Citral presents cytotoxic and genotoxic effects in human cultured cells.

Citral, 3,7-dimethyl-2,6-octadien-1-al, one of the main components of the essential oils obtained from several plants, is used as a food additive and as a fragrance for detergents, cosmetics and other toiletries. The literature shows disparity regarding citral genotoxicity. Thus, the main objective of our work was to evaluate the genotoxic effects of citral in human cell cultures, HepG2 and leukocytes. Cytotoxicity assays (trypan blue and MTT) showed citral toxic effects in HepG2 cells (with metabolizing liver enzymes), which contrasted with the absence of toxicity in leukocytes. After citral exposure, both cell types did not demonstrate clastogenic/aneugenic effects in the micronucleus test. However, for the comet assay, citral exposure lead to significant genotoxic effects in both HepG2 (even to citral low concentrations) and leukocytes. The use of citral must be viewed with caution due to its ability to induce DNA damages, especially after being metabolized by cells with active liver enzymes.

Multi-tasking deep network for tinnitus classification and severity prediction from multimodal structural MR images.

Objective:Subjective tinnitus is an auditory phantom perceptual disorder without an objective biomarker. Fast and efficient diagnostic tools will advance clinical practice by detecting or confirming the condition, tracking change in severity, and monitoring treatment response. Motivated by evidence of subtle anatomical, morphological, or functional information in magnetic resonance images of the brain, we examine data-driven machine learning methods for joint tinnitus classification (tinnitus or no tinnitus) and tinnitus severity prediction.Approach:We propose a deep multi-task multimodal framework for tinnitus classification and severity prediction using structural MRI (sMRI) data. To leverage complementary information multimodal neuroimaging data, we integrate two modalities of three-dimensional sMRI-T1 weighted (T1w) and T2 weighted (T2w) images. To explore the key components in the MR images that drove task performance, we segment both T1w and T2w images into three different components-cerebrospinal fluid, grey matter and white matter, and evaluate performance of each segmented image.Main results:Results demonstrate that our multimodal framework capitalizes on the information across both modalities (T1w and T2w) for the joint task of tinnitus classification and severity prediction.Significance:Our model outperforms existing learning-based and conventional methods in terms of accuracy, sensitivity, specificity, and negative predictive value.

Holmium-Containing Bioactive Glasses Dispersed in Poloxamer 407 Hydrogel as a Theragenerative Composite for Bone Cancer Treatment.

Holmium-containing bioactive glasses can be applied in bone cancer treatment because the holmium content can be neutron activated, having suitable properties for brachytherapy applications, while the bioactive glass matrix can regenerate the bone alterations induced by the tumor. To facilitate the application of these glasses in clinical practice, we proposed a composite based on Poloxamer 407 thermoresponsive hydrogel, with suitable properties for applications as injectable systems. Therefore, in this work, we evaluated the influence of holmium-containing glass particles on the properties of Poloxamer 407 hydrogel (20 w/w.%), including self-assembly ability and biological properties. 58S bioactive glasses (58SiO2-33CaO-9P2O5) containing different Ho2O3 amounts (1.25, 2.5, 3.75, and 5 wt.%) were incorporated into the hydrogel. The formulations were characterized by scanning electron microscopy, differential scanning calorimetry, rheological tests, and [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] MTT cell viability against pre-osteoblastic and osteosarcoma cells. The results evidenced that neither the glass particles dispersed in the hydrogel nor the holmium content in the glasses significantly influenced the hydrogel self-assembly ability (Tmic ~13.8 °C and Tgel ~20 °C). Although, the glass particles considerably diminished the hydrogel viscosity in one order of magnitude at body temperature (37 °C). The cytotoxicity results evidenced that the formulations selectively favored pre-osteoblastic cell proliferation and osteosarcoma cell death. In conclusion, the formulation containing glass with the highest fraction of holmium content (5 wt.%) had the best biological results outcomes aiming its application as theragenerative materials for bone cancer treatment.

Natural compounds as a source of protein tyrosine phosphatase inhibitors: application to the rational design of small-molecule derivatives.

Reversible phosphorylation of tyrosine residues is a key regulatory mechanism for numerous cellular events. Protein tyrosine kinases and protein tyrosine phosphatases (PTPs) have a pivotal role in regulating both normal cell physiology and pathophysiology. Accordingly, deregulated activity of both protein tyrosine kinases and PTPs is involved in the development of numerous congenitically inherited and acquired human diseases, prompting obvious pharmaceutical and academic research interest. The development of compound libraries with higher selective PTP inhibitory activity has been bolstered by the realization that many natural products have such activity and thus are interesting biologically lead compounds, which properties are widely exploited. In addition, more rational approaches have focused on the incorporation of phosphotyrosine mimetics into specific peptide templates (peptidomimetic backbones). Additional factors furthering discovery as well as therapeutic application of new bioactive molecules are the integration of functional genomics, cell biology, structural biology, drug design, molecular screening and chemical diversity. Together, all these factors will lead to new avenues to treat clinical disease based on PTP inhibition.

Seek and destroy: the use of natural compounds for targeting the molecular roots of cancer.

One of the major issues facing anticancer research relies on the intrinsic inability of tumor cells to undergo apoptosis. Additionally, the development of cancer resistance to standard therapy and the great heterogeneity associated with frequent mutations and epigenetic changes make an ever increasing challenge to achieve treatment success. Thus, novel therapeutic approaches to induce cancer demise must be explored. Compelling evidence has shown the ability of naturally-occurring compounds to modulate signal transduction pathways, apoptosis and cell cycle progression, supporting their relevance to anticancer drug discovery. Moreover, millions of years of biological selection have led to an unlimited repertoire of chemical structures unmatched by any synthetic combinatorial library and recent advances in the fields of chemistry and biology are uncovering this still underexplored source of new promising natural agents, opening novel perspectives for the development of alternative strategies to fight cancer. This review presents the current status of natural products in modern oncology, illustrating the importance of some old and new agents, such as antimitotics and apoptosis inducers, as candidates of pharmacological interest in drug development and/or as chemical tools for the elucidation, as well as targeting, of deregulated cancer signaling pathways. Finally, some aspects of chemical modifications done in natural products core aiming to improve their activity and/or effectiveness will be discussed.

Predictive values at risk of falling in physically active and no active elderly with Berg Balance Scale.

BACKGROUND: The consequences of falls are a major cause of autonomy and independence loss among the elderly. In this context, the Berg Balance Scale (BBS) has been widely used to detect the risk of falls in elderly. OBJECTIVE: To evaluate the predictive value of the BBS for fall risk in physically active and inactive elderly subjects. METHODS: The sample included 188 older adults with a mean age of 66 (±9) years. Of these, 91 participated in a regular physical activity program and 96 did not. We analyzed the cut-off scores of 45, 47, 49, 51 and 53 in both groups regarding the sensitivity (S), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of the test, including the positive likelihood ratio (PLR) and negative likelihood ratio (RVN) for diagnosing the risk of falls. RESULTS: The mean BBS score was 54.7 in physically active subjects and 50.8 in inactive subjects, which was statistically significant (ρ=0.001). The best cut-off was a score of 49 for physically inactive subjects, with a sensitivity of 91% and a specificity of 92%. On the other hand, the BBS had low sensitivity (from 0 to 15%) and high specificity (between 83% and 100%) for physically active subjects at the cut-off points analyzed. CONCLUSION: The scale did not achieve sufficient sensitivity to individual differences among physically active older people with higher levels of functional balance ability.

Growth inhibitory activity of a novel lectin from Cliona varians against K562 human erythroleukemia cells.

PURPOSE: In this study, the antitumoral potential of a novel lectin (CvL) purified from the marine sponge Cliona varians was studied in different cancer cell lines. METHODS: CvL cytotoxicity was evaluated in mammalian tumor cells and in normal human peripheral blood lymphocytes by the MTT assay using the same range of concentrations (1-150 microg ml(-1)). The mechanisms involved in K562 cell death were investigated by confocal fluorescence microscopy, flow cytometry and immunoblot. RESULTS: CvL inhibited the growth of human leukemia cells, with IC(50) values of 70 and 100 microg ml(-1) for K562 and JURKAT cells, respectively, but it was ineffective on blood lymphocytes and solid tumor cell lines. K562 cell death occurred 72 h after exposure to the lectin and with signs of apoptosis, as analyzed by DAPI and annexin V/PI staining. Investigation of the possible mediators of this process showed that cell death occurred via a caspase-independent pathway. Confocal fluorescence microscopy indicated a pivotal role for the lysosomal protease cathepsin B in mediating cell death. Accordingly, pre-incubation of K562 cells with the cathepsin inhibitor L-trans-epoxysuccinyl-L-leucylamido-(4-guanidino)butane (E-64) abolished CvL cytotoxic effect. Furthermore, we found upregulation of tumor necrosis factor receptor 1 (TNFR1) and down-modulation of p65 subunit of nuclear factor kappa B (NFkappaB) expression in CvL-treated cells. These effects were accompanied by increased levels of p21 and reduced expression of pRb, suggesting that CvL can induce cell cycle arrest. CONCLUSIONS: Collectively, these findings indicate an antileukemic effect for CvL and suggest that cathepsin B acts as a death mediator in CvL-induced cytotoxicity possibly in an uncharacterized connection with the membrane death receptor pathway.

Predictive values at risk of falling in physically active and no active elderly with Berg Balance Scale / Valores preditivos para o risco de queda em idosos praticantes e não praticantes de atividade física por meio do uso da Escala de Equilíbrio de Berg

BACKGROUND: The consequences of falls are a major cause of autonomy and independence loss among the elderly. In this context, the Berg Balance Scale (BBS) has been widely used to detect the risk of falls in elderly. OBJECTIVE: To evaluate the predictive value of the BBS for fall risk in physically active and inactive elderly subjects. METHODS: The sample included 188 older adults with a mean age of 66 (±9) years. Of these, 91 participated in a regular physical activity program and 96 did not. We analyzed the cut-off scores of 45, 47, 49, 51 and 53 in both groups regarding the sensitivity (S), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of the test, including the positive likelihood ratio (PLR) and negative likelihood ratio (RVN) for diagnosing the risk of falls. RESULTS: The mean BBS score was 54.7 in physically active subjects and 50.8 in inactive subjects, which was statistically significant (ρ=0.001). The best cut-off was a score of 49 for physically inactive subjects, with a sensitivity of 91 percent and a specificity of 92 percent. On the other hand, the BBS had low sensitivity (from 0 to 15 percent) and high specificity (between 83 percent and 100 percent) for physically active subjects at the cut-off points analyzed. CONCLUSION: The scale did not achieve sufficient sensitivity to individual differences among physically active older people with higher levels of functional balance ability.

CONTEXTUALIZAÇÃO: Umas das principais causas da perda da autonomia e independência do idoso são as consequências geradas pelas quedas. Nesse contexto, a Escala de Equilíbrio de Berg (EEB) vem sendo amplamente utilizada para detectar o risco de queda em idosos. Objetivo: Analisar os valores preditivos para o risco de queda em idosos praticantes e não-praticantes de atividade física por meio do uso da EEB. MÉTODOS: Participaram 188 idosos, com média de idade de 66 (±9) anos. Desses, 91 participavam de projetos de atividades físicas, e 96 não praticavam atividade física regularmente. Foram analisados os pontos de corte 45, 47, 49, 51 e 53 em ambos os grupos, quanto à sensibilidade (S), especificidade (E), valor preditivo positivo (VPP) e negativo (VPN) do teste, razão de verossimilhança positiva (RVP) e negativa (RVN) para diagnóstico do risco de queda. RESULTADOS: Evidenciou-se que a média do escore da EEB nos praticantes de atividade física foi de 54,7 pontos; enquanto que, entre os não-praticantes, foi de 50,8, obtendo-se diferença significativa entre os grupos (ρ=0,001). Nos sujeitos não-praticantes de atividade física, o melhor ponto de corte foi em 49 pontos, apresentando S de 91 por cento e E de 92 por cento, enquanto a EEB apresentou baixa S, variando entre 0 por cento e 15 por cento, e alta E, variando entre 83 por cento e 100 por cento nos sujeitos praticantes de atividade física regular nos pontos de corte analisados. CONCLUSÃO: A escala não alcançou S suficiente para diferenças individuais entre idosos com altos níveis de capacidade de equilíbrio dentre aqueles que praticam atividades físicas regularmente.