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1.
Food Microbiol ; 85: 103279, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31500702

RESUMO

Cereulide, a potent toxin produced by Bacillus cereus, is a small, highly heat- and acid-resistant depsipeptide toxin, which confronts food industry with several challenges. Due to the ubiquitous presence of B. cereus in the environment, this opportunistic pathogen can enter food production and processing at almost any stage. Although the bacteria itself might be removed during food processing, the cereulide toxin will most likely not be destroyed or inactivated by these processes. Because of the high toxicity of cereulide and the high incidence rates often observed in connection with foodborne outbreaks, the understanding of the mechanisms of toxin production as well as accurate data on contamination sources and factors promoting toxin formation are urgently needed to prevent contamination and toxin production in food production processes. Over the last decade, considerable progress had been made on the understanding of cereulide toxin biosynthesis in emetic B. cereus, but an overview of current knowledge on this toxin with regards to food industry perspective is lacking. Thus, we aim in this work to summarize data available on extrinsic parameters acting on cereulide toxin synthesis in emetic B. cereus and to discuss the food industry specific challenges related to this toxin. Furthermore, we emphasize how identification of the cardinals in food production processes can lead to novel effective strategies for prevention of toxin formation in the food processing chain and could contribute to the improvement of existing HACCP studies.


Assuntos
Bacillus cereus/metabolismo , Depsipeptídeos/biossíntese , Contaminação de Alimentos/análise , Microbiologia de Alimentos , Doenças Transmitidas por Alimentos/prevenção & controle , Toxinas Bacterianas/biossíntese , Surtos de Doenças/prevenção & controle , Contaminação de Alimentos/prevenção & controle , Manipulação de Alimentos , Indústria Alimentícia/métodos , Indústria Alimentícia/normas
2.
Hematol Oncol ; 37(5): 569-577, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31674027

RESUMO

Romidepsin is a class I selective histone deacetylase (HDAC) inhibitor approved by the Food and Drug Administration (FDA) for relapsed/refractory (R/R) cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), treated with at least one prior systemic therapy. Currently, there is paucity of real-life data on the efficacy and safety of romidepsin in R/R T-cell lymphoma. This national, multicenter study presents real-life data on the efficacy and safety of romidepsin in R/R T-cell lymphoma. Patients diagnosed and treated with romidepsin for R/R CTCL or PTCL between 2013 and 2018 were retrospectively reviewed. Outcomes included overall survival (OS), event-free survival (EFS), overall response rate (ORR), complete response (CR), and adverse events. Fifty-three patients with R/R PTCL (n = 42) or CTCL (n = 11) were included. Among CTCL patients, median OS was not reached, ORR was 25%, and none achieved CR. Among PTCL patients, median OS was 7.1 months, EFS was 1.9 months, ORR rate was 33%, and 12.5% achieved CR. In a univariate analysis, predictors for longer EFS include any response to therapy, number of previous lines, and PTCL subclass (with better results for angioimmunobalstic T-cell lymphoma). In a univariate and multivariate analysis for OS, treatment response was the only factor predicting OS (OR 4.48; CI 95%, 1.57-12.79; P = .005). Most grade 3 and 4 adverse events were hematological (35%). Infections were reported in 34% of patients. This real-life experience with romidepsin confirms the results of the pivotal phase II trials. PTCL subtype and the number of previous lines of therapy have an impact on EFS. In addition, patients who had good response to romidepsin benefited most in terms of both EFS and OS. Efforts should be done to identify those patients.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Depsipeptídeos/uso terapêutico , Linfoma Cutâneo de Células T/tratamento farmacológico , Linfoma de Células T Periférico/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Depsipeptídeos/administração & dosagem , Depsipeptídeos/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma Cutâneo de Células T/mortalidade , Linfoma Cutâneo de Células T/patologia , Linfoma de Células T Periférico/mortalidade , Linfoma de Células T Periférico/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Retratamento , Resultado do Tratamento
3.
Chem Pharm Bull (Tokyo) ; 67(10): 1023-1029, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31582623

RESUMO

The combinatorial synthesis and biological evaluation of destruxins are described herein. First, the total synthesis of destruxin E was achieved, and its absolute configuration was successfully determined to be (S). In addition, the preparation of a combinatorial library based on the structure of destruxins was carried out by the split-and-pool method. Biological evaluation of the resulting analogs against osteoclast-like multinuclear cells (OCLs) revealed that the N-methyl-alanine residue was crucial to inducing morphological changes in OCLs. In particular, functionalization at the ß-position of the proline (Pro) residue was found to be tolerant of the desired biological activity of destruxin E, suggesting that the ß-position of the Pro residue should be a promising site for the introduction of a chemical tag toward the preparation of a molecular probe.


Assuntos
Depsipeptídeos/farmacologia , Proteínas Fúngicas/farmacologia , Osteoclastos/efeitos dos fármacos , Técnicas de Química Combinatória , Depsipeptídeos/síntese química , Depsipeptídeos/química , Proteínas Fúngicas/síntese química , Proteínas Fúngicas/química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
4.
Comput Biol Chem ; 83: 107123, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31561070

RESUMO

The low molecular weight protein tyrosine phosphatase (LMW-PTP) could regulate many signaling pathways, and it had drawn attention as a potential target for cancer. As previous report has indicated that the aplidin could inhibit the LMW-PTP, and thus, the relevant cancer caused by the abnormal regulation of the LMW-PTP could be remission. However, the molecular mechanism of inhibition of the LMW-PTP by the aplidin had not been fully understood. In this study, various computational approaches, namely molecular docking, MDs and post-dynamic analyses were utilized to explore the effect of the aplidin on the LMW-PTP. The results suggested that the intramolecular interactions of the residues in the two sides of the active site (Ser43-Ala55 and Pro121-Asn134) and the P-loop region (Leu13-Ser19) in the LMW-PTP was disturbed owing to the aplidin, meanwhile, the π-π interaction between Tyr131 and Tyr132 might be broken. The Asn15 might be the key residue to break the residues interactions. In a word, this study may provide more information for understanding the effect of inhibition of the aplidin on the LMW-PTP.


Assuntos
Depsipeptídeos/farmacologia , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Domínio Catalítico/efeitos dos fármacos , Depsipeptídeos/química , Inibidores Enzimáticos/química , Humanos , Conformação Molecular , Peso Molecular , Proteínas Tirosina Fosfatases/química , Proteínas Tirosina Fosfatases/metabolismo
5.
Chem Commun (Camb) ; 55(79): 11956-11959, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31531455

RESUMO

Verucopeptin is an inhibitor of hypoxia-inducible factor 1 (HIF-1), which is a promising target for cancer chemotherapy. Here, we report the first total synthesis of verucopeptin via condensation of the depsipeptide core and the polyketide side chain unit including three branched methyl groups after the synthesis of each segment.


Assuntos
Depsipeptídeos/síntese química , Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Alquinos/química , Depsipeptídeos/química , Imidazóis/química , Estrutura Molecular , Policetídeos/química
6.
PLoS Pathog ; 15(9): e1008041, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31553770

RESUMO

Filariae are parasitic nematodes that are transmitted to their definitive host as third-stage larvae by arthropod vectors like mosquitoes. Filariae cause diseases including: lymphatic filariasis with distressing and disturbing symptoms like elephantiasis; and river blindness. Filarial diseases affect millions of people in 73 countries throughout the topics and sub-tropics. The drugs available for mass drug administration, (ivermectin, albendazole and diethylcarbamazine), are ineffective against adult filariae (macrofilariae) at the registered dosing regimen; this generates a real and urgent need to identify effective macrofilaricides. Emodepside, a veterinary anthelmintic registered for treatment of nematode infections in cats and dogs, is reported to have macrofilaricidal effects. Here, we explore the mode of action of emodepside using adult Brugia malayi, one of the species that causes lymphatic filariasis. Whole-parasite motility measurement with Worminator and patch-clamp of single muscle cells show that emodepside potently inhibits motility by activating voltage-gated potassium channels and that the male is more sensitive than the female. RNAi knock down suggests that emodepside targets SLO-1 K channels. We expressed slo-1 isoforms, with alternatively spliced exons at the RCK1 (Regulator of Conductance of Potassium) domain, heterologously in Xenopus laevis oocytes. We discovered that the slo-1f isoform, found in muscles of males, is more sensitive to emodepside than the slo-1a isoform found in muscles of females; and selective RNAi of the slo-1a isoform in female worms increased emodepside potency. In Onchocerca volvulus, that causes river blindness, we found two isoforms in adult females with homology to Bma-SLO-1A and Bma-SLO-1F at the RCK1 domain. In silico modeling identified an emodepside binding pocket in the same RCK1 region of different species of filaria that is affected by these splice variations. Our observations show that emodepside has potent macrofilaricidal effects and alternative splicing in the RCK1 binding pocket affects potency. Therefore, the evaluation of potential sex-dependent effects of an anthelmintic compound is of importance to prevent any under-dosing of one or the other gender of nematodes once given to patients.


Assuntos
Brugia Malayi/efeitos dos fármacos , Brugia Malayi/fisiologia , Depsipeptídeos/farmacologia , Filaricidas/farmacologia , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Processamento Alternativo , Sequência de Aminoácidos , Animais , Sítios de Ligação/genética , Brugia Malayi/genética , Feminino , Filariose/tratamento farmacológico , Filariose/parasitologia , Técnicas de Silenciamento de Genes , Humanos , Canais de Potássio Ativados por Cálcio de Condutância Alta/química , Canais de Potássio Ativados por Cálcio de Condutância Alta/genética , Masculino , Modelos Moleculares , Movimento/efeitos dos fármacos , Movimento/fisiologia , Músculos/efeitos dos fármacos , Músculos/fisiologia , Peptídeos/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Homologia de Sequência de Aminoácidos , Fatores Sexuais
7.
Microbiol Res ; 229: 126329, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31518853

RESUMO

The genus Serratia is a predominantly unexplored source of antimicrobial secondary metabolites. The aim of the current study was thus to isolate and evaluate the antimicrobial properties of biosurfactants produced by Serratia species. Forty-nine (n = 34 pigmented; n = 15 non-pigmented) biosurfactant producing Serratia strains were isolated from environmental sources and selected isolates (n = 11 pigmented; n = 11 non-pigmented) were identified as Serratia marcescens using molecular typing. The swrW gene (serrawettin W1 synthetase) was detected in all the screened pigmented strains and one non-pigmented strain and primers were designed for the detection of the swrA gene (non-ribosomal serrawettin W2 synthetase), which was detected in nine non-pigmented strains. Crude extracts obtained from S. marcescens P1, NP1 and NP2 were chemically characterised using ultra-performance liquid chromatography coupled to electrospray ionisation mass spectrometry (UPLC-ESI-MS), which revealed that P1 produced serrawettin W1 homologues and prodigiosin, while NP1 produced serrawettin W1 homologues and glucosamine derivative A. In contrast, serrawettin W2 analogues were predominantly identified in the crude extract obtained from S. marcescens NP2. Both P1 and NP1 crude extracts displayed broad-spectrum antimicrobial activity against clinical, food and environmental pathogens, such as multidrug-resistant Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus and Cryptococcus neoformans. In contrast, the NP2 crude extract displayed antibacterial activity against a limited range of pathogenic and opportunistic pathogens. The serrawettin W1 homologues, in combination with prodigiosin and glucosamine derivatives, produced by pigmented and non-pigmented S. marcescens strains, could thus potentially be employed as broad-spectrum therapeutic agents against multidrug-resistant bacterial and fungal pathogens.


Assuntos
Antibacterianos/farmacologia , Depsipeptídeos/farmacologia , Lipoproteínas/farmacologia , Peptídeos Cíclicos/farmacologia , Prodigiosina/farmacologia , Serratia marcescens/química , Antibacterianos/química , Antibacterianos/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Depsipeptídeos/química , Depsipeptídeos/metabolismo , Lipoproteínas/química , Lipoproteínas/metabolismo , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Peptídeos Cíclicos/química , Peptídeos Cíclicos/metabolismo , Prodigiosina/química , Prodigiosina/metabolismo , Pseudomonas aeruginosa/efeitos dos fármacos , Metabolismo Secundário , Serratia marcescens/metabolismo , Tensoativos/química , Tensoativos/metabolismo , Tensoativos/farmacologia
8.
Food Chem Toxicol ; 133: 110798, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31473340

RESUMO

In this work, the cytotoxicity of Beauvericin (BEA), lutein (LUT), zeaxanthin (ZEAX) and goji berries extract (GBE) rich in carotenoids, was investigated, as well as cytoprotective effects of these carotenoids against BEA induced-cytotoxicity on Caco-2 cells. Cytotoxicity was carried out using MTT and protein content (PC) assays during 24 and 48 h of exposure. Only BEA showed cytotoxic effect obtaining a reduction in cell proliferation range from 6.5 to 92.8%. Simultaneous combination of LUT and ZEAX with BEA slightly increased cell proliferation compared to BEA tested alone. LUT, ZEAX and GBE showed cytoprotective effects against cytotoxicity induced by BEA on Caco-2 cells. Pre-treatment assays showed the highest cytoprotection effect at the highest dose of BEA assayed (2.5 µM) in 29%, 31% and 35% for LUT, ZEAX and LUT + ZEAX, respectively; GBE showed a cytoprotection of 20%, for the same dose of BEA. The interaction between LUT, ZEAX and BEA studied by means of CI-isobologram method showed a synergism and antagaonism effect for all the combinations tested. These findings highlight that food containing high level of carotenoids, as goji berries, could contribute to reduce the toxicological risk that natural contaminant as BEA mycotoxin in diet can produce to the humans.


Assuntos
Depsipeptídeos/toxicidade , Luteína/farmacologia , Lycium/química , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Zeaxantinas/farmacologia , Células CACO-2 , Citoproteção/efeitos dos fármacos , Sinergismo Farmacológico , Frutas/química , Humanos , Luteína/toxicidade , Micotoxinas/toxicidade , Extratos Vegetais/toxicidade , Substâncias Protetoras/toxicidade , Zeaxantinas/toxicidade
9.
PLoS Pathog ; 15(8): e1007991, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31425551

RESUMO

Latency reversal agents (LRAs) have proven to induce HIV-1 transcription in vivo but are ineffective at decreasing the size of the latent reservoir in antiretroviral treated patients. The capacity of the LRAs to perturb the viral reservoir present in distinct subpopulations of cells is currently unknown. Here, using a new RNA FISH/flow ex vivo viral reactivation assay, we performed a comprehensive assessment of the viral reactivation capacity of different families of LRAs, and their combinations, in different CD4+ T cell subsets. We observed that a median of 16.28% of the whole HIV-reservoir induced HIV-1 transcripts after viral reactivation, but only 10.10% of these HIV-1 RNA+ cells produced the viral protein p24. Moreover, none of the LRAs were powerful enough to reactivate HIV-1 transcription in all CD4+ T cell subpopulations. For instance, the combination of Romidepsin and Ingenol was identified as the best combination of drugs at increasing the proportion of HIV-1 RNA+ cells, in most, but not all, CD4+ T cell subsets. Importantly, memory stem cells were identified as highly resistant to HIV-1 reactivation, and only the combination of Panobinostat and Bryostatin-1 significantly increased the number of cells transcribing HIV within this subset. Overall, our results validate the use of the RNA FISH/flow technique to assess the potency of LRAs among different CD4+ T cell subsets, manifest the intrinsic differences between cells that encompass the latent HIV reservoir, and highlight the difficulty to significantly impact the latent infection with the currently available drugs. Thus, our results have important implications for the rational design of therapies aimed at reversing HIV latency from diverse cellular reservoirs.


Assuntos
Fármacos Anti-HIV/farmacologia , Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Ativação Viral/imunologia , Latência Viral/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , Depsipeptídeos/farmacologia , Diterpenos/farmacologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Carga Viral , Ativação Viral/efeitos dos fármacos , Latência Viral/efeitos dos fármacos
10.
Mar Drugs ; 17(8)2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31426405

RESUMO

Chemical analysis of a cultivation of an Australian Mugil mullet gastrointestinal tract (GIT) derived fungus, Scopulariopsis sp. CMB-F458, yielded the known lipodepsipeptides scopularides A (1) and B (2). A comparative global natural product social (GNPS) molecular networking analysis of ×63 co-isolated fungi, detected two additional fungi producing new scopularides, with Beauveria sp. CMB-F585 yielding scopularides C-G (3-7) and Scopulariopsis sp. CMB-F115 yielding scopularide H (8). Structures inclusive of absolute configurations were assigned by detailed spectroscopic and C3 Marfey's analysis, together with X-ray analyses of 3 and 8, and biosynthetic considerations. Scopularides A-H (1-8) did not exhibit significant growth inhibitory activity against a selection of Gram positive (+ve) and negative (-ve) bacteria, a fungus, or a panel of three human carcinoma cell lines.


Assuntos
Depsipeptídeos/química , Peixes/microbiologia , Trato Gastrointestinal/microbiologia , Scopulariopsis/química , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Austrália , Bactérias/efeitos dos fármacos , Produtos Biológicos/química , Carcinoma/tratamento farmacológico , Linhagem Celular Tumoral , Células Hep G2 , Humanos
11.
Nat Commun ; 10(1): 3268, 2019 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-31332172

RESUMO

Teixobactin represents a new class of antibiotics with novel structure and excellent activity against Gram-positive pathogens and Mycobacterium tuberculosis. Herein, we report a one-pot reaction to conveniently construct the key building block L-allo-Enduracidine in 30-gram scale in just one hour and a convergent strategy (3 + 2 + 6) to accomplish a gram-scale total synthesis of teixobactin. Several analogs are described, with 20 and 26 identified as the most efficacious analogs with 3~8-fold and 2~4-fold greater potency against vancomycin resistant Enterococcus faecalis and methicillin-resistant Staphylococcus aureus respectively in comparison with teixobactin. In addition, they show high efficiency in Streptococcus pneumoniae septicemia mouse model and neutropenic mouse thigh infection model using methicillin-resistant Staphylococcus aureus. We also propose that the antiparallel ß-sheet of teixobactin is important for its bioactivity and an antiparallel dimer of teixobactin is the minimal binding unit for lipid II via key amino acids variations and molecular docking.


Assuntos
Depsipeptídeos/farmacologia , Testes de Sensibilidade Microbiana/métodos , Pneumonia Estafilocócica/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Linhagem Celular Tumoral , Depsipeptídeos/síntese química , Depsipeptídeos/química , Células Hep G2 , Humanos , Camundongos , Modelos Químicos , Simulação de Acoplamento Molecular , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Pneumonia Estafilocócica/microbiologia , Relação Estrutura-Atividade
12.
Chem Commun (Camb) ; 55(63): 9379-9382, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31317975

RESUMO

Small-molecule natural products have been an essential source of pharmaceuticals to treat human diseases, but very little is known about their behavior inside dynamic, live human cells. Here, we demonstrate the first structure-activity-distribution relationship (SADR) study of complex natural products, the anti-cancer antimycin-type depsipeptides, using the emerging bioorthogonal Stimulated Raman Scattering (SRS) Microscopy. Our results show that the intracellular enrichment and distribution of these compounds are driven by their potency and specific protein targets, as well as the lipophilic nature of compounds.


Assuntos
Antimicina A/análogos & derivados , Antineoplásicos/química , Depsipeptídeos/química , Antimicina A/química , Antimicina A/metabolismo , Antimicina A/farmacologia , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Depsipeptídeos/metabolismo , Depsipeptídeos/farmacologia , Células HeLa , Humanos , Células MCF-7 , Microscopia de Fluorescência , Análise Espectral Raman , Relação Estrutura-Atividade
13.
Korean J Parasitol ; 57(3): 243-248, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31284346

RESUMO

The purpose of this study was 2-fold: 1) to investigate the prevalence of gastrointestinal parasite infection in cats reared in Daegu, Republic of Korea and 2) to assess the efficacy and safety of a topical emodepside/praziquantel formulation for cats with parasitic infections. The gastrointestinal parasite infections were examined microscopically using the flotation method. Of 407 cats, 162 (39.8%) were infected by at least one gastrointestinal parasite, including Toxocara cati (63.0%), Toxascaris leonina (31.5%), Taenia taeniaeformis (3.7%), and Cystoisospora felis (1.9%). None of the infected animals had multiple infections. When the data were analyzed according to sex, age, and type of cat, stray cats showed statistically higher prevalence than companion cats (P<0.05). On the 5th day after treatment, no parasitic eggs were detected using microscopic examination. In addition, no adverse effects, such as abnormal behaviors and clinical symptoms, were observed in the cats treated with the drug. These results quantify the prevalence of gastrointestinal parasites in cats in Daegu, Republic of Korea, and show that topical emodepside/praziquantel is a safe and effective choice for treating the parasitic infections in cats.


Assuntos
Anti-Helmínticos/administração & dosagem , Doenças do Gato/tratamento farmacológico , Depsipeptídeos/administração & dosagem , Trato Gastrointestinal/parasitologia , Enteropatias Parasitárias/veterinária , Praziquantel/administração & dosagem , Animais , Doenças do Gato/parasitologia , Gatos , Composição de Medicamentos , Quimioterapia Combinada , Feminino , Enteropatias Parasitárias/tratamento farmacológico , Enteropatias Parasitárias/parasitologia , Masculino , República da Coreia , Taenia/efeitos dos fármacos , Taenia/isolamento & purificação , Taenia/fisiologia , Toxascaris/efeitos dos fármacos , Toxascaris/isolamento & purificação , Toxascaris/fisiologia , Toxocara/efeitos dos fármacos , Toxocara/isolamento & purificação , Toxocara/fisiologia
14.
ACS Chem Biol ; 14(8): 1811-1818, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31283172

RESUMO

The bacterial endosymbiont (Burkholderia rhizoxinica) of the rice seedling blight fungus (Rhizopus microsporus) harbors a large number of cryptic biosynthesis gene clusters. Genome mining and sequence similarity networks based on an encoded nonribosomal peptide assembly line and the associated pyrrole-forming enzymes in the symbiont indicated that the encoded metabolites are unique among a large number of tentative pyrrole natural products in diverse and unrelated bacterial phyla. By performing comparative metabolic profiling using a mutant generated with an improved pheS Burkholderia counterselection marker, we found that the symbionts' biosynthetic pathway is mainly activated under salt stress and exclusively in symbiosis with the fungal host. The cryptic metabolites were fully characterized as novel pyrrole-substituted depsipeptides (endopyrroles). A broader survey showed that endopyrrole production is a hallmark of geographically distant endofungal bacteria, which produce the peptides solely under symbiotic conditions.


Assuntos
Depsipeptídeos/biossíntese , Pirróis/metabolismo , Simbiose/fisiologia , Burkholderiaceae/genética , Burkholderiaceae/metabolismo , Genoma Bacteriano/fisiologia , Genômica/métodos , Família Multigênica/fisiologia , Estudo de Prova de Conceito , Rhizopus/metabolismo
15.
Invest Ophthalmol Vis Sci ; 60(8): 3254-3263, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31361305

RESUMO

Purpose: Abnormal blood vessel formation is a defining feature of many blinding eye diseases. Targeting abnormal angiogenesis by inhibiting VEGF has revolutionized the treatment of many ocular angiogenic diseases over the last decade. However, a substantial number of patients are refractory to anti-VEGF treatment or may develop resistance over time. The objective of this study was to determine the efficacy and the mechanism of action of Apratoxin S4 in ocular angiogenesis. Methods: Retinal vascular cell proliferation, migration, and the ability to form tube-like structure were studied in vitro. Ex vivo aortic ring, choroid, and metatarsal assays were used to study Apratoxin S4's impact on vessel outgrowth in a multicellular environment. Apratoxin S4 was also tested in mouse models of oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV), and in a rabbit model of persistent retinal neovascularization (PRNV). Western blot and ELISA were used to determine the expression of key angiogenic regulators after Apratoxin S4 treatment. Results: Apratoxin S4 strongly inhibits retinal vascular cell activation by suppressing multiple angiogenic pathways. VEGF-activated vascular cells and angiogenic vessels are more susceptible to Apratoxin S4 treatment than quiescent vascular cells and vessels. Both intraperitoneal and intravitreal delivery of Apratoxin S4 are able to impede ocular neovascularization in vivo. Apratoxin S4 specifically attenuates pathological ocular angiogenesis and exhibits a combinatorial inhibitory effect with standard-of-care VEGF inhibitor drug (aflibercept). Conclusions: Apratoxin S4 is a potent antiangiogenic drug that inhibits the activation of retinal endothelial cells and pericytes through mediating multiple angiogenic pathways.


Assuntos
Depsipeptídeos/administração & dosagem , Neovascularização Retiniana/tratamento farmacológico , Vasos Retinianos/patologia , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Feminino , Humanos , Injeções Intravítreas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Coelhos , Neovascularização Retiniana/patologia , Vasos Retinianos/efeitos dos fármacos , Resultado do Tratamento
16.
Mar Drugs ; 17(6)2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31163697

RESUMO

Largazole, isolated from a marine Cyanobacterium of the genus Symploca, is a potent and selective Class I HDAC (histone deacetylation enzymes) inhibitor. This natural 16-membered macrocyclic depsipeptide features an interesting side chain unit, namely 3-hydroxy-7-mercaptohept-4-enoic acid, which occurs in many other natural sulfur-containing HDAC inhibitors. Notably, one similar fragment, where the amide moiety replaces the trans alkene moiety, appears in Psammaplin A, another marine natural product with potent HDAC inhibitory activities. Inspired by such a structural similarity, we hypothesized the fluoroolefin moiety would mimic both the alkene moiety in Largazole and the amide moiety in Psammaplin A, and thus designed and synthesized two novel fluoro olefin analogs of Largazole. The preliminary biological assays showed that the fluoro analogs possessed comparable Class I HDAC inhibitory effects, indicating that this kind of modification on the side chain of Largazole was tolerable.


Assuntos
Organismos Aquáticos/química , Cianobactérias/química , Depsipeptídeos/síntese química , Depsipeptídeos/farmacologia , Dissulfetos/química , Inibidores de Histona Desacetilases/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologia , Tirosina/análogos & derivados , Alcenos/química , Depsipeptídeos/química , Ativação Enzimática/efeitos dos fármacos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Histona Desacetilases/metabolismo , Tiazóis/química , Tirosina/química
17.
Arch Insect Biochem Physiol ; 101(4): e21586, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31180597

RESUMO

This study examined the effect of two natural toxins (a venom from the parasitic wasp Habrobracon hebetor and destruxin A from the entomopathogenic fungus Metarhizium anisopliae), and one pathogen (the entomopathogenic fungus Isaria fumosorosea) on the activity of basic digestive enzymes in the midgut of the cockroach Periplaneta americana. Simultaneously, the role of adipokinetic hormones (AKH) in the digestive processes was evaluated. The results showed that all tested toxins/pathogens elicited stress responses when applied into the cockroach body, as documented by an increase of AKH level in the central nervous system. The venom from H. hebetor showed no effect on digestive enzyme activities in the ceca and midgut in vitro. In addition, infection by I. fumosorosea caused a decrease in activity of all enzymes in the midgut and a variable decrease in activity in the ceca; application of AKHs did not reverse the inhibition. Destruxin A inhibited the activity of all enzymes in the midgut but none in the ceca in vitro; application of AKHs did reverse this inhibition, and no differences between both cockroach AKHs were found. Overall, the results demonstrated the variable effect of the tested toxins/pathogens on the digestive processes of cockroaches as well as the variable ability of AKH to counteract these effects.


Assuntos
Depsipeptídeos/toxicidade , Hormônios de Inseto/farmacologia , Oligopeptídeos/farmacologia , Periplaneta/efeitos dos fármacos , Ácido Pirrolidonocarboxílico/análogos & derivados , Venenos de Vespas/toxicidade , Animais , Ativação Enzimática , Trato Gastrointestinal/enzimologia , Periplaneta/enzimologia , Ácido Pirrolidonocarboxílico/farmacologia
18.
Ann Hematol ; 98(9): 2139-2150, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31240472

RESUMO

The randomized phase III ADMYRE trial evaluated plitidepsin plus dexamethasone (DXM) versus DXM alone in patients with relapsed/refractory multiple myeloma after at least three but not more than six prior regimens, including at least bortezomib and lenalidomide or thalidomide. Patients were randomly assigned (2:1) to receive plitidepsin 5 mg/m2 on D1 and D15 plus DXM 40 mg on D1, D8, D15, and D22 (arm A, n = 171) or DXM 40 mg on D1, D8, D15, and D22 (arm B, n = 84) q4wk. The primary endpoint was progression-free survival (PFS). Median PFS without disease progression (PD) confirmation (IRC assessment) was 2.6 months (arm A) and 1.7 months (arm B) (HR = 0.650; p = 0.0054). Median PFS with PD confirmation (investigator's assessment) was 3.8 months (arm A) and 1.9 months (arm B) (HR = 0.611; p = 0.0040). Median overall survival (OS, intention-to-treat analysis) was 11.6 months (arm A) and 8.9 months (arm B) (HR = 0.797; p = 0.1261). OS improvement favoring arm A was found when discounting a crossover effect (37 patients crossed over from arm B to arm A) (two-stage method; HR = 0.622; p = 0.0015). The most common grade 3/4 treatment-related adverse events (% of patients arm A/arm B) were fatigue (10.8%/1.2%), myalgia (5.4%/0%), and nausea (3.6%/1.2%), being usually transient and reversible. The safety profile does not overlap with the toxicity observed with other agents used in multiple myeloma. In conclusion, efficacy data, the reassuring safety profile, and the novel mechanism of action of plitidepsin suggest that this combination can be an alternative option in patients with relapsed/refractory multiple myeloma after at least three prior therapy lines.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Bortezomib/administração & dosagem , Depsipeptídeos/administração & dosagem , Dexametasona/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Lenalidomida/administração & dosagem , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Talidomida/administração & dosagem
19.
Expert Opin Drug Saf ; 18(7): 563-571, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31070945

RESUMO

INTRODUCTION: Dysregulation of histone deacetylase (HDAC) activity is an epigenetic hallmark of multiple myeloma (MM), leading to aberrant gene expression and cellular signaling in myeloma cell growth, survival and resistance to therapy. Hyper-methylation at diagnosis is a frequent observation, which eventually may convert to hypo-methylation during advanced phases. AREAS COVERED: A literature search on 'HDAC inhibitors' and 'multiple myeloma' was carried out using PubMed and Google Scholar in the preparation of this overview on clinical efficacy and safety data. EXPERT OPINION: First-generation non-selective HDAC inhibitors have demonstrated minimal single-agent activity in refractory MM. Subsequently, combination therapy has proven an improvement in progression-free survival (PFS) but not response rates. The main concerns are associated with toxicities. Ongoing studies on new and more selective agents, i.e. Romidepsin or Ricolinostat, are promising in terms of better efficacy and less toxicity.


Assuntos
Antineoplásicos/administração & dosagem , Inibidores de Histona Desacetilases/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Depsipeptídeos/administração & dosagem , Depsipeptídeos/efeitos adversos , Intervalo Livre de Doença , Regulação Neoplásica da Expressão Gênica , Inibidores de Histona Desacetilases/efeitos adversos , Histona Desacetilases/efeitos dos fármacos , Histona Desacetilases/genética , Humanos , Mieloma Múltiplo/genética , Panobinostat/administração & dosagem , Panobinostat/efeitos adversos , Resultado do Tratamento
20.
Int J Mol Sci ; 20(9)2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31067645

RESUMO

The caseinolytic protease proteolytic subunit (ClpP) is a serine protease playing an important role in proteostasis of eukaryotic organelles and prokaryotic cells. Alteration of ClpP function has been proved to affect the virulence and infectivity of a number of pathogens. Increased bacterial resistance to antibiotics has become a global problem and new classes of antibiotics with novel mechanisms of action are needed. In this regard, ClpP has emerged as an attractive and potentially viable option to tackle pathogen fitness without suffering cross-resistance to established antibiotic classes and, when not an essential target, without causing an evolutionary selection pressure. This opens a greater window of opportunity for the host immune system to clear the infection by itself or by co-administration with commonly prescribed antibiotics. A comprehensive overview of the function, regulation and structure of ClpP across the different organisms is given. Discussion about mechanism of action of this protease in bacterial pathogenesis and human diseases are outlined, focusing on the compounds developed in order to target the activation or inhibition of ClpP.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Depsipeptídeos/farmacologia , Endopeptidase Clp/metabolismo , Antibacterianos/química , Bactérias/efeitos dos fármacos , Bactérias/enzimologia , Proteínas de Bactérias/agonistas , Proteínas de Bactérias/química , Depsipeptídeos/química , Desenho de Drogas , Endopeptidase Clp/química
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