RESUMO
Ecotoxicological studies aim to assess the potential environmental risks of various products. This implies the use of various biological models and tests on live animals. In case of handling fish and mammals, ethical rules have to be respected. The use of anaesthesia is considered to be the best way to ensure animal welfare. Eugenol and electro-narcosis are among the most popular chemical and physical anaesthetics used in fisheries and by field biologists. In this study, the genetic and endocrine impacts of these anaesthetics were assessed in order to establish whether the use of such methods could skew the results of ecotoxicological studies. Twenty yellow European eels (Anguilla anguilla) were submitted to Eugenol (50mg/L) and electro-narcosis until they reached a level of deep anaesthesia, while 20 other eels were kept aware. Five anaesthetized and five unanaesthetized eels were sacrificed and analysed directly after treatment and after 1, 7 and 21 days of recovery. At the brain level, Eugenol triggered an increase in the transcription level of genes encoding proteins involved in oxidative stress responses (catalase expression 2.5-fold, mitochondrial superoxide dismutase expression 3-fold), probably due to a hypoxic event during anaesthesia. Later impacts were detected in muscles 21 days after anaesthesia (ATP synthase subunit 6 3-fold, NADH deshydrogenase subunit 5 4-fold and mitochondrial superoxide dismutase 3-fold increased) revealing oxidative stress from an accrued mitochondrial respiratory metabolism. Hormone dosages showed that the use of Eugenol reduced the release of plasma cortisol during anaesthesia. However, this impact seemed to be reversible within one day. In case of electro-narcosis, no significant variation in transcriptional levels could be detected between anaesthetized and unanaesthetized eels. Our results suggest that the use of Eugenol as an aesthetic in ecotoxicological studies measuring gene expression or plasma cortisol concentration is not appropriate, while electro-narcosis does not seem to have any impact, at least on the parameters taken into consideration in this study.
Assuntos
Anestésicos/toxicidade , Anguilla/fisiologia , Eletronarcose/efeitos adversos , Eugenol/toxicidade , Poluentes Químicos da Água/toxicidade , Anestésicos/metabolismo , Anguilla/genética , Anguilla/metabolismo , Animais , Catalase/metabolismo , Disruptores Endócrinos/toxicidade , Sistema Endócrino/efeitos dos fármacos , Sistema Endócrino/metabolismo , Expressão Gênica/efeitos dos fármacos , Hidrocortisona/sangueRESUMO
Formerly called normal pressure hydrocephalus, communicating chronic hydrocephalus (CCH) is a condition affecting 0.1 to 0.5% of patients over 60years of age. The pathophysiology of this disease is poorly understood, but a defect in cerebrospinal fluid (CSF) resorption appears to be commonly defined as the cause of the neurological disorders. The last important discovery is the description of the glymphatic system and its implication in CCH and CSF resorption. Comorbidities (Alzheimer's disease, microangiopathy, parkinsonism) are very frequent, and involve a diagnostic challenge. The clinical presentation is based on the Hakim and Adams triad, comprising gait disorders, mainly impairing walking, cognitive disorders, affecting executive functions, episodic memory, visuospatial cognition, and sphincter disorders as urinary incontinence (detrusor hyperactivity). The diagnosis is suspected through a set of arguments, combining the clinical presentation, the radiological data of the magnetic resonance imaging (MRI) showing a ventriculomegaly associated with signs of transependymomous resorption of the CSF and disappearance of the cortical sulci, and the clinical response to the depletion of CSF. In the presence of all these elements, or a strong clinical suspicion, the standard treatment will be of a permanent CSF shunt, using a ventriculoatrial or ventriculoperitoneal shunt. The effectiveness of this treatment defines the diagnosis. The clinical improvement is better when treatment occurs early after the onset of the disorders, reaching 75 to 90% of motor improvement.
Assuntos
Doença de Alzheimer , Hidrocefalia de Pressão Normal , Derivações do Líquido Cefalorraquidiano , Humanos , Hidrocefalia de Pressão Normal/diagnóstico , Hidrocefalia de Pressão Normal/epidemiologia , Imageamento por Ressonância Magnética , Derivação VentriculoperitonealRESUMO
Ascoviruses are disseminated among larvae in lepidopteran populations by parasitic wasps during oviposition. Ascovirus relationships with these wasps vary from pathogenic to mutualistic, and experimentally can be shown possibly to be commensal non-pathogenic virus having little or no effect. Most ascoviruses are pathogens that female wasps vector mechanically. Other ascoviruses have a more intimate relationship with their wasp vectors in that their genome is stably maintained in all wasp nuclei through several generations by vertical transmission. In this relationship, these viruses are mutualistic, enhancing the successful development of the wasp larvae by suppressing lepidopteran defence mechanisms. The DpAV4 ascovirus is a mutualist in certain Diadromus wasps but is pathogenic or not when vectored by other species of this genus. These various biologies suggest that ascovirus/wasp relationships depend on wasp regulatory factors that control virus replication. Thus, certain ascoviruses can potentially have either a pathogenic, mutualistic, or non-pathogenic relationship with a specific wasp vector, the type of relationship being dependent upon the species system in which the relationship evolved. Finally, because ascoviruses appear to be related to ichnoviruses (Polydnaviridae), the DpAV4/Diadromus system constitutes a possible interesting intermediate between the pathogenic ascoviruses and symbiotic viruses that evolved to be ichnoviruses.
Assuntos
Ascoviridae/patogenicidade , Lepidópteros/parasitologia , Filogenia , Simbiose , Vespas/virologia , Animais , Ascoviridae/genética , Ascoviridae/fisiologia , Proteínas do Capsídeo/genética , Proteínas de Insetos/genética , Proteínas de Insetos/fisiologia , Larva/virologia , Especificidade da Espécie , Replicação ViralRESUMO
Podophyllotoxin, a natural lignan, is a good inhibitor of tubulin polymerization with antitumoral properties but it is too toxic for therapeutic use. In order to obtain less toxic drugs, several heterolignans have been prepared. We presented the synthesis and preliminary pharmacological properties of 4-aza-2,3-didehydropodophyllotoxins (dihydropyrrole [3,4-b]quinolin-1-ones), a new azalignan series. A straightforward synthesis was described according to a multicomponent reaction in a one-pot procedure. Starting from an aniline, an aromatic aldehyde, and a cyclic B-diketone, many substituted analogues could be prepared. Our lead, the 4-aza-2,3-didehydropodophyllotoxin, is extremely cytotoxic on various tumor cell lines, active in vivo on murine tumors. Like podophyllotoxin, this drug inhibits microtubule assembly without any effect on depolymerization.
Assuntos
Antineoplásicos/síntese química , Compostos Aza/síntese química , Podofilotoxina/análogos & derivados , Podofilotoxina/síntese química , Animais , Antineoplásicos/farmacologia , Compostos Aza/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Microtúbulos/efeitos dos fármacos , Podofilotoxina/farmacologia , Relação Estrutura-AtividadeRESUMO
Bone formation and structure have been shown repeatedly to be altered after spaceflight. However, it is not known whether these changes are related to a stress-related altered status of the corticosteroid axis. We investigated the role of corticosteroids on spaceflight-induced effects in rat pelvis and thoracic vertebrae. Thirty-six male Sprague-Dawley rats were assigned to a flight, flight control, or vivarium group (n = 12/group). Bilateral adrenalectomy was performed in six rats per group, the additional six rats undergoing sham surgery. Adrenalectomized (ADX) rats were implanted with corticosteroid pellets. On recovery from spaceflight, thoracic vertebrae and the whole pelvis were removed and processed for biochemistry, histomorphometry, or bone cell culture studies. The 17-day spaceflight resulted in decreased bone volume (BV) in the cotyle area of pelvic bones (-12%; p < 0.05) associated with approximately 50% inhibition of bone formation in the cancellous area of pelvic metaphyses and in thoracic vertebral bodies. The latter effect was associated with a decreased number of endosteal bone cells isolated from the bone surface (BS) in these samples (-42%; p < 0.05). This also was associated with a decreased number of alkaline phosphatase positive (ALP+) endosteal bone cells at 2 days and 4 days of culture, indicating decreased osteoblast precursor cell recruitment. Maintaining basal serum corticosterone levels in flight-ADX rats did not counteract the impaired bone formation in vertebral or pelvic bones. Moreover, the decreased ex vivo number of total and ALP+ endosteal bone cells induced by spaceflight occurred independent of endogenous corticosteroid hormone levels. These results indicate that the microgravity-induced inhibition of bone formation and resulting decreased trabecular bone mass in specific areas of weight-bearing skeleton in growing rats occur independently of endogenous glucocorticoid secretion.
Assuntos
Corticosteroides/farmacologia , Corticosteroides/fisiologia , Densidade Óssea/fisiologia , Desenvolvimento Ósseo/fisiologia , Ossos Pélvicos/fisiologia , Voo Espacial , Adrenalectomia , Animais , Densidade Óssea/efeitos dos fármacos , Desenvolvimento Ósseo/efeitos dos fármacos , Cálcio/análise , Masculino , Modelos Animais , Técnicas de Cultura de Órgãos , Ossos Pélvicos/citologia , Ossos Pélvicos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Vértebras Torácicas/citologia , Vértebras Torácicas/efeitos dos fármacos , Vértebras Torácicas/fisiologiaRESUMO
We show that oligodeoxyribonucleotides (oligos) composed of alpha- and beta-anomeric sections can be used as antisense compounds. An octamer has been chosen as an effector domain to form a substrate for RNaseH. This octamer is complementary to the translation start site of the pim-1 protooncogene mRNA. Chimeric alpha-beta oligos and their beta-analogs have a similar binding affinity for their target. These oligos also direct efficient RNaseH-mediated cleavage of target mRNA. Among all alpha-beta oligos studied, one with an alpha-fragment bound by its 3'-end to the 3'-end of the beta-octamer is the most resistant to nucleolytic digestion in biological media. The alpha-beta oligos have been found to inhibit in vitro translation of pim-1 RNA with specificity.
Assuntos
Oligonucleotídeos Antissenso/farmacologia , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas/genética , Animais , Sequência de Bases , Sangue , Meios de Cultura , Eritroblastos , Globinas/genética , Humanos , Hidrólise , Camundongos , Dados de Sequência Molecular , Oligonucleotídeos Antissenso/metabolismo , Biossíntese de Proteínas , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-pim-1 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Coelhos , Ribonuclease H/metabolismoRESUMO
With the aim of obtaining new antitumoral agents, a series of 5,8-quinazolinediones was prepared. 5-Amino-6-methoxyquinazoline was oxidized by Fremy's salt to give 6-methoxy-5,8-quinazolinedione. Nucleophilic substitution reaction at C6, electrophilic substitution at C7, and synthesis of 7-amino-6-methoxy-5,8-quinazolinedione, the parent compound of streptonigrin, were studied. These compounds were tested for cytotoxic properties on L1210 leukemia cells in vitro. One of them, 6,7-bis(1-aziridinyl)-5,8-quinazolinedione, which exhibits a high cytotoxic activity (ID50 = 0.08 microM), was further screened in standard antitumor systems, including L1210 leukemia, P388 lymphocytic leukemia, sarcoma 180, and B16 melanocarcinoma. This drug gives a significant antitumoral effect on P388 leukemia but is inactive on other experimental models. Moreover, this compound was found to be highly mutagenic for Salmonella typhimurium TA98 and TA100 strains (Ames test), suggesting that DNA damage could be responsible for its cytotoxicity.
Assuntos
Antineoplásicos/síntese química , Quinazolinas/síntese química , Animais , Antineoplásicos/uso terapêutico , Leucemia L1210/tratamento farmacológico , Leucemia P388/tratamento farmacológico , Camundongos , Testes de Mutagenicidade , Quinazolinas/uso terapêutico , Sarcoma 180/tratamento farmacológicoRESUMO
A series of heterocyclic quinones, 6-substituted and 6,7-disubstituted 4-(alkylamino)-5,8-quinazolinediones, have been synthesized in order to evaluate their in vitro cytotoxicity on L1210 leukemia cells. Among 14 derivatives that have been prepared and studied for the structure-activity relationship, the most potent cytotoxic compound on L1210 leukemia cells was the 6,7-bis(1-aziridinyl)-4-[[3-(N,N-dimethylamino)propyl]amino]-5,8- quinazolinedione (24). This compound has been tested with the use of a cell-image processor on MCF-7 human mammary and HBL human melanoma cell lines. The results show that compound 24 influences cell proliferation and blocks both cells lines in the S phase. In vivo antineoplastic activity of compound 24 has been demonstrated on a broad spectrum of murine experimental models, but it was found highly toxic and produced long-delayed deaths.
Assuntos
Antineoplásicos/síntese química , Aziridinas/síntese química , Neoplasias Experimentais/tratamento farmacológico , Quinazolinas/síntese química , Animais , Aziridinas/química , Aziridinas/farmacologia , Aziridinas/uso terapêutico , Neoplasias da Mama , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Leucemia L1210 , Leucemia Experimental/tratamento farmacológico , Melanoma Experimental/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Estrutura Molecular , Quinazolinas/química , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Sarcoma Experimental/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
Proteins isolated from the host cocoon of Acrolepiopsis assectella (Lepidoptera: Yponomeutoidea) act as kairomones for host acceptance by the endoparasitoid wasp Diadromus pulchellus Wesmael (Hymenoptera: Ichneumonidae). In this study, morphological, ultrastructural and electrophysiological studies were carried out in order to identify the contact chemoreceptive sensilla on the parasitoid antennae that perceive the protein kairomones. Three types of sensillum on the antennae of the females were found to have a chemosensory function. The receptor cell(s) of one sensillar type were shown to give a positive electrophysiological response to protein kairomones. This sensillar type is apically multiporous and female specific. Consequently, this sensillum could be the one implicated in the perception of the protein kairomone that triggers the host-acceptance behaviour of D. pulchellus females.
Assuntos
Lepidópteros/química , Lepidópteros/parasitologia , Feromônios/farmacologia , Vespas/efeitos dos fármacos , Vespas/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Eletrofisiologia , Feminino , Interações Hospedeiro-Parasita/efeitos dos fármacos , Órgãos dos Sentidos/anatomia & histologia , Órgãos dos Sentidos/efeitos dos fármacos , Órgãos dos Sentidos/fisiologia , Órgãos dos Sentidos/ultraestrutura , Vespas/anatomia & histologia , Vespas/ultraestruturaRESUMO
Previous studies have shown that the satellite DNAs in Hymenoptera account for 1-25% of the genome. They mainly correspond to a single family, or to several subfamilies having the same evolutionary origin. We have now showed that the satellite DNAs in the genomes of the hymenopterans Diadromus pulchellus, Diadromus collaris, Eupelmus vuilletti and Eupelmus orientalis are transcribed in both males and females. Satellite DNA transcripts could only be extracted with NP40/Urea, indicating that they are strongly associated with proteins. The satellite DNA in D. pulchellus was transcribed on the two DNA strands. The satellite DNA transcripts were single-stranded and not polyadenylated in vivo. The transcripts were found in embryos, larvae and imagos stages. The transcripts detected included one major transcript (1.9 kb) and several discrete smaller transcripts. The in vivo synthesis of these satellite DNA transcripts was explored by identifying their putative initiation sites.
Assuntos
DNA Satélite/genética , Himenópteros/genética , Transcrição Gênica , Sequência de Aminoácidos , Animais , Feminino , Proteínas de Insetos/genética , Larva/genética , Masculino , Dados de Sequência MolecularRESUMO
Skeletal changes associated with spaceflight in the rat have been well documented, but few data are available on bone tissue and bone cell metabolism after subsequent on-Earth recovery. We therefore investigated the effects of microgravity and subsequent recovery on trabecular bone morphology and cellular activities in rat humeri and thoracic vertebrae and compared histomorphometric parameters in caudal vertebrae with the behavior of vertebral osteoblastic cells in culture. We report here that humeral weight showed normal growth during the experiment but was unaffected by spaceflight or recovery from spaceflight. However, the 14-day spaceflight resulted in inhibition of static indexes of bone formation in humeral proximal metaphyses and thoracic vertebral bodies. This was associated with a decrease in bone volume in humeral metaphyses. After 14 days of on-Earth recovery, osteoblastic and osteoid surfaces returned toward normal and bone volume was normalized in humeri, whereas the static bone formation parameters were not restored in thoracic vertebrae. In addition, histological indexes of bone formation and osteoblastic cell growth in vitro were not affected by spaceflight in caudal vertebrae. This study shows that rat humeri and thoracic and caudal vertebrae exhibit different patterns of response to spaceflight and subsequent on-Earth recovery, which could be due, at least in part, to the different loading pattern of these bones, and also to differences in bone turnover rate.
Assuntos
Úmero/anatomia & histologia , Voo Espacial , Coluna Vertebral/anatomia & histologia , Fosfatase Alcalina/metabolismo , Animais , Desenvolvimento Ósseo/fisiologia , Divisão Celular/fisiologia , Células Cultivadas , Úmero/citologia , Úmero/enzimologia , Masculino , Osteoblastos/fisiologia , Ratos , Ratos Sprague-Dawley , Coluna Vertebral/citologia , Coluna Vertebral/enzimologia , Vértebras Torácicas/anatomia & histologia , Vértebras Torácicas/citologia , Vértebras Torácicas/enzimologia , Ausência de Peso/efeitos adversosRESUMO
Rat head-down hindlimb suspension (HS) has been shown to induce hindlimb cancellous bone loss. As HS is known to associate unloading with progressive disappearance of hindlimb muscle contractions, we investigated whether persisting muscle motion could modify suspension-induced bone disorders or even prevent them. Chronic electrical stimulation (ES) was applied to leg muscles of rats during 3-wk hindlimb suspension, the lack of support for hindlimbs maintaining a hypodynamic situation. The histomorphometric characteristics of the proximal tibial metaphysis were analyzed. At the end of this protocol of combined suspension and stimulation, trabecular bone loss remained similar to that of nonstimulated HS animals. However, trabecular bone cell activity parameters showed greater bone formation after muscle stimulation in unloaded animals, with significantly increased osteoblastic, osteoid, and mineralizing surfaces. In addition, periosteal mineral apposition rate and cancellous bone formation rate, markedly decreased by suspension, were not significantly different in suspended stimulated compared with normal loaded animals. This enhanced formation activity could be related to persistence of muscle activity, as shown by partial preservation of muscle mass. However, direct electrical effects on bone cannot be excluded. Thus, despite muscle stimulation, with enhanced bone formation, isolated suppression of hypokinesia has not been able to counteract bone effects of unloading. This finding supports the hypothesis of the importance of mechanical loading to maintain bone architecture.
Assuntos
Osso e Ossos/fisiologia , Membro Posterior/fisiologia , Músculo Esquelético/fisiologia , Animais , Peso Corporal/fisiologia , Densidade Óssea/fisiologia , Osso e Ossos/metabolismo , Estimulação Elétrica , Masculino , Ratos , Ratos WistarRESUMO
Growth plate width and cartilage organization are altered during skeletal unloading in growing rats. Immunohistochemical studies have identified TGF-beta in calcified cartilage, and TGF-beta is known to induce mitogenic effects on chondrocytes in vitro. On the other hand, IGF-1 was shown to be expressed in the proximal tibial growth plate and to mediate GH-induced longitudinal bone growth in rats. We therefore investigated the effect of recombinant human (rh) IGF-1 and rhTGF-beta2 infusion on the changes induced by unloading in the cellular organization of the growth plate in growing rats. Hindlimb unloading for 14 days induced a 13% reduction in growth cartilage height in the proximal tibia. This effect was mostly related to a 17% and 14% decrease in the proliferative zone height and chondrocyte number, respectively. In unloaded rats treated with a systemic infusion of rhTGF-beta2 (2microg/kg/day) the number of chondrocytes in the proliferative zone was not different from those of normal loaded animals. In contrast, rhIGF-1 treatment at a 2mg/kg/day dose was not effective in counteracting the effects of unloading on growth plate height and chondrocyte number. These results show that systemic administration of rhTGF-beta2 prevents in large part the reduced growth of chondrocytes in the proliferative zone and the reduced epiphyseal growth plate growth induced by unloading in rats.
Assuntos
Condrócitos/efeitos dos fármacos , Lâmina de Crescimento/efeitos dos fármacos , Fator de Crescimento Transformador beta/farmacologia , Animais , Divisão Celular/efeitos dos fármacos , Condrócitos/fisiologia , Lâmina de Crescimento/fisiologia , Humanos , Fator de Crescimento Insulin-Like I/farmacologia , Masculino , Ratos , Ratos Wistar , Proteínas Recombinantes/farmacologiaRESUMO
We have studied the binding of the hybrid netropsin-flavin (Net-Fla) molecule onto four sequences containing four A. T base pairs. Molecular mechanics minimizations in vacuo show numerous minimal conformations separated by one base pair. 400 ps molecular dynamics simulations in vacuo have been performed using the lowest minima as the starting conformations. During these simulations, the flavin moiety of the drug makes two hydrogen bonds with an amino group of a neighboring guanine. A 200 ps molecular dynamics simulation in explicit water solution suggests that the binding of Net-Fla upon the DNA substrate is enhanced by water bridges. A water molecule bridging the amidinium of Net-Fla to the N3 atom of an adenine seems to be stuck in the drug-DNA complex during the whole simulation. The fluctuations of the DNA helical parameters and of the torsion angles of the sugar-phosphate backbone are very similar in the simulations in vacuo and in water. The time auto-correlation functions for the DNA helical parameters decrease rapidly in the picosecond range in vacuo. The same functions computed from the water solution molecular dynamics simulations seem to have two modes: the rapid mode is similar to the behavior in vacuo, and is followed by a slower mode in the 10 ps range.
Assuntos
DNA/química , DNA/metabolismo , Flavinas/química , Netropsina/química , Netropsina/metabolismo , Sítios de Ligação , Simulação por Computador , Transferência de Energia , Flavinas/metabolismo , Modelos Moleculares , Conformação Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Soluções , Fatores de Tempo , Vácuo , ÁguaRESUMO
The synthesis of 2,3-bis(2-pyridyl)-5,8-quinoxalinediones has been carried out in order to provide new antitumor drugs related to streptonigrin. Some derivatives have been found to possess significant cytotoxic properties and their mechanism of action has been studied. They were found to induce single-strand cleavage of covalently closed circular DNA (ccc-DNA). This biological activity requires an apparent in situ reduction (NADH activation) of the quinone to a hydroquinone or semiquinone radical, is facilitated by the presence of Cu(II), and involves activation of molecular oxygen to highly reactive radical species. Thus, although less active than the parent drugs, these molecules provide an attractive rationale for the observed cytotoxic and antitumor potency, as well as the cell-free single strand DNA cleavage efficacy of that family of drugs.
Assuntos
Quelantes/síntese química , Piridinas/síntese química , Quinoxalinas/síntese química , Animais , Sobrevivência Celular/efeitos dos fármacos , Fenômenos Químicos , Química , Cobre , DNA/efeitos dos fármacos , Dano ao DNA , Fluorescência , Radicais Livres , Leucemia L1210/patologia , Desnaturação de Ácido Nucleico , Piridinas/farmacologia , Quinoxalinas/farmacologia , ViscosidadeRESUMO
Four antitumoral 5,8-quinazolinediones were examined for their ability to induce mutation in Salmonella typhimurium. Each compound was tested at several concentrations in 4 strains. Relationships were established between the structure of the quinones and their mutagenic activities. The mutagenicity was influenced by (i) the nature of the substituent(s) of the quinonic moiety: the methoxyquinone had no mutagenic properties and the aziridinylquinones were mutagenic in the 4 strains with or without activation by S9 mix; (ii) the presence or the absence of a diaminopolymethylenic chain in the 4 position; (iii) the monomeric or the dimeric structure of the tested compound. Interestingly, the data indicated that the aziridinylquinazolinedione bearing the dimethylaminopropylamino chain in the 4 position was less mutagenic and had greater antitumor activity than the dimeric quinone.
Assuntos
Antineoplásicos/efeitos adversos , Aziridinas/toxicidade , Quinazolinas/toxicidade , Aziridinas/química , Extratos Hepáticos , Testes de Mutagenicidade , Quinazolinas/química , Salmonella typhimurium/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Six heterocyclic quinones with topoisomerase I inhibiting properties and cytotoxic activities on L1210 leukemia cells were studied for their mutagenicity in four strains of Salmonella typhimurium. The tested compounds are 3-methoxyindolo[3,2-c]quinoline-1,4-diones and their derivatives in which the common pyrroloquinoline nucleus is annelated either with a benzene or a cyclohexane on a pyridine ring. Almost all quinones were found to be direct-acting mutagens at different levels in all strains, mainly TA97a and TA98. Relations were established between their structure and their mutagenic activities. The mutagenicity was found to be influenced (i) by the nature of the fourth nucleus: the pyridinic compounds were the most active, the non-aromatic ones were practically inactive; (ii) by the presence of a methyl group in the 6-position that decreased the mutagenicity. Then, the mutagenic properties were compared with the topoisomerase I inhibiting property that is one of the possible mechanisms of action for these cytotoxic quinones. The results indicated a correlation between mutagenicity and enzyme inhibiting properties.
Assuntos
Leucemia L1210/patologia , Mutagênicos/toxicidade , Quinonas/farmacologia , Inibidores da Topoisomerase I , Animais , Divisão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Testes de Mutagenicidade , Quinonas/toxicidade , Salmonella typhimurium/genética , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A series of seven 6-methylindolo[3,2-c]quinoline-1,4-diones substituted either in the 2 position or in 3 position by various groups were examined for their ability to induce mutation in the Ames test at several concentrations in four strains of Salmonella typhimurium (TA97, TA98, TA100, and TA102). First, relationships were established between their mutagenic activities and either the nature or the position of the substituent on the quinonic nucleus. Compounds substituted in the 2 position were less mutagenic than the 3 isomers. In the second study, the mutagenic properties were compared to the in vitro antitumor activity. Interestingly, some very cytotoxic quinones were only weak mutagens. So where the cytotoxicity is similar, the less mutagenic compounds may be suitable for clinical use as antitumor drugs, in order to avoid important side effects; the Ames test can then be used guide the selection of molecules for further in vivo antitumor screening. It can also be very helpful in selecting the best candidate molecules to be synthesized.
Assuntos
Mutagênicos/toxicidade , Quinolonas/toxicidade , Animais , Biotransformação , Sobrevivência Celular , Leucemia L1210 , Mutagênicos/química , Mutagênicos/farmacocinética , Quinolonas/química , Quinolonas/farmacocinética , Salmonella typhimurium/efeitos dos fármacos , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Two soluble sericin-like polypeptides, B1 and B2, from leek moth (Acrolepiopsis assectella) cocoons trigger host-acceptance behaviour in the parasitoid, Diadromus pulchellus (Proc. Roy. Soc. London B 269 (2002) 1879). We found that these polypeptides were particularly cysteine-rich and lost their ability to trigger host-acceptance behaviour after being denatured and purified. This suggests that inter-disulphide bonds and the secondary structure of B1 and B2 are important for their biological activity. We also isolated six insoluble polypeptides (or polypeptides of low solubility) from A. assectella cocoons. At least four of these polypeptides triggered host-acceptance behaviour. The strongest responses were observed with P22, a light-chain fibroin or a seroin-peptide, and P100, a sericin-like polypeptide that is probably more strongly associated with the silk core than are B1 and B2. In conclusion, several polypeptides from different parts of the A. assectella silk-cocoon (the insoluble core and coating of the silk thread) are able to elicit host-acceptance behaviour in D. pulchellus females. These polypeptides belong to different silk protein families and are used as kairomones by this specialist parasitoid.
Assuntos
Himenópteros/fisiologia , Lepidópteros/fisiologia , Lepidópteros/parasitologia , Seda/química , Seda/fisiologia , Animais , Feminino , Peso Molecular , Desnaturação Proteica , Estrutura Secundária de ProteínaRESUMO
Mining operations in areas of the boreal forest have caused salinity issues to be a major concern for reclamation. One of the factors determining successful reclamation is the ability of species to self-propagate. The effects of salinity on the seedling emergence and early growth of three boreal forest conifers: Picea mariana, Picea glauca, and Pinus banksiana were determined. Seeds were planted in sand moistened with solutions of various concentrations of sodium chloride or sodium sulfate. Seedling emergence was monitored on a daily basis and growth parameters assessed after 6 weeks. The emergence of Pinus banksiana seedlings was least affected by salinity, and at certain concentrations, emergence even appeared to be stimulated by the presence of salt. Picea glauca was the most sensitive of the species studied. Hypertrophia was observed in all species at high concentrations of Na2SO4, and an increase in salt levels caused a corresponding reduction in seedling height and weight, root length and number of lateral roots.