Global Longitudinal Strain for the Early Detection of Chemotherapy-Induced Cardiotoxicity: A Systematic Review and Meta-analysis.

AIMS: Left ventricular ejection fraction is used to monitor patients undergoing cardiotoxic chemotherapy. A decrease in left ventricular ejection fraction represents a relatively late stage of systolic involvement. Global longitudinal strain has been studied to detect early changes in left ventricular myocardial contractile function. The aim of the present study was to evaluate the global longitudinal strain measurement in the early detection of cardiotoxicity induced by cardiotoxic chemotherapeutic agents. MATERIALS AND METHODS: A study search strategy based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was carried out to report systematic reviews. A search on PubMed, EMBASE, Web of Science and SCOPUS was carried out using the following keywords: 'echocardiography' and 'cardiotoxicity' and their variations, without language or date restrictions (until March 2021). RESULTS: In total, 4873 articles were identified for title and abstract analysis. The systematic review included 10 studies comprising 661 patients with cancer, including mainly breast cancer and haematological malignancies, mainly treated with anthracyclines. The meta-analysis included four studies: patients with cardiotoxicity showed a reduction in strain, compared with baseline, 14.13% greater than patients without cardiotoxicity (95% confidence interval 5.07-23.19; P < 0.01). No heterogeneity was observed between studies (I2 = 0). CONCLUSION: The meta-analysis showed that strain is a tool with proper predictive capacity for the detection of cardiotoxicity.

Feedbacks and adaptive capabilities of the PI3K/Akt/mTOR axis in acute myeloid leukemia revealed by pathway selective inhibition and phosphoproteome analysis.

Acute myeloid leukemia (AML) primary cells express high levels of phosphorylated Akt, a master regulator of cellular functions regarded as a promising drug target. By means of reverse phase protein arrays, we examined the response of 80 samples of primary cells from AML patients to selective inhibitors of the phosphatidylinositol 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) axis. We confirm that >60% of the samples analyzed are characterized by high pathway phosphorylation. Unexpectedly, however, we show here that targeting Akt and mTOR with the specific inhibitors Akti 1/2 and Torin1, alone or in combination, result in paradoxical Akt phosphorylation and activation of downstream signaling in 70% of the samples. Indeed, we demonstrate that cropping Akt or mTOR activity can stabilize the Akt/mTOR downstream effectors Forkhead box O and insulin receptor substrate-1, which in turn potentiate signaling through upregulation of the expression/phosphorylation of selected growth factor receptor tyrosine kinases (RTKs). Activation of RTKs in turn reactivates PI3K and downstream signaling, thus overruling the action of the drugs. We finally demonstrate that dual inhibition of Akt and RTKs displays strong synergistic cytotoxic effects in AML cells and downmodulates Akt signaling to a much greater extent than either drug alone, and should therefore be explored in AML clinical setting.

Multifaceted roles of GSK-3 and Wnt/ß-catenin in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention.

Glycogen synthase kinase-3 (GSK-3) is well documented to participate in a complex array of critical cellular processes. It was initially identified in rat skeletal muscle as a serine/threonine kinase that phosphorylated and inactivated glycogen synthase. This versatile protein is involved in numerous signaling pathways that influence metabolism, embryogenesis, differentiation, migration, cell cycle progression and survival. Recently, GSK-3 has been implicated in leukemia stem cell pathophysiology and may be an appropriate target for its eradication. In this review, we will discuss the roles that GSK-3 plays in hematopoiesis and leukemogenesis as how this pivotal kinase can interact with multiple signaling pathways such as: Wnt/ß-catenin, phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/Akt/mammalian target of rapamycin (mTOR), Ras/Raf/MEK/extracellular signal-regulated kinase (ERK), Notch and others. Moreover, we will discuss how targeting GSK-3 and these other pathways can improve leukemia therapy and may overcome therapeutic resistance. In summary, GSK-3 is a crucial regulatory kinase interacting with multiple pathways to control various physiological processes, as well as leukemia stem cells, leukemia progression and therapeutic resistance. GSK-3 and Wnt are clearly intriguing therapeutic targets.

Desenvolvimento da camomila, rendimento e qualidade do óleo essencial em diferentes idades de colheita / Development of chamomile and essential oil yield and quality at different harvesting times

A camomila é uma planta herbácea, anual e aromática com várias propriedades medicinais. No Brasil, vem sendo cultivada em área representativa na região Sul devido, principalmente, às exigências climáticas da espécie, e por ter sido introduzida por imigrantes europeus nesta região. A colheita da camomila é realizada em várias colheitas, contudo, a idade adequada da planta para o início desta atividade, objetivado a maior produção de capítulos florais, bem como o rendimento e qualidade de óleos essenciais, ainda não foi determinada para a espécie. Neste trabalho, investigou-se o efeito de diferentes épocas de colheita no desenvolvimento de capítulos florais e no acúmulo e qualidade do óleo essencial da camomila. O experimento foi conduzido no município de Piraquara (PR). O delineamento experimental foi inteiramente casualizado, com cinco tratamentos (85, 92, 99, 106 e 113 dias após a emergência das plântulas) e cinco repetições. Após cada colheita, avaliou-se o acúmulo de massa seca de capítulos, rendimento, produção e composição do óleo essencial. A extração de óleo foi realizada por hidrodestilação e as amostras analisadas por cromatografia gasosa. Concluiu-se que aos 85 dias após a emergência (DAE) os capítulos apresentaram maior rendimento de óleo. Porém, após três semanas ocorreu a maior produção de massa de capítulos, resultando em maiores médias de produtividade de óleo essencial. A partir de 113 DAE houve redução do rendimento de óleo essencial e no teor de alguns constituintes.

Chamomile is an aromatic herb with many medicinal properties. In Brazil, it is cultivated on an extensive area in the Southern region mainly because of its climatic conditions for this culture. Chamomile harvesting is done by several cuttings of the entire plant, but the ideal starting point of this activity to obtain high production of flower heads has not been determined. This work investigated the effect of the harvesting period of chamomile on flower head development and essential oil accumulation. The experiment was carried out at field conditions in Piraquara, Paraná, Brazil. The experimental design was completely randomized with five treatments (85, 92, 99, 106 and 113 days after emergency) and five replications. After each harvest, dry mass accumulation and essential oil yield and quality were evaluated. Essential oil extraction was performed by hydrodistillation, and the sample was analyzed by gas chromatography. When harvested 85 days after emergency, the flower heads presented the highest essential oil content, but three weeks later the highest flower head dry mass was obtained, which resulted on great essential oil productivity. From 113 days after emergency, there is a reduction in essential oil yield and production.

Desenvolvimento vegetativo e produção de óleo essencial de patchouli (Pogostemon cablin (Blanco) Benth. ) após a aplicação de ácido giberélico e extrato de alga marinha / Development and essential oil production of Pogostemon cablin (Blanco) Benth. patchouli after applying gibberellic acid and seaweed extract

Pogostemon cablin (Blanco) Benth., comumente conhecido como patchouli, é uma espécie aromática utilizada pela indústria de perfumes devido a fragrância amadeirada e propriedade fixadora do óleo essencial. Fatores que afetam o teor dos constituintes do óleo essencial devem ser avaliados visando obter matéria prima de melhor qualidade. O experimento foi conduzido em casa de vegetação com delineamento inteiramente casualizado em esquema fatorial 2x3 e 4 repetições, sendo dois níveis de giberelina (0 e 200 mg L-1) e três níveis de extrato de alga marinha (0, 15 e 30 mg L-1). A aplicação dos reguladores vegetais foi realizada 30 dias após o plantio das mudas, e a avaliação do experimento deu-se 45 dias após a aplicação dos tratamentos. Não houve diferença significativa para a altura das plantas, a concentração de extrato de alga marinha de 15 mg L-1 promoveu aumento no número de folhas em relação à testemunha e a concentração de 30 mg L-1 promoveu decréscimo. Em relação à área foliar e ao número de folhas houve relação inversa para os níveis de extrato de alga marinha, onde o tratamento com maior concentração do regulador resultou em aumento da área foliar e redução do número de folhas. O teor de óleo essencial foi superior após a aplicação de 15 mg L-1 de extrato alga marinha isoladamente ou combinado com GA3. A produtividade do óleo essencial também aumentou com a aplicação 15 mg L-1 de extrato de alga marinha e quando utilizado somente GA3. A utilização de extrato de alga marinha aumentou a concentração de patchoulol no óleo essencial.

Pogostemon cablin (Blanco) Benth., commonly known as patchouli, is an aromatic species used by the perfume industry due to its woody fragrance and the fixative characteristic of its essential oil. Factors affecting the content of the constituents of essential oils should be evaluated in order to obtain raw materials with better quality. The experiment was carried out in a greenhouse in a completely randomized 2x3 factorial arrangement and four replications, with two levels of gibberellin (0 and 200 mg L-1) and three levels of seaweed extract (0, 15 and 30 mg L-1). Plant regulators were applied thirty days after planting the seedlings; the experiment was evaluated forty-five days after the treatments. There was no significant difference in plant height; the 15 mg L-1 concentration of seaweed extract promoted an increase in the number of leaves in relation to the control; and the 30 mg L-1 concentration promoted a decrease. In relation to leaf area and leaf number, there was an inverse relationship for the seaweed extract levels, in which the treatment with higher a concentration of the regulator resulted in an increased leaf area, reducing the number of leaves. The essential oil content was higher after applying 15 mg L-1 of seaweed extract alone or combined with GA3. The yield of essential oil also increased by applying 15 mg L-1 of seaweed extract and when only GA3 was used. The use of seaweed extract increased the patchoulol concentration in the essential oil.

Dual Inhibition of Phosphatidylinositol 3-Kinase and Mammalian Target of Rapamycin: a Therapeutic Strategy for Acute Leukemias.

The phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) are two major signaling molecules in the PI3K/Akt/mTOR signal transduction cascade. This pathway is a key regulator of a wide range of physiological cell processes which include proliferation, differentiation, survival, metabolism, exocytosis, motility, and autophagy. However, aberrantly upregulated PI3K/Akt/mTOR signaling characterizes many types of cancers where it negatively influences response to therapeutic treatments. Therefore, targeting PI3K/Akt/mTOR signaling with small molecule inhibitors could improve cancer patient outcome. The PI3K/Akt/mTOR signaling network is activated in acute leukemias of both myelogenous and lymphoid lineage, where it correlates with poor prognosis and enhanced drug-resistance. The catalytic sites of PI3K and mTOR share a high degree of sequence homology. This feature has allowed the synthesis of ATP-competitive compounds that targeted the catalytic site of both PI3K and mTOR (e.g. PI-103, NVP-BEZ235). In preclinical settings, dual PI3K/mTOR inhibitors displayed a much stronger cytotoxicity against leukemic cells than either PI3K inhibitors or allosteric mTOR inhibitors, such as rapamycin and its derivatives (rapalogs). At variance with rapamycin/rapalogs, dual PI3K/mTOR inhibitors targeted both mTOR complex 1 and mTOR complex 2, and inhibited the rapamycin-resistant phosphorylation of eukaryotic initiation factor 4E-binding protein 1, resulting in a marked inhibition of oncogenetic protein translation in leukemic cells. Hence, they strongly reduced the proliferation rate and induced an important apoptotic response. Here, we reviewed the evidence documenting that dual PI3K/mTOR inhibitors represent a promising option for future targeted therapies of leukemic patients.

Activation of nuclear inositide signalling pathways during erythropoietin therapy in low-risk MDS patients.

Inositide signaling pathways can have a role in the Myelodysplastic Syndromes (MDS) progression to acute myeloid leukemia. Erythropoietin (EPO) is currently used in low-risk MDS, where it successfully corrects anemia in 50-70% of patients. However, some MDS patients are refractory to this treatment and little is known about the exact molecular mechanisms underlying the effect of EPO in these subjects. Here, we investigated the role of inositide pathways in low-risk MDS treated with EPO, mainly focusing on the Akt/PI-PLC (Phosphoinositide-Phospholipase C) gamma1 axis, which is activated by the EPO receptor, and PI-PLCbeta1/Cyclin D3 signaling, as Cyclin D3 is associated with hematopoietic proliferation and differentiation. Interestingly, EPO responder patients showed a specific activation of both the Akt/PI-PLCgamma1 pathway and beta-Globin gene expression, while nonresponders displayed an increase in PI-PLCbeta1 signaling. Moreover, in normal CD34+ cells induced to erythroid differentiation, PI-PLCbeta1 overexpression abrogated both EPO-induced Akt phosphorylation and beta-Globin expression. Overall, these findings suggest that PI-PLCbeta1 can act as a negative regulator of erythroid differentiation and confirm the involvement of Akt/PI-PLCgamma1 pathway in EPO signaling, therefore contributing to the comprehension of the effect of EPO in low-risk MDS and possibly paving the way to the identification of MDS patients at higher risk of refractoriness to EPO treatment.

Epigenetic regulation of nuclear PI-PLCbeta1 signaling pathway in low-risk MDS patients during azacitidine treatment.

Phosphoinositide-phospholipase C (PI-PLC) beta1 can be considered a specific target for demethylating therapy in high-risk myelodysplastic syndrome (MDS) patients, as azacitidine treatment has been associated with a PI-PLCbeta1-specific promoter demethylation, and induction of PI-PLCbeta1 gene and protein expression. However, little is known about the molecular effect of azacitidine in low-risk MDS or the functional mechanisms linked with azacitidine effect on PI-PLCbeta1 promoter. In the present study, we further investigated the role of epigenetic regulation of PI-PLCbeta1, mainly focusing on the structure of the PI-PLCbeta1 promoter. We first examined the effect of azacitidine on PI-PLCbeta1 promoter methylation and gene expression in low-risk MDS. Moreover, we studied the expression of key molecules associated with the nuclear inositide signaling pathways, such as cyclin D3. By applying a chromatin immunoprecipitation method, we also studied the correlation between the demethylating effect of azacitidine and the degree of recruitment to PI-PLCbeta1 promoter of some transcription factors implicated in hematopoietic stem cell proliferation and differentiation, as well as of the methyl-CpG-binding domain proteins, which specifically interact with methylated DNA. Taken together, our results hint at a specific involvement of PI-PLCbeta1 in epigenetic mechanisms, and are particularly consistent with the hypothesis of a role for PI-PLCbeta1 in azacitidine-induced myeloid differentiation.

Conteúdo polifenólico e atividade antioxidante dos frutos da palmeira Juçara (Euterpe edulis Martius) / Polyphenolic content and antioxidant capacity of fruits of Juçara (Euterpe edulis Martius) palm tree

O conteúdo polifenólico e a atividade antioxidante do extrato do fruto de Euterpe edulis Martius foram avaliados. Esta espécie é uma palmeira conhecida como Juçara, nativa da Mata Atlântica e utilizada para a extração de palmito. O processo de extração do palmito acarreta a morte da planta, uma vez que esta apresenta estipe único. A elevada demanda ocasionou a escassez deste recurso natural. Muitas espécies da Mata Atlântica podem ser utilizadas pelo manejo sustentável para a preservação e exploração econômica pelas comunidades locais. O fruto da palmeira Juçara pode ser uma das alternativas de manejo sustentável dos recursos naturais da Mata Atlântica. A capacidade antioxidante do fruto pode ser utilizada como justificativa para a aplicação como alimento nutricional. O conteúdo polifenólico do fruto foi determinado pelo método de Folin-Ciocalteau e os resultados obtidos foram: 10,31 ± 0,25%, 12,42 ± 0,89%, 12,75 ± 0,94%, para o extrato bruto, fração acetato de etila e fração remanescente, respectivamente. A atividade antioxidante foi determinada pelos métodos de redução do complexo fosfomolibdênico e DPPH. O extrato bruto e as frações acetato de etila e remanescente apresentaram atividade antioxidante, sendo que as duas últimas demonstraram maior atividade indicando que o conteúdo polifenólico pode ser responsável por esta atividade.

The polyphenolic content and the antioxidant activity of Euterpe edulis Martius fruit extract were assessed. This species is a Palm tree known as Juçara, native to Atlantic Forest and used for palm heart extraction. The process of palm heart extraction leads to the death of the plant since the latter has one single stem. The high demand has resulted in the depletion of this natural resource. Many species from Atlantic Forest can be used by means of sustainable management for the preservation and economic exploration by local communities. The fruit of Juçara palm can be one of the sustainable management alternatives for the Atlantic Forest natural resources. The antioxidant capacity of this fruit can justify its application as nutritional food. The fruit polyphenolic content was determined by the Folin-Ciocalteau method and the obtained results were: 10.31 ± 0.25%, 12.42 ± 0.89%, 12.75 ± 0.94% for crude extract, acetyl acetate and remaining fractions, respectively. The antioxidant capacity was determined through the phosphomolybdenium complex and DPPH methods. The crude extract and the acetyl acetate and remaining fractions showed antioxidant activity, and the latter two showed higher activity, indicating that polyphenolic content may be responsible for this activity.

Avaliação do extrato etanólico de Ottonia martiana Miq. para o controle de duas doenças florestais / Evaluation of Ottonia martiana Miq. alcoholic extract to control two forest diseases

Metabólitos secundários presentes em plantas medicinais apresentam várias propriedades biológicas incluindo a atividade antifúngica. Esse estudo avaliou o potencial antifúngico da planta medicinal Ottonia martiana no controle da pinta-preta em erva-mate (Ilex paraguariensis) e do mofo-cinzento em eucalipto (Eucalyptus dunnii). Extrato etanólico (EBEtOH) dos órgãos totais (raízes, caules, folhas e frutos) foi preparado e testado na concentração de 1000 μg mL-1 contra os patógenos Cylindrocladium spathulatum (pinta-preta) e Botrytis cinerea (mofo-cinzento). Bioensaios in vitro (germinação de esporos e bioautografia direta) e in vivo (teste de patogenicidade em mudas) mostraram que o EBEtOH reduziu o crescimento micelial dos patógenos testados e a germinação dos esporos de C. spathulatum e estimulou a germinação de esporos de B. cinerea. O teste de patogenicidade mostrou que o controle da pinta-preta em erva-mate e do mofo cinzento em eucalipto não é viável usando-se a concentração testada de EBEtOH de O. martiana. Na bioautografia direta, foram detectadas zonas de inibição de crescimento micelial dos fungos e que foram relacionadas com a presença de piperovatina.

Secondary metabolites from medicinal plants have several biological properties, including antifungal activity. This study evaluated the antifungal potential of the medicinal plant Ottonia martiana to control maté leaf spot (Ilex paraguariensis) and eucalypt gray mould (Eucalyptus dunnii). Ethanol extract (EBEtOH) of the total parts (roots, stems, leaves and fruits) was prepared at the concentration of 1000 μg mL-1 and tested against Cylindrocladium spathulatum (maté leaf spot) and Botrytis cinerea (eucalypt gray mould). In vitro bioassays (spore germination and direct bioautography) and in vivo bioassays (pathogenicity test in seedlings) showed that EBEtOH reduced the mycelial growth of the tested pathogens and the germination of C. spathulatum spores and stimulated the germination of B. cinerea spores. The pathogenicity test showed that the control of maté leaf spot and eucalypt gray mould is not viable using the tested concentration of O. martiana EBEtOH. Zones of mycelial growth inhibition were detected in direct bioautography and were related to the presence of piperovatine.

Targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling network in cancer stem cells.

Cancer stem cells (CSCs) comprise a subset of hierarchically organized, rare cancer cells with the ability to initiate cancer in xenografts of genetically modified murine models. CSCs are thought to be responsible for tumor onset, self-renewal/maintenance, mutation accumulation, and metastasis. The existence of CSCs could explain the high frequency of neoplasia relapse and resistance to all of currently available therapies, including chemotherapy. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is a key regulator of physiological cell processes which include proliferation, differentiation, apoptosis, motility, metabolism, and autophagy. Nevertheless, aberrantly upregulated PI3K/Akt/mTOR signaling characterizes many types of cancers where it negatively influences prognosis. Several lines of evidence indicate that this signaling system plays a key role also in CSC biology. Of note, CSCs are more sensitive to pathway inhibition with small molecules when compared to healthy stem cells. This observation provides the proof-of-principle that functional differences in signaling transduction pathways between CSCs and healthy stem cells can be identified. Here, we review the evidence which links the signals deriving from the PI3K/Akt/mTOR network with CSC biology, both in hematological and solid tumors. We then highlight how therapeutic targeting of PI3K/Akt/mTOR signaling with small molecule inhibitors could improve cancer patient outcome, by eliminating CSCs.

Multiple forms of PKR present in the nuclei of acute leukemia cells represent an active kinase that is responsive to stress.

A number of cancers possess constitutive activity of the dsRNA-dependent kinase, PKR. Inhibition of PKR in these cancers leads to tumor cell death. We recently reported the increased presence of PKR phosphorylated on Thr451 (p-T451 PKR) in clinical samples from myelodysplastic syndrome (MDS) patients and acute leukemia cell lines. Whereas p-T451 PKR in low-risk patient samples or PTEN-positive acute leukemia cell lines was mostly cytoplasmic, in high-risk patient samples and acute leukemia cell lines deficient in PTEN, p-T451 PKR was mainly nuclear. As nuclear activity of PKR has not been previously characterized, we examined the status of nuclear PKR in acute leukemia cell lines. Using antibodies to N-terminus, C-terminus and the kinase domain in conjunction with a proteomics approach, we found that PKR exists in diverse molecular weight forms in the nucleus. Analysis of PKR transcripts by reverse transcriptase-PCR, and PKR-derived peptides by MS/MS revealed that these forms were the result of post-translational modifications (PTMs). Biochemical analysis demonstrated that nuclear PKR is an active kinase that can respond to stress. Given the association of PKR with PTEN and the Fanconi complex, these results indicate that PKR likely has other previously unrecognized roles in nuclear signaling that may contribute to leukemic development.

Synergistic induction of PI-PLCß1 signaling by azacitidine and valproic acid in high-risk myelodysplastic syndromes.

The association between azacitidine (AZA) and valproic acid (VPA) has shown high response rates in high-risk myelodysplastic syndromes (MDS) cases with unfavorable prognosis. However, little is known about the molecular mechanisms underlying this therapy, and molecular markers useful to monitor the disease and the effect of the treatment are needed. Phosphoinositide-phospholipase C (PI-PLC) ß1 is involved in both genetic and epigenetic mechanisms of MDS progression to acute myeloid leukemia. Indeed, AZA as a single agent was able to induce PI-PLCß1 expression, therefore providing a promising new tool in the evaluation of response to demethylating therapies. In this study, we assessed the efficacy of the combination of AZA and VPA on inducing PI-PLCß1 expression in high-risk MDS patients. Furthermore, we observed an increase in Cyclin D3 expression, a downstream target of PI-PLCß1 signaling, therefore suggesting a potential combined activity of AZA and VPA in high-risk MDS in activating PI-PLCß1 signaling, thus affecting cell proliferation and differentiation. Taken together, our findings might open up new lines of investigations aiming at evaluating the role of the activation of PI-PLCß1 signaling in the epigenetic therapy, which may also lead to the identification of innovative targets for the epigenetic therapy of high-risk MDS.

Teor e composição de óleo essencial de rizomas de gengibre (Zingiber officinale Roscoe) após diferentes períodos de secagem / Essential oil yield and composition of ginger (Zingiber officinale Roscoe) rhizomes after different drying periods

A produção de gengibre no Paraná concentra-se no município de Morretes, ocupando uma área de plantio de aproximadamente 300 ha. O objetivo deste trabalho foi avaliar o teor e a composição do óleo essencial de rizomas de gengibre produzidos em Morretes e submetidos a diferentes períodos de secagem em temperatura ambiente. O delineamento experimental foi inteiramente casualizado, em esquema fatorial 5 x 5, com quatro repetições (quatro plantas por repetição), avaliando cinco procedências e cinco períodos de secagem a temperatura ambiente (0, 15, 30, 45 e 60 dias). As extrações de óleo essencial foram realizadas por hidrodestilação em aparelho graduado Clevenger durante três horas e a análise dos constituintes foi realizada por meio de cromatografia em fase gasosa acoplada à espectrometria de massas. A secagem de rizomas de gengibre em temperatura ambiente por até 60 dias resultou na diminuição de teores de óleo essencial na maioria das procedências. Os constituintes geranial e o neral apresentaram maior concentração em todas as procedências e tiveram teores superiores com o aumento nos períodos de secagem. Os teores de geraniol e acetato de geranila foram inferiores após a secagem em todas as procedências, assim como eucaliptol, canfeno, zingibereno e β-bisaboleno na maioria das procedências.

Ginger production in Paraná State, Brazil, has predominated in Morretes Municipality, with around 300 ha cultivated area. The aim of this work was to evaluate the essential oil yield and composition of ginger rhizomes produced in Morretes and subjected to different drying periods at room temperature. Experimental design was completely randomized, in a 5x5 factorial arrangement, with four replicates (four plants each), five origins and five drying periods at room temperature (0, 15, 30, 45 and 60 days). The essential oil was extracted by hydrodistillation in a Clevenger-type device for 3h and the constituents were analyzed by gas chromatography-mass spectrometry (GC/MS). The drying of ginger rhizomes at room temperature for up to 60 days decreased the essential oil yield in most origins. Geranial and neral levels were higher in all origins and as drying periods were longer. Geraniol and geranyl acetate levels decreased after drying in all origins, as well as eucalyptol, camphene, zingiberene and β-bisabolene in most origins.

Expression of phosphoinositide-specific phospholipase C isoenzymes in cultured astrocytes activated after stimulation with lipopolysaccharide.

Signal transduction pathways, involved in cell cycle and activities, depend on various components including lipid signalling molecules, such as phosphoinositides and related enzymes. Many evidences support the hypothesis that inositol lipid cycle is involved in astrocytes activation during neurodegeneration. Previous studies investigated the pattern of expression of phosphoinositide-specific phospholipase C (PI-PLC) family isoforms in astrocytes, individuating in cultured neonatal rat astrocytes, supposed to be quiescent cells, the absence of some isoforms, accordingly to their well known tissue specificity. The same study was conducted in cultured rat astrocytoma C6 cells and designed a different pattern of expression of PI-PLCs in the neoplastic counterpart, accordingly to literature suggesting a PI signalling involvement in tumour progression. It is not clear the role of PI-PLC isoforms in inflammation; recent data demonstrate they are involved in cytokines production, with special regard to IL-6. PI-PLCs expression in LPS treated neonatal rat astrocytes performed by using RT-PCR, observed at 3, 6, 18 and 24 h intervals, expressed: PI-PLC beta1, beta4 and gamma1 in all intervals analysed; PI-PLC delta1 at 6, 18 and 24 h; PI-PLC delta3 at 6 h after treatment. PI-PLC beta3, delta4 and epsilon, present in untreated astrocytes, were not detected after LPS treatment. Immunocytochemical analysis, performed to visualize the sub-cellular distribution of the expressed isoforms, demonstrated different patterns of localisation at different times of exposure. These observations suggest that PI-PLCs expression and distribution may play a role in ongoing inflammation process of CNS.

Genotoxic activity of Eucalyptus globulus essential oil in Aspergillus nidulans diploid cells.

Eucalyptus globulus essential oil was evaluated for its genotoxic potential using a somatic segregation assay and a diploid strain of the fungus Aspergillus nidulans, heterozygous for nutritional and conidia color markers. The main compounds of the current essential oil sample were eucalyptol (49.0 %), alpha-pinene (8.9), beta-pinene (1.5), globulol (6.9), alpha-eudesmol (1.12), spathulenol (1.42), gamma-cadinene (1.45), trans-beta-elemenone (1.23) and aromandendrene (2.3), totaling 74 % of oil. Oil at 0.12 and 0.25 microL/mL was found to increase the mitotic instability of the original diploid strain and the number of diploid mitotic recombinants of A. nidulans. The genotoxicity of the oil was associated with the induction of mitotic crossing-over or with oil-broken chromosomes.

Nuclear phosphatidylinositol 3,4,5-trisphosphate, phosphatidylinositol 3-kinase, Akt, and PTen: emerging key regulators of anti-apoptotic signaling and carcinogenesis.

Inositol lipid-derived second messengers have long been known to have an important regulatory role in cell physiology. Phosphatidylinositol 3-kinase (PI3K) synthesizes the second messenger 3,4,5'-phosphatidylinositol trisphosphate (Ptdlns 3,4,5P3) which controls a multitude of cell functions. Down-stream of PI3K/PtdIns 3,4,5P3 is the serine/threonine protein kinase Akt (protein kinase B, PKB). Since the PI3K/ PtdIns 3,4,5P3 /Akt pathway stimulates cell proliferation and suppresses apoptosis, it has been implicated in carcinogenesis. The lipid phosphatase PTEN is a negative regulator of this signaling network. Until recently, it was thought that this signal transduction cascade would promote its anti-apoptotic effects when activated in the cytoplasm. Several lines of evidence gathered over the past 20 years, have highlighted the existence of an autonomous nuclear inositol lipid cycle, strongly suggesting that lipids are important components of signaling pathways operating at the nuclear level. PI3K, PtdIns(3,4,5)P3, Akt, and PTEN have been identified within the nucleus and recent findings suggest that they are involved in cell survival also by operating in this organelle, through a block of caspase-activated DNase and inhibition of chromatin condensation. Here, we shall summarize the most updated and intriguing findings about nuclear PI3K/ PtdIns(3,4,5)P3/Akt/PTEN in relationship with carcinogenesis and suppression of apoptosis.