Efavirenz, an antiretroviral drug, is a class 2 according to the biopharmaceutics classification system. Many dissolution enhancement systems have been tried and our group had success using wet milling to decrease particle size and granules were obtained by spray and freeze drying. In this paper we present data related to the upgrade in the process, raising the solids concentration in the suspension from 10 to 50% (m/v) and changing the drying step for a fluid bed granulation. After that, tablets were obtained. Granules and tablets were fully evaluated and a pharmacokinetic study was also performed with the granules. By powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FTIR) it was possible to prove that there was no phase transition in the sample after milling and drying. Dissolution efficiency of 4 from 5 granules was higher than 90%, considering 83% for the raw material. Tablets were technically approved but the dissolution was impacted and just 2 out of 11 showed results > 80%. A high enhancement in the bioavailability was also observed, around 172%. So, it is possible to conclude that efavirenz microcrystals with enhanced dissolution and bioavailability can be formulated into tablets and are a viable system to develop a new drug product. Efavirenz process 1 50 m/v mv m v (m/v granulation Xray X ray PXRD (PXRD FTIR (FTIR 90 90% 83 material 80 80% observed 172 172% So product 9 8 17

This study details the preparation, antileishmanial assay, and in silico analysis of twenty 2-hydroxy-3-(1,2,3-triazolyl)propyl vanillin derivatives. These compounds were synthesized in three steps and evaluated against Leishmania infantum, Leishmania amazonensis, and Leishmania braziliensis promastigotes. Compounds 3s and 3t were the most effective, showing good activity against all Leishmania species tested. Molecular docking indicated that all compounds bind favorably to the sterol 14α-demethylase (CYP51) enzyme from L. infantum. ADMET (absorption, distribution, metabolism, excretion and toxicity) analysis indicated good oral bioavailability, non blood-brain barrier penetration, and high gastrointestinal absorption. Posaconazole and compounds 3e, 3s, and 3t remained stable in the CYP51 binding region during 100 ns molecular dynamics (MD) simulations. Root mean square deviation (RMSD) and root mean square fluctuations (RMSF) analyses from the MD trajectory revealed significant conformational fluctuations of the CYP51 N-terminal, suggesting occasional expulsion of 3e, potentially explaining its higher IC50 (half-maximal inhibitory concentration) values. Pairwise decomposition analyses from molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations highlighted the importance of hydrophobic residues in interacting with the synthesized derivatives. preparation assay 2hydroxy31,2,3triazolylpropyl 2hydroxy3123triazolylpropyl hydroxytriazolylpropyl 2 hydroxy 3 1,2,3 triazolyl propyl 1 derivatives infantum amazonensis promastigotes s t effective tested 14αdemethylase αdemethylase 14α demethylase α CYP (CYP51 L absorption, absorption (absorption distribution metabolism toxicity bioavailability bloodbrain blood brain penetration 3e e CYP5 10 (MD simulations RMSD (RMSD RMSF (RMSF Nterminal, Nterminal N terminal, terminal N-terminal IC IC5 halfmaximal half maximal concentration values PoissonBoltzmann Poisson Boltzmann MM/PBSA MMPBSA MM PBSA (MM/PBSA 2hydroxy31 3triazolylpropyl triazolylpropyl 123 1,2, (CYP5 2hydroxy3 12 1,2 (CYP 2hydroxy 1,

ABSTRACT: More and more countries are incorporating new safety, health and food safety regulations, responding to the growing concern about the use of antibiotic growth promoters (APC) in animal production, the scientific community has been forced to seek new alternatives that reduce or replace the use of (APC), with the ability to safeguard public health. Within these alternatives, phytobiotics are considered a very promising option, since they are natural substances made up of complex bioactive compounds. This document reviews the different applications and functionality of phytobiotics in animal production. Firstly, the main effects and mechanism of action are shown, highlighting and explaining their functionality as antioxidants, anti-inflammatory, antimicrobial, growth promoters, improvers of the organoleptic characteristics of foods and reduces the generation of gases that cause the greenhouse effect. Second, notable applications of phytobiotics to different species of zootechnical interest and their effect are reviewed. Finally, their bioavailability and the current and future challenges of phytobiotics are investigated.

RESUMEN: Cada vez más países van incorporando nuevas normativas de inocuidad, seguridad sanitaria y alimentaria, respondiendo a la progresiva preocupación por el uso de antibióticos promotores de crecimiento (APC) en producción animal; la comunidad científica se ha visto obligado a buscar nuevas alternativas que reduzcan o sustituyan el uso de APC, con la capacidad de salvaguardar la salud pública. Dentro de esas alternativas, los fitobióticos son considerados una opción muy prometedora, ya que son sustancias naturales constituidas por complejos compuestos bioactivos. Este documento revisa las distintas aplicaciones y la funcionalidad de los fitobióticos en la producción animal. En primer lugar, se manifiesta los principales efectos y mecanismo de acción, destacando y explicando su funcionalidad como antioxidantes, antiinflamatorios, antimicrobianos, promotores de crecimiento, mejoradores de las características organolépticas de los alimentos y reductores de la generación de gases causantes del efecto invernadero, Segundo, se revisan aplicaciones destacadas de los fitobióticos a las distintas especies de interés zootécnico y su efecto que estos tienen. Finalmente, se indaga su biodisponibilidad y los desafíos actuales y futuros de los fitobióticos.

Abstract The therapeutic potential of medicinal plants is known as an alternative in treatment of human affections; in effect, the conventional application of these medicinal sources has several limitations like low bioavailability, solubility and stability, which affect its pharmacological efficacy. In recent decades, extraordinary advances have been made in new drug delivery systems using nanocarriers. This work consisted in determining the in vitro antifungal activity of the methanolic extract of Euphorbia tirucalli formulated in polymeric nanoparticles. The antifungal activity was determined by the microdilution method in 96-well microplates, applying nanoparticles loaded with plant extract (NP-Ext) obtained by nanoprecipitation on clinical isolates of Trichophyton rubrum and T. interdigitalis. Regarding the nanoparticles, the lots used did not present significant differences in their physicochemical characteristics, with a size of 91.885 ± 1.621nm, polydispersity index of 0.152 ± 0.025 and Z-potential of -6.047 ± 0.987. The quantification of the extract in the polymeric matrix was determined by infrared spectroscopy (FTIR), where an efficiency and encapsulation percentage of 22.15 ± 0.82 and 2.95 ± 0.11, respectively, were obtained. The in vitro antifungal activity of the crude and formulated extract was obtained calculating the Minimum Inhibitory Concentration (MIC) of each one; a MIC of 125 µg/mL was obtained against T. rubrum and T. interdigitalis with the crude extract, while a MIC value of 55.55 and 0.1 µg/mL was obtained with NP-Ext, respectively, against these same. Conclusions: biological activity is closely linked to the phytochemical profile of the extract; while the improvement of said potential with the NP-Ext with the dosage form was directly related to the physicochemical characteristics of the nanocarrier. affections effect bioavailability stability efficacy decades nanocarriers 96well well 96 microplates NPExt NP Ext (NP-Ext T 91885 91 885 91.88 1621nm nm 1 621nm 1.621nm 0152 0 152 0.15 0025 025 0.02 Zpotential Z 6.047 6047 6 047 -6.04 0987 987 0.987 FTIR, FTIR , (FTIR) 2215 22 15 22.1 082 82 0.8 295 2 95 2.9 011 11 0.11 respectively (MIC one 12 µgmL µg mL 5555 55 55.5 01 0. NPExt, Ext, same Conclusions nanocarrier 9 9188 88 91.8 015 002 02 0.0 6.04 604 04 -6.0 098 98 0.98 (FTIR 221 22. 08 8 29 2. 555 5 55. 918 91. 00 6.0 60 -6. 09 0.9 6. -6 -

Resumo O potencial terapêutico das plantas medicinais é conhecido como alternativa para o tratamento das afecções humanas. Com efeito, a aplicação convencional dessas fontes medicinais apresenta diversas limitações, como baixa biodisponibilidade, solubilidade e estabilidade, que afetam sua eficácia farmacológica. Nas últimas décadas, avanços extraordinários foram feitos em novos sistemas de liberação de fármacos usando nanocarreadores. Este trabalho consistiu na determinação da atividade antifúngica in vitro do extrato metanólico de Euphorbia tirucalli, formulado em nanopartículas poliméricas. A atividade antifúngica foi determinada pelo método de microdiluição em microplacas de 96 poços, aplicando-se nanopartículas carregadas com extrato vegetal (NP-Ext) obtido por nanoprecipitação sobre isolados clínicos de Trichophyton rubrum e Trichophyton interdigitalis. Em relação às nanopartículas, os lotes utilizados não apresentaram diferenças significativas em suas características físico-químicas, com tamanho de 91,885 ± 1,621 nm, índice de polidispersão de 0,152 ± 0,025 e potencial Z de -6,047 ± 0,987. A quantificação do extrato na matriz polimérica foi determinada por espectroscopia de infravermelho (FT/IR), em que foram obtidas eficiência e porcentagem de encapsulamento de 22,15 ± 0,82 e 2,95 ± 0,11, respectivamente. A atividade antifúngica in vitro do extrato bruto e formulado foi calculada por meio da Concentração Inibitória Mínima (CIM) de cada um. Obteve-se uma CIM de 125 µg/mL contra T. rubrum e T. interdigitalis com o extrato bruto, enquanto o valor de CIM com NP-Ext contra estes mesmos fungos foi de, respectivamente, 55,55 e 0,1 µg/mL. Conclusões: a atividade biológica está intimamente ligada ao perfil fitoquímico do extrato, enquanto a melhora desse potencial com o NP-Ext com a forma farmacêutica esteve diretamente relacionada às características físico-químicas do nanocarreador. humanas efeito limitações biodisponibilidade estabilidade farmacológica décadas nanocarreadores tirucalli poliméricas 9 poços aplicandose aplicando se NPExt NP Ext (NP-Ext físicoquímicas, físicoquímicas físico químicas, químicas 91885 91 885 91,88 1621 1 621 1,62 nm 0152 0 152 0,15 0025 025 0,02 6,047 6047 6 047 -6,04 0987 987 0,987 FT/IR, FTIR FT/IR , FT IR (FT/IR) 2215 22 15 22,1 082 82 0,8 295 2 95 2,9 011 11 0,11 respectivamente (CIM um Obtevese Obteve 12 µgmL µg mL T 5555 55 55,5 01 0, Conclusões nanocarreador 9188 88 91,8 162 62 1,6 015 002 02 0,0 6,04 604 04 -6,0 098 98 0,98 (FT/IR 221 22, 08 8 29 2, 555 5 55, 918 91, 16 1, 00 6,0 60 -6, 09 0,9 6, -6 -

Resumo O cádmio (Cd) é um dos metais pesados não essenciais que é liberado no meio ambiente de forma natural ou antropogênica. São metais tóxicos altamente persistentes que prejudicam excepcionalmente as atividades industriais e agrícolas, contaminando o solo, a água e os alimentos. Sua resistência de longa duração no solo e na água resulta em acúmulo e absorção pelas plantas, levando à cadeia alimentar. Isso se torna um sério problema global que ameaça humanos e animais como componentes da cadeia alimentar. Os organismos vivos, principalmente os humanos, são expostos ao Cd através das plantas como uma das principais fontes de alimento vegetativo. Este artigo de revisão concentra-se nos sintomas das plantas afetadas pela toxicidade do Cd. A absorção de Cd desencadeia vários sintomas visíveis e invisíveis por plantas poluídas, como crescimento atrofiado, clorose, necrose e murcha. Além disso, são elaborados fatores que afetam a absorção e translocação de Cd nas plantas para entender o mecanismo que contribui para o seu acúmulo. A partir do conhecimento do acúmulo de Cd, esta revisão também discutiu as técnicas de fitorremediação - fitoextração, fitoestimulação, fitoestabilização, fitovolatização e rizofiltração na biorremediação do Cd.

Abstract Cadmium (Cd) is one of non-essential heavy metals which is released into environment naturally or anthropogenically. It is highly persistent toxic metals that are exceptionally distressing industrial and agriculture activities by contaminating soil, water and food. Its long-duration endurance in soil and water results in accumulation and uptake into plants, leading to the food chain. This becomes a serious global problem threatening humans and animals as food chain components. Living organisms, especially humans, are exposed to Cd through plants as one of the main vegetative food sources. This review paper is concentrated on the symptoms of the plants affected by Cd toxicity. The absorption of Cd triggers several seen and unseen symptoms by polluted plants such as stunted growth, chlorosis, necrosis and wilting. Apart from that, factors that affect the uptake and translocation of Cd in plants are elaborated to understand the mechanism that contributes to its accumulation. By insight of Cd accumulation, this review also discussed the phytoremediation techniques-phytoextraction, phytostimulation, phytostabilization, phytovolatization and rhizofiltration in bioremediating the Cd.

ABSTRACT: Chrysin flavonoid has been presented as having numerous and promising bioactive effects, such as antioxidant, anticonvulsant, antihypertensive, anti-inflammatory, antineoplastic, antihyperlipidemic, and antidepressant. However, one of the main challenges for advances in studies on the bioactivity of chrysin is its low bioavailability in humans. Thus, aiming to overcome this barrier, several studies have demonstrated the bioactive potential of capsules containing chrysin. The objective of this review was to present the main methodologies used for the encapsulation of chrysin, and its main biological effects demonstrated so far. Our intention is to offer ways to advancement of research in the area of flavonoid encapsulation. As for the encapsulation techniques, it was found that they are diverse, and the most recurrent encapsulating agents were PEG, PLGA polymers and their derivatives, in addition to other agents, such as PCL, albumin, lipids and chitosan.The bioactive effects of the capsules are also numerous, and anticarcinogenic effects are the most frequent, in addition to other effects such as antioxidant, antidiabetic, antimicrobial and neuroprotective. In conclusion, we verified a lack of use of green techniques for the encapsulation of chrysin, and the production of lipid-water emulsions and the dissolution of chrysin in ethanol seems to be alternatives in this regard. In addition, bioactive potential of these capsules can be evaluated in other experimental models, and should advance to clinical trials and application in food formulations. ABSTRACT antioxidant anticonvulsant antihypertensive antiinflammatory, antiinflammatory anti inflammatory, inflammatory anti-inflammatory antineoplastic antihyperlipidemic antidepressant However humans Thus barrier far diverse PEG derivatives PCL albumin chitosanThe chitosan frequent antidiabetic neuroprotective conclusion lipidwater lipid water regard models formulations

RESUMO: O flavonoide crisina tem sido apresentado como tendo numerosos e promissores efeitos bioativos, como antioxidante, anticonvulsivante, anti-hipertensivo, anti-inflamatório, antineoplásico, anti-hiperlipidêmico e antidepressivo. No entanto, um dos principais desafios para o avanço dos estudos sobre a bioatividade da crisina é sua baixa biodisponibilidade em humanos. Assim, visando superar essa barreira, diversos estudos têm demonstrado o potencial bioativo de cápsulas contendo crisina. O objetivo desta revisão é apresentar as principais metodologias utilizadas para o encapsulamento da crisina e seus principais efeitos biológicos demonstrados até o momento. Nossa intenção é oferecer caminhos para o avanço das pesquisas na área de encapsulação de flavonoides. Quanto às técnicas de encapsulamento, verificou-se que são diversas, e os agentes encapsulantes mais recorrentes são os polímeros PEG, PLGA e seus derivados, além de outros agentes como PCL, albumina, lipídeos e quitosana. Os efeitos bioativos das cápsulas também são numerosos, sendo os efeitos anticarcinogênicos os mais frequentes, além de outros efeitos como antioxidante, antidiabético, antimicrobiano e neuroprotetor. Em conclusão, verificamos a falta de utilização de técnicas verdes para o encapsulamento de crisina, e a produção de emulsões lipídeo-água e dissolução da crisina em etanol parecem ser alternativas neste aspecto. Além disso, o potencial bioativo destas cápsulas pode ainda ser avaliado em outros modelos experimentais, e deve-se avançar para ensaios clínicos e aplicação em formulações alimentícias. RESUMO antioxidante anticonvulsivante antihipertensivo, antihipertensivo anti hipertensivo, hipertensivo anti-hipertensivo antiinflamatório, antiinflamatório inflamatório, inflamatório anti-inflamatório antineoplásico antihiperlipidêmico hiperlipidêmico antidepressivo entanto humanos Assim barreira momento flavonoides verificouse verificou se diversas PEG derivados PCL albumina quitosana frequentes antidiabético neuroprotetor conclusão lipídeoágua lipídeo água aspecto disso experimentais devese deve alimentícias

Abstract Mangroves buffer metals transfer to coastal areas though strong accumulation in sediments making necessary to investigate metals’ bioavailability to plants at the rhizosphere. This work evaluates the effect of mangrove root activity, through iron plaque formation, on the mobility of iron and copper its influence on metals’ uptake, and translocation through simultaneous histochemical analysis. The Fe2+ and Fe3+ contents in porewaters ranged from 0.02 to 0.11 µM and 1.0 to 18.3 µg.l-1, respectively, whereas Cu concentrations were below the method’s detection limit (<0.1 µM). In sediments, metal concentrations ranged from 12,800 to 39,500 µg.g-1 for total Fe and from 10 to 24 µg.g-1 for Cu. In iron plaques, Cu concentrations ranged from 1.0 to 160 µg.g-1, and from 19.4 to 316 µg.g-1 in roots. Fe concentrations were between 605 to 36,000 µg.g-1 in the iron plaques and from 2,100 to 62,400 µg.g-1 in roots. Histochemical characterization showed Fe3+ predominance at the tip of roots and Fe2+ in more internal tissues. A. schaueriana showed significant amounts of Fe in pneumatophores and evident translocation of this metal to leaves and excretion through salt glands. Iron plaques formation was essential to the Fe and Cu regulation and translocation in tissues of mangrove plants. rhizosphere activity uptake analysis Fe2 Fe3 002 0 02 0.0 011 11 0.1 1 1. 183 18 3 18. µg.l1, µgl1 µgl µg.l 1, µg l µg.l-1 respectively methods method s <0.1 01 (<0. µM. . µM) 12800 12 800 12,80 39500 39 500 39,50 µg.g1 µgg1 µgg µg.g g µg.g- 2 16 µg.g1, 194 19 4 19. 31 60 36000 36 000 36,00 2100 100 2,10 62400 62 400 62,40 A glands 00 0. l1 µg.l1 µg.l- <0. (<0 1280 80 12,8 3950 50 39,5 g1 6 3600 36,0 210 2,1 6240 40 62,4 <0 (< 128 8 12, 395 5 39, 360 36, 21 2, 624 62, < (

ABSTRACT The objective of this study was to assess the impact of supplementing quail diets with organic selenium (Se) at various concentrations and inorganic Se on performance, egg quality, and storage time under different conditions. In the performance trial, 360 quail aged 27 weeks were included in a completely randomized design comprising six treatments: Basal Diet; 0.15, 0.30, 0.45, and 0.60 ppm of organic Se; and 0.60 ppm of inorganic Se, supplemented “on top” of the basal diet. Six replications were used, each with 10 birds per experimental unit. For the evaluation of storage time and conditions, 720 quail eggs were employed in a completely randomized design. The design featured a 6×5×2 factorial arrangement consisting of six treatments derived from the performance trial, five storage times (7, 14, 21, 28, and 35 days), and two storage forms (refrigerated and non-refrigerated). Each replication contained one egg, totaling 12 replications. Results indicated no significant effect of organic or inorganic Se supplementation in the diets on performance or egg quality. However, Se concentration increased linearly in eggs from quail fed increasing levels of this nutrient. Selenium supplementation affected storage time and egg quality under refrigerated and room-temperature conditions. In conclusion, on-top Se supplementation at concentrations ranging from 0.15 to 0.60 ppm, whether in organic or inorganic forms, does not impact quail performance. Nevertheless, it leads to increased Se deposition in eggs, contributing to the maintenance of egg quality throughout the storage period. (Se conditions trial 36 2 Diet 015 0 15 030 30 0.30 045 45 0.45 060 60 0.6 top diet used 1 unit 72 652 6 5 6×5× 7, 7 (7 14 21 28 3 days, days , days) nonrefrigerated. nonrefrigerated non . non-refrigerated) However nutrient roomtemperature room temperature conclusion ontop 0.1 Nevertheless period 01 03 0.3 04 4 0.4 06 0. 65 6×5 ( non-refrigerated 6×

RESUMO Objetivou-se avaliar a suplementação de selênio orgânico (Se org.) em diferentes concentrações e de selênio inorgânico (Se inorg.) nas rações de codornas sobre o desempenho; qualidade dos ovos; e tempo e condições de armazenamento. No ensaio de desempenho foram utilizadas 360 codornas com 27 semanas de idade, distribuídas em delineamento inteiramente casualizado (DIC) composto por seis tratamentos: Ração Basal; 0,15; 0,30; 0,45; e 0,60 ppm de Se org. e 0,60 ppm de Se inorg. suplementados on top à ração basal, com seis repetições e dez aves por unidade experimental. Para avaliar o tempo e condições de armazenamento foram utilizados 720 ovos de codornas distribuídos em DIC, com esquema fatorial 6x5x2 (sendo seis tratamentos provenientes do ensaio de desempenho; cinco tempos de estocagem (7, 14, 21, 28 e 35 dias); e duas formas de estocagem (refrigerada e não refrigerada), com doze repetições contendo um ovo cada. Não houve efeito na suplementação de Se org. e Se inorg. nas rações sobre desempenho e qualidade dos ovos. Houve aumento linear na concentração de Se nos ovos de codornas alimentadas com níveis crescentes deste nutriente. Houve efeito da suplementação com selênio sobre o tempo de estocagem na qualidade de ovos mantidos sob refrigeração e em temperatura ambiente. Conclui-se que a suplementação, on top, de níveis entre 0,15 e 0,60 ppm de selênio nas formas orgânica ou inorgânica, não altera o desempenho das codornas, acentuando, contudo, a deposição desse mineral nos ovos, favorecendo a manutenção da qualidade ao longo do tempo de armazenamento. Objetivouse Objetivou se org inorg 36 2 idade DIC (DIC Basal 015 0 15 0,30 030 30 0,45 045 45 060 60 0,6 basal experimental 72 xx x 6x5x sendo 7, 7 (7 14 21 3 dias dias) refrigerada refrigerada, , refrigerada) cada nutriente ambiente Concluise Conclui 0,1 inorgânica acentuando contudo 01 1 0,3 03 0,4 04 4 06 6 0, (

Resumen Objetivo Mapear las evidencias disponibles sobre las acciones del óxido nítrico en la fisiopatología de la sepsis y su relación con la gravedad de pacientes sépticos. Métodos Revisión de alcance de acuerdo con la metodología del Joanna Briggs Institute. Se realizó una búsqueda de estudios que evidenciaron las acciones del óxido nítrico en la sepsis y si su aumento estaba asociado a la gravedad de pacientes sépticos. Dos revisores independientes hicieron el mapeo de la información utilizando un instrumento de extracción de datos previamente elaborado. Los datos se analizaron respecto a su relevancia, para luego extraerlos y sintetizarlos. Resultados De 1342 estudios, se incluyeron 11 en la revisión. El primero fue publicado en 2017 y el último en 2022. La mayoría se realizó en Estados Unidos, China y Alemania. Los estudios presentaron información referente a las acciones del óxido nítrico, sintetizando su biodisponibilidad y los inhibidores endógenos relacionados con su producción, además de abordar la relación del óxido nítrico con la gravedad de la sepsis. Conclusión La producción de óxido nítrico fisiológico durante la sepsis actúa como protector vascular, principalmente en la microcirculación. Sin embargo, en altas concentraciones, contribuye a la disfunción vascular, que subvierte la fisiología de la regulación de la presión arterial, causa una profunda vasodilatación e hipotensión refractaria y aumenta la gravedad de pacientes sépticos. Registro da revisão de escopo no Open Science Framework: https://doi.org/10.17605/OSF.IO/MXDK2 sépticos Institute elaborado relevancia sintetizarlos 134 1 revisión 201 2022 Unidos Alemania vascular microcirculación embargo concentraciones arterial Framework https//doi.org/10.17605/OSF.IO/MXDK2 httpsdoiorg1017605OSFIOMXDK2 httpsdoiorgOSFIOMXDK https //doi.org/10.17605/OSF.IO/MXDK2 doi org 10 17605 OSF IO MXDK2 MXDK https://doi.org/10.17605/OSF.IO/MXDK 13 20 202 https//doi.org/10.17605/OSF.IO/MXDK httpsdoiorg OSFIOMXDK httpsdoiorg1017605OSFIOMXDK doiorg1017605OSFIOMXDK2 doiorgOSFIOMXDK //doi.org/10.17605/OSF.IO/MXDK 1760 2 doiorg doiorg1017605OSFIOMXDK 176 17

Abstract Objective Map the available evidence on the actions of nitric oxide in the pathophysiology of sepsis and its relationship with the severity of sepsis in patients. Method Scoping review following the Joanna Briggs Institute methodology. A search was carried out for studies that highlighted the actions of nitric oxide in sepsis, informing whether its increase is associated with the severity of sepsis in patients. Two independent reviewers mapped the information using a previously designed data extraction instrument. The data was analyzed for its relevance and then extracted and synthesized. Results Eleven of 1342 studies were included in the review. The first of them was published in 2017 and the last in 2022. Most of them were developed in the USA, China, and Germany. Studies have reported the actions and bioavailability of nitric oxide and endogenous inhibitors related to its production, and related nitric oxide to the severity of sepsis. Conclusion The physiological production of nitric oxide during sepsis acts as a vascular protector, mainly in the microcirculation but contributes to vascular dysfunction in high concentrations, subverting the regulation of blood pressure, causing deep vasodilation and refractory hypotension, and increasing the severity of sepsis in patients. Registration of the scoping review in the Open Science Framework: https://doi.org/10.17605/OSF.IO/MXDK2 patients methodology instrument synthesized 134 201 2022 USA China Germany protector concentrations pressure hypotension Framework https//doi.org/10.17605/OSF.IO/MXDK2 httpsdoiorg1017605OSFIOMXDK2 httpsdoiorgOSFIOMXDK https //doi.org/10.17605/OSF.IO/MXDK2 doi org 10 17605 OSF IO MXDK2 MXDK https://doi.org/10.17605/OSF.IO/MXDK 13 20 202 https//doi.org/10.17605/OSF.IO/MXDK httpsdoiorg OSFIOMXDK httpsdoiorg1017605OSFIOMXDK doiorg1017605OSFIOMXDK2 doiorgOSFIOMXDK //doi.org/10.17605/OSF.IO/MXDK 1 1760 2 doiorg doiorg1017605OSFIOMXDK 176 17

Resumo Objetivo Mapear as evidências disponíveis sobre as ações do óxido nítrico na fisiopatologia da sepse e sua relação com a gravidade de pacientes sépticos. Método Revisão de escopo de acordo com a metodologia do Joanna Briggs Institute. Realizou-se busca por estudos que evidenciaram as ações do óxido nítrico na sepse e se o seu aumento está associado à gravidade de pacientes sépticos. Dois revisores independentes fizeram o mapeamento das informações utilizando um instrumento de extração de dados previamente elaborado. Os dados foram analisados quanto à sua relevância, sendo posteriormente extraídos e sintetizados. Resultados De 1342 estudos, 11 foram incluídos na revisão. O primeiro foi publicado em 2017 e o último, em 2022. A maioria foi desenvolvida nos Estados Unidos, na China e na Alemanha. Os estudos apresentaram informações referentes as ações do óxido nítrico, sintetizando sua biodisponibilidade e os inibidores endógenos relacionados a sua produção, além de abordarem a relação do óxido nítrico com a gravidade da sepse. Conclusão A produção de óxido nítrico fisiológico durante a sepse atua como protetor vascular, principalmente na microcirculação, porém, em altas concentrações, contribui para a disfunção vascular, que subverte a fisiologia da regulação da pressão arterial, causando profunda vasodilatação e hipotensão refratária e aumentando a gravidade de pacientes sépticos. sépticos Institute Realizouse Realizou elaborado relevância sintetizados 134 1 revisão 201 último 2022 Unidos Alemanha vascular microcirculação porém concentrações arterial 13 20 202 2

Abstract Background: The bioactive peptides derived from snake venoms of the Viperidae family species have been promising as therapeutic candidates for neuroprotection due to their ability to prevent neuronal cell loss, injury, and death. Therefore, this study aimed to evaluate the cytoprotective effects of a synthetic proline-rich oligopeptide 7a (PRO-7a; <EDGPIPP) from Bothrops jararaca snake, on oxidative stress-induced toxicity in neuronal PC12 cells and astrocyte-like C6 cells. Methods: Both cells were pre-treated for four hours with different concentrations of PRO-7a, submitted to H2O2-induced damage for 20 h, and then the oxidative stress markers were analyzed. Also, two independent neuroprotective mechanisms were investigated: a) L-arginine metabolite generation via argininosuccinate synthetase (AsS) activity regulation to produce agmatine or polyamines with neuroprotective properties; b) M1 mAChR receptor subtype activation pathway to reduce oxidative stress and neuron injury. Results: PRO-7a was not cytoprotective in C6 cells, but potentiated the H2O2-induced damage to cell integrity at a concentration lower than 0.38 μM. However, PRO-7a at 1.56 µM, on the other hand, modified H2O2-induced toxicity in PC12 cells by restoring cell integrity, mitochondrial metabolism, ROS generation, and arginase indirect activity. The α-Methyl-DL-aspartic acid (MDLA) and L-NΩ-Nitroarginine methyl ester (L-Name), specific inhibitors of AsS and nitric oxide synthase (NOS), which catalyzes the synthesis of polyamines and NO from L-arginine, did not suppress PRO-7a-mediated cytoprotection against oxidative stress. It suggested that its mechanism is independent of the production of L-arginine metabolites with neuroprotective properties by increased AsS activity. On the other hand, the neuroprotective effect of PRO-7a was blocked in the presence of dicyclomine hydrochloride (DCH), an M1 mAChR antagonist. Conclusions: For the first time, this work provides evidence that PRO-7a-induced neuroprotection seems to be mediated through M1 mAChR activation in PC12 cells, which reduces oxidative stress independently of AsS activity and L-arginine bioavailability. Background loss injury death Therefore prolinerich proline rich PRO7a PROa PRO (PRO-7a <EDGPIPP EDGPIPP stressinduced induced PC PC1 astrocytelike astrocyte like C Methods pretreated pre treated PRO7a, 7a, H2O2induced HOinduced H2O2 H O 2 h analyzed Also investigated Larginine L arginine (AsS b M Results 038 0 38 0.3 μM However 156 1 56 1.5 µM hand metabolism αMethylDLaspartic α Methyl DL aspartic MDLA (MDLA LNΩNitroarginine NΩ Nitroarginine LName, LName Name , (L-Name) NOS, NOS (NOS) Larginine, arginine, PRO7amediated PROamediated DCH, DCH (DCH) antagonist Conclusions time PRO7ainduced PROainduced bioavailability HO H2O 03 3 0. 15 5 1. (L-Name (NOS amediated (DCH ainduced

Abstract Scaffolds with osteoconductivity, biocompatibility and good mechanical properties are promising for local drug release of sodium alendronate (ALN), a first-choice drug for treatment of bone tissue diseases, with low bioavailability. The viability to manufacture poly (L-lactic acid) (PLLA)/poly (methyl methacrylate) (PMMA) filaments containing ALN in different proportions, through extrusion, followed by scaffolds using 3D printing by fusion deposition modelling (FDM) and to investigate the influence of processes in mixtures drove this study. Differential scanning calorimetry (DSC), spectroscopy in the infrared region with Fourier transform (FTIR/ATR), and X-ray diffractometry (XRD) analysis indicated that PMMA decelerates crystallinity and confers malleability to PLLA/ALN mixture, besides its good processability and miscibility with PLLA and no relevant changes in physicochemical properties of components. Field emission scanning electron microscopy (SEM/FEG) showed good interfacial compatibility between PLLA/PMMA and homogeneously dispersed drug crystals in matrix. PLLA-PMMA-ALN scaffolds were manufactured by accurate with interesting properties for bone tissue engineering. osteoconductivity ALN, , (ALN) firstchoice first choice diseases bioavailability Llactic L lactic acid PLLA/poly PLLApoly /poly methyl methacrylate (PMMA proportions extrusion D FDM (FDM study DSC, DSC (DSC) FTIR/ATR, FTIRATR FTIR/ATR FTIR ATR (FTIR/ATR) Xray X ray XRD (XRD PLLAALN mixture components SEM/FEG SEMFEG SEM FEG (SEM/FEG PLLAPMMA matrix PLLAPMMAALN engineering (ALN (DSC (FTIR/ATR

Abstract Thiosemicarbazones are promising classes of compounds with antitumor activity. For this study, six 2,4-dihydroxy-benzylidene-thiosemicarbazones compounds were synthesized. These compounds were submitted to different assays in silico, in vitro and in vivo to evaluate the toxicological, antioxidant and antitumor effects. The in silico results were evaluated by the SwissADME and pkCSM platforms and showed that all compounds had good oral bioavailability profiles. The in vitro and in vivo toxicity assays showed that the compounds showed low cytotoxicity against different normal cells and did not promote hemolytic effects. The single dose acute toxicity test (2000 mg/kg) showed that none of the compounds were toxic to mice. In in vitro antioxidant activity assays, the compounds showed moderate to low activity, with PB17 standing out for the ABTS radical capture assay. The in vivo antioxidant activity highlighted the compounds 1, 6 and 8 that promoted a significant increase in the concentration of liver antioxidant enzymes. Finally, all compounds showed promising antitumor activity against different cell lines, especially MCF-7 and DU145 lines, in addition, they inhibited the growth of sarcoma 180 at concentrations lower than 50 mg/kg. These results showed that the evaluated compounds can be considered as potential antitumor agents. study 2,4dihydroxybenzylidenethiosemicarbazones 24dihydroxybenzylidenethiosemicarbazones dihydroxybenzylidenethiosemicarbazones 2,4 dihydroxy benzylidene thiosemicarbazones 2 4 synthesized toxicological effects profiles 2000 (200 mg/kg mgkg mg kg mice PB PB1 assay 1 enzymes Finally lines MCF7 MCF 7 MCF- DU DU14 addition 18 5 agents 4dihydroxybenzylidenethiosemicarbazones 24 2, 200 (20 DU1 20 (2 (

Abstract The study evaluated the use of nano copper in semi-purified diets for laying quails and its effect on performance, metabolic state, and bioavailability. A total of 160 (180-days-old) quails were distributed in a completely randomized design, in a 3x3+1 factorial. The copper sources used were copper sulfate, copper oxide, and nano copper oxide, at levels of 200, 400, and 800 ppm each, totaling nine treatments plus a negative control (with no copper inclusion). The following variables were determined: weight gain, feed intake, egg production, egg weight, hemoglobin, hematocrit, Cu in the tissues and Cu bioavailability. Data were subjected to analysis of variance at 5% probability. The effect of sources and levels, as well as the interaction between the factors were evaluated. When interaction was observed, the effect of sources was evaluated separately by the Tukey’s test and the effect of levels by regression, both at 5% probability. Copper nano oxide can be used at up to 800 ppm in the diet of laying quails without altering the productive performance, and with higher bioavailability than conventional copper oxide. Hemoglobin increases with the inclusion of 200 and 400 ppm of nano copper oxide and the hematocrit with 400 ppm. semipurified semi purified performance state 16 180daysold daysold 180 days old (180-days-old design 3x31 x 3x3 1 3x3+ factorial sulfate 80 each inclusion. . inclusion) determined gain intake production hemoglobin 5 probability observed Tukeys Tukey s regression 20 40 18 3x 8 2 4

Staphylococcus aureus is known worldwide as the principal cause of human bacterial infections; as well as methicillin-resistant Staphylococcus aureus (MRSA), is a major cause of hospital-acquired infections that are becoming increasingly difficult to combat because of emerging resistance to all current antibiotic classes. This work aims to carry out a theoretical study of molecules derived from beta-lactam compounds with possible potential antibiotic activity on Staphylococcus aureus. Therefore, computational chemistry tools were used to describe the interactions between potentially active molecules and the transpeptidase and beta-lactamase enzyme. These molecules were docked with transpeptidase and beta-lactamase enzymes, and all of them showed a higher affinity for transpeptidase (−1.81 kcal mol−1) than the reference molecule (methicillin), but only two showed a lower affinity for beta-lactamase (−6.8 kcal mol−1). The two ligands that presented the best ranking docking results were subjected to molecular dynamics simulations to assess conformational stability through root mean square deviation (RMSD) and root mean square fluctuation (RMSF) analysis. According to simulation, the ligands that bind to the proteins do not cause significant conformational changes in the structures of the proteins. The absorption, distribution, metabolism, and excretion (ADME) properties of the molecules with the lowest affinity for beta-lactamase were estimated. The ADME properties predict that the molecules would have good bioavailability. methicillinresistant methicillin resistant MRSA, MRSA , (MRSA) hospitalacquired hospital acquired classes betalactam beta lactam Therefore betalactamase lactamase enzyme enzymes −1.81 181 1 81 (−1.8 mol−1 mol1 mol methicillin, (methicillin) −6.8 68 6 8 (−6. mol−1. . RMSD (RMSD RMSF (RMSF analysis simulation absorption distribution metabolism (ADME estimated bioavailability (MRSA −1.8 18 (−1. mol− (methicillin −6. (−6 −1. (−1 −6 (− −1 − (

Abstract Cancer is a complex and multifactorial disease characterized by uncontrolled cell growth and is one of the main causes of death in the world. This work aimed to evaluate a small series of 10 different indole-thiosemicarbazone compounds as potential antitumor agents. This is a pioneering study. For this, the antioxidant and cytotoxic capacity against normal and tumor cells was evaluated. The results showed that the compounds were able to promote moderate to low antioxidant activity for the ABTS radical scavenging assay. ADMET in silico assays showed that the compounds exhibited good oral bioavailability. As for toxicity, they were able to promote low cytotoxicity against normal cells, in addition to not being hemolytic. The compounds showed promising in vitro antitumor activity against the T47D, MCF-7, Jurkat and DU-145 strains, not being able to inhibit the growth of the Hepg2 strain. Through this in vitro study, it can be concluded that the compounds are potential candidates for antitumor agents. world 1 indolethiosemicarbazone indole thiosemicarbazone agents study evaluated assay bioavailability toxicity hemolytic T47D TD T D MCF7, MCF7 MCF 7, 7 MCF-7 DU145 DU 145 DU-14 strains Hepg strain MCF- DU14 14 DU-1 DU1 DU-