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https://www.readbyqxmd.com/read/28392275/exploring-the-influence-of-indololactone-structure-on-selectivity-for-binding-to-the-c1-domains-of-pkc%C3%AE-pkc%C3%AE%C2%B5-and-rasgrp
#1
Eleonora Elhalem, Lucía Gandolfi Donadío, Xiaoling Zhou, Nancy E Lewin, Lia C Garcia, Christopher C Lai, James A Kelley, Megan L Peach, Peter M Blumberg, María J Comin
C1 domain-containing proteins, such as protein kinase C (PKC), have a central role in cellular signal transduction. Their involvement in many diseases, including cancer, cardiovascular disease, and immunological and neurological disorders has been extensively demonstrated and has prompted a search for small molecules to modulate their activity. By employing a diacylglycerol (DAG)-lactone template, we have been able to develop ultra potent analogs of diacylglycerol with nanomolar binding affinities approaching those of complex natural products such as phorbol esters and bryostatins...
March 10, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28272610/some-limitations-of-an-approach-to-the-assembly-of-bryostatins-by-ring-closing-metathesis
#2
Raphaël Dumeunier, Thomas Gregson, Somhairle MacCormick, Hiroki Omori, Eric J Thomas
Preliminary studies into the use of ring-closing metathesis (RCM) in a convergent approach for the total synthesis of bryostatins are described. An ester that would have provided an advanced intermediate for a synthesis of a 20-deoxybryostatin by a RCM was prepared from an unsaturated acid and alcohol corresponding to the C1-C16 and C17-C27 fragments. However, studies of the formation of the C16-C17 double-bond by RCM were not successful and complex mixtures of products were obtained. To provide an insight into factors that may be involved in hindering RCM in this system, a slightly simplified C1-C16 acid and modified C17-C25 alcohols were prepared and their use for the synthesis of analogues of bryostatins was investigated...
March 8, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28271111/syntheses-of-c17-c27-fragments-of-20-deoxybryostatins-for-assembly-using-julia-and-metathesis-reactions
#3
Matthew Ball, Thomas Gregson, Hiroki Omori, Eric J Thomas
Two approaches to the synthesis of compounds corresponding to the C17-C27 fragment of the 20-deoxybryostatins are described. The first approach is based on the palladium(0) catalysed coupling of tin enolates, generated in situ from enol acetates using tributyltin methoxide, with vinylic bromides. The vinylic bromides were prepared using the Sharpless asymmetric dihydroxylation to introduce the hydroxyl groups corresponding to those at C25 and C26 in the bryostatins. Following several steps to introduce alkynyl ester functionality, the stereoselective addition of a tributyltin cuprate followed by tributyltin-bromine exchange gave the required vinylic bromides...
March 8, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28178410/strategies-to-extend-thrombolytic-time-window-for-ischemic-stroke-treatment-an-unmet-clinical-need
#4
REVIEW
Ike Dela Peña, Cesar Borlongan, Guofang Shen, Willie Davis
To date, reperfusion with tissue plasminogen activator (tPA) remains the gold standard treatment for ischemic stroke. However, when tPA is given beyond 4.5 hours of stroke onset, deleterious effects of the drug ensue, especially, hemorrhagic transformation (HT), which causes the most significant morbidity and mortality in stroke patients. An important clinical problem at hand is to develop strategies that will enhance the therapeutic time window for tPA therapy and reduce the adverse effects (especially HT) of delayed tPA treatment...
January 2017: Journal of Stroke
https://www.readbyqxmd.com/read/28146052/expansion-of-t-cells-with-interleukin-21-for-adoptive-immunotherapy-of-murine-mammary-carcinoma
#5
Christine K Zoon, Wen Wan, Laura Graham, Harry D Bear
We previously demonstrated that culturing antigen-sensitized draining lymph node (DLN) lymphocytes from BALB/c mice in interleukin (IL)-7/15 after activation with bryostatin/ionomycin (B/I) is superior to culture in IL-2 for expansion, differentiation to cluster of differentiation (CD)8+ cells and anti-tumor activity. We sought to determine whether the substitution or addition of IL-21 to culture had a similar effect. DLN lymphocytes were antigen-sensitized with 4T1 mammary carcinoma 10 days prior to harvest, activated with B/I, and expanded in culture for 7 days with either IL-2, IL-21, IL-2/21, IL-7/15, or IL-7/15/21...
January 29, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27994072/hiv-1-latency-reversing-agents-prostratin-and-bryostatin-1-induce-blood-brain-barrier-disruption-inflammation-and-modulate-leukocyte-adhesion-transmigration
#6
Clélia Dental, Alizé Proust, Michel Ouellet, Corinne Barat, Michel J Tremblay
A shock-and-kill approach involving the simultaneous treatment of HIV-1-infected patients with latency-reversing agents (LRAs) and combination antiretroviral therapy was proposed as a means to eradicate viral reservoirs. Currently available LRAs cannot discriminate between HIV-1-infected and uninfected cells. Therefore, the risks and benefits of using broad-spectrum LRAs need to be carefully evaluated, particularly in the CNS, where inflammation and leukocyte transmigration must be tightly regulated. We used a real-time impedance-sensing system to dynamically record the impact of different classes of LRAs on the integrity of tight monolayers of the immortalized human cerebral microvascular endothelial cell line hCMEC/D3...
December 19, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27993846/nonnucleoside-reverse-transcriptase-inhibitors-reduce-hiv-1-production-from-latently-infected-resting-cd4-t-cells-following-latency-reversal
#7
Jennifer M Zerbato, Gilda Tachedjian, Nicolas Sluis-Cremer
Therapeutic strategies that target the latent HIV-1 reservoir in resting CD4(+) T cells of infected individuals are always administered in the presence of combination antiretroviral therapy. Using a primary cell of HIV-1 latency, we evaluated whether different antiviral drug classes affected latency reversal (as assessed by extracellular virus production) by anti-CD3/CD28 monoclonal antibodies or bryostatin 1. We found that the nonnucleoside reverse transcriptase inhibitors efavirenz and rilpivirine significantly decreased HIV-1 production, by ≥1 log...
March 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27978828/integrin-fak-signaling-rapidly-and-potently-promotes-mitochondrial-function-through-stat3
#8
Nishant P Visavadiya, Matthew P Keasey, Vladislav Razskazovskiy, Kalpita Banerjee, Cuihong Jia, Chiharu Lovins, Gary L Wright, Theo Hagg
BACKGROUND: STAT3 is increasingly becoming known for its non-transcriptional regulation of mitochondrial bioenergetic function upon activation of its S727 residue (S727-STAT3). Lengthy mitochondrial dysfunction can lead to cell death. We tested whether an integrin-FAK-STAT3 signaling pathway we recently discovered regulates mitochondrial function and cell survival, and treatments thereof. METHODS: Cultured mouse brain bEnd5 endothelial cells were treated with integrin, FAK or STAT3 inhibitors, FAK siRNA, as well as integrin and STAT3 activators...
December 15, 2016: Cell Communication and Signaling: CCS
https://www.readbyqxmd.com/read/27941949/in-vitro-effects-of-the-small-molecule-protein-kinase-c-agonists-on-hiv-latency-reactivation
#9
Jessica Brogdon, Widade Ziani, Xiaolei Wang, Ronald S Veazey, Huanbin Xu
The persistence of latently HIV-infected cellular reservoirs represents the major obstacle to virus eradication in patients under antiretroviral therapy (ART). Cure strategies to eliminate these reservoirs are thus needed to reactivate proviral gene expression in latently infected cells. In this study, we tested optimal concentrations of PKC agonist candidates (PEP005/Ingenol-3-angelate, prostratin, bryostatin-1, and JQ1) to reactivate HIV latency in vitro, and examined their effects on cell survival, activation and epigenetic histone methylation after treatment alone or in combination in cell line and isolated CD4 T cells from SIV-infected macaques...
December 12, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27785754/nuclear-accumulation-of-histone-deacetylase-4-hdac4-exerts-neurotoxicity-in-models-of-parkinson-s-disease
#10
Qimei Wu, Xiaoyu Yang, Lei Zhang, Yu Zhang, Linyin Feng
Histone deacetylase 4 (HDAC4) is a class II HDAC which is highly expressed in the brain. Previous reports have shown that HDAC4 is essential for normal brain physiology and its deregulation leads to several neurodegenerative disorders. However, it remains unclear whether dysregulation of HDAC4 is specifically involved in the development of Parkinson's disease. In this study, we demonstrate that intracellular trafficking of HDAC4 is important in regulating dopaminergic cell death. While HDAC4 normally localizes to the cytoplasm, nuclear accumulation of HDAC4 was observed in dopaminergic neurons overexpressing A53T mutant α-synuclein treated with MPP(+)/MPTP in vitro and in vivo...
October 26, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27714213/the-evolution-of-a-stereoselective-synthesis-of-the-c1-c16-fragment-of-bryostatins
#11
Matthew Ball, Anne Baron, Ben Bradshaw, Raphaël Dumeunier, Matthew O'Brien, Eric J Thomas
The development of a synthesis of the C1-C16 fragment of bryostatins in which the key step is a stereoselective oxy-Michael reaction used to assemble the cis-2,6-disubstituted tetrahydropyran with the exocyclic alkene already installed, is described. Following early work using Stille reactions to prepare precursors for oxy-Michael reactions, a more efficient route was devised based on a ketophosphonate-aldehyde condensation to prepare the key dienone. Synthesis of the aldehyde required for the ketophosphonate condensation involved the highly stereoselective addition of a diorganocuprate derived from allylmagnesium bromide and copper(i) iodide to the methyl 5-hydroxyhex-2-ynoate prepared by ring-opening of a protected glycidol using lithiated methyl propiolate...
October 12, 2016: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/27713589/replacement-of-the-bryostatin-a-and-b-pyran-rings-with-phenyl-rings-leads-to-loss-of-high-affinity-binding-with-pkc
#12
Mark E Petersen, Noemi Kedei, Nancy E Lewin, Peter M Blumberg, Gary E Keck
We describe a convergent synthesis of a bryostatin analogue in which the natural A- and B-ring pyrans have been replaced by phenyl rings. The new analogue exhibited PMA like behavior in cell assays, but failed to maintain high affinity binding for PKC, despite retaining an unaltered C-ring 'binding domain'.
October 19, 2016: Tetrahedron Letters
https://www.readbyqxmd.com/read/27676096/evaluation-of-chromane-based-bryostatin-analogues-prepared-via-hydrogen-mediated-c-c-bond-formation-potency-does-not-confer-bryostatin-like-biology
#13
John M Ketcham, Ivan Volchkov, Te-Yu Chen, Peter M Blumberg, Noemi Kedei, Nancy E Lewin, Michael J Krische
The synthesis and biological evaluation of chromane-containing bryostatin analogues WN-2-WN-7 and the previously reported salicylate-based analogue WN-8 are described. Analogues WN-2-WN-7 are prepared through convergent assembly of the chromane-containing fragment B-I with the "binding domain" fragment A-I or its C26-des-methyl congener, fragment A-II. The synthesis of fragment B-I features enantioselective double C-H allylation of 1,3-propanediol to form the C2-symmetric diol 3 and Heck cyclization of bromo-diene 5 to form the chromane core...
October 12, 2016: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/27664855/comparative-analysis-of-the-anti-chikungunya-virus-activity-of-novel-bryostatin-analogs-confirms-the-existence-of-a-pkc-independent-mechanism
#14
Rana Abdelnabi, Daryl Staveness, Katherine E Near, Paul A Wender, Leen Delang, Johan Neyts, Pieter Leyssen
Previously, we reported that salicylate-based analogs of bryostatin protect cells from chikungunya virus (CHIKV)-induced cell death. Interestingly, 'capping' the hydroxyl group at C26 of a lead bryostatin analog, a position known to be crucial for binding to and modulation of protein kinase C (PKC), did not abrogate the anti-CHIKV activity of the scaffold, putatively indicating the involvement of a pathway independent of PKC. The work detailed in this study demonstrates that salicylate-derived analog 1 and two capped analogs (2 and 3) are not merely cytoprotective compounds, but act as selective and specific inhibitors of CHIKV replication...
November 15, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27590822/lack-of-overt-genome-reduction-in-the-bryostatin-producing-bryozoan-symbiont-candidatus-endobugula-sertula
#15
Ian J Miller, Niti Vanee, Stephen S Fong, Grace E Lim-Fong, Jason C Kwan
The uncultured bacterial symbiont "Candidatus Endobugula sertula" is known to produce cytotoxic compounds called bryostatins, which protect the larvae of its host, Bugula neritina The symbiont has never been successfully cultured, and it was thought that its genome might be significantly reduced. Here, we took a shotgun metagenomics and metatranscriptomics approach to assemble and characterize the genome of "Ca Endobugula sertula." We found that it had specific metabolic deficiencies in the biosynthesis of certain amino acids but few other signs of genome degradation, such as small size, abundant pseudogenes, and low coding density...
November 15, 2016: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/27545045/single-cell-characterization-of-viral-translation-competent-reservoirs-in-hiv-infected-individuals
#16
Amy E Baxter, Julia Niessl, Rémi Fromentin, Jonathan Richard, Filippos Porichis, Roxanne Charlebois, Marta Massanella, Nathalie Brassard, Nirmin Alsahafi, Gloria-Gabrielle Delgado, Jean-Pierre Routy, Bruce D Walker, Andrés Finzi, Nicolas Chomont, Daniel E Kaufmann
HIV cure efforts are hampered by limited characterization of the cells supporting HIV replication in vivo and inadequate methods for quantifying the latent viral reservoir in patients receiving antiretroviral therapy. We combine fluorescent in situ RNA hybridization with detection of HIV protein and flow cytometry, enabling detection of 0.5-1 gag-pol mRNA(+)/Gag protein(+)-infected cells per million. In the peripheral blood of untreated persons, active HIV replication correlated with viremia and occurred in CD4 T cells expressing T follicular helper cell markers and inhibitory co-receptors...
September 14, 2016: Cell Host & Microbe
https://www.readbyqxmd.com/read/27494208/synthesis-and-biological-evaluation-of-several-bryostatin-analogues-bearing-a-diacylglycerol-lactone-c-ring
#17
David O Baumann, Kevin M McGowan, Noemi Kedei, Megan L Peach, Peter M Blumberg, Gary E Keck
As an initial step in designing a simplified bryostatin hybrid molecule, three bryostatin analogues bearing a diacylglycerol lactone-based C-ring, which possessed the requisite pharmacophores for binding to protein kinase C (PKC) together with a modified bryostatin-like A- and B-ring region, were synthesized and evaluated. Merle 46 and Merle 47 exhibited binding affinity to PKC alpha with Ki values of 7000 ± 990 and 4940 ± 470 nM, respectively. Reinstallation of the trans-olefin and gem-dimethyl group present in bryostatin 1 in Merle 48 resulted in improved binding affinity, 363 ± 42 nM...
September 2, 2016: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/27472877/pkc-activation-counteracts-adam10-deficit-in-hud-silenced-neuroblastoma-cells
#18
Nicoletta Marchesi, Marialaura Amadio, Claudia Colombrita, Stefano Govoni, Antonia Ratti, Alessia Pascale
Neuronal ELAV/Hu (nELAV) are RNA-binding proteins that mainly regulate gene expression by increasing the stability and/or translation rate of target mRNAs bearing ARE (adenine and uracil-rich elements) sequences. Among nELAV target transcripts there is ADAM10, an α-secretase involved in the non-amyloidogenic processing of the amyloid-β protein precursor (AβPP) which leads to the production of the neuroprotective sAβPPα peptide. The aim of this study was to evaluate if nELAV depletion affects ADAM10 expression in human SH-SY5Y neuroblastoma cells...
September 6, 2016: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/27428432/the-effect-of-latency-reversal-agents-on-primary-cd8-t-cells-implications-for-shock-and-kill-strategies-for-human-immunodeficiency-virus-eradication
#19
Victoria E Walker-Sperling, Christopher W Pohlmeyer, Patrick M Tarwater, Joel N Blankson
Shock and kill strategies involving the use of small molecules to induce viral transcription in resting CD4+ T cells (shock) followed by immune mediated clearance of the reactivated cells (kill), have been proposed as a method of eliminating latently infected CD4+ T cells. The combination of the histone deacetylase (HDAC) inhibitor romidepsin and protein kinase C (PKC) agonist bryostatin-1 is very effective at reversing latency in vitro. However, we found that primary HIV-1 specific CD8+ T cells were not able to eliminate autologous resting CD4+ T cells that had been reactivated with these drugs...
June 2016: EBioMedicine
https://www.readbyqxmd.com/read/27372854/oocyte-activation-and-latent-hiv-1-reactivation-ampk-as-a-common-mechanism-of-action-linking-the-beginnings-of-life-and-the-potential-eradication-of-hiv-1
#20
Jahahreeh Finley
In all mammalian species studied to date, the initiation of oocyte activation is orchestrated through alterations in intracellular calcium (Ca(2+)) signaling. Upon sperm binding to the oocyte plasma membrane, a sperm-associated phospholipase C (PLC) isoform, PLC zeta (PLCζ), is released into the oocyte cytoplasm. PLCζ hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to produce diacylglycerol (DAG), which activates protein kinase C (PKC), and inositol 1,4,5-trisphosphate (IP3), which induces the release of Ca(2+) from endoplasmic reticulum (ER) Ca(2+) stores...
August 2016: Medical Hypotheses
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