 2023: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://read.qxmd.com/read/36985522/study-on-pharmacokinetics-and-metabolic-profiles-of-novel-potential-plk-1-inhibitors-by-uhplc-ms-ms-combined-with-uhplc-q-orbitrap-hrms
#27
JOURNAL ARTICLE
Lin Wang, Hui Lei, Jing Lu, Wenyan Wang, Chunjiao Liu, Yunjie Wang, Yifei Yang, Jingwei Tian, Jianzhao Zhang
PLK-1 (Polo-like kinase-1) plays an essential role in cytokinesis, and its aberrant expression is considered to be keenly associated with a wide range of cancers. It has been selected as an appealing target and small-molecule inhibitors have been developed and studied in clinical trials. Unfortunately, most have been declared as failures due to the poor therapeutic response and off-target toxicity. In the present study, a novel potent PLK-1 inhibitor, compound 7a , was designed and synthetized. 1 H NMR, 13 C NMR, 19 F NMR and mass spectrum were comprehensively used for the compound characterization...
March 10, 2023: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://read.qxmd.com/read/36919909/human-polo-like-kinase-inhibitors-as-antiplasmodials
#28
JOURNAL ARTICLE
Monica J Bohmer, Jinhua Wang, Eva S Istvan, Madeline R Luth, Jennifer E Collins, Edward L Huttlin, Lushun Wang, Nimisha Mittal, Mingfeng Hao, Nicholas P Kwiatkowski, Steven P Gygi, Ratna Chakrabarti, Xianming Deng, Daniel E Goldberg, Elizabeth A Winzeler, Nathanael S Gray, Debopam Chakrabarti
Protein kinases have proven to be a very productive class of therapeutic targets, and over 90 inhibitors are currently in clinical use primarily for the treatment of cancer. Repurposing these inhibitors as antimalarials could provide an accelerated path to drug development. In this study, we identified BI-2536, a known potent human polo-like kinase 1 inhibitor, with low nanomolar antiplasmodial activity. Screening of additional PLK1 inhibitors revealed further antiplasmodial candidates despite the lack of an obvious orthologue of PLKs in Plasmodium ...
March 15, 2023: ACS Infectious Diseases
https://read.qxmd.com/read/36865333/development-of-cell-permeable-nanobret-probes-for-the-measurement-of-plk1-target-engagement-in-live-cells
#29
Xuan Yang, Jeffery L Smith, Michael T Beck, Jennifer M Wilkinson, Ani Michaud, James D Vasta, Matthew B Robers, Timothy M Willson
PLK1 is a protein kinase that regulates mitosis and is both an important oncology drug target and a potential anti-target of drugs for the DNA damage response pathway or anti-infective host kinases. To expand the range of live cell NanoBRET target engagement assays to include PLK1 we developed an energy transfer probe based on the anilino-tetrahydropteridine chemotype found in several selective PLK inhibitors. Probe 11 was used to configure NanoBRET target engagement assays for PLK1, PLK2, and PLK3 and measure the potency of several known PLK inhibitors...
February 26, 2023: bioRxiv
https://read.qxmd.com/read/36865292/mechanisms-of-nuclear-pore-complex-disassembly-by-the-mitotic-polo-like-kinase-1-plk-1-in-c-elegans-embryos
#30
Sylvia Nkombo Nkoula, Griselda Velez-Aguilera, Batool Ossareh-Nazari, Lucie Van Hove, Cristina Ayuso, Véronique Legros, Guillaume Chevreux, Laura Thomas, Géraldine Seydoux, Peter Askjaer, Lionel Pintard
UNLABELLED: The nuclear envelope, which protects and organizes the interphase genome, is dismantled during mitosis. In the C. elegans zygote, nuclear envelope breakdown (NEBD) of the parental pronuclei is spatially and temporally regulated during mitosis to promote the unification of the parental genomes. During NEBD, Nuclear Pore Complex (NPC) disassembly is critical for rupturing the nuclear permeability barrier and removing the NPCs from the membranes near the centrosomes and between the juxtaposed pronuclei...
February 22, 2023: bioRxiv
https://read.qxmd.com/read/36840034/apoptotic-mechanisms-of-quercetin-in-liver-cancer-recent-trends-and-advancements
#31
REVIEW
Gautam Sethi, Prangya Rath, Abhishek Chauhan, Anuj Ranjan, Renuka Choudhary, Seema Ramniwas, Katrin Sak, Diwakar Aggarwal, Isha Rani, Hardeep Singh Tuli
Due to rising incidence rates of liver cancer and worries about the toxicity of current chemotherapeutic medicines, the hunt for further alternative methods to treat this malignancy has escalated. Compared to chemotherapy, quercetin, a flavonoid, is relatively less harmful to normal cells and is regarded as an excellent free-radical scavenger. Apoptotic cell death of cancer cells caused by quercetin has been demonstrated by many prior studies. It is present in many fruits, vegetables, and herbs. Quercetin targets apoptosis, by upregulating Bax, caspase-3, and p21 while downregulating Akt, PLK-1, cyclin-B1, cyclin-A, CDC-2, CDK-2, and Bcl-2...
February 20, 2023: Pharmaceutics
https://read.qxmd.com/read/36812406/unusually-high-affinity-of-the-plk-inhibitors-ro3280-and-gsk461364-to-hsa-and-its-possible-pharmacokinetic-implications
#32
JOURNAL ARTICLE
Jesús Fernández-Sainz, Pedro J Pacheco-Liñán, Consuelo Ripoll, Joaquín González-Fuentes, José Albaladejo, Iván Bravo, Andrés Garzón-Ruiz
The binding processes of two Polo-like kinase inhibitors, RO3280 and GSK461364, to the human serum albumin (HSA) protein as well as the protonation equilibria of both compounds have been studied combining absorbance and fluorescence spectroscopy experiments together with density functional theory calculations. We found that the charge states of RO3280 and GSK461364 are +2 and +1, respectively, at the physiological pH. Nevertheless, RO3280 binds to HSA in the charge state +1 prior to a deprotonation pre-equilibrium...
February 22, 2023: Molecular Pharmaceutics
https://read.qxmd.com/read/36810816/inhibition-of-polo-like-kinase-1-plk1-triggers-cell-apoptosis-via-ros-caused-mitochondrial-dysfunction-in-colorectal-carcinoma
#33
JOURNAL ARTICLE
Ya Feng, Tianjiao Li, Zhoujun Lin, Yin Li, Xiao Han, Xiaolin Pei, Zhenkun Fu, Qiao Wu, Di Shao, Chenggang Li
BACKGROUND: Colorectal cancer (CRC) is one of the most frequently diagnosed cancers. Polo-like kinase 1 (PLK1), a member of the serine/threonine kinase PLK family, is the most investigated and essential in the regulation of cell cycle progression, including chromosome segregation, centrosome maturation and cytokinesis. However, the nonmitotic role of PLK1 in CRC is poorly understood. In this study, we explored the tumorigenic effects of PLK1 and its potential as a therapeutic target in CRC...
February 22, 2023: Journal of Cancer Research and Clinical Oncology
https://read.qxmd.com/read/36769174/poly-l-lysine-to-fight-antibiotic-resistances-of-pseudomonas-aeruginosa
#34
JOURNAL ARTICLE
Adeline Cezard, Delphine Fouquenet, Virginie Vasseur, Katy Jeannot, Fabien Launay, Mustapha Si-Tahar, Virginie Hervé
Pseudomonas aeruginosa is a major hospital-associated pathogen that can cause severe infections, most notably in patients with cystic fibrosis (CF) or those hospitalized in intensive care units. Given its remarkable ability to resist antibiotics, P. aeruginosa eradication has grown more challenging. Therefore, there is an urgent need to discover and develop new strategies that can counteract P. aeruginosa -resistant strains. Here, we evaluated the efficacy of poly-L-lysine (pLK) in combination with commonly used antibiotics as an alternative treatment option against P...
February 2, 2023: International Journal of Molecular Sciences
https://read.qxmd.com/read/36753621/bulk-biopolyelectrolyte-complexes-from-homopolypeptides-solid-salt-bridges
#35
JOURNAL ARTICLE
Zachary A Digby, Yuhui Chen, Khalil Akkaoui, Joseph B Schlenoff
Salt bridges, pairings between oppositely charged amino acids, are dispersed throughout proteins to assist folding and interactions. Biopolyelectrolyte complexes (BioPECs) were made between the homopolypeptides poly-l-arginine (PLR) and poly-l-lysine (PLK) with sodium triphosphate (STPP), as well as from polypeptide-only combinations. Viscoelastic measurements on these high salt bridge density materials showed many were solid, even glassy, in nature. Although the polypeptide-phosphate complexes had similar moduli at room temperature, the PLR-STPP complex displayed an unusual melting event above 70 °C not seen in PLK-STPP...
February 8, 2023: Biomacromolecules
https://read.qxmd.com/read/36711457/mitotic-events-depend-on-regulation-of-plk-1-levels-by-the-mitochondrial-protein-spd-3
#36
Yu-Zen Chen, Vitaly Zimyanin, Stefanie Redemann
In metazoans, Polo Kinase (Plk1) controls several mitotic events including nuclear envelope breakdown, centrosome maturation and kinetochore assembly. Here we show that mitotic events regulated by Polo Like Kinase (PLK-1) in early C. elegans embryos depend on the mitochondrial-localized protein SPD-3. spd-3 mutant one-cell embryos contain abnormally positioned mitotic chromosomes and prematurely and asymmetrically disassemble the nuclear lamina. Nuclear envelope breakdown (NEBD) in C. elegans requires direct dephosphorylation of lamin by PLK-1...
January 12, 2023: bioRxiv
https://read.qxmd.com/read/36700544/recruitment-of-polo-like-kinase-couples-synapsis-to-meiotic-progression-via-inactivation-of-chk-2
#37
JOURNAL ARTICLE
Liangyu Zhang, Weston T Stauffer, John S Wang, Fan Wu, Zhouliang Yu, Chenshu Liu, Hyung Jun Kim, Abby F Dernburg
Meiotic chromosome segregation relies on synapsis and crossover recombination between homologous chromosomes. These processes require multiple steps that are coordinated by the meiotic cell cycle and monitored by surveillance mechanisms. In diverse species, failures in chromosome synapsis can trigger a cell cycle delay and/or lead to apoptosis. How this key step in 'homolog engagement' is sensed and transduced by meiotic cells is unknown. Here we report that in C. elegans , recruitment of the Polo-like kinase PLK-2 to the synaptonemal complex triggers phosphorylation and inactivation of CHK-2, an early meiotic kinase required for pairing, synapsis, and double-strand break induction...
January 26, 2023: ELife
https://read.qxmd.com/read/36673375/antitumor-effects-of-poplar-propolis-on-dlbcl-su-dhl-2-cells
#38
JOURNAL ARTICLE
Xiaoqing Liu, Yuanyuan Tian, Ao Yang, Chuang Zhang, Xiaoqing Miao, Wenchao Yang
Propolis is resinous natural product produced by Western honeybees using beeswax and plant and bud exudates, which has a wide range of biological activities, including antioxidation, antibacterial, anti-inflammation, immune regulation, antitumor, and so on. Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer, and accounts for about 30% of all lymphomas. The effect of poplar propolis on DLBCL has not been reported. The IC50 of propolis on the proliferation of DLBCL SU-DHL-2 cell line and its proteins and gene expressions were detected by CCK-8 kit, label-free proteomic, and RT-PCR...
January 7, 2023: Foods (Basel, Switzerland)
https://read.qxmd.com/read/36614085/elucidating-the-interaction-between-pyridoxine-5-phosphate-oxidase-and-dopa-decarboxylase-activation-of-b6-dependent-enzyme
#39
JOURNAL ARTICLE
Mohammed H Al Mughram, Mohini S Ghatge, Glen E Kellogg, Martin K Safo
Pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, serves as a cofactor for scores of B6-dependent (PLP-dependent) enzymes involved in many cellular processes. One such B6 enzyme is dopa decarboxylase (DDC), which is required for the biosynthesis of key neurotransmitters, e.g., dopamine and serotonin. PLP-dependent enzymes are biosynthesized as apo-B6 enzymes and then converted to the catalytically active holo-B6 enzymes by Schiff base formation between the aldehyde of PLP and an active site lysine of the protein...
December 30, 2022: International Journal of Molecular Sciences
https://read.qxmd.com/read/36458309/peitc-a-resounding-molecule-averts-metastasis-in-breast-cancer-cells-in-vitro-by-regulating-pkc%C3%AE-aurora-a-interplay
#40
JOURNAL ARTICLE
Souvick Biswas, Elizabeth Mahapatra, Salini Das, Madhumita Roy, Sutapa Mukherjee
BACKGROUND/AIM: Intricate association and aberrant activation of serine/threonine kinase (STK) family proteins like Polo-like kinase (PLK1) and Aurora kinase (Aurora A abruptly regulate mitotic entry whereas activation of PKCδ), another important member of STK family conversely induces apoptosis which is preceded by cell cycle arrest. These STKs are considered as major determinant of oncogenicity. Therefore, the contributory role of Aurora A/PLK-1 axis in mitotic control and PKCδ in apoptosis control and their reciprocity in cancer research is an emerging area to explore...
November 2022: Heliyon
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