RESUMO
Cold temperatures have been posited as a key driver of polyploidy (possession of multiple chromosome sets). However, high temperatures associated with fire, and the indirect impact of post-fire environments in polypoid formation and establishment deserve more attention for a comprehensive understanding of polyploid ecology, evolution, and current distributions.
Assuntos
Incêndios , Poliploidia , Evolução Biológica , Temperatura BaixaRESUMO
The regulations for fitness to drive after a cerebrovascular accident in the German Driving License Regulations (FeV) and the German Evaluation Guidelines for Driving Ability (BGL). are not up to date with the current medical knowledge and not consistent with regulations regarding cardiovascular diseases. This position paper presented by six medical and neuropsychological societies in Germany provides a guideline for the assessment of driving ability after diagnosis of a cerebrovascular disease and addresses three major questions: If there is a functional limitation, how can it be compensated for? What is the risk of sudden loss of control while driving in the future? Are there behavioral or personality changes or cognitive deficiencies interfering with safety while driving? Recommendations for the assessment of driving ability in different cerebrovascular diseases are presented. This article is a translation of the position paper published in Nervenarzt: Marx, P., Hamann, G.F., Busse, O. et al. Nervenarzt 90(4): 388-398.
RESUMO
Mitochondria are cellular organelles with crucial functions in the generation and distribution of ATP, the buffering of cytosolic Ca2+ and the initiation of apoptosis. Compounds that interfere with these functions are termed mitochondrial toxins, many of which are derived from microbes, such as antimycin A, oligomycin A, and ionomycin. Here, we identify the mycotoxin phomoxanthone A (PXA), derived from the endophytic fungus Phomopsis longicolla, as a mitochondrial toxin. We show that PXA elicits a strong release of Ca2+ from the mitochondria but not from the ER. In addition, PXA depolarises the mitochondria similarly to protonophoric uncouplers such as CCCP, yet unlike these, it does not increase but rather inhibits cellular respiration and electron transport chain activity. The respiration-dependent mitochondrial network structure rapidly collapses into fragments upon PXA treatment. Surprisingly, this fragmentation is independent from the canonical mitochondrial fission and fusion mediators DRP1 and OPA1, and exclusively affects the inner mitochondrial membrane, leading to cristae disruption, release of pro-apoptotic proteins, and apoptosis. Taken together, our results suggest that PXA is a mitochondrial toxin with a novel mode of action that might prove a useful tool for the study of mitochondrial ion homoeostasis and membrane dynamics.
Assuntos
Mitocôndrias/efeitos dos fármacos , Membranas Mitocondriais/efeitos dos fármacos , Micotoxinas/toxicidade , Xantonas/toxicidade , Animais , Ascomicetos/metabolismo , Cálcio/metabolismo , Linhagem Celular , Transporte de Elétrons/efeitos dos fármacos , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Humanos , Camundongos , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo , Micotoxinas/metabolismo , Xantonas/metabolismoRESUMO
Dibromohemibastadin-1 (DBHB) is an already known potent inhibitor of blue mussel phenoloxidase (which is a key enzyme involved in bioadhesion). Within this study, the potentiality of DBHB against microfouling has been investigated. The activity of DBHB was evaluated on key strains of bacteria and microalgae involved in marine biofilm formation and bioassays assessing impact on growth, adhesion and biofilm formation were used. To assess the efficiency of DBHB when included in a matrix, DBHB varnish was prepared and the anti-microfouling activity of coatings was assessed. Both in vitro and in situ immersions were carried out. Confocal Laser Scanning Microscopy (CLSM) was principally used to determine the biovolume and average thickness of biofilms developed on the coatings. Results showed an evident efficiency of DBHB as compound and varnish to reduce the biofilm development. The mode of action seems to be based principally on a perturbation of biofilm formation rather than on a biocidal activity in the tested conditions.
Assuntos
Biofilmes/efeitos dos fármacos , Materiais Revestidos Biocompatíveis/farmacologia , Ecossistema , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Bactérias/crescimento & desenvolvimento , Aderência Bacteriana/efeitos dos fármacos , Incrustação Biológica , Contagem de Células , Microalgas/efeitos dos fármacos , Pintura , Plâncton/citologia , Plâncton/efeitos dos fármacosRESUMO
Since the banning of several families of compounds in antifouling (AF) coatings, the search for environmentally friendly AF compounds has intensified. Natural sources of AF compounds have been identified in marine organisms and can be used to create analogues in laboratory. In a previous study, we identified that dibromohemibastadin-1 (DBHB) is a promising AF molecule, leading to the inhibition of the activity of phenoloxidase, an enzyme involved in the attachment of mussels to surfaces. This paper describes the activity of the DBHB on biofilm formation and its detachment and on bacterial adhesion and communication: quorum sensing. DBHB has an anti-biofilm activity without affecting adhesion of marine and terrestrial bacteria at a dose of 10 µM. Moreover, DBHB activity on quorum sensing (QS) is demonstrated at doses of 8 and 16 µM. The activity of DBHB on QS is compared to kojic acid, a quorum sensing inhibitor already described. This compound is a promising environmentally friendly molecule potentially useful for the inhibition of microfouling.
Assuntos
Organismos Aquáticos/química , Bactérias/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Produtos Biológicos/farmacologia , Incrustação Biológica , Monofenol Mono-Oxigenase/metabolismo , Pironas/farmacologia , Percepção de Quorum/efeitos dos fármacosRESUMO
Mangrove associated endophytes are treasure chests for bioprospecting especially in light of the need for new anticancer leads that are necessary to overcome drug resistance of cancer cells. This review highlights the potent anti-tumour compound phomoxanthone A (PXA), which represents a tetrahydroxanthone atropisomer derived from the mangrove-associated fungus Phomopsis longicolla. PXA displayed strong anti-tumour activity when tested against a panel of solid (including cisplatin resistant) tumour cell lines or of blood cancer cell lines with IC50 values in the submicromolar range whereas it was up to 100 folds less active against peripheral blood mononuclear cells (PBMC) from healthy donors. The anti-tumour activity of PXA was demonstrated to be due to an induction of caspase 3 dependent apoptosis. At the same time PXA was shown to activate immune cells such as murine T-lymphocytes, NK cells and macrophages which might help in fighting resistance during cancer chemotherapy. Structure activity studies that involved several naturally occurring as well as semisynthetic derivatives of PXA indicated the position of the biaryl linkage and the acetyl substituents as structural features that are important for the activity of this natural product.
Assuntos
Fungos/química , Neoplasias/tratamento farmacológico , Áreas Alagadas , Xantonas/uso terapêutico , Animais , Anticarcinógenos/química , Anticarcinógenos/farmacologia , Anticarcinógenos/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Xantonas/química , Xantonas/farmacologiaRESUMO
Hemibastadin derivatives, including the synthetically-derived 5,5'-dibromohemibastadin-1 (DBHB), are potent inhibitors of blue mussel phenoloxidase (PO), which is a key enzyme involved in the firm attachment of this invertebrate to substrates and, thus, a promising molecular target for anti-fouling research. For a systematic investigation of the enzyme inhibitory activity of hemibastadin derivatives, we have synthesized nine new congeners, which feature structural variations of the DBHB core structure. These structural modifications include, e.g., different halogen substituents present at the aromatic rings, different amine moieties linked to the (E)-2-(hydroxyimino)-3-(4-hydroxyphenyl)propionic acid, the presence of free vs. substituted aromatic hydroxyl groups and a free vs. methylated oxime group. All compounds were tested for their inhibitory activity towards the target enzyme in vitro, and IC50 values were calculated. Derivatives, which structurally closely resemble sponge-derived hemibastadins, revealed superior enzyme inhibitory properties vs. congeners featuring structural moieties that are absent in the respective natural products. This study suggests that natural selection has yielded structurally-optimized antifouling compounds.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/metabolismo , Mytilus edulis/efeitos dos fármacos , Mytilus edulis/metabolismo , Poríferos/química , Poríferos/metabolismo , Animais , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Relação Estrutura-AtividadeRESUMO
Sponge derived bromotyrosines are a multifaceted class of marine bioactive compounds that are important for the chemical defense of sponges but also for drug discovery programs as well as for technical applications in the field of antifouling constituents. These compounds, which are mainly accumulated by Verongid sponges, exhibit a diverse range of bioactivities including antibiotic, cytotoxic and antifouling effects. In spite of the simple biogenetic building blocks, which consist only of brominated tyrosine and tyramine units, an impressive diversity of different compounds is obtained through different linkages between these precursors and through structural modifications of the side chains and/or aromatic rings resembling strategies that are known from combinatorial chemistry. As examples for bioactive, structurally divergent bromotyrosines psammaplin A, Aplysina alkaloids featuring aerothionin, aeroplysinin-1 and the dienone, and the bastadins, including the synthetically derived hemibastadin congeners, have been selected for this review. Whereas all of these natural products are believed to be involved in the chemical defense of sponges, some of them may also be of particular relevance to drug discovery due to their interaction with specific molecular targets in eukaryotic cells. These targets involve important enzymes and receptors, such as histone deacetylases (HDAC) and DNA methyltransferases (DNMT), which are inhibited by psammaplin A, as well as ryanodine receptors that are targeted by bastadine type compounds. The hemibastadins such as the synthetically derived dibromohemibastadin are of particular interest due to their antifouling activity. For the latter, a phenoloxidase which catalyzes the bioglue formation needed for firm attachment of fouling organisms to a given substrate was identified as a molecular target. The Aplysina alkaloids finally provide a vivid example for dynamic wound induced bioconversions of natural products that generate highly efficient chemical weapons precisely when and where needed.
Assuntos
Poríferos/química , Tirosina/análogos & derivados , Acetonitrilas/química , Acetonitrilas/metabolismo , Animais , Cicloexenos/química , Cicloexenos/metabolismo , Dissulfetos/química , Descoberta de Drogas , Ecossistema , Humanos , Estrutura Molecular , Poríferos/metabolismo , Tirosina/biossíntese , Tirosina/química , Tirosina/metabolismoRESUMO
It has been discovered during the past few years that demosponges of the order Verongida such as Aplysina cavernicola exhibit chitin-based skeletons. Verongida sponges are well known to produce bioactive brominated tyrosine derivatives. We could recently demonstrate that brominated compounds do not exclusively occur in the cellular matrix but also in the skeletons of the marine sponges Aplysina cavernicola and Ianthella basta. Our measurements imply that these yet unknown compounds are strongly, possibly covalently bound to the sponge skeletons. In the present work, we determined the skeletal amino acid composition of the demosponge A. cavernicola especially with respect to the presence of halogenated amino acids. The investigations of the skeletons before and after MeOH extraction confirmed that only a small amount of the brominated skeleton-bound compounds dissolves in MeOH. The main part of the brominated compounds is strongly attached to the skeletons but can be extracted for example by using Ba(OH)2. Various halogenated tyrosine derivatives were identified by GC-MS and LC-MS in these Ba(OH)2 extracts of the skeletons.
Assuntos
Aminoácidos/metabolismo , Osso e Ossos/metabolismo , Poríferos/metabolismo , Animais , Quitina/metabolismo , Halogenação/fisiologia , Tirosina/metabolismoRESUMO
Demosponges possess a skeleton made of a composite material with various organic constituents and/or siliceous spicules. Chitin is an integral part of the skeleton of different sponges of the order Verongida. Moreover, sponges of the order Verongida, such as Aplysina cavernicola or Ianthella basta, are well-known for the biosynthesis of brominated tyrosine derivates, characteristic bioactive natural products. It has been unknown so far whether these compounds are exclusively present in the cellular matrix or whether they may also be incorporated into the chitin-based skeletons. In the present study, we therefore examined the skeletons of A. cavernicola and I. basta with respect to the presence of bromotyrosine metabolites. The chitin-based-skeletons isolated from these sponges indeed contain significant amounts of brominated compounds, which are not easily extractable from the skeletons by common solvents, such as MeOH, as shown by HPLC analyses in combination with NMR and IR spectroscopic measurements. Quantitative potentiometric analyses confirm that the skeleton-associated bromine mainly withstands the MeOH-based extraction. This observation suggests that the respective, but yet unidentified, brominated compounds are strongly bound to the sponge skeletons, possibly by covalent bonding. Moreover, gene fragments of halogenases suggested to be responsible for the incorporation of bromine into organic molecules could be amplified from DNA isolated from sponge samples enriched for sponge-associated bacteria.
Assuntos
Quitina/química , Poríferos/química , Tirosina/análogos & derivados , Animais , Quitina/isolamento & purificação , Cromatografia Líquida de Alta Pressão , DNA/metabolismo , Espectroscopia de Ressonância Magnética , Poríferos/genética , Potenciometria , Solventes/química , Espectrofotometria Infravermelho , Tirosina/química , Tirosina/isolamento & purificação , Tirosina/metabolismoRESUMO
Bastadins-6, -9 and -16 isolated from the marine sponge Ianthella basta displayed in vitro cytostatic and/or cytotoxic effects in six human and mouse cancer cell lines. The in vitro growth inhibitory effects of these bastadins were similar in cancer cell lines sensitive to pro-apoptotic stimuli versus cancer cell lines displaying various levels of resistance to pro-apoptotic stimuli. While about ten times less toxic than the natural cyclic bastadins, the synthetically derived 5,5'-dibromohemibastadin-1 (DBHB) displayed not only in vitro growth inhibitory activity in cancer cells but also anti-angiogenic properties. At a concentration of one tenth of its in vitro growth inhibitory concentration, DBHB displayed actual antimigratory effects in mouse B16F10 melanoma cells without any sign of cytotoxicity and/or growth inhibition. The serum concentration used in the cell culture media markedly influenced the DBHB-induced antimigratory effects in the B16F10 melanoma cell population. We are currently developing a specific inhalation formulation for DBHB enabling this compound to avoid plasmatic albumin binding through its direct delivery to the lungs to combat primary as well as secondary (metastases) tumors.
Assuntos
Inibidores da Angiogênese/farmacologia , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Éteres Difenil Halogenados/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Éteres Difenil Halogenados/uso terapêutico , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Concentração Inibidora 50 , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Poríferos/química , Ligação Proteica , Albumina Sérica/químicaRESUMO
The first naturally occurring trimeric hemibastadin congener, sesquibastadin 1 (1), and the previously reported bastadins 3, 6, 7, 11, and 16 (2-6) were isolated from the marine sponge Ianthella basta, collected in Indonesia. The structure of 1 was elucidated on the basis of 1D and 2D NMR measurements and by HRMS. Among all the isolated compounds, the linear sesquibastadin 1 (1) and bastadin 3 (2) showed the strongest inhibition rates for at least 22 protein kinases (IC(50) = 0.1-6.5 µM), while the macrocyclic bastadins (3-6) demonstrated a strong cytotoxic potential against the murine lymphoma cell line L5178Y (IC(50) = 1.5-5.3 µM).