Risk prediction of pulse wave for hypertensive target organ damage based on frequency-domain feature map.

The application of deep learning to the classification of pulse waves in Traditional Chinese Medicine (TCM) related to hypertensive target organ damage (TOD) is hindered by challenges such as low classification accuracy and inadequate generalization performance. To address these challenges, we introduce a lightweight transfer learning model named MobileNetV2SCP. This model transforms time-domain pulse waves into 36-dimensional frequency-domain waveform feature maps and establishes a dedicated pre-training network based on these maps to enhance the learning capability for small samples. To improve global feature correlation, we incorporate a novel fusion attention mechanism (SAS) into the inverted residual structure, along with the utilization of 3 × 3 convolutional layers and BatchNorm layers to mitigate model overfitting. The proposed model is evaluated using cross-validation results from 805 cases of pulse waves associated with hypertensive TOD. The assessment metrics, including Accuracy (92.74 %), F1-score (91.47 %), and Area Under Curve (AUC) (97.12 %), demonstrate superior classification accuracy and generalization performance compared to various state-of-the-art models. Furthermore, this study investigates the correlations between time-domain and frequency-domain features in pulse waves and their classification in hypertensive TOD. It analyzes key factors influencing pulse wave classification, providing valuable insights for the clinical diagnosis of TOD.

Melatonin supplementation in obese mothers reduces hypothalamic inflammation and enhances thermogenesis in mice progeny.

Maternal obesity might induce obesity and metabolic alterations in the progeny. The study aimed to determine the effect of supplementing obese mothers with Mel (Mel) on thermogenesis and inflammation. C57BL/6 female mice (mothers) were fed from weaning to 12 weeks control diet (C, 17% kJ as fat) or a high-fat diet (HF, 49% kJ as fat) and then matted with male mice fed the control diet. Melatonin (10 mg/kg daily) was supplemented to mothers during gestation and lactation, forming the groups C, CMel, HF, and HFMel (n = 10/group). Twelve-week male offspring were studied (plasma biochemistry, immunohistochemistry, protein, and gene expressions at the hypothalamus - Hyp, subcutaneous white adipose tissue - sWAT, and interscapular brown adipose tissue - iBAT). Comparing HFMel vs. HF offspring, fat deposits and plasmatic proinflammatory markers decreased. Also, HFMel showed decreased Hyp proinflammatory markers and neuropeptide Y (anabolic) expression but improved proopiomelanocortin (catabolic) expression. Besides, HFMel sWAT adipocytes changed to a beige phenotype with-beta-3 adrenergic receptor and uncoupling protein-1 activation, concomitant with browning genes activation, triggering the iBAT thermogenic activity. In conclusion, compelling evidence indicated the beneficial effects of supplementing obese mothers with Mel on the health of their mature male offspring. Mel led to sWAT browning-related gene enhancement, increased iBAT thermogenis, and mitigated hypothalamic inflammation. Also, principal component analysis of the data significantly separated the untreated obese mother progeny from the progeny of treated obese mothers. If confirmed in humans, the findings encourage a future guideline recommending Mel supplementation during pregnancy and breastfeeding.

Development of gummy bear supplements and in vitro exploration of antioxidant and antiproliferative potential of Nuciferine.

BACKGROUND: Nuciferine's extensive therapeutic potential, including its robust antioxidant properties, is explored in response to the growing consumer preference for value-added organic foods. OBJECTIVE: This study focuses on the formulation of gummy bear supplements fortified with nuciferine from Nelumbonucifera. The research highlights nuciferine's ability to combat oxidative stress induced by reactive oxygen species (ROS) and examines its application in maintaining basal ROS levels during oxidative stress conditions in skin melanoma cells. METHODS: Characterization of extracted nuciferine through FTIR and UV-vis spectroscopy ensures product quality, while sensory evaluation compares honey and sugar as natural sweeteners for optimal flavor and consumer preference. SK-Mel-28 cellular ROS levels were measured using 2',7' -dichlorofluorescin diacetate dye before and after nuciferine treatment. SK-Mel-28 cell viability and dose response of nuciferine treatment was assessed using MTT assay. RESULTS: Nuciferine shows potent inhibition of SK-Mel-28 cell proliferation with an IC50 of 39.31 ± 5.280 µg/ml and showed no cytotoxicity in normal L6 skeletal muscle cells. This study compares the sensory properties of honey and sugar based gummy bear formulations. CONCLUSION: This project aims to create a high-quality, health-promoting dietary supplement that aligns with the evolving trends in organic nutrition and antioxidant supplementation.

Variations in nutritional profile of honey produced by various species of genus Apis / Variações no perfil nutricional do mel produzido por várias espécies do gênero Apis

The medicinal attributes of honey appears to overshadow its importance as a functional food. Consequently, several literatures are rife with ancient uses of honey as complementary and alternative medicine, with relevance to modern day health care, supported by evidence-based clinical data, with little attention given to honey’s nutritional functions. The moisture contents of honey extracted from University of Veterinary and Animal Sciences, Lahore honey bee farm was 12.19% while that of natural source was 9.03 ± 1.63%. Similarly, ash and protein contents of farmed honey recorded were 0.37% and 5.22%, respectively. Whereas ash and protein contents of natural honey were 1.70 ± 1.98% and 6.10 ± 0.79%. Likewise fat, dietary fiber and carbohydrates contents of farmed source documented were 0.14%, 1.99% and 62.26% respectively. Although fat, dietary fiber and carbohydrates contents of honey taken from natural resource were 0.54 ± 0.28%, 2.76 ± 1.07% and 55.32 ± 2.91% respectively. Glucose and fructose contents of honey taken out from honeybee farm were 27% and 34% but natural source were 22.50 ± 2.12% and 28.50 ± 3.54%. Glucose and fructose contents of honey taken out from honeybee farm were 27% and 34% but natural source were 22.50 ± 2.12% and 28.50 ± 3.54%. Similarly, sucrose and maltose contents of farmed honey were 2.5% and 12% while in natural honey were 1.35 ± 0.49% and 8.00 ± 1.41% respectively. The present study indicates that such as moisture, carbohydrates, sucrose and maltose contents were higher farmed honey as compared to the natural honey. In our recommendation natural honey is better than farmed honey.

Os atributos medicinais do mel parecem ofuscar sua importância como alimento funcional. Consequentemente, várias literaturas estão repletas de usos antigos do mel como medicina complementar e alternativa, com relevância para os cuidados de saúde modernos, apoiados por dados clínicos baseados em evidências, com pouca atenção dada às funções nutricionais do mel. O teor de umidade do mel extraído da Universidade de Veterinária e Ciências Animais, fazenda de abelhas de Lahore, foi de 12,19%, enquanto o de fonte natural foi de 9,03 ± 1,63%. Da mesma forma, os teores de cinzas e proteínas do mel cultivado foram de 0,37% e 5,22%, respectivamente. Já os teores de cinzas e proteínas do mel natural foram de 1,70 ± 1,98% e 6,10 ± 0,79%. Da mesma forma, os teores de gordura, fibra dietética e carboidratos de origem cultivada documentados foram de 0,14%, 1,99% e 62,26%, respectivamente. Embora os teores de gordura, fibra alimentar e carboidratos do mel retirado dos recursos naturais fossem de 0,54 ± 0,28%, 2,76 ± 1,07% e 55,32 ± 2,91%, respectivamente. Os conteúdos de glicose e frutose do mel retirado da fazenda de abelhas foram de 27% e 34%, mas a fonte natural foi de 22,50 ± 2,12% e 28,50 ± 3,54%. Os conteúdos de glicose e frutose do mel retirado da fazenda de abelhas foram de 27% e 34%, mas a fonte natural foi de 22,50 ± 2,12% e 28,50 ± 3,54%. Da mesma forma, os teores de sacarose e maltose no mel cultivado foram de 2,5% e 12%, enquanto no mel natural foram de 1,35 ± 0,49% e 8,00 ± 1,41%, respectivamente. O presente estudo indica que os teores de umidade, carboidratos, sacarose e maltose foram maiores no mel cultivado em comparação ao mel natural. Em nossa recomendação, o mel natural é melhor que o mel de cultivo.

Variations in nutritional profile of honey produced by various species of genus Apis

Abstract The medicinal attributes of honey appears to overshadow its importance as a functional food. Consequently, several literatures are rife with ancient uses of honey as complementary and alternative medicine, with relevance to modern day health care, supported by evidence-based clinical data, with little attention given to honeys nutritional functions. The moisture contents of honey extracted from University of Veterinary and Animal Sciences, Lahore honey bee farm was 12.19% while that of natural source was 9.03 ± 1.63%. Similarly, ash and protein contents of farmed honey recorded were 0.37% and 5.22%, respectively. Whereas ash and protein contents of natural honey were 1.70 ± 1.98% and 6.10 ± 0.79%. Likewise fat, dietary fiber and carbohydrates contents of farmed source documented were 0.14%, 1.99% and 62.26% respectively. Although fat, dietary fiber and carbohydrates contents of honey taken from natural resource were 0.54 ± 0.28%, 2.76 ± 1.07% and 55.32 ± 2.91% respectively. Glucose and fructose contents of honey taken out from honeybee farm were 27% and 34% but natural source were 22.50 ± 2.12% and 28.50 ± 3.54%. Glucose and fructose contents of honey taken out from honeybee farm were 27% and 34% but natural source were 22.50 ± 2.12% and 28.50 ± 3.54%. Similarly, sucrose and maltose contents of farmed honey were 2.5% and 12% while in natural honey were 1.35 ± 0.49% and 8.00 ± 1.41% respectively. The present study indicates that such as moisture, carbohydrates, sucrose and maltose contents were higher farmed honey as compared to the natural honey. In our recommendation natural honey is better than farmed honey.

Resumo Os atributos medicinais do mel parecem ofuscar sua importância como alimento funcional. Consequentemente, várias literaturas estão repletas de usos antigos do mel como medicina complementar e alternativa, com relevância para os cuidados de saúde modernos, apoiados por dados clínicos baseados em evidências, com pouca atenção dada às funções nutricionais do mel. O teor de umidade do mel extraído da Universidade de Veterinária e Ciências Animais, fazenda de abelhas de Lahore, foi de 12,19%, enquanto o de fonte natural foi de 9,03 ± 1,63%. Da mesma forma, os teores de cinzas e proteínas do mel cultivado foram de 0,37% e 5,22%, respectivamente. Já os teores de cinzas e proteínas do mel natural foram de 1,70 ± 1,98% e 6,10 ± 0,79%. Da mesma forma, os teores de gordura, fibra dietética e carboidratos de origem cultivada documentados foram de 0,14%, 1,99% e 62,26%, respectivamente. Embora os teores de gordura, fibra alimentar e carboidratos do mel retirado dos recursos naturais fossem de 0,54 ± 0,28%, 2,76 ± 1,07% e 55,32 ± 2,91%, respectivamente. Os conteúdos de glicose e frutose do mel retirado da fazenda de abelhas foram de 27% e 34%, mas a fonte natural foi de 22,50 ± 2,12% e 28,50 ± 3,54%. Os conteúdos de glicose e frutose do mel retirado da fazenda de abelhas foram de 27% e 34%, mas a fonte natural foi de 22,50 ± 2,12% e 28,50 ± 3,54%. Da mesma forma, os teores de sacarose e maltose no mel cultivado foram de 2,5% e 12%, enquanto no mel natural foram de 1,35 ± 0,49% e 8,00 ± 1,41%, respectivamente. O presente estudo indica que os teores de umidade, carboidratos, sacarose e maltose foram maiores no mel cultivado em comparação ao mel natural. Em nossa recomendação, o mel natural é melhor que o mel de cultivo.

Variations in nutritional profile of honey produced by various species of genus Apis / Variações no perfil nutricional do mel produzido por várias espécies do gênero Apis

Abstract The medicinal attributes of honey appears to overshadow its importance as a functional food. Consequently, several literatures are rife with ancient uses of honey as complementary and alternative medicine, with relevance to modern day health care, supported by evidence-based clinical data, with little attention given to honey's nutritional functions. The moisture contents of honey extracted from University of Veterinary and Animal Sciences, Lahore honey bee farm was 12.19% while that of natural source was 9.03 ± 1.63%. Similarly, ash and protein contents of farmed honey recorded were 0.37% and 5.22%, respectively. Whereas ash and protein contents of natural honey were 1.70 ± 1.98% and 6.10 ± 0.79%. Likewise fat, dietary fiber and carbohydrates contents of farmed source documented were 0.14%, 1.99% and 62.26% respectively. Although fat, dietary fiber and carbohydrates contents of honey taken from natural resource were 0.54 ± 0.28%, 2.76 ± 1.07% and 55.32 ± 2.91% respectively. Glucose and fructose contents of honey taken out from honeybee farm were 27% and 34% but natural source were 22.50 ± 2.12% and 28.50 ± 3.54%. Glucose and fructose contents of honey taken out from honeybee farm were 27% and 34% but natural source were 22.50 ± 2.12% and 28.50 ± 3.54%. Similarly, sucrose and maltose contents of farmed honey were 2.5% and 12% while in natural honey were 1.35 ± 0.49% and 8.00 ± 1.41% respectively. The present study indicates that such as moisture, carbohydrates, sucrose and maltose contents were higher farmed honey as compared to the natural honey. In our recommendation natural honey is better than farmed honey.

Resumo Os atributos medicinais do mel parecem ofuscar sua importância como alimento funcional. Consequentemente, várias literaturas estão repletas de usos antigos do mel como medicina complementar e alternativa, com relevância para os cuidados de saúde modernos, apoiados por dados clínicos baseados em evidências, com pouca atenção dada às funções nutricionais do mel. O teor de umidade do mel extraído da Universidade de Veterinária e Ciências Animais, fazenda de abelhas de Lahore, foi de 12,19%, enquanto o de fonte natural foi de 9,03 ± 1,63%. Da mesma forma, os teores de cinzas e proteínas do mel cultivado foram de 0,37% e 5,22%, respectivamente. Já os teores de cinzas e proteínas do mel natural foram de 1,70 ± 1,98% e 6,10 ± 0,79%. Da mesma forma, os teores de gordura, fibra dietética e carboidratos de origem cultivada documentados foram de 0,14%, 1,99% e 62,26%, respectivamente. Embora os teores de gordura, fibra alimentar e carboidratos do mel retirado dos recursos naturais fossem de 0,54 ± 0,28%, 2,76 ± 1,07% e 55,32 ± 2,91%, respectivamente. Os conteúdos de glicose e frutose do mel retirado da fazenda de abelhas foram de 27% e 34%, mas a fonte natural foi de 22,50 ± 2,12% e 28,50 ± 3,54%. Os conteúdos de glicose e frutose do mel retirado da fazenda de abelhas foram de 27% e 34%, mas a fonte natural foi de 22,50 ± 2,12% e 28,50 ± 3,54%. Da mesma forma, os teores de sacarose e maltose no mel cultivado foram de 2,5% e 12%, enquanto no mel natural foram de 1,35 ± 0,49% e 8,00 ± 1,41%, respectivamente. O presente estudo indica que os teores de umidade, carboidratos, sacarose e maltose foram maiores no mel cultivado em comparação ao mel natural. Em nossa recomendação, o mel natural é melhor que o mel de cultivo.

Exploring the anticancer and antioxidant properties of Vicia faba L. pods extracts, a promising source of nutraceuticals.

Background: Pulse crops are considered the major sources of proteins, dietary fiber, micronutrients, and bioactive phytochemicals. Among the numerous pulse crops, broad beans (Vicia faba L.) have received particular attention due to their nutraceutical, functional and economic importance. Our attention was mainly focused on the broad bean pods (VFs), which are the primary by-product of the domestic and industrial processing of broad beans and an attractive source of valuable ingredients. Methods: In order to investigate the VFs properties, the flours from broad beans of three different harvest periods were extracted with acetone, methanol and 70% aqueous ethanol and the dried extracts were analyzed, qualitatively and quantitatively, and tested for their antioxidant through DPPH and ABTS assay and anticancer activities using the MTT assay and immunofluorescence analysis. Results: The VF extracts demonstrated a good in vitro radical scavenging activity from the first stage of collection of all the V. faba L. extracts. Additionally, the extracts were tested for their cytotoxicity against a panel of cancer and normal cells and the outcomes indicated the ethanol extract as the most active against the melanoma cell line Sk-Mel-28, without affecting the viability of the normal cells. Finally, we found out that the ethanol extract interfered with the microtubules organization, leading to the cancer cells death by apoptosis.

Efficacy of pharmacologic treatment in tinnitus patients without specific or treatable origin: A network meta-analysis of randomised controlled trials.

BACKGROUND: Although tinnitus has a prevalence between 20 and 42.8%, the currently recommended management for tinnitus, such as tinnitus support and psychologic therapies, are relatively time-consuming and expensive. Several new pharmacologic treatments designed for tinnitus patients without specific origin had been developed but their efficacy remains unclear. METHODS: The current Network Meta-Analysis (NMA) of randomised controlled trials (RCTs) was conducted to evaluate the efficacy of different pharmacologic treatments for tinnitus management in tinnitus patients without specific or treatable origin (i.e. primary tinnitus). Databases were searched from inception to April 5th, 2021. All network meta-analytic procedures were conducted under the frequentist model. We calculated the effect size of outcomes with different rating scales with standardized mean difference. PROSPERO registration: CRD42020177742. FINDINGS: Overall, 36 RCTs were included with 2,761 participants. The main results revealed that pharmacologic interventions with brain-acting effect (for example, amitriptyline, acamprosate, and gabapentin) and those with anti-inflammation/anti-oxidant effect (for example, intra-tympanic dexamethasone injection plus oral melatonin) were associated with superior improvement in tinnitus severity and response rate compared to placebo/control. Oral amitriptyline were associated with the highest improvement in tinnitus severity and the fourth highest response rate. None of the investigated interventions was associated with different changes in quality of life compared to placebo/control. All the investigated treatments were associated with similar drop-out rate to placebo/control. INTERPRETATION: The current NMA suggests a potential role for treatments with brain-acting effect (for example, amitriptyline, acamprosate, and gabapentin) or anti-inflammation/anti-oxidant effect (for example, intra-tympanic dexamethasone injection plus oral melatonin) as the preferable effective treatments for tinnitus without specific or treatable origin. FUNDING: none.

Novel mannosylerythritol lipid biosurfactant structures from castor oil revealed by advanced structure analysis.

Mannosylerythritol lipids (MELs) are glycolipid biosurfactants produced by fungi of the Ustilaginaceae family in the presence of hydrophobic carbon sources like plant oils. In the present study, we investigated the structural composition of MELs produced from castor oil using seven different microorganisms and compared them to MEL structures resulting from other plant oils. Castor oil is an industrially relevant plant oil that presents as an alternative to currently employed edible plant oils like rapeseed or soybean oil. The main fatty acid in castor oil is the mono-hydroxylated ricinoleic acid, providing the possibility to produce novel MEL structures with interesting features. Analysis of the produced MELs from castor oil by different chromatographic and mass spectrometry techniques revealed that all seven microorganisms were generally able to integrate hydroxylated fatty acids into the MEL molecule, although at varying degrees. These novel MELs containing a hydroxy fatty acid (4-O-[2'-O-alka(e)noyl-3'-O-hydroxyalka(e)noyl-4'/6'-O-acetyl-ß-D-mannopyranosyl]-erythritol) were more hydrophilic than conventional MEL and therefore showed a different elution behavior in chromatography. Large shares of novel hydroxy MELs (around 50% of total MELs) were found for the two MEL-B/C producing species Ustilago siamensis and Ustilago shanxiensis, but also for the MEL-A/B/C producer Moesziomyces aphidis (around 25%). In addition, tri-acylated hydroxylated MELs with a third long-chain fatty acid esterified to the free hydroxyl group of the hydroxy fatty acid were identified for some species. Overall, production of MEL from castor oil with the investigated organisms provided a complex mixture of various novel MEL structures that can be exploited for further research.

Uso de agentes naturais no manejo da mucosite oral / Use of natural agents in the management of oral mucositis

A mucosite oral (MO) é uma grave complicação dos tratamentos antineoplásicos, caracterizada pela presença de lesões erosivas e ulcerativas na mucosa oral, que podem causar uma diminuição significativa na qualidade de vida do paciente. Realizar uma revisão de literatura sobre o uso de agentes naturais na prevenção e tratamento da MO induzida por quimioterapia e/ou radioterapia. Artigos científicos foram pesquisados nas bases de dados SciELO, LILACS e Medline/PubMed, utilizando-se os descritores chamomile, propolis, honey, aloe, chemotherapy-induced oral mucositis e phytotherapeutic drug. A partir dessa busca e dos critérios de inclusão adotados, 22 artigos foram selecionados. Na maioria dos estudos analisados, o uso de produtos naturais, como camomila, própolis, mel e aloe vera, foi capaz de diminuir a incidência da MO e a severidade dessas lesões e, além disso, permitiu um melhor controle da dor local, sendo considerada uma boa opção terapêutica. O uso de produtos naturais tornou-se um importante método alternativo para tratamento e prevenção da MO, pois é uma terapia de baixo custo, que apresenta menos reações adversas e que podem ser implementadas pelos profissionais da saúde bucal... (AU)

Oral mucositis (OM) is a serious complication of antineoplastic treatments, characterized by the presence of erosive and ulcerative lesions in the oral mucosa, which may cause a significant decrease in the quality of life of the patient. To perform a literature review about the use of natural agents in the prevention and treatment of OM induced by chemotherapy and/or radiotherapy. Scientific articles were searched in the Scielo, Lilacs and Medline / PubMed databases using the descriptors chamomile, propolis, honey, aloe, chemotherapy-induced oral mucositis and phytotherapeutic drugs. From that research and according to the inclusion criteria, 22 articles were selected to compose this literature review. In most of the analyzed studies, the use of natural products, such as chamomile, propolis, honey and aloe vera was able to decrease the incidence of OM and the severity of these leions, and also allowed a better control of local pain, thus being considered a good therapeutic option. The use of natural products became an important alternative method for the treatment and prevention of OM, since it is a low-cost treatment, which presents less adverse effects and that can be implemented by oral health professionals... (AU)

La mucositis oral (MO) es una complicación grave de los tratamientos antineoplásicos, caracterizada por la presencia de lesiones erosivas y ulcerativas en la mucosa oral, que pueden provocar una disminución significativa de la calidad de vida del paciente. Realizar una revisión de la literatura sobre el uso de agentes naturales en la prevención y el tratamiento de la MO inducida por quimioterapia y / o radioterapia. Se realizaron búsquedas de artículos científicos en las bases de datos SciELO, LILACS y Medline/PubMed, utilizando los descriptores Manzanilla; Própolis; Miel; Aloe; Estomatitis; Medicamentos Fitoterápicos. De esta búsqueda y de los criterios de inclusión adoptados se seleccionaron 22 artículos. En la mayoría de los estudios analizados, el uso de productos naturales, como manzanilla, própolis, miel y aloe vera, consiguió reducir la incidencia de MO y la gravedad de estas lesiones y, además, permitió un mejor control del dolor local, siendo considerada una buena opción terapéutica. El uso de productos naturales se ha convertido en un método alternativo importante para el tratamiento y prevención de la MO, por ser una terapia de bajo costo, que tiene menos reacciones adversas y que puede ser implementada por profesionales de la salud bucal... (AU)

22ß-hydroxytingenone induces apoptosis and suppresses invasiveness of melanoma cells by inhibiting MMP-9 activity and MAPK signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: 22ß-hydroxytingenone (22-HTG) is a quinonemethide triterpene isolated from Salacia impressifolia (Miers) A. C. Smith (family Celastraceae), which has been used in traditional medicine to treat a variety of diseases, including dengue, renal infections, rheumatism and cancer. However, the anticancer effects of 22-HTG and the underlying molecular mechanisms in melanoma cells have not yet been elucidated. AIM OF THE STUDY: The present study investigated apoptosis induction and antimetastatic potencial of 22-HTG in SK-MEL-28 human melanoma cells. MATERIALS AND METHODS: First, the in vitro cytotoxic activity of 22-HTG in cultured cancer cells was evaluated. Then, cell viability was determined using the trypan blue assay in melanoma cells (SK-MEL-28), which was followed by cell cycle, annexin V-FITC/propidium iodide assays (Annexin/PI), as well as assays to evaluate mitochondrial membrane potential, production of reactive oxygen species (ROS) using flow cytometry. Fluorescence microscopy using acridine orange/ethidium bromide (AO/BE) staining was also performed. RT-qPCR was carried out to evaluate the expression of BRAF, NRAS, and KRAS genes. The anti-invasiveness potential of 22-HTG was evaluated in a three-dimensional (3D) model of reconstructed human skin. RESULTS: 22-HTG reduced viability of SK-MEL-28 cells and caused morphological changes, as cell shrinkage, chromatin condensation, and nuclear fragmentation. Furthermore, 22-HTG caused apoptosis, which was demonstrated by increased staining with AO/BE and Annexin/PI. The apoptosis may have been caused by mitochondrial instability without the involvement of ROS production. The expression of BRAF, NRAS, and KRAS, which are important biomarkers in melanoma development, was reduced by the 22-HTG treatment. In the reconstructed skin model, 22-HTG was able to decrease the invasion capacity of melanoma cells in the dermis. CONCLUSIONS: Our data indicate that 22-HTG has anti-tumorigenic properties against melanoma cells through the induction of cell cycle arrest, apoptosis and inhibition of invasiveness potential, as observed in the 3D model. As such, the results provide new insights for future work on the utilization of 22-HTG in malignant melanoma treatment.

A randomized controlled phase II clinical trial on mRNA electroporated autologous monocyte-derived dendritic cells (TriMixDC-MEL) as adjuvant treatment for stage III/IV melanoma patients who are disease-free following the resection of macrometastases.

BACKGROUND: Autologous monocyte-derived mRNA co-electroporated dendritic cells with mRNA encoding CD40 ligand (CD40L), CD70 and a constitutively activated TLR4 (caTLR4) (referred to as TriMixDC-MEL) have anti-tumor activity in advanced melanoma patients. We investigated the safety and activity of adjuvant TriMixDC-MEL in stage III/IV melanoma patients. MATERIALS AND METHODS: Forty-one patients were randomly assigned to treatment with TriMixDC-MEL (n = 21) and standard follow-up (n = 20). "Cross-over" was allowed at the time of non-salvageable recurrence. The primary endpoint was the percentage of patients alive and disease-free at 1-year. For a subset of patients, (formalin-fixed paraffin-embedded), tumor tissue samples were available for mRNA expression profiling and PD-L1 immunohistochemical staining. RESULTS: Baseline characteristics were well balanced. One-year after randomization, 71% of patients in the study arm were alive and free of disease compared to 35% in the control arm. After a median follow-up of 53 months (range 3-67), 23 patients experienced a non-salvageable melanoma recurrence (TriMixDC-Mel arm n = 9 and control arm n = 14).The median time to non-salvageable recurrence was superior in the TriMixDC-MEL arm (median 8 months (range 1-6) vs. not reached; log-rank p 0.044). TriMixDC-MEL-related adverse events (AE) consisted of transient local skin reactions, flu-like symptoms and post-infusion chills. No grade ≥ 3 AE's occurred. The mRNA expression profiling revealed four genes (STAT2, TPSAB1, CD9 and CSF2) as potential predictive biomarkers. CONCLUSION: TriMixDC-MEL id/iv as adjuvant therapy is tolerable and may improve the 1-year disease-free survival rate. Combination of optimized autologous monocyte-derived DC-formulations warrants further investigation in combination with currently approved adjuvant therapy options.

Xanthan gum-based hydrogel containing nanocapsules for cutaneous diphenyl diselenide delivery in melanoma therapy.

The aim of this study was to further evaluate the antitumoral effect of (PhSe)2-loaded polymeric nanocapsules (NC (PhSe)2) against a resistant melanoma cell line (SK-Mel-103) and develop a xanthan gum-based hydrogel intending the NC (PhSe)2 cutaneous application. For the in vitro evaluation, cells were incubated with free (PhSe)2 or NC (PhSe)2 (0.7-200 µM) and after 48 h the MTT assay, propidium iodide uptake (necrosis marker) and nitrite levels were assessed. The hydrogels were developed by thickening of the NC (PhSe)2 suspension or (PhSe)2 solution with xanthan gum and characterized in terms of average diameter, polydispersity index, pH, drug content, spreadability, rheological profiles and in vitro permeation in human skin. The results showed that NC (PhSe)2 provided a superior antitumoral effect in comparison to free (PhSe)2 (IC50 value of 47.43 µM and 65.05 µM, respectively) and increased the nitrite content. Both compound forms induced propidium iodide uptake, suggesting a necrosis-related pathway could be involved in the cytotoxic action of (PhSe)2. All hydrogels showed pH values around 7, drug content close to the theoretical values (5 mg/g) and mean diameter in the nanometric range. Besides, formulations were classified as non-Newtonian flow with pseudoplastic behavior and suitable spreadability factor. Skin permeation studies revealed that the compound content was higher for the nano-based hydrogel in the dermis layer, demonstrating its superior permeation, achieved by the compound encapsulation. It is the first report on an adequate formulation development for cutaneous application of NC (PhSe)2 that could be used as an adjuvant treatment in melanoma therapy.

The Development of an Antimicrobial Contact Lens - From the Laboratory to the Clinic.

Contact lens wear is generally safe and provides excellent vision. However, contact lens wear is often associated with the risk of developing ocular surface infection and inflammation, and in severe cases, the infection can result in loss of vision. Antimicrobial peptide-coated contact lenses have been made to help reduce the incidence of infection and inflammation. This paper reviews the research progress from conception, through the laboratory and preclinical tests to the latest information on clinical testing of an antimicrobial contact lens. We provide insights into the pathways followed and pitfalls that have been encountered. The journey has not always been linear or smooth, but has resulted in some of the first published clinical testing of antimicrobial peptide-coated contact lenses in humans. We hope this may help lead to the development and commercialisation of antimicrobial contact lenses in the future.

Uso de la miel en el manejo de las úlceras crónicas de miembros inferiores en el adulto. Revisión sistemática / Use of honey in the management of chronic leg ulcers in adults. Systematic review. / Uso de mel no tratamento de úlceras crônicas dos membros inferiores no adulto. Revisão sistemática

Introducción: las úlceras en miembros inferiores hacen parte de las enfermedades crónicas que afectan a la población mundial, las cuales generan deterioro en la calidad de vida de quienes las padecen. La miel es un alimento natural utili-zado a lo largo de la historia de la humanidad con fines curativos para el manejo de las lesiones en la piel; sin embargo, el beneficio de su uso en el tratamiento de las úlceras de miembros inferiores no ha sido definido, ya que la evidencia actual es controversial. Objetivo: evaluar la mejor evidencia científica disponible para determinar los beneficios de la miel en el tratamiento de las úlceras crónicas de miembros inferiores en la población adulta. Metodología: se realizó una revisión sistemática de la literatura de ensayos clínicos controlados, aleatorizados en las bases de datos PubMed, Ovid, ProQuest, EBSCO, BIREME. Se incluyeron 9 ensayos clínicos controlados. Se evaluó la calidad metodológica según los parámetros de PeDro y se utilizaron criterios de la colaboración Cochrane para definir la presencia de sesgos de cada estudio. Resultados: ocho de los 9 estudios incluidos reportaron desenlaces favorables en el uso de la miel. Los estudios conta- ron con buena calidad metodológica en su desarrollo, pero evidenciaron un riesgo poco claro de sesgo. Conclusión: la evidencia disponible no permite establecer la utilidad de la miel en el manejo de las úlceras de miembros inferiores. La evidencia actual muestra poca claridad en términos de sesgos, por lo que es necesario realizar nuevos ensayos clínicos, con mejores criterios de intervención, para poder establecer el beneficio del uso de la miel en esta enfermedad

Background: Leg ulcer are part of chronic diseases that affect word population, generating a big burden in quality of life. Honey is a natural food used along humanity history as a topic medicine for skin conditions. The benefits of using honey as a treatment of chronic leg ulcers has not been clarified because off controversial evidence. Objectives: This review assess the best scientific evidence to establish the benefits of using honey in chronic leg ulcers in adult population. Methods: A systematic Review of randomized clinical trials was made in PubMed, Ovid, ProQuest, EBSCO and BIREME databases. 9 controlled clinical trials were included. Methodological quality was assessed using PeDro criteria. Risk of bias was assessed using Cochrane parameters. Results: Eight of nine clinical trials included reported beneficial outcomes using honey in chronical leg ulcers treatment. Trials were made with good methodological quality however their had unclear risk of bias. Conclusion: Available evidence does not let define the usefulness of applying honey in chronic leg ulcers. Data is unclear in terms of bias; thus, it is necessary to perform new randomized clinical trials with better intervention criteria to define if using topical honey in chronic leg ulcers is beneficial or not compared with conventional treatment

Introdução: as úlceras nos membros inferiores fazem parte das doenças crônicas que afetam a po- pulação mundial, as quais geram deterioração na qualidade de vida daqueles que sofrem com elas. O mel é um alimento natural usado ao longo da história da humanidade para fins de cura no tratamento de lesões de pele; no entanto, o benefício de seu uso no tratamento de úlceras nos membros inferio- res não foi definido, pois a evidência atual é controversa. Objetivo: avaliar a melhor evidência científica disponível para determinar os benefícios do mel no tratamento de úlceras crônicas de membros inferiores na população adulta. Metodologia: foi realizada uma revisão sistemática da literatura de ensaios clínicos controlados, randomizados nas bases de dados PubMed, Ovid, ProQuest, EBSCO, BIREME. Nove ensaios clínicos controlados foram incluídos. A qualidade metodológica foi avaliada de acordo com os parâmetros PeDro e os critérios da Cochrane Collaboration foram utilizados para definir a presença de viés em cada estudo. Resultados: Oito dos 9 estudos incluídos relataram resultados favoráveis no uso do mel. Os estudos tiveram boa qualidade metodológica em seu desenvolvimento, mas mostraram um risco claro de viés. Conclusão: a evidência disponível não permite estabelecer a utilidade do mel no manejo de úlceras nos membros inferiores. A evidência atual mostra pouca clareza em termos de vieses, portanto, é ne- cessário realizar novos ensaios clínicos, com melhores critérios de intervenção, a fim de estabelecer o benefício do uso do mel nesta doença.

Photodynamic therapy using zinc phthalocyanine with low dose of diode laser combined with doxorubicin is a synergistic combination therapy for human SK-MEL-3 melanoma cells.

Chemotherapy is a generally used anticancer strategy for melanoma and it may have improved outcomes in combination with other approaches. One such strategy is photodynamic therapy (PDT), where a photosensitizer (PS) generates reactive oxygen species (ROS) after illumination of target cells. Interestingly, in low doses and high doses of light sources, special cellular responses can be induced. Regarding this fact, in this study, the combination of zinc phthalocyanine (ZnPc)-PDT and Doxorubicin (DOX) was applied at low and high dose of diode laser to treat SK-MEL-3 cells. Cytotoxic effects were determined by MTT assay for assessment synergistic effects were estimated by calculation of Combination Index (CI); that synergistic effects were observed in most groups. In low dose of laser irradiation higher synergism effects were observed. Significant changes of ROS were not observed with combinations, but autophagy, subG1 and G2/M phase cell cycle arrest, decreased cell migration ability and apoptosis induction were significantly increased compared to either treatment alone. The expression of caspase-8, -9, -3 and Bcl-2 genes revealed caspase-dependent apoptosis in all groups. Moreover, ZnPc-PDT and chemo-PDT down-regulated the expression of MMP-9 and Vimentin genes that impaired cell migration. In conclusion, it can be suggested that pre-treatment with ZnPc-PDT has high effects to sensitize SK-MEL-3 cells to DOX, in particular with low dose of diode laser.

Extraction, isolation and in vitro evaluation of affinisine from Tabernaemontana catharinensis in human melanoma cells.

Plant compounds have been identified as new drug prototypes. In this line, this work aimed to isolate the indole alkaloid affinisine from Tabernaemontana catharinensis and test its antitumor activity. The alkaloid was isolated by silica gel open column chromatography from the ethanolic extract of the stem of T. catharinensis. Afterwards, this molecule was characterized by high-resolution mass spectrometry and nuclear magnetic resonance. In the next step, the cytotoxicity of the compound was tested against human melanoma cell lines (A375, WM1366 and SK-MEL-28) and a normal skin cell line (CCD-1059Sk) using a MTT (3-4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Cells treated with affinisine were evaluated by flow cytometry to analyze apoptosis and the induction of cell cycle arrest, to evaluate the dead mechanism. The metabolite was isolated in a 0.2% yield relative to the extract. Cytotoxic activity of the molecule was observed at 48 h, resulting in considerable growth inhibition rates in melanoma cells, especially in WM1366, which had the lowest IC50 (32.86 ± 2.54 µg/mL). The apoptosis rate was lower in A375 (56.66 and 86.71% with 57 and 65 µg/mL, respectively). Moreover, affinisine was able to significantly induce cell cycle arrest in different phases in the A375 and WM1366 cell lines. However, in SK-MEL-28 cells, cycle arrest was not observed. In summary, this compound significantly decreased the viability of tumor cells in a dose- and time-dependent manner for all evaluated lineages, reduced cell viability by the apoptosis mechanism and presented prominent activities of cell cycle arrest. In this way, the use of antineoplastic agents is among the most widely used therapeutic measures for the control and treatment of cancer. Affinisine is a promising prototype in the search for new drugs to treat cancer.

Análise comparativa dos efeitos do mel, do óleo-serina de copaíba e de um produto comercial (fibrinolisina, desoxirribonuclease e cloranfenicol) na cicatrização por segunda intenção, em ratos / Comparative analysis of the effects of honey, copaiba oil-resin and a commercial product (fibrinolysin, deoxyribonuclease and chloramphenicol) on second intention healing, in rats

RESUMO Objetivo: comparar a cicatrização, por segunda intenção, sob os efeitos da aplicação tópica de mel, óleo-resina de copaíba e um produto comercial (fibrinolisina, desoxirribonuclease e cloranfenicol) a um grupo controle, em ratos. Métodos: ressecção de pele, com 1cm de diâmetro, foi realizada no dorso de 40 ratos alocados em quatro grupos de dez animais. Todas as feridas foram limpas, diariamente, com 2ml de solução de NaCl 0,9%. O primeiro grupo (controle - GC) ficou restrito a tal procedimento. Nas feridas do segundo (GM), terceiro (GO) e quarto grupos (GF), após limpeza, aplicou-se, respectivamente, 1ml de mel, 1ml de óleo-resina de copaíba e 1ml de creme contendo fibrinolisina, desoxirribonuclease e cloranfenicol. Ocluíram-se as feridas com gaze estéril. Imediatamente após a incisão e nos dias três, sete e 14 do experimento, as feridas foram copiadas e, usando planimetria, analisou-se a contração. Após a eutanásia, a histologia foi utilizada para avaliação da reação inflamatória e do colágeno nas cicatrizes. Resultados: a redução da área da ferida do GM (p=0,003), GO (p=0,011) e GF (p=0,002) foram superiores ao do GC. A quantidade de colágeno tipo I presente no GM e no GO foi superior aos grupos GC e GF (p<0,05). Houve predominância do estágio inflamatório crônico no GM (p=0,004), GO (p<0,001) e GF (p=0,003) quando comparados ao GC. Conclusão: o uso tópico do mel e do óleo-resina de copaíba aumenta a contração da ferida, a presença de colágeno tipo I e acelera a cicatrização.

ABSTRACT Objective: to compare the healing by second intention under the effects of topical application of honey, copaíba oil-resin and a commercial product (fibrinolysin, deoxyribonuclease and chloramphenicol) with a control group in rats. Methods: we carried out a skin resection, 1cm in diameter, on the back of 40 rats allocated to four groups of ten animals. All wounds were cleaned daily with 2ml of 0.9% NaCl solution. The first group (control - GC) was restricted to such procedure. In the wounds of the second (GM), third (GO) and fourth groups (GF), after cleaning, we respectively applied 1ml of honey, 1ml of copaíba oil-resin and 1ml of cream containing fibrinolysin, deoxyribonuclease and chloramphenicol. The wounds were occluded with sterile gauze. Immediately after the incision and on days three, seven and 14 of the experiment, the wounds were copied and contraction was analyzed using planimetry. After euthanasia, we histologically evaluated the inflammatory reaction and collagen in the scars. Results: the reduction of the wound area of GM (p=0.003), GO (p=0.011) and GF (p=0.002) were higher than the GC. The amount of type-I collagen present in GM and GO was higher than in GC and GF groups (p<0.05). There was a predominance of chronic inflammatory stage in GM (p=0.004), GO (p<0.001) and GF (p=0.003) when compared with GC. Conclusion: the topical use of honey and copaíba oil-resin increases wound contraction, the presence of type-I collagen and accelerates healing.

Whole-transcriptomic Profile of SK-MEL-3 Melanoma Cells Treated with the Histone Deacetylase Inhibitor: Trichostatin A.

BACKGROUND: Malignant melanoma cells can rapidly acquire phenotypic properties making them resistant to radiation and mainline chemotherapies such as decarbonize or kinase inhibitors that target RAS-proto-oncogene independent auto-activated mitogen-activated protein kinases (MAPK)/through dual specificity mitogen-activated protein kinase (MEK). Both drug resistance and inherent transition from melanocytic nevi to malignant melanoma involve the overexpression of histone deacetylases (HDACs) and a B-Raf proto-oncogene (BRAF) mutation. MATERIALS AND METHODS: In this work, the effects of an HDAC class I and II inhibitor trichostatin A (TSA) on the whole transcriptome of SK-MEL-3 cells carrying a BRAF mutation was examined. RESULTS: The data obtained show that TSA was an extremely potent HDAC inhibitor within SK-MEL-3 nuclear lysates, where TSA was then optimized for appropriate sub-lethal concentrations for in vitro testing. The whole-transcriptome profile shows a basic phenotype dominance in the SK-MEL-3 cell line for i) synthesis of melanin, ii) phagosome acidification, iii) ATP hydrolysis-coupled proton pumps and iv) iron transport systems. While TSA did not affect the aforementioned major systems, it evoked a dramatic change to the transcriptome: reflected by a down-regulation of 810 transcripts and up-regulation of 833, with fold-change from -15.27 to +31.1 FC (p<0.00001). Largest differentials were found for the following transcripts: Up-regulated: Tetraspanin 13 (TSPAN13), serpin family i member 1 (SERPINI1), ATPase Na+/K+ transporting subunit beta 2 (ATP1B2), nicotinamide nucleotide adenylyl transferase 2 (NMNAT2), platelet-derived growth factor receptor-like (PDGFRL), cytochrome P450 family 1 subfamily A member 1 (CYP1A1), prostate androgen-regulated mucin-like protein 1 (PARM1), secretogranin II (SCG2), SYT11 (synaptotagmin 11), rhophilin associated tail protein 1 like (ROPN1L); down-regulated: polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), carbonic anhydrase 14 (CAXIV), BCL2-related protein A1 (BCL2A1), protein kinase C delta (PRKCD), transient receptor potential cation channel subfamily M member 1 (TRPM1), ubiquitin associated protein 1 like (UBAP1L), glutathione peroxidase 8 (GPX8), interleukin 16 (IL16), tumor protein p53 (TP53), and serpin family H member 1 (SERPINH1). There was no change to any of the HDAC transcripts (class I, II and IV), the sirtuin HDAC family (1-6) or the BRAF proto-oncogene v 599 transcripts. However, the data showed that TSA down-regulated influential transcripts that drive the BRAF-extracellular signal-regulated kinase (ERK)1/2 oncogenic pathway (namely PRKCD and MYC proto-oncogene which negatively affected the cell-cycle distribution. Mitotic inhibition was corroborated by functional pathway analysis and flow cytometry confirming halt at the G2 phase, occurring in the absence of toxicity. CONCLUSION: TSA does not alter HDAC transcripts nor BRAF itself, but down-regulates critical components of the MAPK/MEK/BRAF oncogenic pathway, initiating a mitotic arrest.

O mel-derivado de Lactobacillus rhamnosus alivia a infecção gastro-intestinal induzida pelo Helicobacter pylori-e inflamação gástrica em C57Bl/6 ratos: um estudo imuno-histológico / Honey-derived lactobacillus rhamnosus alleviates helicobacter pylori-induced gastro-intestinal infection and gastric inflammation in c57bl/6 mice: an immuno-histologic study

ABSTRACT BACKGROUND: Helicobacter pylori (H. pylori) has been introduced by since 1983 by Marshal and Warren to play the main role in the pathophysiology of gastritis and gastric ulcers. Almost half of the world population1 is infected by H. pylori. Current therapeutic regimen against H. pylori includes the use of a proton pump inhibitor plus two or more antibiotics. However, the efficacy of this regimen is decreasing mainly due to antibiotic resistance and side effects of medications. This fact has resulted in public interest in other therapeutic options and the role of probiotics merits special attention in this regard. OBJECTIVE: This study aims to evaluate the efficacy of honey-derived Lactobacillus rhamnosus on H. pylori-induced gastric inflammation and gastro-intestinal infection in C57BL/6 Mice. METHODS: The 24 C57BL/6 Mice were randomly divided into three groups of eight mice each. All the mice were fed with 1cc suspension containing 5*1010 CFU/ mL of ATCC43504 strains of H. pylori for 3 consecutive days, twice daily via polyethylene gavage tubes. At the end of 4th week, infection with H. pylori was confirmed with stool Ag (ELISA) and following sacrifice of one mouse from each group, histopathologic study confirmed gastritis. The groups were subjected to different therapies as stated, 1: without Bismuth (Bi), Omeprazole (Om) and L. rhamnosus prescription, 2: Bi, Om and Clarithromycin (Cl) and 3: Bi, Om plus 1cc of suspension of 109 CFU/mL of L. rhamnosus. After 2 weeks, the stool was analyzed for Ag and the mice were sacrificed for evaluation of histopathologic changes. RESULTS: Treatment with L. rhamnosus group provided Zero titer of stool Ag and was associated with improved gastric inflammation in all subjects, similar to the clarithromycin group. CONCLUSION: Honey-derived L. rhamnosus probiotics provides similar results as clarithromycin in terms of improvement of H. pylori infection and gastritis in C57BL/6 Mice model, without its cons of antibiotic resistance.

RESUMO CONTEXTO: O Helicobacter pylori (H. pylori) foi reconhecido em 1983 por Marechal e Warren como protagonista principal na fisiopatologia de gastrite e úlceras gástricas. Quase metade da população mundial está infectada por H. pylori. O regime terapêutico atual contra H. pylori inclui o uso de um inibidor da bomba de prótons associada a dois ou mais antibióticos. No entanto, a eficácia deste regime está diminuindo principalmente devido à resistência aos antibióticos e efeitos colaterais de medicamentos. Este fato resultou no interesse público em outras opções terapêuticas e o papel dos probióticos merece atenção especial a este respeito. OBJETIVO: Este estudo visa avaliar a eficácia do mel-derivado do Lactobacillus rhamnosus na inflamação gástrica e infecção gastrointestinal H. pylori-induzida em camundongos C57Bl/6. MÉTODOS: Vinte e quatro camundongos C57Bl/6 foram divididos aleatoriamente em três grupos de oito camundongos cada. Todos os ratos foram alimentados com suspensão de 1cc contendo 5*1010 UFC/mL de cepas ATCC43504 de H. pylori por 3 dias consecutivos, duas vezes por dia através de gavagem por tubos de polietileno. No final da 4ª semana, a infecção com H. pylori foi confirmada pelo antígeno fecal (ELISA) e após o sacrifício de um rato de cada grupo, o estudo histopatológico confirmou gastrite. Os grupos foram submetidos a diferentes terapias, como indicado, 1: sem prescrição de bismuto (BI), Omeprazol (Om) e L. rhamnosus, 2: Bi, Om e claritromicina (CL) e 3: Bi, Om mais 1cc de suspensão de 109 UFC/mL de L. rhamnosus. Após 2 semanas, as fezes foram analisadas para o antígeno e os ratos foram sacrificados para a avaliação das alterações histopatológicas. RESULTADOS: O tratamento com o grupo L. rhamnosus forneceu o título zero de antígeno e foi associado com a inflamação gástrica melhorada em todos os camundongos, similar ao grupo claritromicina. CONCLUSÃO: O probiótico mel-derivado L. rhamnosus fornece resultados semelhantes ao da claritromicina em termos de melhoria da infecção H. pylori e gastrite em C57Bl/6 camundongos modelos, sem os inconvenientes de resistência aos antibióticos.