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https://www.readbyqxmd.com/read/29788787/review-of-bioactive-secondary-metabolites-from-marine-bryozoans-in-the-progress-of-new-drugs-discovery
#1
Xiang Rong Tian, Hai Feng Tang, Xiao Lin Tian, Jia Jun Hu, Li Li Huang, Kirk R Gustafson
Marine bryozoans play an important role for the discovery of novel bioactive compounds among marine organisms. In this review, we summarize 164 new secondary metabolites including macrocyclic lactones, sterols, alkaloids, sphingolipids and so forth from 24 marine bryozoans in the last two decades. The structural features, bioactivity, structure-activity relationship, mechanism and strategies to address the resupply of these scarce secondary metabolites are discussed. The structural and bioactive diversity of the secondary metabolites from marine bryozoans indicated the possibility of using these compounds, especially bryostatin 1 (1), bryostatin analog (BA1), alkaloids (50, 53, 127-128 and 134-139), sphingolipids sulfates (148 and 149) and sulfur-containing aromatic compound (160), as the starting points for new drug discovery...
May 23, 2018: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/29779653/chemoenzymatic-dissection-of-polyketide-%C3%AE-branching-in-the-bryostatin-pathway
#2
Samuel T Slocum, Andrew N Lowell, Ashootosh N Tripathi, Vikram V Shende, Janet L Smith, David H Sherman
β-Branching is an expansion upon canonical polyketide synthase extension that allows for the installation of diverse chemical moieties in several natural products. Several of these moieties are unique among natural products, including the two vinyl methylesters found in the core structure of bryostatins. This family of molecules is derived from an obligate bacterial symbiont of a sessile marine bryozoan, Bugula neritina. Within this family, bryostatin 1 has been investigated as an anticancer, neuroprotective, and immunomodulatory compound...
2018: Methods in Enzymology
https://www.readbyqxmd.com/read/29710707/loss-in-pkc-epsilon-causes-downregulation-of-mnsod-and-bdnf-expression-in-neurons-of-alzheimer-s-disease-hippocampus
#3
Abhik Sen, Thomas J Nelson, Daniel L Alkon, Jarin Hongpaisan
Oxidative stress and amyloid-β (Aβ) oligomers have been implicated in Alzheimer's disease (AD). The growth and maintenance of neuronal networks are influenced by brain derived neurotrophic factor (BDNF) expression, which is promoted by protein kinase C epsilon (PKCɛ). We investigated the reciprocal interaction among oxidative stress, Aβ, and PKCɛ levels and subsequent PKCɛ-dependent MnSOD and BDNF expression in hippocampal pyramidal neurons. Reduced levels of PKCɛ, MnSOD, and BDNF and an increased level of Aβ were also found in hippocampal neurons from autopsy-confirmed AD patients...
April 25, 2018: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/29693282/protein-kinase-c-activator-bryostatin-1-modulates-proteasome-function
#4
Tapan K Khan, Thomas J Nelson
Proteasome activity in ubiquitin-proteasome pathway plays a pivotal role in degradation and clearance of aggregated, oxidized, damaged, and misfolded unwanted proteins to control protein homeostasis or proteostasis. Proteasome activity decreases with cellular senescence, aging, and age-related diseases. Therefore, enhancement of impaired proteasome function by molecular biological and/or pharmacological intervention is an active area of research. Bryostatin-1, a naturally occurring macrocyclic lactone, activates PKC isozymes (specifically, -α and -ϵ) at sub-nanomolar concentrations, but downregulates at higher concentrations...
April 25, 2018: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29572053/exposure-to-far-infrared-rays-attenuates-methamphetamine-induced-recognition-memory-impairment-via-modulation-of-the-muscarinic-m1-receptor-nrf2-and-pkc
#5
Huynh Nhu Mai, Naveen Sharma, Eun-Joo Shin, Bao Trong Nguyen, Phuong Tram Nguyen, Ji Hoon Jeong, Choon-Gon Jang, Eun-Hee Cho, Seung-Yeol Nah, Nam Hun Kim, Toshitaka Nabeshima, Hyoung-Chun Kim
We demonstrated that activation of protein kinase Cδ (PKCδ) and inactivation of the glutathione peroxidase-1 (GPx-1)-dependent systems are critical for methamphetamine (MA)-induced recognition memory impairment. We also demonstrated that exposure to far-infrared rays (FIR) causes induction of the glutathione (GSH)-dependent system, including induction of the GPx-1 gene. Here, we investigated whether exposure to FIR rays affects MA-induced recognition memory impairment and whether it modulates PKC, cholinergic receptors, and the GSH-dependent system...
June 2018: Neurochemistry International
https://www.readbyqxmd.com/read/29555470/acute-stress-enhances-learning-and-memory-by-activating-acid-sensing-ion-channels-in-rats
#6
Shunjie Ye, Rong Yang, Qiuju Xiong, Youhua Yang, Lianying Zhou, Yeli Gong, Changlei Li, Zhenhan Ding, Guohai Ye, Zhe Xiong
Acute stress has been shown to enhance learning and memory ability, predominantly through the action of corticosteroid stress hormones. However, the valuable targets for promoting learning and memory induced by acute stress and the underlying molecular mechanisms remain unclear. Acid-sensing ion channels (ASICs) play an important role in central neuronal systems and involves in depression, synaptic plasticity and learning and memory. In the current study, we used a combination of electrophysiological and behavioral approaches in an effort to explore the effects of acute stress on ASICs...
April 15, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29531819/mechanism-of-inhibition-of-shiga-toxigenic-escherichia-coli-subab-cytotoxicity-by-steroids-and-diacylglycerol-analogues
#7
Kinnosuke Yahiro, Sayaka Nagasawa, Kimitoshi Ichimura, Hiroki Takeuchi, Kohei Ogura, Hiroyasu Tsutsuki, Takeshi Shimizu, Sunao Iyoda, Makoto Ohnishi, Hirotaro Iwase, Joel Moss, Masatoshi Noda
Shiga toxigenic Escherichia coli (STEC) are responsible for a worldwide foodborne disease, which is characterized by severe bloody diarrhea and hemolytic uremic syndrome (HUS). Subtilase cytotoxin (SubAB) is a novel AB5 toxin, which is produced by Locus for Enterocyte Effacement (LEE)-negative STEC. Cleavage of the BiP protein by SubAB induces endoplasmic reticulum (ER) stress, followed by induction of cytotoxicity in vitro or lethal severe hemorrhagic inflammation in mice. Here we found that steroids and diacylglycerol (DAG) analogues (e...
December 2018: Cell Death Discovery
https://www.readbyqxmd.com/read/29517836/deletion-of-the-c26-methyl-substituent-from-the-bryostatin-analogue-merle-23-has-negligible-impact-on-its-biological-profile-and-potency
#8
Xiguang Zhao, Noemi Kedei, Alexandra Michalowski, Nancy E Lewin, Gary E Keck, Peter M Blumberg
Important strides are being made in understanding the effects of structural features of bryostatin 1, a candidate therapeutic agent for cancer and dementia, in conferring its potency toward protein kinase C and the unique spectrum of biological responses that it induces. A critical pharmacophoric element in bryostatin 1 is the secondary hydroxy group at the C26 position, with a corresponding primary hydroxy group playing an analogous role in binding of phorbol esters to protein kinase C. Herein, we describe the synthesis of a bryostatin homologue in which the C26 hydroxy group is primary, as it is in the phorbol esters, and show that its biological activity is almost indistinguishable from that of the corresponding compound with a secondary hydroxy group...
March 8, 2018: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/29440425/bryostatin-1-alleviates-experimental-multiple-sclerosis
#9
Michael D Kornberg, Matthew D Smith, Hasti Atashi Shirazi, Peter A Calabresi, Solomon H Snyder, Paul M Kim
Multiple sclerosis (MS) is an inflammatory disorder targeting the central nervous system (CNS). The relapsing-remitting phase of MS is largely driven by peripheral activation of autoreactive T-helper (Th) 1 and Th17 lymphocytes. In contrast, compartmentalized inflammation within the CNS, including diffuse activation of innate myeloid cells, characterizes the progressive phase of MS, the most debilitating phase that currently lacks satisfactory treatments. Recently, bryostatin-1 (bryo-1), a naturally occurring, CNS-permeable compound with a favorable safety profile in humans, has been shown to act on antigen-presenting cells to promote differentiation of lymphocytes into Th2 cells, an action that might benefit Th1-driven inflammatory conditions such as MS...
February 27, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29424951/synthesis-and-biological-evaluation-of-fluorescent-bryostatin-analogues
#10
Thomas J Cummins, Noemi Kedei, Agnes Czikora, Nancy E Lewin, Sharon Kirk, Mark E Petersen, Kevin M McGowan, Jin-Qiu Chen, Xiaoling Luo, Randall C Johnson, Sarangan Ravichandran, Peter M Blumberg, Gary E Keck
To investigate the cellular distribution of tumor-promoting vs. non-tumor-promoting bryostatin analogues, we synthesized fluorescently labeled variants of two bryostatin derivatives that have previously shown either phorbol ester-like or bryostatin-like biological activity in U937 leukemia cells. These new fluorescent analogues both displayed high affinity for protein kinase C (PKC) binding and retained the basic properties of the parent unlabeled compounds in U937 assays. The fluorescent compounds showed similar patterns of intracellular distribution in cells, however; this argues against an existing hypothesis that various patterns of intracellular distribution are responsible for differences in biological activity...
April 16, 2018: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/29392180/redor-nmr-reveals-multiple-conformers-for-a-protein-kinase-c-ligand-in-a-membrane-environment
#11
Hao Yang, Daryl Staveness, Steven M Ryckbosch, Alison D Axtman, Brian A Loy, Alexander B Barnes, Vijay S Pande, Jacob Schaefer, Paul A Wender, Lynette Cegelski
Bryostatin 1 (henceforth bryostatin) is in clinical trials for the treatment of Alzheimer's disease and for HIV/AIDS eradication. It is also a preclinical lead for cancer immunotherapy and other therapeutic indications. Yet nothing is known about the conformation of bryostatin bound to its protein kinase C (PKC) target in a membrane microenvironment. As a result, efforts to design more efficacious, better tolerated, or more synthetically accessible ligands have been limited to structures that do not include PKC or membrane effects known to influence PKC-ligand binding...
January 24, 2018: ACS Central Science
https://www.readbyqxmd.com/read/29351079/syphacia-muris-infection-in-rats-attenuates-colorectal-carcinogenesis-through-oxidative-stress-and-gene-expression-alterations-implications-for-modulatory-effects-by-bryostatin-1
#12
Elsayed I Salim, Samar F Harras, Aisha G Abdalla, Mohmmed H Mona
Accumulating evidence suggest that some infectious agents may interfere in the natural progression of neoplasia. This study examined the association between chronic infection with adult Syphacia muris parasites and 1,2-dimethylhydrazine (DMH)-induced colorectal carcinogenesis in rats. In addition, the conceivable therapeutic effect of Bryostatin-1, a potent extract of the marine Bryozoan, Bugulane ritina, was investigated against this combined effect.DMH administration has induced aberrant crypt foci (ACF), surrogate biomarkers for colorectal carcinogenesis, while the S...
March 26, 2018: Acta Parasitologica
https://www.readbyqxmd.com/read/29298886/class-1-selective-histone-deacetylase-hdac-inhibitors-enhance-hiv-latency-reversal-while-preserving-the-activity-of-hdac-isoforms-necessary-for-maximal-hiv-gene-expression
#13
Thomas D Zaikos, Mark M Painter, Nadia T Sebastian Kettinger, Valeri H Terry, Kathleen L Collins
Combinations of drugs that affect distinct mechanisms of HIV latency aim to induce robust latency reversal leading to cytopathicity and elimination of the persistent HIV reservoir. Thus far, attempts have focused on combinations of protein kinase C (PKC) agonists and pan-histone deacetylase inhibitors (HDIs) despite the knowledge that HIV gene expression is regulated by class 1 histone deacetylases. We hypothesized that class 1-selective HDIs would promote more robust HIV latency reversal in combination with a PKC agonist than pan-HDIs because they preserve the activity of proviral factors regulated by non-class 1 histone deacetylases...
March 15, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29228979/contrasting-effect-of-the-latency-reversing-agents-bryostatin-1-and-jq1-on-astrocyte-mediated-neuroinflammation-and-brain-neutrophil-invasion
#14
Alizé Proust, Corinne Barat, Mathieu Leboeuf, Jean Drouin, Michel J Tremblay
BACKGROUND: Despite effectiveness of the combined antiretroviral therapy, HIV-1 persists in long-lived latently infected cells. Consequently, new therapeutic approaches aimed at eliminating this latent reservoir are currently being developed. A "shock and kill" strategy using latency-reversing agents (LRA) to reactivate HIV-1 has been proposed. However, the impact of LRA on the central nervous system (CNS) remains elusive. METHODS: We used human fetal astrocytes and investigated the effects of several LRA on their functional and secretory activities...
December 11, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/29210495/total-synthesis-of-bryostatin-8-using-an-organosilane-based-strategy
#15
Yuebao Zhang, Qianyou Guo, Xianwei Sun, Ji Lu, Yanjun Cao, Qiang Pu, Zhiwen Chu, Lu Gao, Zhenlei Song
Convergent total synthesis of bryostatin 8 has been accomplished by an organosilane-based strategy. The C ring is constructed stereoselectively through a geminal bis(silane)-based [1,5]-Brook rearrangement, and the B ring through geminal bis(silane)-based Prins cyclization, thus efficiently joining the northern and southern parts of the molecule.
January 22, 2018: Angewandte Chemie
https://www.readbyqxmd.com/read/29115558/bryostatin-1-causes-attenuation-of-tpa%C3%A2-mediated-tumor-promotion-in-mouse-skin
#16
Ning Zeng, Yi Xu, Yiping Wu, Tang Hongbo, Min Wu
The present study was designed to investigate the tumor inhibitory potential of bryostatin 1 in a 12‑O‑tetradecanoylphorbol‑13‑acetate (TPA)‑induced mouse model of skin cancer. The radical inhibition potential of various doses of bryostatin 1 was investigated against 2,2‑diphenyl‑1‑picrylhydrazyl (DPPH) bleach in vitro. The DPPH radical potential was observed compared with treatment with 5, 10, 15, 20, 25 and 30 µM doses of bryostatin 1. In vivo, bryostatin 1 prevented the TPA‑mediated increase in the level of H2O2 and myeloperoxidase in mouse epidermal tissue...
January 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29109995/total-synthesis-of-7-des-o-pivaloyl-7-o-benzylbryostatin-10
#17
Anthony P Green, Simon Hardy, Alan T L Lee, Eric J Thomas
The first total synthesis of a derivative of a 20-deoxybryostatin, namely 7-des-O-pivaloyl-7-O-benzylbryostatin 10 is described. Preliminary studies demonstrated that the modified Julia reactions of 2-benzothiazolylsulfones corresponding to the C17-C27 fragment with aldehydes corresponding to the C1-C16 fragment, provided an efficient and stereoselective assembly of advanced intermediates with the (E)-16,17-double-bond. The synthesis of the C1-C16 fragment was then modified so that the C1 acid was present as its allyl ester before the Julia coupling...
November 15, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/29109991/synthetic-approaches-to-the-c11-c27-fragments-of-bryostatins
#18
Anthony P Green, Simon Hardy, Eric J Thomas
The modified Julia reaction and acyl carbanion chemistry, especially reactions of 2-lithiated dithianes, have been investigated for the synthesis of intermediates that are the synthetic equivalents of the C11-C27 fragments of bryostatins. The modified Julia reaction using 2-benzothiazolylsulfones was found to be more useful for the formation of the C16-C17 double-bond than the classical Julia reaction using phenylsulfones, and bulky sulfones gave very good (E)-stereoselectivity. The alkylation of a dithiane monoxide that corresponded to a C19-acyl carbanion using (E)-1-bromobut-2-ene was efficient but the use of a more complex allylic bromide corresponding to the C20-C27 fragment of the bryostatins was unsuccessful, possibly due to competing elimination reactions...
November 15, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/29066536/making-bryostatin-1-through-smart-chemistry
#19
(no author information available yet)
Scientists have come up with an efficient, scalable way to chemically synthesize bryostatin 1, a marine-derived natural PKC modulator that has been in scarce supply, impeding a thorough evaluation of its therapeutic potential.
December 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29026042/scalable-synthesis-of-bryostatin-1-and-analogs-adjuvant-leads-against-latent-hiv
#20
Paul A Wender, Clayton T Hardman, Stephen Ho, Matthew S Jeffreys, Jana K Maclaren, Ryan V Quiroz, Steven M Ryckbosch, Akira J Shimizu, Jack L Sloane, Matthew C Stevens
Bryostatin 1 is an exceedingly scarce marine-derived natural product that is in clinical development directed at HIV/AIDS eradication, cancer immunotherapy, and the treatment of Alzheimer's disease. Despite this unique portfolio of indications, its availability has been limited and variable, thus impeding research and clinical studies. Here, we report a total synthesis of bryostatin 1 that proceeds in 29 total steps (19 in the longest linear sequence, >80% average yield per step), collectively produces grams of material, and can be scaled to meet clinical needs (~20 grams per year)...
October 13, 2017: Science
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