Transdentinal effects of S-PRG fillers on odontoblast-like cells.

OBJECTIVES: To investigate the transdentinal effects of surface reaction-type pre-reacted glass-ionomer (S-PRG) fillers on odontoblast-like cells. METHODS: An eluate of S-PRG fillers was obtained by dissolving the particles in distilled water (1:1 m/v). Dentin discs with similar permeability were mounted into artificial pulp chambers and MDPC-23 cells were seeded on their pulpal surface. The occlusal surface was treated with (n = 10): ultrapure water (negative control - NC), hydrogen peroxide (positive control - PC), S-PRG eluate exposure for 1 min (S-PRG 1 min), or S-PRG filler eluate exposure for 30 min (S-PRG 30 min). After 24 h, cell viability (alamarBlue) and morphology (SEM) were evaluated. The extract obtained from transdentinal diffusion was applied to MDPC-23 pre-cultured in plates for another 24 h to evaluate viability (alamarBlue, 1, 3, and 7 days), gene expression of Col1a1, Alpl, Dspp, and Dmp1 (RT-qPCR, 1 and 7 days), and mineralization (Alizarin Red, 7 days). Data were analyzed with ANOVA (α = 5 %). RESULTS: While S-PRG 1 min did not differ from NC, S-PRG 30 min reduced 17.9 % viability of cells from discs. S-PRG treatments resulted in low cell detaching from dentin, and the remaining cells exhibited typical morphology or minor cytoplasmic contraction. S-PRG 30 min slightly increased cell viability (6 %) 1 day after contact with the extract. S-PRG treatments upregulated the expression of the investigated genes, especially after 1 day. S-PRG 30 min stimulated mineralization activity by 39.7 %. CONCLUSIONS: S-PRG filler eluate does not cause transdentinal cytotoxicity on odontoblast-like cells, and long-term exposure can stimulate their dentinogenic-related mineralization activity. SIGNIFICANCE: The transdentinal elution of ions from S-PRG fillers is not expected to be harmful to the dental pulp and may exert bioactive effects by inducing dentin matrix deposition through the metabolism of underlying odontoblasts.

Impairment Assessment in Adult ADHD and Related Disorders: Current Opinions From Clinic and Research.

OBJECTIVES: Assessing functional impairment is one of the essential components in the clinical evaluation of ADHD in adulthood, serving both diagnostic and outcome evaluation purposes. However, clinicians and researchers may face challenges in selecting suitable instruments due to variations in accessibility and quality of instruments. METHODS: We conducted an online survey involving an international group of 92 respondents engaged in clinical practice and/or research on ADHD. The survey aimed to evaluate current practices in assessing impairment in adult ADHD and related disorders, while also identifying areas requiring adaptation or potential new developments. RESULTS: Our findings revealed that clinicians and researchers utilize a diverse range of instruments for assessing impairment in adults with ADHD, including some that may lack adequate properties for this purpose. Notably, dissatisfaction with current practice standards was expressed, underscoring the need for novel assessment approaches and improved psychometric properties. CONCLUSION: It is evident that research endeavors are warranted to either refine existing measures or devise new ones for assessing functional impairment in adult ADHD. Emphasis should be placed on disseminating instruments that enhance accessibility in both research and clinical settings, and facilitate streamlined administration and interpretation.

Gingival proteomics reveals the role of TGF beta and YAP/TAZ signaling in Raine syndrome fibrosis.

Raine syndrome (RNS) is a rare autosomal recessive osteosclerotic dysplasia. RNS is caused by loss-of-function disease-causative variants of the FAM20C gene that encodes a kinase that phosphorylates most of the secreted proteins found in the body fluids and extracellular matrix. The most common RNS clinical features are generalized osteosclerosis, facial dysmorphism, intracerebral calcifications and respiratory defects. In non-lethal RNS forms, oral traits include a well-studied hypoplastic amelogenesis imperfecta (AI) and a much less characterized gingival phenotype. We used immunomorphological, biochemical, and siRNA approaches to analyze gingival tissues and primary cultures of gingival fibroblasts of two unrelated, previously reported RNS patients. We showed that fibrosis, pathological gingival calcifications and increased expression of various profibrotic and pro-osteogenic proteins such as POSTN, SPARC and VIM were common findings. Proteomic analysis of differentially expressed proteins demonstrated that proteins involved in extracellular matrix (ECM) regulation and related to the TGFß/SMAD signaling pathway were increased. Functional analyses confirmed the upregulation of TGFß/SMAD signaling and subsequently uncovered the involvement of two closely related transcription cofactors important in fibrogenesis, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). Knocking down of FAM20C confirmed the TGFß-YAP/TAZ interplay indicating that a profibrotic loop enabled gingival fibrosis in RNS patients. In summary, our in vivo and in vitro data provide a detailed description of the RNS gingival phenotype. They show that gingival fibrosis and calcifications are associated with, and most likely caused by excessed ECM production and disorganization. They furthermore uncover the contribution of increased TGFß-YAP/TAZ signaling in the pathogenesis of the gingival fibrosis.

Multiple habitats drive the functional diversity of fish assemblages in a tropical estuary.

Understanding estuarine diversity patterns is crucial to highlight the ecological value of coastal ecosystems for fish assemblages. To increase our knowledge, we investigated the functional diversity of fish assemblages in five estuarine habitats (sandy beaches, mudflats, seagrass meadows, mangrove fringes, and estuarine riparian vegetation) in a tropical estuary of Brazil. Functional diversity metrics were assessed considering seven fish functional traits and calculated using functional indices, PCoA (functional spaces), and community-weighted mean (CWM). Then, a unified RLQ and fourth-corner analysis were used to evaluate environment-trait relationships. A total of 27,036 individuals of 119 species were recorded in all habitats. Functional diversity showed similar trends to estuarine habitats, which were more driven by the spatial configuration rather than by their structure, emphasizing the importance of environmental heterogeneity. There was a greater occupation of functional space to habitats located in the lower estuary compared to the upper estuary. Furthermore, body shapes and trophic guilds were the most common traits related to changes in functional diversity between habitats. The RLQ analysis revealed differences in trait composition between habitats influenced by salinity and transparency, although the fourth corner method did not show a significant relationship between fish functional traits and environmental variables. Our results suggest that the mosaic of habitats support the high functional diversity of fishes in tropical estuaries.

Genetically modified ZIKA virus as a microRNA-sensitive oncolytic virus against central nervous system tumors.

Here we introduce a first-in-class microRNA-sensitive oncolytic Zika virus (ZIKV) for virotherapy application against central nervous system (CNS) tumors. The described methodology produced two synthetic modified ZIKV strains that are safe in normal cells, including neural stem cells, while preserving brain tropism and oncolytic effects in tumor cells. The microRNA-sensitive ZIKV introduces genetic modifications in two different virus sites: first, in the established 3'UTR region, and secondly, in the ZIKV protein coding sequence, demonstrating for the first time that the miRNA inhibition systems can be functional outside the UTR RNA sites. The total tumor remission in mice bearing human CNS tumors, including metastatic tumor growth, after intraventricular and systemic modified ZIKV administration, confirms the promise of this virotherapy as a novel agent against brain tumors-highly deadly diseases in urgent need of effective advanced therapies.

Modalidades Fisioterapêuticas no Manejo da Dor Neuropática Induzida pelo Tratamento do Câncer de Mama: Revisãoda Literatura / Physiotherapeutic Modalities in the Management of Neuropathic Pain Induced by Breast Cancer Treatment: Literature Review / Modalidades Fisioterapéuticas en el Manejo Del Dolor Neuropático Inducido por el Tratamiento del Cáncer de Mama: Revisión de la Literatura

A sobrevida de mulheres após o tratamento do câncer de mama tem aumentado em virtude de avanços na detecção precoce e terapias disponíveis. Porém, as sobreviventes comumente enfrentam efeitos adversos após o tratamento que representam grande carga física e psicológica. Além da fadiga, a dor é o sintoma persistente mais frequente após o tratamento. Objetivo: Sistematizar os resultados de ensaios clínicos randomizados sobre a intervenção fisioterapêutica na dor neuropática periférica induzida pelos tratamentos para o câncer de mama. Método: Busca realizada nas bases de dados MEDLINE via portal PubMed e Cochrane. Foram selecionados ensaios clínicos randomizados publicados a partir de 2017, em língua inglesa, que abordassem as modalidades fisioterapêuticas como intervenção, a dor neuropática periférica induzida por tratamentos oncológicos como desfecho, e mulheres sobreviventes ao câncer de mama como população de interesse. A qualidade metodológica dos estudos foi avaliada pela ferramenta Cochrane para o risco de viés. Resultados: Quatro estudos foram revisados na íntegra. Majoritariamente, os efeitos adversos do tratamento oncológico se devem a regimes quimioterápicos à base de taxanos. Os desfechos avaliados incluem, além da dor, demais sinais neuropáticos e influência nas atividades de vida diária. Os estudos variaram quanto à intervenção e fase de tratamento. Apenas um dos estudos demonstrou resultado significativamente positivo a favor do grupo intervenção. Conclusão: Estudos clínicos randomizados disponibilizam evidências escassas quanto aos efeitos positivos da intervenção fisioterapêutica na dor neuropática periférica induzida pelos tratamentos para o câncer de mama.

Women's survival after breast cancer treatment has increased due to advances in early detection and available therapies. However, great physical and psychological burden are the result of adverse effects that survivors commonly face. In addition to fatigue, pain is the most common persistent symptom after cancer treatment. Objective: Systematize the results of randomized clinical trials on physiotherapeutic intervention in peripheral neuropathic pain induced by breast cancer treatments . Method:The search was carried out on the MEDLINE databases via PubMed and Cochrane portals. Randomized clinical trials published since 2017 in English, that addressed physiotherapeutic modalities as intervention, peripheral neuropathic pain induced by oncological treatments as outcome were selected, and the population of interest were women surviving breast cancer. The Cochrane-risk-of-bias tool was applied to evaluate the methodological quality of the studies. Results: Four studies were fully reviewed. Most of the adverse effects of cancer treatment are due to taxane-based chemotherapy regimens. The outcomes assessed include, in addition to pain, other neuropathic signs and influence on activities of daily living. The studies varied in terms of intervention and treatment phase. Only one of the studies demonstrated a significantly positive result in favor of the intervention group. Conclusion: Randomized clinical studies provide scant evidence regarding the positive effects of physiotherapeutic intervention on peripheral neuropathic pain induced by breast cancer treatments.

La supervivencia de las mujeres después del tratamiento del cáncer de mama ha aumentado debido a los avances en la detección temprana y las terapias disponibles. Sin embargo, los supervivientes suelen enfrentarse a efectos adversos después del tratamiento que representan una gran carga física y psicológica. Además de la fatiga, el dolor es el síntoma persistente más común después del tratamiento del cáncer. Objetivo: Sistematizar los resultados de ensayos clínicos aleatorizados sobre intervención fisioterapéutica en el dolor neuropático periférico inducido por tratamientos para el cáncer de mama. Método: La búsqueda se realizó en las bases de datos MEDLINE a través de los portales PubMed y Cochrane. Se seleccionaron ensayos clínicos aleatorizados publicados desde 2017, en inglés, que abordaron modalidades fisioterapéuticas como intervención, dolor neuropático periférico inducido por tratamientos oncológicos como resultado y mujeres sobrevivientes de cáncer de mama como población de interés. La calidad metodológica de los estudios se evaluó mediante la herramienta Cochrane de Riesgo de Sesgo. Resultados: Se revisaron en su totalidad cuatro estudios. La mayoría de los efectos adversos del tratamiento del cáncer se deben a los regímenes de quimioterapia basados en taxanos. Los resultados evaluados incluyen, además del dolor, otros signos neuropáticos y su influencia en las actividades de la vida diaria. Los estudios variaron en términos de intervención y fase de tratamiento. Sólo uno de los estudios demostró un resultado significativamente positivo a favor del grupo de intervención. Conclusión: Los estudios clínicos aleatorizados aportan escasa evidencia sobre los efectos positivos de la intervención fisioterapéutica sobre el dolor neuropático periférico inducido por los tratamientos del cáncer de mama

Conditional expression of NanoLuc luciferase through a multimodular system offers rapid detection of antimalarial drug activity.

Conditional gene expression is a powerful tool to investigate putative vaccine and drug targets, especially in a haploid organism such as Plasmodium falciparum. Inducible systems based on regulation of either transcription, translation, protein or mRNA stability, among others, allow switching on an off the expression of any desired gene causing specific gain or loss of function phenotypes. However, those systems can be cumbersome involving the construction of large plasmids and generation of multiple transgenic parasite lines. In addition, the dynamic range of regulation achieved is not predictable for each individual gene and can be insufficient to generate detectable phenotypes when the genes of interest are silenced. Here, we combined up to three distinct inducible systems to regulate the expression of a single gene. Expression of the reporter NanoLuc luciferase was regulated over 40-fold, which correlates to the regulation achieved by each individual system multiplied by each other. We applied the conditionally expressed NanoLuc to evaluate the effect of fast-acting antimalarials such as chloroquine and artesunate as well as of slower-acting ones such as atovaquone. The conditionally expressed reporter allowed faster and more reliable detection of toxicity to the parasite, which correlated to the expected action of each compound. Bioluminescence achieved by the expression of this inducible highly sensitive reporter is therefore a promising tool to investigate the temporal effect of potential new antimalarials. This single plasmid combination system might also prove useful to achieve sufficient regulation of genes of interest to produce loss-of-function phenotypes.

COVID-19 and candiduria: an investigation of the risk factors and immunological aspects.

Secondary fungal infections are frequently observed in COVID-19 patients. However, the occurrence of candiduria in these patients and its risk factors are underexplored. We evaluated the risk factors of candiduria in COVID-19 patients, including inflammatory mediators that could be used as prognostic markers. Clinical information, laboratory test results, and outcomes were collected from severely ill COVID-19 patients with and without candiduria. Candida species identification, antifungal susceptibility, and plasma inflammatory mediators' measurements were performed. Regression logistic and Cox regression model were used to evaluate the risk factors. A higher risk of longer hospitalization and mortality were observed in patients with candiduria compared to those with COVID-19 only. Candiduria was caused by Candida albicans, C. glabrata, and C. tropicalis. Isolates with intermediate susceptibility to voriconazole and resistant to caspofungin were identified. Classic factors such as the use of corticosteroids and antibacterials, the worsening of renal function, and hematological parameters (hemoglobin and platelets) were found to predispose to candiduria. The mediators IL-1ß, IL-1ra, IL-2, CXCL-8, IL-17, IFN-γ, basic FGF, and MIP-1ß were significantly increased in patients with COVID-19 and candiduria. Furthermore, IFN-γ, IL-1ra, and CXCL-8 were associated with the occurrence of candiduria in COVID-19 patients, whereas basic FGF, IL-1ß, and CXCL-8 were associated with the risk of death in these patients. Classical and immunological factors were associated with worse prognosis among patients with COVID-19 and candiduria. Some mediators, especially CXCL-8, can be a reliable biomarker of fungal coinfection and may guide the diagnostic and the treatment of these patients.

Mucoadhesive gellan gum-based and carboxymethyl cellulose -based hydrogels containing gemcitabine and papain for bladder cancer treatment.

Local treatment of bladder cancer faces several limitations such as short residence time or low permeation through urothelium tissue. The aim of this work was to develop patient-friendly mucoadhesive gel formulations combining gemcitabine and the enzyme papain for improved intravesical chemotherapy delivery. Hydrogels based on two different polysaccharides, gellan gum and sodium carboxymethylcellulose (CMC), were prepared with either native papain or papain nanoparticles (nanopapain) to explore for the first time their use as permeability enhancers through bladder tissue. Gel formulations were characterized regarding enzyme stability, rheological behavior, retention on bladder tissue and bioadhesion, drug release properties, permeation capacity, and biocompatibility. After 90 days of storage, the enzyme loaded in the CMC gels retained up to 83.5 ± 4.9 % of its activity in the absence of the drug, and up to 78.1 ± 5.3 with gemcitabine. The gels were mucoadhesive and the enzyme papain showed mucolytic action, which resulted in resistance against washing off from the urothelium and enhanced permeability of gemcitabine in the ex vivo tissue diffusion tests. Native papain shortened lag-time tissue penetration to 0.6 h and enhanced 2-fold drug permeability All formulations demonstrated pseudoplastic behavior and no irritability. Overall, the developed formulations have potential as an upgraded alternative to intravesical therapy for bladder cancer treatment.

Effect of periodontal therapy on insulin resistance in adults with dysglycemia and periodontitis: a systematic review and meta-analysis.

OBJECTIVES: This systematic review and meta-analysis aimed to address whether non-surgical periodontal therapy (NSPT) can affect insulin resistance, estimated by the homeostasis model assessment (HOMA), in adults with prediabetes or type 2 diabetes mellitus and periodontitis. MATERIALS AND METHODS: Six electronic databases and the gray literature were systematically searched for interventional studies reporting NSPT effect on insulin resistance. Seven studies met the eligibility criteria to be synthesized in the qualitative analysis, six reporting change in HOMA-IR, three reporting change in HOMA-%S, and two in HOMA-ß. Among them, four were pooled in a meta-analysis of standardized mean difference (SMD) of HOMA-IR; comparing pre- and post-intervention values, three were pooled considering HOMA-%S as outcome, and two studies were summarized considering SMD of HOMA-%S between intervention and control groups. HOMA-ß results were qualitatively synthetized. RESULTS: With low level of certainty, NSPT significantly reduced HOMA-IR, when compared with pre-intervention data (SMD, -0.35, 95% CI -0.63 to 0.07, p=0.02). There were no significant changes in HOMA-%S or in HOMA-ß scores. The level of certainty was very low and moderate, respectively. CONCLUSIONS: Assertions about a causal link between NSPT and insulin resistance are weak and conflicting, although our more robust results point out to the absence of effect. . CLINICAL RELEVANCE: Because further high-quality studies assessing the relationship between periodontitis and insulin resistance are need, the findings of the current systematic review are limited to give recommendations for clinicians. However, while identifying a lack of research in humans with T2D concerning periodontitis and insulin resistance, this study reinforces the need of multicenter well-designed randomized clinical trials.

Natural Compounds as Non-Nucleoside Inhibitors of Zika Virus Polymerase through Integration of In Silico and In Vitro Approaches.

Although the past epidemic of Zika virus (ZIKV) resulted in severe neurological consequences for infected infants and adults, there are still no approved drugs to treat ZIKV infection. In this study, we applied computational approaches to screen an in-house database of 77 natural and semi-synthetic compounds against ZIKV NS5 RNA-dependent RNA-polymerase (NS5 RdRp), an essential protein for viral RNA elongation during the replication process. For this purpose, we integrated computational approaches such as binding-site conservation, chemical space analysis and molecular docking. As a result, we prioritized nine virtual hits for experimental evaluation. Enzymatic assays confirmed that pedalitin and quercetin inhibited ZIKV NS5 RdRp with IC50 values of 4.1 and 0.5 µM, respectively. Moreover, pedalitin also displayed antiviral activity on ZIKV infection with an EC50 of 19.28 µM cell-based assays, with low toxicity in Vero cells (CC50 = 83.66 µM) and selectivity index of 4.34. These results demonstrate the potential of the natural compounds pedalitin and quercetin as candidates for structural optimization studies towards the discovery of new anti-ZIKV drug candidates.

Structure and Chemical Composition of ca. 10-Million-Year-Old (Late Miocene of Western Amazon) and Present-Day Teeth of Related Species.

Molecular information has been gathered from fossilized dental enamel, the best-preserved tissue of vertebrates. However, the association of morphological features with the possible mineral and organic information of this tissue is still poorly understood in the context of the emerging area of paleoproteomics. This study aims to compare the morphological features and chemical composition of dental enamel of extinct and extant terrestrial vertebrates of Crocodylia: Purussaurus sp. (extinct) and Melanosuchus niger (extant), and Rodentia: Neoepiblema sp. (extinct) and Hydrochoerus hydrochaeris (extant). To obtain structural and chemical data, superficial and internal enamel were analyzed by Scanning Electron Microscopy (SEM) and Energy Dispersive Spectroscopy (SEM-EDS). Organic, mineral, and water content were obtained using polarizing microscopy and microradiography on ground sections of four teeth, resulting in a higher organic volume than previously expected (up to 49%). It is observed that both modern and fossil tooth enamel exhibit the same major constituents: 36.7% Ca, 17.2% P, and 41% O, characteristic of hydroxyapatite. Additionally, 27 other elements were measured from superficial enamel by inductively coupled mass spectrometry (ICP-MS). Zinc was the most abundant microelement detected, followed by Pb, Fe, Mg, and Al. Morphological features observed include enamel rods in the rodent teeth, while incremental lines and semiprismatic enamel were observed in the alligator species. The fossil enamel was in an excellent state for microscopic analyses. Results show that all major dental enamel's physical, chemical, and morphological features are present both in extant and extinct fossil tooth enamel (>8.5 Ma) in both taxa.

Biochemical and histopathological responses in Nile tilapia exposed to a commercial insecticide mixture containing dinotefuran and lambda-cyhalothrin.

The indiscriminate use of pesticides has led to an increased risk of environmental contamination and pest resistance worldwide, favoring the development of less hazardous formulations. The commercial insecticide ZEUS® (Ihara, Brazil) combining dinotefuran and lambda-cyhalothrin was recently formulated in order to meet the environmental sustainability and food security. However, little is known about the potential toxic effects of ZEUS® to aquatic species. Thus, we report, for the first time, the biochemical and histological responses in tilapia (Oreochromis niloticus) following 96 h exposure to 0.01 mg/L, 0.05 mg/L and 0.1 mg/L ZEUS®. Different biochemical endpoints, including acetylcholinesterase (AChE), gamma-glutamyltransferase (GGT) and alkaline phosphatase (ALP), were assessed as potential biomarkers of insecticide effects. Glutathione S-transferase (GST) was evaluated as a marker of phase II biotransformation, and histopathological changes were measured to indicate gill alterations following ZEUS® exposure. After 96 h exposure, ZEUS® treatment increased GST activity in the liver of fish exposed to the highest concentration, while the intermediate dose increased both renal GGT and hepatic ALP activities. These findings reflect the importance of the liver and kidneys in the detoxification of ZEUS® and highlight the need to understand further toxicity effects. Likewise, the histopathological analysis of gills provided evidence that ZEUS® caused moderate damages. Despite biomarkers alterations reported for O. niloticus following ZEUS® exposure, by comparing our findings with data on toxicity of individual compounds, the commercial ZEUS® mixture seems to present similar or even lower adverse effects on freshwater fish.

The impact of COVID-19 on antimicrobial prescription and drug resistance in fungi and bacteria.

Secondary infections are one of the complications in COVID-19 patients. We aimed to analyze the antimicrobial prescriptions and their influence on drug resistance in fungi and bacteria isolated from severely ill COVID-19 patients. Seventy-nine severely ill COVID-19 hospitalized patients with secondary bacterial or fungal infections were included. We analyzed the prescribed antimicrobial regimen for these patients and the resistance profiles of bacterial and fungal isolates. In addition, the association between drug resistance and patients' outcome was analyzed using correlation tests. The most prescribed antibacterial were ceftriaxone (90.7% of patients), vancomycin (86.0%), polymyxin B (74.4%), azithromycin (69.8%), and meropenem (67.4%). Micafungin and fluconazole were used by 22.2 and 11.1% of patients, respectively. Multidrug-resistant (MDR) infections were a common complication in severely ill COVID-19 patients in our cohort since resistant bacteria strains were isolated from 76.7% of the patients. Oxacillin resistance was observed in most Gram-positive bacteria, whereas carbapenem and cephalosporin resistance was detected in most Gram-negative strains. Azole resistance was identified among C. glabrata and C. tropicalis isolates. Patients who used more antimicrobials stayed hospitalized longer than the others. The patient's age and the number of antibacterial agents used were associated with the resistance phenotype. The susceptibility profile of isolates obtained from severely ill COVID-19 patients highlighted the importance of taking microbial resistance into account when managing these patients. The continuous surveillance of resistant/MDR infection and the rational use of antimicrobials are of utmost importance, especially for long-term hospitalized patients with COVID-19.

Mucoadhesive Polymers and Their Applications in Drug Delivery Systems for the Treatment of Bladder Cancer.

Bladder cancer (BC) is the tenth most common type of cancer worldwide, affecting up to four times more men than women. Depending on the stage of the tumor, different therapy protocols are applied. Non-muscle-invasive cancer englobes around 70% of the cases and is usually treated using the transurethral resection of bladder tumor (TURBIT) followed by the instillation of chemotherapy or immunotherapy. However, due to bladder anatomy and physiology, current intravesical therapies present limitations concerning permeation and time of residence. Furthermore, they require several frequent catheter insertions with a reduced interval between doses, which is highly demotivating for the patient. This scenario has encouraged several pieces of research focusing on the development of drug delivery systems (DDS) to improve drug time residence, permeation capacity, and target release. In this review, the current situation of BC is described concerning the disease and available treatments, followed by a report on the main DDS developed in the past few years, focusing on those based on mucoadhesive polymers as a strategy. A brief review of methods to evaluate mucoadhesion properties is also presented; lastly, different polymers suitable for this application are discussed.

Does environmental heterogeneity explain ß diversity of estuarine fish assemblages? Example from a tropical estuary under the influence of a semiarid climate, Brazil.

Estuarine fish assemblages are often sensitive to environmental conditions, because fluctuation in physico-chemical conditions at different spatial and seasonal scales can directly influence species distributions. In this way, we conducted a field survey to investigate the role of estuarine gradient (environmental heterogeneity) in fish α and ß diversity. The study was carried out in three zones in Mamanguape River estuary according to salinity and geomorphology features during an atypical climatic event in 2015. In total, 18,084 specimens of 125 species were captured. Additive partitioning of diversity analysis detected a higher proportion of beta diversity among estuarine zones during the rainy (ß3 = 58.6%) and dry season (ß3 = 40.94%) and were higher than expected by chance (Propexp> obs <0.001). Decomposing ß-diversity analysis showed that total ß-diversity (ßsor) results were more dominated by species turnover (ßsim) than nestedness (ßnes) in both seasons. Forward selection procedure and db-RDA identified salinity, coarse sand and chlorophyll-a as the main environmental variables influencing ßsor and site distance from estuary mouth and split as the main landscape variables. Variation partitioning analysis revealed more contribution to the pure fraction of environmental variables to fish species turnover, however, both pure fraction of environmental and landscape variables significantly contributed to ßsim. Our study highlighted the importance to environmental heterogeneity and connectivity to promote fish diversity across the Mamanguape River estuary. Thus, future conservation policies should focus on maintaining these two components to guarantee its nursery ground role to estuarine fish assemblages.

Biophysical studies of the interaction of hRSV Non-Structural 1 protein with natural flavonoids and their acetylated derivatives by spectroscopic techniques and computational simulations.

Human respiratory syncytial virus (hRSV) infections are one of the most causes of acute lower respiratory tract infections in children and elderly. The development of effective antiviral therapies or preventive vaccines against hRSV is not available yet. Thus, it is necessary to search for protein targets to combat this viral infection, as well as potential ways to block them. Non-Structural 1 (NS1) protein is an important factor for viral replication success since reduces the immune response by interacting with proteins in the type I interferon pathway. The influence of NS1 on the cell's immune response denotes the potential of its inhibition, being a possible target of treatment against hRSV infection. Here, it was studied the interaction of hRSV NS1 with natural flavonoids chrysin, morin, kaempferol, and myricetin and their mono-acetylated chrysin and penta-acetylated morin derivatives using spectroscopic techniques and computational simulations. The fluorescence data indicate that the binding affinities are on the order of 105 M-1, which are directly related to the partition coefficient of each flavonoid with Pearson's correlation coefficients of 0.76-0.80. The thermodynamic analysis suggests that hydrophobic interactions play a key role in the formation of the NS1/flavonoid complexes, with positive values of enthalpy and entropy changes. The computational approach proposes that flavonoids bind in a region of NS1 formed between the C-terminal α3-helix and the protein core, important for its biological function, and corroborate with experimental data revealing that hydrophobic contacts are important for the binding. Therefore, the present study provides relevant molecular details for the development of a possible new strategy to fight infections caused by hRSV.

Impact of Seasonal and Organ-Related Fluctuations on the Anthelmintic Properties and Chemical Profile of Cladium mariscus (L.) Pohl Extracts.

The use of plants and their metabolites stands as a promising option to tackle parasitic infections by gastrointestinal nematodes (GIN) in integrated control strategies. Still, the influence of environmental and phenological factors, and their interactions, in the wild on the metabolomics and biological properties of target plant species, is often disregarded. In this work, we hypothesized that variations in the anthelmintic (AH) properties and chemical composition of extracts from the salt tolerant species Cladium mariscus L. Pohl (sawgrass) may be influenced by seasonal factors and organ-parts. To test this hypothesis, acetone/water extracts were prepared from dried biomass obtained from aerial organs collected from sawgrass in consecutive seasons and tested against Haemonchus contortus and Trichostrongylus colubriformis by the larval exsheathment inhibition assay (LEIA) and egg hatching inhibition assay (EHIA). To ascertain the role of plant organ, the activity of leaves and inflorescences extracts from summer samples was compared. The role of polyphenols in the anthelmintic activity depending on GINs and fluctuations across seasons and plant organs was assessed using polyvinylpolypyrrolidone (PVPP), coupled with an in-depth chemical profiling analysis using high-performance liquid chromatography completed with electrospray ionization mass spectrometric detection (HPLC-ESI-MSn). Main differences in anthelmintic activities were observed for summer and autumn samples, for both assays. Moreover, inflorescences' extracts were significantly more active than those from leaves against both parasite species on EHIA and against H. contortus on LEIA. Application of PVPP totally inhibit the AH effects based on EHIA and only partly for LEIA. Non-treated PVPP extracts were predominantly composed of flavan-3-ols, proanthocyanidins, luteolin and glycosylated flavonoids, while two flavonoid glycosides were quantified in all PVPP-treated samples. Thus, the activity of such compounds should be further explored, although some unknown metabolites remain to be identified. This study reinforces the hypothesis of the AH potential of sawgrass and of its polyphenolic metabolites uses as nutraceutical and/or phytotherapeutic drugs.

Microstructure of the hoof capsule of pigmented and partial albino buffaloes.

In this study, atomic force microscopy (AFM), microtomography (MCT-2D and MCT-3D) and energy-dispersive X-ray fluorescence spectrometry (EDXRF) were used to generate parameters of the microstructure of the hoof capsule of pigmented and partial albino buffaloes. Seventy-two digits of adult pigmented buffaloes and 16 of partial albino buffaloes were used and equally divided into thoracic and pelvic limbs and medial and lateral claws. Fragments of 10 mm × 10 mm of the dorsal wall, abaxial wall and pre-bulbar sole were collected. The parametric assumptions were tested using a Shapiro-Wilk test (normality). The independent t-test was used to compare the means at a 5% significance level. AFM demonstrated that the hoof surface of pigmented buffaloes presented with higher average surface roughness (Ra) and root mean square roughness (Rms) (p < 0.05) than the hoof surface of partial albino buffaloes. MCT-2D revealed that pigmented buffaloes had extra tubular keratin with a higher density than intratubular keratin. No pores were observed in the hoof capsule of the buffalo digits. MCT-3D demonstrated that pigmented buffaloes have a higher percentage of large and intermediate horn tubules than partial albino buffaloes. However, this difference was not statistically significant. Partial albino buffaloes showed a statistically higher number of horn tubules/mm2 than pigmented buffaloes (p < 0.05). EDXRF revealed a higher amount of sulphur (S) in the hoof capsule of pigmented buffaloes, and the partial albino buffaloes presented a higher number of minerals such as calcium (Ca), potassium (K), zinc (Zn) and copper (Cu).

Antiproliferative effects of metformin in cellular models of pheochromocytoma.

Pheochromocytomas (PCCs) are rare neuroendocrine tumors derived from adrenal medulla chromaffin cells. Malignancy and recurrence are rare but demand effective treatment. Metformin exerts antiproliferative effects in several cancer cell lines. We thus evaluated the effects of metformin on cell viability and proliferation, cellular respiration and AMPK-AKT-mTOR-HIFA proliferation pathway on a rat PCC cell line (PC12-Adh). We then addressed metformin's effects on the AMPK-AKT-mTOR-HIFA pathway on two human primary cultures: one from a VHL-mutant PCC and other from a sporadic PCC. Metformin (20 mM) inhibited PC12-Adh cell proliferation, and decreased oxygen consumption, ATP production and proton leak, in addition to loss of mitochondrial membrane potential. Further, metformin induced AMPK phosphorylation and impaired AMPK-PI3k-AKT-mTOR pathway activation. The mTOR pathway was also inhibited in human VHL-related PCC cells, however, in an AMPK-independent manner. Metformin-induced decrease of HIF1A levels was likely mediated by proteasomal degradation. Altogether our results suggest that metformin impairs PCC cellular proliferation.