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[PMID]:28590053
[Au] Autor:Khan TK; Wender PA; Alkon DL
[Ad] Endereço:Center for Neurodegenerative Diseases, Blanchette Rockefeller Neurosciences Institute at West Virginia University, Morgantown, West Virginia.
[Ti] Título:Bryostatin and its synthetic analog, picolog rescue dermal fibroblasts from prolonged stress and contribute to survival and rejuvenation of human skin equivalents.
[So] Source:J Cell Physiol;233(2):1523-1534, 2018 Feb.
[Is] ISSN:1097-4652
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Skin health is associated with the day-to-day activity of fibroblasts. The primary function of fibroblasts is to synthesize structural proteins, such as collagen, extracellular matrix proteins, and other proteins that support the structural integrity of the skin and are associated with younger, firmer, and more elastic skin that is better able to resist and recover from injury. At sub-nanomolar concentrations (0.03-0.3 nM), bryostatin-1 and its synthetic analog, picolog (0.1-10 nM) sustained the survival and activation of human dermal fibroblasts cultured under the stressful condition of prolonged serum deprivation. Bryostatin-1 treatment stabilized human skin equivalents (HSEs), a bioengineered combination of primary human skin cells (keratinocytes and dermal fibroblasts) on an extracellular matrix composed of mainly collagen. Fibroblasts activated by bryostatin-1 protected the structural integrity of HSEs. Bryostatin-1 and picolog prolonged activation of Erk in fibroblasts to promote cell survival. Chronic stress promotes the progression of apoptosis. Dermal fibroblasts constitutively express all components of Fas associated apoptosis, including caspase-8, an initiator enzyme of apoptosis. Prolong bryostatin-1 treatment reduced apoptosis by decreasing caspase-8 and protected dermal fibroblasts. Our data suggest that bryostatin-1 and picolog could be useful in anti-aging skincare, and could have applications in tissue engineering and regenerative medicine.
[Mh] Termos MeSH primário: Briostatinas/farmacologia
Derme/efeitos dos fármacos
Fibroblastos/efeitos dos fármacos
Rejuvenescimento
Estresse Fisiológico
Engenharia Tecidual/métodos
[Mh] Termos MeSH secundário: Adulto
Idoso
Apoptose/efeitos dos fármacos
Proteínas Reguladoras de Apoptose/metabolismo
Briostatinas/síntese química
Linhagem Celular
Sobrevivência Celular/efeitos dos fármacos
Técnicas de Cocultura
Colágeno/metabolismo
Meios de Cultura Livres de Soro/metabolismo
Derme/metabolismo
Derme/patologia
Relação Dose-Resposta a Droga
Ativação Enzimática
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Feminino
Fibroblastos/metabolismo
Fibroblastos/patologia
Seres Humanos
Queratinócitos/metabolismo
Masculino
Meia-Idade
Transdução de Sinais/efeitos dos fármacos
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apoptosis Regulatory Proteins); 0 (Bryostatins); 0 (Culture Media, Serum-Free); 0 (picolog); 9007-34-5 (Collagen); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170608
[St] Status:MEDLINE
[do] DOI:10.1002/jcp.26043


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[PMID]:28934369
[Au] Autor:Marsden MD; Loy BA; Wu X; Ramirez CM; Schrier AJ; Murray D; Shimizu A; Ryckbosch SM; Near KE; Chun TW; Wender PA; Zack JA
[Ad] Endereço:Department of Medicine, Division of Hematology and Oncology, University of California Los Angeles, Los Angeles, California, United States of America.
[Ti] Título:In vivo activation of latent HIV with a synthetic bryostatin analog effects both latent cell "kick" and "kill" in strategy for virus eradication.
[So] Source:PLoS Pathog;13(9):e1006575, 2017 Sep.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The ability of HIV to establish a long-lived latent infection within resting CD4+ T cells leads to persistence and episodic resupply of the virus in patients treated with antiretroviral therapy (ART), thereby preventing eradication of the disease. Protein kinase C (PKC) modulators such as bryostatin 1 can activate these latently infected cells, potentially leading to their elimination by virus-mediated cytopathic effects, the host's immune response and/or therapeutic strategies targeting cells actively expressing virus. While research in this area has focused heavily on naturally-occurring PKC modulators, their study has been hampered by their limited and variable availability, and equally significantly by sub-optimal activity and in vivo tolerability. Here we show that a designed, synthetically-accessible analog of bryostatin 1 is better-tolerated in vivo when compared with the naturally-occurring product and potently induces HIV expression from latency in humanized BLT mice, a proven and important model for studying HIV persistence and pathogenesis in vivo. Importantly, this induction of virus expression causes some of the newly HIV-expressing cells to die. Thus, designed, synthetically-accessible, tunable, and efficacious bryostatin analogs can mediate both a "kick" and "kill" response in latently-infected cells and exhibit improved tolerability, therefore showing unique promise as clinical adjuvants for HIV eradication.
[Mh] Termos MeSH primário: Fármacos Anti-HIV/farmacologia
Briostatinas/farmacologia
Linfócitos T CD4-Positivos/virologia
HIV-1/efeitos dos fármacos
Latência Viral/efeitos dos fármacos
[Mh] Termos MeSH secundário: Briostatinas/química
Infecções por HIV/tratamento farmacológico
Infecções por HIV/imunologia
HIV-1/isolamento & purificação
Seres Humanos
Ativação Viral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (Bryostatins); 37O2X55Y9E (bryostatin 1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171028
[Lr] Data última revisão:
171028
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170922
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006575


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[PMID]:28232750
[Au] Autor:Ryckbosch SM; Wender PA; Pande VS
[Ad] Endereço:Departments of Chemistry and of Chemical & Systems Biology, Stanford University, Stanford, California, 94305, USA.
[Ti] Título:Molecular dynamics simulations reveal ligand-controlled positioning of a peripheral protein complex in membranes.
[So] Source:Nat Commun;8(1):6, 2017 02 23.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Bryostatin is in clinical trials for Alzheimer's disease, cancer, and HIV/AIDS eradication. It binds to protein kinase C competitively with diacylglycerol, the endogenous protein kinase C regulator, and plant-derived phorbol esters, but each ligand induces different activities. Determination of the structural origin for these differing activities by X-ray analysis has not succeeded due to difficulties in co-crystallizing protein kinase C with relevant ligands. More importantly, static, crystal-lattice bound complexes do not address the influence of the membrane on the structure and dynamics of membrane-associated proteins. To address this general problem, we performed long-timescale (400-500 µs aggregate) all-atom molecular dynamics simulations of protein kinase C-ligand-membrane complexes and observed that different protein kinase C activators differentially position the complex in the membrane due in part to their differing interactions with waters at the membrane inner leaf. These new findings enable new strategies for the design of simpler, more effective protein kinase C analogs and could also prove relevant to other peripheral protein complexes.Natural supplies of bryostatin, a compound in clinical trials for Alzheimer's disease, cancer, and HIV, are scarce. Here, the authors perform molecular dynamics simulations to understand how bryostatin interacts with membrane-bound protein kinase C, offering insights for the design of bryostatin analogs.
[Mh] Termos MeSH primário: Briostatinas/química
Proteínas de Membrana/antagonistas & inibidores
Simulação de Dinâmica Molecular
Proteína Quinase C/antagonistas & inibidores
Inibidores de Proteínas Quinases/química
Água/química
[Mh] Termos MeSH secundário: Adjuvantes Imunológicos/química
Adjuvantes Imunológicos/farmacologia
Antineoplásicos/química
Antineoplásicos/farmacologia
Ligação Competitiva
Briostatinas/farmacologia
Membrana Celular/química
Membrana Celular/efeitos dos fármacos
Membrana Celular/enzimologia
Diglicerídeos/química
Diglicerídeos/metabolismo
Seres Humanos
Ligantes
Proteínas de Membrana/química
Proteínas de Membrana/metabolismo
Ésteres de Forbol/química
Ésteres de Forbol/metabolismo
Ésteres de Forbol/farmacologia
Ligação Proteica
Proteína Quinase C/química
Proteína Quinase C/metabolismo
Inibidores de Proteínas Quinases/farmacologia
Termodinâmica
Água/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (1,2-diacylglycerol); 0 (Adjuvants, Immunologic); 0 (Antineoplastic Agents); 0 (Bryostatins); 0 (Diglycerides); 0 (Ligands); 0 (Membrane Proteins); 0 (Phorbol Esters); 0 (Protein Kinase Inhibitors); 059QF0KO0R (Water); 37O2X55Y9E (bryostatin 1); 60857-08-1 (prostratin); EC 2.7.11.13 (Protein Kinase C)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170225
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-016-0015-8


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[PMID]:27994072
[Au] Autor:Dental C; Proust A; Ouellet M; Barat C; Tremblay MJ
[Ad] Endereço:Axe des Maladies Infectieuses et Immunitaires, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Quebec City, Quebec G1V 4G2, Canada; and.
[Ti] Título:HIV-1 Latency-Reversing Agents Prostratin and Bryostatin-1 Induce Blood-Brain Barrier Disruption/Inflammation and Modulate Leukocyte Adhesion/Transmigration.
[So] Source:J Immunol;198(3):1229-1241, 2017 Feb 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo: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. Results show that prostratin and bryostatin-1 can significantly damage the integrity of an endothelial monolayer. Moreover, prostratin and bryostatin-1 induce secretion of some proinflammatory cytokines and an increase of ICAM-1 expression. Additional studies demonstrated that prostratin and bryostatin-1 also affect adhesion and transmigration of CD4 and CD8 T cells as well as monocytes in an in vitro human blood-brain barrier (BBB) model. Prostratin and bryostatin-1 could thus be considered as potent regulators of BBB permeability and inflammation that influence leukocyte transport across the BBB. Altogether, these findings contribute to a better understanding of the potential risks and benefits of using a shock-and-kill approach with LRAs on the normal physiological functions of the BBB.
[Mh] Termos MeSH primário: Barreira Hematoencefálica/efeitos dos fármacos
Briostatinas/farmacologia
HIV-1/fisiologia
Leucócitos/efeitos dos fármacos
Ésteres de Forbol/farmacologia
Latência Viral/efeitos dos fármacos
[Mh] Termos MeSH secundário: Acetamidas/farmacologia
Azacitidina/análogos & derivados
Azacitidina/farmacologia
Azepinas/farmacologia
Briostatinas/efeitos adversos
Adesão Celular/efeitos dos fármacos
Moléculas de Adesão Celular/análise
Movimento Celular/efeitos dos fármacos
Células Cultivadas
Quimiocina CCL2/fisiologia
Citocinas/secreção
Seres Humanos
Inflamação/induzido quimicamente
Molécula 1 de Adesão Intercelular/análise
Leucócitos/fisiologia
Ésteres de Forbol/efeitos adversos
Quinazolinas/farmacologia
Receptores de Superfície Celular/análise
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetamides); 0 (Azepines); 0 (BIX 01294); 0 (Bryostatins); 0 (CCL2 protein, human); 0 (Cell Adhesion Molecules); 0 (Chemokine CCL2); 0 (Cytokines); 0 (F11R protein, human); 0 (Phorbol Esters); 0 (Quinazolines); 0 (Receptors, Cell Surface); 126547-89-5 (Intercellular Adhesion Molecule-1); 37O2X55Y9E (bryostatin 1); 60857-08-1 (prostratin); 776B62CQ27 (decitabine); LA133J59VU (hexamethylene bisacetamide); M801H13NRU (Azacitidine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170815
[Lr] Data última revisão:
170815
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:161221
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1600742


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[PMID]:27993846
[Au] Autor:Zerbato JM; Tachedjian G; Sluis-Cremer N
[Ad] Endereço:Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
[Ti] Título:Nonnucleoside Reverse Transcriptase Inhibitors Reduce HIV-1 Production from Latently Infected Resting CD4 T Cells following Latency Reversal.
[So] Source:Antimicrob Agents Chemother;61(3), 2017 Mar.
[Is] ISSN:1098-6596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo: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.
[Mh] Termos MeSH primário: Fármacos Anti-HIV/farmacologia
Benzoxazinas/farmacologia
Briostatinas/farmacologia
HIV-1/efeitos dos fármacos
Rilpivirina/farmacologia
Replicação Viral/efeitos dos fármacos
[Mh] Termos MeSH secundário: Adjuvantes Imunológicos/farmacologia
Anticorpos Monoclonais/farmacologia
Anticorpos Antivirais/farmacologia
Antígenos CD28/antagonistas & inibidores
Antígenos CD28/genética
Antígenos CD28/imunologia
Complexo CD3/genética
Complexo CD3/imunologia
Linfócitos T CD4-Positivos/efeitos dos fármacos
Linfócitos T CD4-Positivos/virologia
Expressão Gênica
HIV-1/genética
HIV-1/crescimento & desenvolvimento
Seres Humanos
Interleucina-2/farmacologia
Cultura Primária de Células
Latência Viral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adjuvants, Immunologic); 0 (Anti-HIV Agents); 0 (Antibodies, Monoclonal); 0 (Antibodies, Viral); 0 (Benzoxazines); 0 (Bryostatins); 0 (CD28 Antigens); 0 (CD3 Complex); 0 (Interleukin-2); 37O2X55Y9E (bryostatin 1); FI96A8X663 (Rilpivirine); JE6H2O27P8 (efavirenz)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161221
[St] Status:MEDLINE


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[PMID]:27664855
[Au] Autor:Abdelnabi R; Staveness D; Near KE; Wender PA; Delang L; Neyts J; Leyssen P
[Ad] Endereço:KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium.
[Ti] Título:Comparative analysis of the anti-chikungunya virus activity of novel bryostatin analogs confirms the existence of a PKC-independent mechanism.
[So] Source:Biochem Pharmacol;120:15-21, 2016 Nov 15.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo: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. Further, a detailed comparative analysis of the effect of the non-capped versus the two capped analogs revealed that compound 1 acts both at early and late stages in the chikungunya virus replication cycle, while the capped analogs only interfere with a later stage process. Co-dosing with the PKC inhibitors sotrastaurin and Gö6976 counteracts the antiviral activity of compound 1 without affecting that of capped analogs 2 and 3, providing further evidence that the latter elicit their anti-CHIKV activity independently of PKC. Remarkably, treatment of CHIKV-infected cells with a combination of compound 1 and a capped analog resulted in a pronounced synergistic antiviral effect. Thus, these salicylate-based bryostatin analogs can inhibit CHIKV replication through a novel, yet still elusive, non-PKC dependent pathway.
[Mh] Termos MeSH primário: Antivirais/farmacologia
Briostatinas/farmacologia
Vírus Chikungunya/efeitos dos fármacos
Desenho de Drogas
Proteína Quinase C/metabolismo
Proteínas Virais/metabolismo
[Mh] Termos MeSH secundário: Acetilação
Animais
Antivirais/agonistas
Antivirais/antagonistas & inibidores
Antivirais/química
Briostatinas/agonistas
Briostatinas/antagonistas & inibidores
Briostatinas/química
Carbazóis/química
Carbazóis/farmacologia
Linhagem Celular
Cercopithecus aethiops
Vírus Chikungunya/crescimento & desenvolvimento
Vírus Chikungunya/metabolismo
Sinergismo Farmacológico
Regulação Viral da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Isoenzimas/antagonistas & inibidores
Isoenzimas/química
Isoenzimas/metabolismo
Cinética
Metilação
Proteína Quinase C/antagonistas & inibidores
Proteína Quinase C/química
Proteína Quinase C/genética
Inibidores de Proteínas Quinases/química
Inibidores de Proteínas Quinases/farmacologia
Pirróis/química
Pirróis/farmacologia
Quinazolinas/química
Quinazolinas/farmacologia
Vírus da Floresta de Semliki/efeitos dos fármacos
Vírus da Floresta de Semliki/crescimento & desenvolvimento
Vírus da Floresta de Semliki/metabolismo
Vírus Sindbis/efeitos dos fármacos
Vírus Sindbis/crescimento & desenvolvimento
Vírus Sindbis/metabolismo
Proteínas Virais/antagonistas & inibidores
Proteínas Virais/química
Proteínas Virais/genética
Replicação Viral/efeitos dos fármacos
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (Bryostatins); 0 (Carbazoles); 0 (Isoenzymes); 0 (Protein Kinase Inhibitors); 0 (Pyrroles); 0 (Quinazolines); 0 (Viral Proteins); 136194-77-9 (Go 6976); 7I279E1NZ8 (sotrastaurin); EC 2.7.11.13 (Protein Kinase C)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171115
[Lr] Data última revisão:
171115
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160925
[St] Status:MEDLINE


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[PMID]:27590822
[Au] Autor:Miller IJ; Vanee N; Fong SS; Lim-Fong GE; Kwan JC
[Ad] Endereço:Pharmaceutical Sciences Division, University of Wisconsin-Madison, Madison, Wisconsin, USA.
[Ti] Título:Lack of Overt Genome Reduction in the Bryostatin-Producing Bryozoan Symbiont "Candidatus Endobugula sertula".
[So] Source:Appl Environ Microbiol;82(22):6573-6583, 2016 Nov 15.
[Is] ISSN:1098-5336
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo: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. We also identified homologs to genes associated with insect pathogenesis in other gammaproteobacteria, and these genes may be involved in host-symbiont interactions and vertical transmission. Metatranscriptomics revealed that these genes were highly expressed in a reproductive host, along with bry genes for the biosynthesis of bryostatins. We identified two new putative bry genes fragmented from the main bry operon, accounting for previously missing enzymatic functions in the pathway. We also determined that a gene previously assigned to the pathway, bryS, is not expressed in reproductive tissue, suggesting that it is not involved in the production of bryostatins. Our findings suggest that "Ca Endobugula sertula" may be able to live outside the host if its metabolic deficiencies are alleviated by medium components, which is consistent with recent findings that it may be possible for "Ca Endobugula sertula" to be transmitted horizontally. IMPORTANCE: The bryostatins are potent protein kinase C activators that have been evaluated in clinical trials for a number of indications, including cancer and Alzheimer's disease. There is, therefore, considerable interest in securing a renewable supply of these compounds, which is currently only possible through aquaculture of Bugula neritina and total chemical synthesis. However, these approaches are labor-intensive and low-yielding and thus preclude the use of bryostatins as a viable therapeutic agent. Our genome assembly and transcriptome analysis for "Ca Endobugula sertula" shed light on the metabolism of this symbiont, potentially aiding isolation and culturing efforts. Our identification of additional bry genes may also facilitate efforts to express the complete pathway heterologously.
[Mh] Termos MeSH primário: Briostatinas/biossíntese
Briozoários/microbiologia
Gammaproteobacteria/genética
Genoma Bacteriano
Simbiose
[Mh] Termos MeSH secundário: Animais
Gammaproteobacteria/metabolismo
Perfilação da Expressão Gênica
Larva/microbiologia
Metagenômica
Filogenia
Pseudogenes
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bryostatins); 37O2X55Y9E (bryostatin 1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160904
[St] Status:MEDLINE


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[PMID]:27428432
[Au] Autor:Walker-Sperling VE; Pohlmeyer CW; Tarwater PM; Blankson JN
[Ad] Endereço:Center for AIDS Research, Department of Medicine, Johns Hopkins University School of Medicine, USA.
[Ti] Título:The Effect of Latency Reversal Agents on Primary CD8+ T Cells: Implications for Shock and Kill Strategies for Human Immunodeficiency Virus Eradication.
[So] Source:EBioMedicine;8:217-229, 2016 Jun.
[Is] ISSN:2352-3964
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo: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. We tested the hypothesis that the drugs affected primary CD8+ T cell function and found that both agents had inhibitory effects on the suppressive capacity of HIV-specific CD8+ T cells from patients who control viral replication without antiretroviral therapy (elite suppressors/controllers). The inhibitory effect was additive and multi-factorial in nature. These inhibitory effects were not seen with prostratin, another PKC agonist, either alone or in combination with JQ1, a bromodomain-containing protein 4 inhibitor. Our results suggest that because of their adverse effects on primary CD8+ T cells, some LRAs may cause immune-suppression and therefore should be used with caution in shock and kill strategies.
[Mh] Termos MeSH primário: Linfócitos T CD8-Positivos/imunologia
Infecções por HIV/imunologia
Infecções por HIV/virologia
HIV-1/fisiologia
Latência Viral
[Mh] Termos MeSH secundário: Terapia Antirretroviral de Alta Atividade
Biomarcadores
Briostatinas/farmacologia
Contagem de Linfócito CD4
Linfócitos T CD4-Positivos/efeitos dos fármacos
Linfócitos T CD4-Positivos/imunologia
Linfócitos T CD4-Positivos/metabolismo
Linfócitos T CD4-Positivos/virologia
Linfócitos T CD8-Positivos/efeitos dos fármacos
Linfócitos T CD8-Positivos/metabolismo
Citocinas/metabolismo
Depsipeptídeos/farmacologia
Feminino
Infecções por HIV/tratamento farmacológico
Antígenos HLA-A/imunologia
Antígenos HLA-B/imunologia
Seres Humanos
Imunomodulação/efeitos dos fármacos
Ativação Linfocitária/imunologia
Masculino
Receptores de Antígenos de Linfócitos T/metabolismo
Carga Viral
Ativação Viral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Bryostatins); 0 (Cytokines); 0 (Depsipeptides); 0 (HLA-A Antigens); 0 (HLA-B Antigens); 0 (Receptors, Antigen, T-Cell); 37O2X55Y9E (bryostatin 1); CX3T89XQBK (romidepsin)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160719
[St] Status:MEDLINE


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[PMID]:27330081
[Au] Autor:Sen A; Hongpaisan J; Wang D; Nelson TJ; Alkon DL
[Ad] Endereço:From the Blanchette Rockefeller Neurosciences Institute, Morgantown, West Virginia 26505 asen@brni.org.
[Ti] Título:Protein Kinase Cϵ (PKCϵ) Promotes Synaptogenesis through Membrane Accumulation of the Postsynaptic Density Protein PSD-95.
[So] Source:J Biol Chem;291(32):16462-76, 2016 08 05.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Protein kinase Cϵ (PKCϵ) promotes synaptic maturation and synaptogenesis via activation of synaptic growth factors such as BDNF, NGF, and IGF. However, many of the detailed mechanisms by which PKCϵ induces synaptogenesis are not fully understood. Accumulation of PSD-95 to the postsynaptic density (PSD) is known to lead to synaptic maturation and strengthening of excitatory synapses. Here we investigated the relationship between PKCϵ and PSD-95. We show that the PKCϵ activators dicyclopropanated linoleic acid methyl ester and bryostatin 1 induce phosphorylation of PSD-95 at the serine 295 residue, increase the levels of PSD-95, and enhance its membrane localization. Elimination of the serine 295 residue in PSD-95 abolished PKCϵ-induced membrane accumulation. Knockdown of either PKCϵ or JNK1 prevented PKCϵ activator-mediated membrane accumulation of PSD-95. PKCϵ directly phosphorylated PSD-95 and JNK1 in vitro Inhibiting PKCϵ, JNK, or calcium/calmodulin-dependent kinase II activity prevented the effects of PKCϵ activators on PSD-95 phosphorylation. Increase in membrane accumulation of PKCϵ and phosphorylated PSD-95 (p-PSD-95(S295)) coincided with an increased number of synapses and increased amplitudes of excitatory post-synaptic potentials (EPSPs) in adult rat hippocampal slices. Knockdown of PKCϵ also reduced the synthesis of PSD-95 and the presynaptic protein synaptophysin by 30 and 44%, respectively. Prolonged activation of PKCϵ increased synapse number by 2-fold, increased presynaptic vesicle density, and greatly increased PSD-95 clustering. These results indicate that PKCϵ promotes synaptogenesis by activating PSD-95 phosphorylation directly through JNK1 and calcium/calmodulin-dependent kinase II and also by inducing expression of PSD-95 and synaptophysin.
[Mh] Termos MeSH primário: Hipocampo/metabolismo
Peptídeos e Proteínas de Sinalização Intracelular/biossíntese
Proteínas de Membrana/biossíntese
Proteína Quinase C-épsilon/metabolismo
Membranas Sinápticas/metabolismo
[Mh] Termos MeSH secundário: Animais
Briostatinas/farmacologia
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo
Proteína 4 Homóloga a Disks-Large
Ativação Enzimática/efeitos dos fármacos
Ativação Enzimática/fisiologia
Células HEK293
Seres Humanos
Peptídeos e Proteínas de Sinalização Intracelular/genética
Proteínas de Membrana/genética
Proteína Quinase 8 Ativada por Mitógeno/genética
Proteína Quinase 8 Ativada por Mitógeno/metabolismo
Fosforilação/efeitos dos fármacos
Fosforilação/fisiologia
Proteína Quinase C-épsilon/genética
Ratos
Membranas Sinápticas/genética
Sinaptofisina/biossíntese
Sinaptofisina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bryostatins); 0 (DLG4 protein, human); 0 (Disks Large Homolog 4 Protein); 0 (Dlg4 protein, rat); 0 (Intracellular Signaling Peptides and Proteins); 0 (Membrane Proteins); 0 (SYP protein, human); 0 (Synaptophysin); 0 (Syp protein, rat); 37O2X55Y9E (bryostatin 1); EC 2.7.1.- (Prkce protein, rat); EC 2.7.11.13 (PRKCE protein, human); EC 2.7.11.13 (Protein Kinase C-epsilon); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 8)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160623
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.730440


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[PMID]:26941170
[Au] Autor:Sun MK; Hongpaisan J; Alkon DL
[Ad] Endereço:Blanchette Rockefeller Neurosciences Institute, Morgantown, West Virginia masun@brni.org mksun@brni-jhu.org.
[Ti] Título:Rescue of Synaptic Phenotypes and Spatial Memory in Young Fragile X Mice.
[So] Source:J Pharmacol Exp Ther;357(2):300-10, 2016 May.
[Is] ISSN:1521-0103
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Fragile X syndrome (FXS) is characterized by synaptic immaturity, cognitive impairment, and behavioral changes. The disorder is caused by transcriptional shutdown in neurons of thefragile X mental retardation 1gene product, fragile X mental retardation protein. Fragile X mental retardation protein is a repressor of dendritic mRNA translation and its silencing leads to dysregulation of synaptically driven protein synthesis and impairments of intellect, cognition, and behavior, and FXS is a disorder that currently has no effective therapeutics. Here, young fragile X mice were treated with chronic bryostatin-1, a relatively selective protein kinase Cεactivator, which induces synaptogenesis and synaptic maturation/repair. Chronic treatment with bryostatin-1 rescues young fragile X mice from the disorder phenotypes, including normalization of most FXS abnormalities in 1) hippocampal brain-derived neurotrophic factor expression, 2) postsynaptic density-95 levels, 3) transformation of immature dendritic spines to mature synapses, 4) densities of the presynaptic and postsynaptic membranes, and 5) spatial learning and memory. The therapeutic effects were achieved without downregulation of metabotropic glutamate receptor (mGluR) 5 in the hippocampus and are more dramatic than those of a late-onset treatment in adult fragile X mice. mGluR5 expression was in fact lower in fragile X mice and its expression was restored with the bryostatin-1 treatment. Our results show that synaptic and cognitive function of young FXS mice can be normalized through pharmacological treatment without downregulation of mGluR5 and that bryostatin-1-like agents may represent a novel class of drugs to treat fragile X mental retardation at a young age and in adults.
[Mh] Termos MeSH primário: Síndrome do Cromossomo X Frágil/tratamento farmacológico
Transtornos da Memória/tratamento farmacológico
Memória Espacial/efeitos dos fármacos
Sinapses/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Fator Neurotrófico Derivado do Encéfalo/metabolismo
Briostatinas/farmacologia
Espinhas Dendríticas/efeitos dos fármacos
Proteína 4 Homóloga a Disks-Large
Ativadores de Enzimas/farmacologia
Proteína do X Frágil de Retardo Mental/genética
Síndrome do Cromossomo X Frágil/patologia
Síndrome do Cromossomo X Frágil/psicologia
Guanilato Quinases/genética
Guanilato Quinases/metabolismo
Hipocampo/efeitos dos fármacos
Hipocampo/metabolismo
Masculino
Aprendizagem em Labirinto/efeitos dos fármacos
Proteínas de Membrana/genética
Proteínas de Membrana/metabolismo
Transtornos da Memória/etiologia
Transtornos da Memória/psicologia
Camundongos
Terminações Pré-Sinápticas/efeitos dos fármacos
Terminações Pré-Sinápticas/metabolismo
Proteína Quinase C-épsilon/efeitos dos fármacos
Receptor de Glutamato Metabotrópico 5/metabolismo
Receptores Pré-Sinápticos/efeitos dos fármacos
Sinapses/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Brain-Derived Neurotrophic Factor); 0 (Bryostatins); 0 (Disks Large Homolog 4 Protein); 0 (Dlg4 protein, mouse); 0 (Enzyme Activators); 0 (Grm5 protein, mouse); 0 (Membrane Proteins); 0 (Receptor, Metabotropic Glutamate 5); 0 (Receptors, Presynaptic); 139135-51-6 (Fragile X Mental Retardation Protein); 37O2X55Y9E (bryostatin 1); EC 2.7.11.13 (Protein Kinase C-epsilon); EC 2.7.4.8 (Guanylate Kinases)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160305
[St] Status:MEDLINE
[do] DOI:10.1124/jpet.115.231100



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