Xanthones for melanogenesis inhibition: Molecular docking and QSAR studies to understand their anti-tyrosinase activity.

The human skin is constantly exposed to external factors that affect its integrity, UV radiation being one of the main stress factors. The repeated exposure to this radiation leads to increased production of Reactive Oxygen Species (ROS) which activate a series of processes involved in photoaging. Excessive UV exposure also exacerbates melanin production leading to a variety of pigmentation disorders. Xanthones are reported to exhibit properties that prevent deleterious effects of UV exposure and high levels of ROS in the organism, so in this work a wide library of xanthones with different patterns of substitution was synthesized and tested for their inhibitory activity against the skin enzymes tyrosinase, elastase, collagenase and hyaluronidase, many of which were evaluated for the first time. Most of the compounds were tyrosinase inhibitors, with the best one (xanthone 27) presenting an IC50 of 1.9 µM, which is approximately 6 times lower than the IC50 of the positive control kojic acid. Concerning the other enzymes, only one compound presented IC50 lower than 150 µM in elastase inhibition (xanthone 14 = 91.8 µM) and none in collagenase and hyaluronidase inhibition. A QSAR model for tyrosinase inhibitory activity was built using six molecular descriptors, with a partial negative surface area descriptor and the relative number of oxygen atoms being positively contributing to the tyrosinase inhibitory activity. Docking using AutoDock Vina shows that all the tested compounds have more affinity to mushroom tyrosinase than kojic acid. Docking results implied that the tyrosinase inhibitory mechanisms of xanthonic derivatives are attributed to an allosteric interaction. Taken together, these data suggest that xanthones might be useful scaffolds for the development of new and promising candidates for the treatment of pigmentation-related disorders and for skin whitening cosmetic products.

Data Imputation and Body Weight Variability Calculation Using Linear and Nonlinear Methods in Data Collected From Digital Smart Scales: Simulation and Validation Study.

BACKGROUND: Body weight variability (BWV) is common in the general population and may act as a risk factor for obesity or diseases. The correct identification of these patterns may have prognostic or predictive value in clinical and research settings. With advancements in technology allowing for the frequent collection of body weight data from electronic smart scales, new opportunities to analyze and identify patterns in body weight data are available. OBJECTIVE: This study aims to compare multiple methods of data imputation and BWV calculation using linear and nonlinear approaches. METHODS: In total, 50 participants from an ongoing weight loss maintenance study (the NoHoW study) were selected to develop the procedure. We addressed the following aspects of data analysis: cleaning, imputation, detrending, and calculation of total and local BWV. To test imputation, missing data were simulated at random and using real patterns of missingness. A total of 10 imputation strategies were tested. Next, BWV was calculated using linear and nonlinear approaches, and the effects of missing data and data imputation on these estimates were investigated. RESULTS: Body weight imputation using structural modeling with Kalman smoothing or an exponentially weighted moving average provided the best agreement with observed values (root mean square error range 0.62%-0.64%). Imputation performance decreased with missingness and was similar between random and nonrandom simulations. Errors in BWV estimations from missing simulated data sets were low (2%-7% with 80% missing data or a mean of 67, SD 40.1 available body weights) compared with that of imputation strategies where errors were significantly greater, varying by imputation method. CONCLUSIONS: The decision to impute body weight data depends on the purpose of the analysis. Directions for the best performing imputation methods are provided. For the purpose of estimating BWV, data imputation should not be conducted. Linear and nonlinear methods of estimating BWV provide reasonably accurate estimates under high proportions (80%) of missing data.

Correction: A novel scaling methodology to reduce the biases associated with missing data from commercial activity monitors.

[This corrects the article DOI: 10.1371/journal.pone.0235144.].

A novel scaling methodology to reduce the biases associated with missing data from commercial activity monitors.

BACKGROUND: Commercial physical activity monitors have wide utility in the assessment of physical activity in research and clinical settings, however, the removal of devices results in missing data and has the potential to bias study conclusions. This study aimed to evaluate methods to address missingness in data collected from commercial activity monitors. METHODS: This study utilised 1526 days of near complete data from 109 adults participating in a European weight loss maintenance study (NoHoW). We conducted simulation experiments to test a novel scaling methodology (NoHoW method) and alternative imputation strategies (overall/individual mean imputation, overall/individual multiple imputation, Kalman imputation and random forest imputation). Methods were compared for hourly, daily and 14-day physical activity estimates for steps, total daily energy expenditure (TDEE) and time in physical activity categories. In a second simulation study, individual multiple imputation, Kalman imputation and the NoHoW method were tested at different positions and quantities of missingness. Equivalence testing and root mean squared error (RMSE) were used to evaluate the ability of each of the strategies relative to the true data. RESULTS: The NoHoW method, Kalman imputation and multiple imputation methods remained statistically equivalent (p<0.05) for all physical activity metrics at the 14-day level. In the second simulation study, RMSE tended to increase with increased missingness. Multiple imputation showed the smallest RMSE for Steps and TDEE at lower levels of missingness (<19%) and the Kalman and NoHoW methods were generally superior for imputing time in physical activity categories. CONCLUSION: Individual centred imputation approaches (NoHoW method, Kalman imputation and individual Multiple imputation) offer an effective means to reduce the biases associated with missing data from activity monitors and maximise data retention.

Motivation: key to a healthy lifestyle in people with diabetes? Current and emerging knowledge and applications.

AIM: Motivation to take up and maintain a healthy lifestyle is key to diabetes prevention and management. Motivations are driven by factors on the psychological, biological and environmental levels, which have each been studied extensively in various lines of research over the past 25 years. Here, we analyse and reflect on current and emerging knowledge on motivation in relation to lifestyle behaviours, with a focus on people with diabetes or obesity. Structured according to psychological, (neuro-)biological and broader environmental levels, we provide a scoping review of the literature and highlight frameworks used to structure motivational concepts. Results are then put in perspective of applicability in (clinical) practice. RESULTS: Over the past 25 years, research focusing on motivation has grown exponentially. Social-cognitive and self-determination theories have driven research on the key motivational concepts 'self-efficacy' and 'self-determination'. Neuro-cognitive research has provided insights in the processes that are involved across various layers of a complex cortical network of motivation, reward and cognitive control. On an environmental - more upstream - level, motivations are influenced by characteristics in the built, social, economic and policy environments at various scales, which have provided entry points for environmental approaches influencing behaviour. CONCLUSIONS: Current evidence shows that motivation is strongly related to a person's self-efficacy and capability to initiate and maintain healthy choices, and to a health climate that supports autonomous choices. Some approaches targeting motivations have been shown to be promising, but more research is warranted to sustainably reduce the burden of diabetes in individuals and populations.

Potential of synthetic chalcone derivatives to prevent marine biofouling.

Biofouling represents a major economic, environmental and health concern for which new eco-friendly solutions are needed. International legislation has restricted the use of biocidal-based antifouling coatings, and increasing efforts have been applied in the search for environmentally friendly antifouling agents. This research work deals with the assessment of the interest of a series of synthetic chalcone derivatives for antifouling applications. Sixteen chalcone derivatives were synthesized with moderate yields (38-85%). Antifouling bioactivity of these compounds was assessed at different levels of biological organization using both anti-macrofouling and anti-microfouling bioassays, namely an anti-settlement assay using mussel (Mytilus galloprovincialis) larvae, as well as marine bacteria and microalgal biofilms growth inhibition bioassays. Results showed that three compounds (11, 12, and 16) were particularly active against the settlement of mussel larvae (EC50 7.24-34.63 µM), being compounds 12 and 16 also able to inhibit the growth of microfouling species (EC50 4.09-20.31 µM). Moreover, the most potent compounds 12 and 16 were found to be non-toxic to the non-target species Artemia salina (<10% mortality at 25 µM). A quantitative structure-activity relationship model predicted that descriptors describing the ability of molecules to form hydrogen bonds and encoding the shape, branching ratio and constitutional diversity of the molecule were implied in the antifouling activity against the settlement of mussel larvae. This work elucidates for the first time the relevance of synthesizing chalcone derivatives to generate new non-toxic products to prevent marine biofouling.

Cross-sectional and prospective associations between moderate to vigorous physical activity and sedentary time with adiposity in children.

BACKGROUND: Physical activity (PA) and sedentary time (SED) have both been suggested as potential risk factors for adiposity in children. However, there is paucity of data examining the temporal associations between these variables. OBJECTIVE: This study aimed to analyze the cross-sectional and prospective associations between PA, SED and body composition in children. METHODS: A total of 510 children (age at baseline 10.1±0.8, age at follow-up 11.8±0.9) from six Portuguese schools from the Oeiras Municipality participated in this study. PA and SED were measured by accelerometry and trunk fat mass (TFM) and body fat mass (BFM) were measured by dual energy X-ray absorptiometry. Fat mass index (FMI) was calculated as BFM divided by height squared. Several regression models adjusted for age, sex, maturity status, follow-up duration, baseline levels of the outcome variable and SED or moderate to vigorous PA (MVPA) were performed. RESULTS: MVPA (min per day) was cross-sectionally inversely associated with adiposity indexes (FMI, TFM and BFM). Adiposity indexes were inversely associated with time in MVPA. In prospective analyses, MVPA was associated with a lower levels of FMI (ß=-0.37, 95% confidence interval (CI): -0.49 to -0.26, P<0.001), TFM (ß=-0.20, 95% CI: -0.29 to -0.10, P<0.001) and BFM (ß=-0.37, 95% CI: -0.49 to -0.26, P<0.001). When the model was adjusted for age, sex, maturity status and for baseline levels of the outcome variables MVPA remained a significant predictor of lower adiposity indexes (FMI: ß=-0.09, 95% CI: -0.16 to -0.01, P<0.05; TFM: ß=-0.08, 95% CI: -0.15 to -0.01, P<0.05; BFM: ß=-0.07, 95% CI: -0.15 to 0.00, P<0.05). Adiposity was not associated with MVPA when modeled as the exposure in prospective analyses. SED was not related with adiposity indexes, except for the relationship with FMI. CONCLUSIONS: In cross-sectional and prospective analyses, MVPA is associated with lower adiposity independent of covariates and SED. Results suggest that promoting MVPA is important for preventing gain in adiposity in healthy children.

Effect of a school-based intervention on physical activity and quality of life through serial mediation of social support and exercise motivation: the PESSOA program.

The aim of this study was to explore the effects of social support and behavioral regulation of exercise on physical activity (PA) and quality of life (QoL), in a Portuguese school-based intervention. We hypothesized that serial mediation effects would be present leading to greater levels of PA and QoL. The sample comprised 1042 students (549 boys), aged 10-16 years, BMI = 19.31 ± 3.51, allocated to two groups of schools: control (n = 207) and intervention (n = 835). This study will report the 24 months results of the program, which aimed to develop healthy lifestyles. Questionnaires were used to measure PA, QoL, motivation to exercise and social support. There was no direct impact of the intervention on QoL or PA. Serial mediation analyses were conducted. Social support (P < 0.019) and intrinsic motivation (P = 0.085) increased more on intervention group. Indirect effects were observed in all serial mediation models. The positive indirect effects on PA and QoL were explained by the increase on peer/parent support in serial with the increase in intrinsic motivation (P < 0.01). Parental support led to an increase on external motivation (P < 0.05), which buffered the effects of the intervention. This school-based intervention promoted the development of social support and motivational mechanisms that explained higher levels of PA and QoL.

Utilização de plantas medicinais com atividade antimicrobiana por usuários do serviço público de saúde em Campina Grande - Paraíba / Use of medicinal plants with antimicrobial activity by users of the Public Health System in Campina Grande - Paraíba, Brazil

O estudo avalia a utilização de plantas medicinais com atividade antimicrobiana pelos usuários do Sistema Único de Saúde do município de Campina Grande- PB, Brasil. Trata-se de um estudo descritivo, transversal, com abordagem quantitativa, cuja amostra constituiu-se de 220 usuários conduzido no período de Agosto de 2008 a Janeiro de 2009. A pesquisa foi realizada através de um roteiro de entrevistas não estruturada. Dentre os participantes do estudo, 65,0% utilizavam plantas medicinais, das quais Punica granatum L., Anacardium occidentale L., e Stryphnodendron adstringens foram as mais citadas. Observou-se que houve prevalência do gênero feminino na utilização. A maioria dos indivíduos obtém plantas medicinais no comércio local utilizando-as por indicação de familiares. Foi observado que 5,0% dos entrevistados afirmam já ter sofrido algum evento adverso decorrente do uso de plantas medicinais. Assim sugere-se que as informações sobre o uso da flora medicinal adquiridas nas comunidades locais, combinadas a estudos químicos/farmacológicos realizados em laboratórios especializados e a capacitação da equipe de saúde favorecerá a implementação da Portaria nº 971/2006, que tem como objetivo a garantia de acesso a plantas medicinais e fitoterápicos com segurança, eficácia e qualidade.

This study evaluates the use of medicinal plants with antimicrobial activity by users of the Unified Health System in Campina Grande Municipality, Paraíba, Brazil. This is a descriptive and transversal study with a quantitative approach, the sample of which consisted of 220 users, and was carried out from August 2008 to April 2009. The research was developed through an unstructured interview process. Among the study participants, 65.0% used medicinal plants, of which Punica granatum L., Anacardium occidentale L. and Stryphnodendron adstringens were most cited. There was prevalence of females. Most individuals obtain medicinal plants in the local market, using them as suggested by relatives. Results indicated that 5.0% of the interviewees stated to have suffered adverse event resulting from the use of medicinal plants. Thus, information about the use of medicinal plants, acquired in local communities, combined to chemical/pharmacological studies performed in specialized laboratories and the qualification of health professionals, will favor the implementation of Decree no. 971/2006, which aims to ensure access to medicinal plants and herbal medicines with safety, efficacy and quality.

Three decades of P-gp inhibitors: skimming through several generations and scaffolds.

Many tumor cells become resistant to commonly used cytotoxic drugs due to the overexpression of ATP-binding cassette (ABC) transporters, namely P-glycoprotein (P-gp). The discovery of the reversal of multidrug resistance (MDR) by verapamil occured in 1981, and in 1968 MDR Chinese hamster cell lines were isolated for the first time. Since then, P-gp inhibitors have been intensively studied as potential MDR reversers. Initially, drugs to reverse MDR were not specifically developed for inhibiting P-gp; in fact, they had other pharmacological properties, as well as a relatively low affinity for MDR transporters. An example of this first generation P-gp inhibitors is verapamil. The second generation included more specific with less side-effect inhibitors, such as dexverapamil or dexniguldipine. A third generation of P-gp inhibitors comprised compounds such as tariquidar, with high affinity to P-gp at nanomolar concentrations. These generations of inhibitors of P-gp have been examined in preclinical and clinical studies; however, these trials have largely failed to demonstrate an improvement in therapeutic efficacy. Therefore, new and innovative strategies, such as the fallback to natural products, the design of peptidomimetics and dual activity ligands emerged as a fourth generation of P-gp inhibitors. The chemistry of P-gp inhibitors, as well as their in vitro, in vivo and clinical trials are discussed, and the most recent advances concerning Pgp modulators are reviewed.

Chemical composition and antifungal activity of the essential oil of Thymbra capitata.

The composition and the antifungal activity of the essential oil of Thymbra capitata on Candida, Aspergillus and dermatophyte strains were studied. Twenty-two samples of the essential oils from the aerial parts of the plant were obtained by hydrodistillation and analysed by GC and GC-MS. All samples are of the carvacrol type, with a high content of carvacrol (60.0 - 65.8 %) and its biogenetic precursors, gamma-terpinene (8.2 - 9.5 %) and p-cymene (6.0 - 7.5 %). The minimal inhibitory concentration (MIC) and the minimal lethal concentration (MLC) were used to evaluate the antifungal activity against Candida (7 clinical isolates and 3 ATCC type strains), Aspergillus (5 clinical isolates, 2 CECT and 2 ATCC type strains) and 5 dermatophyte clinical strains. To clarify its mechanism of action on Candida strains, the inhibition of germ tube and a flow cytometry assay with propidium iodide (PI) were used. The oil exhibited antifungal activity for all the tested strains, particularly for dermatophytes, with MIC values ranging from 0.08 to 0.32 microL/mL. Regarding Candida, concentrations lower than the MIC values prevented germ tube formation. After a short incubation time the cells incorporated quickly PI, meaning that the fungicidal effect is mainly due to direct lesion of the membrane.

Chemical composition and antifungal activity of the essential oil of Origanum virens on Candida species.

The composition and the antifungal activity of the essential oil of Origanum virens on Candida species were studied. The essential oil was obtained from the aerial parts of the plant by hydrodistillation and analyzed by GC and GC-MS. The oil was characterized by its high content of carvacrol (68.1 %) and its biogenetic precursors, gamma-terpinene (9.9 %) and p-cymene (4.5 %). The minimal inhibitory concentration (MIC) and the minimal lethal concentration (MLC) were used to evaluate the antifungal activity against Candida strains (7 clinical isolates and 3 ATCC type strains). The inhibition of germ tube formation and flow cytometry, using the fluorescent probe propidium iodide (PI), were used to evaluate their mechanisms of action. MIC and MLC values were similar for most tested strains, ranging from 0.16 to 0.32 microL/mL. Concentrations lower than MIC values strongly prevent germ tube formation. The fungicidal effect is primarily due to an extensive lesion of the membrane.

Study of the cellular turnover in the small intestine of the lactent Didelphis albiventris.

A 1% trypan blue aqueous solution, buffered to pH 7.3, orally administrated was used as a tracer in an attempt to establish the cellular turnover in the small intestine epithelium of the lactent marsupial Didelphis albiventris. The complex trypan blue-milk albumin was captured by the cells lining the proximal, medium and distal segment of small intestine, differing from the rodents which are unable to absorb the dye by endocytosis at the level of the proximal small intestine. A complete cellular turnover was observed in the proximal small intestine 7 d after treatment, whilst in the medium and distal segments 8 d were required for the turnover to be completed.