Physical exercise is essential for increasing ventricular contractility in hypertensive rats treated with losartan.

The treatment of hypertensive patients with losartan is very common. Despite the reduction in blood pressure, its effects on cardiac contractility and sympathetic autonomic drive are still controversial. In turn, aerobic physical training (APT) also presents an important therapeutic option, providing significant improvements in cardiovascular autonomic control, however little is known about its effects on cardiac contractility, especially when associated with losartan. Therefore, we investigated in spontaneously hypertensive rats (SHR) the effects of losartan and APT on cardiac hemodynamics and functionality, with emphasis on autonomic tonic balance and cardiac contractility. Sixty-four SHR (18 weeks old) were divided into four groups (N = 16): vehicle; vehicle submitted to APT through swimming for 12 weeks; treated with losartan (5 mg·kg-1·d-1) for 12 weeks; and treated with losartan associated with APT. The groups were submitted to cardiac morphological and functional analysis by echocardiography; double blockade of cardiac autonomic receptors with atropine and propranolol; and coronary bed reactivity and left ventricular contractility analyses by the Langendorff technique. APT improved functional parameters and autonomic balance by reducing sympathetic drive and/or increasing vagal drive. In contrast, it promoted a concentric remodeling of the left ventricle (LV). Treatment with losartan reduced sympathetic autonomic drive and cardiac morphological parameters, but there were no significant gains in cardiac functionality and contractility. When combined, the concentric remodeling of the LV to APT was abolished and gains in cardiac functionality and contractility were observed. Our findings suggest that the effects of losartan and APT are complementary and should be applied together in the treatment of hypertension. In spontaneously hypertensive rats, the combination of aerobic physical training with losartan treatment was crucial to greater blood pressure reductions and an increase in left ventricular contractility. Furthermore, losartan treatment prevented the concentric left ventricular remodeling caused by aerobic physical training.

The central role of pyruvate metabolism on the epigenetic maturation and transcriptional profile of bovine oocytes.

In brief: Pyruvate metabolism is one of the main metabolic pathways during oocyte maturation. This study demonstrates that pyruvate metabolism also regulates the epigenetic and molecular maturation in bovine oocytes. Abstract: Pyruvate, the final product of glycolysis, undergoes conversion into acetyl-CoA within the mitochondria of oocytes, serving as a primary fuel source for the tricarboxylic acid (TCA) cycle. The citrate generated in the TCA cycle can be transported to the cytoplasm and converted back into acetyl-CoA. This acetyl-CoA can either fuel lipid synthesis or act as a substrate for histone acetylation. This study aimed to investigate how pyruvate metabolism influences lysine 9 histone 3 acetylation (H3K9ac) dynamics and RNA transcription in bovine oocytes during in vitro maturation (IVM). Bovine cumulus-oocyte complexes were cultured in vitro for 24 h, considering three experimental groups: Control (IVM medium only), DCA (IVM supplemented with sodium dichloroacetate, a stimulant of pyruvate oxidation into acetyl-CoA), or IA (IVM supplemented with sodium iodoacetate, a glycolysis inhibitor). The results revealed significant alterations in oocyte metabolism in both treatments, promoting the utilization of lipids as an energy source. These changes during IVM affected the dynamics of H3K9ac, subsequently influencing the oocyte's transcriptional activity. In the DCA and IA groups, a total of 148 and 356 differentially expressed genes were identified, respectively, compared to the control group. These findings suggest that modifications in pyruvate metabolism trigger the activation of metabolic pathways, particularly lipid metabolism, changing acetyl-CoA availability and H3K9ac levels, ultimately impacting the mRNA content of in vitro matured bovine oocytes.

Adaptative response to changes in pyruvate metabolism on the epigenetic landscapes and transcriptomics of bovine embryos.

The epigenetic reprogramming that occurs during the earliest stages of embryonic development has been described as crucial for the initial events of cell specification and differentiation. Recently, the metabolic status of the embryo has gained attention as one of the main factors coordinating epigenetic events. In this work, we investigate the link between pyruvate metabolism and epigenetic regulation by culturing bovine embryos from day 5 in the presence of dichloroacetate (DCA), a pyruvate analog that increases the pyruvate to acetyl-CoA conversion, and iodoacetate (IA), which inhibits the glyceraldehyde-3-phosphate dehydrogenase (GAPDH), leading to glycolysis inhibition. After 8 h of incubation, both DCA and IA-derived embryos presented higher mitochondrial membrane potential. Nevertheless, in both cases, lower levels of acetyl-CoA, ATP-citrate lyase and mitochondrial membrane potential were found in blastocysts, suggesting an adaptative metabolic response, especially in the DCA group. The metabolic alteration found in blastocysts led to changes in the global pattern of H3K9 and H3K27 acetylation and H3K27 trimethylation. Transcriptome analysis revealed that such alterations resulted in molecular differences mainly associated to metabolic processes, establishment of epigenetic marks, control of gene expression and cell cycle. The latter was further confirmed by the alteration of total cell number and cell differentiation in both groups when compared to the control. These results corroborate previous evidence of the relationship between the energy metabolism and the epigenetic reprogramming in preimplantation bovine embryos, reinforcing that the culture system is decisive for precise epigenetic reprogramming, with consequences for the molecular control and differentiation of cells.

Protective effect of exogenous melatonin on testicular histopathology and histomorphometry of adult rats with domperidone-induced hyperprolactinemia.

Hyperprolactinemia is a pathological condition resulting from increased prolactin that directly affects reproduction, as this condition inhibits the release of LH, FSH and gonadal steroidogenesis, bringing several negative clinical associations in reproduction. In contrast, melatonin (MEL) plays an important role in the regulation of steroidogenesis and modulates damages to the process of spermatogenesis. The objective was to analyze the protective effects of exogenous melatonin on the testis of hyperprolactinemic adult rats. Forty-eight male rats were used, divided into two treatment periods: 30 and 60 days, each treatment was subdivided into three groups: Control, Hyper (hyperprolactinemia), and Hyper+MEL (hyperprolactinemia and melatonin). Treatment with melatonin was 200 µg/100 g, subcutaneously. Induction of hyperprolactinemia was obtained with a dose of 4 mg/kg of domperidone, subcutaneously. The results of the histopathology demonstrated that the animals in the Hyper group presented degeneration of germ cells when compared to the control. In addition, the degenerations were presented in smaller quantities in the Hyper+MEL, in both treatment periods, evidencing the benefits of the melatonin in gonadal regeneration. The Hyper group of both treatment periods showed a decrease in tubular diameter, epithelium height, and tubular area, in addition to a decrease in Sertoli cells, when compared to the control and the Hyper+MEL group. In conclusion, the hyperprolactinemia can affect the germinal epithelium and testicular microstructure; the exogenous melatonin has a protective effect against hyperprolactinemia, reducing testicular damage.

Subtilisin of Leishmania amazonensis as Potential Druggable Target: Subcellular Localization, In Vitro Leishmanicidal Activity and Molecular Docking of PF-429242, a Subtilisin Inhibitor.

Subtilisin proteases, found in all organisms, are enzymes important in the post-translational steps of protein processing. In Leishmania major and L. donovani, this enzyme has been described as essential to their survival; however, few compounds that target subtilisin have been investigated for their potential as an antileishmanial drug. In this study, we first show, by electron microscopy and flow cytometry, that subtilisin has broad localization throughout the cytoplasm and membrane of the parasite in the promastigote form with foci in the flagellar pocket. Through in silico analysis, the similarity between subtilisin of different Leishmania species and that of humans were determined, and based on molecular docking, we evaluated the interaction capacity of a serine protease inhibitor against both life cycle forms of Leishmania. The selected inhibitor, known as PF-429242, has already been used against the dengue virus, arenaviruses, and the hepatitis C virus. Moreover, it proved to have antilipogenic activity in a mouse model and caused hypolipidemia in human cells in vitro. Here, PF-429242 significantly inhibited the growth of L. amazonensis promastigotes of four different strains (IC50 values = 3.07 ± 0.20; 0.83 ± 0.12; 2.02 ± 0.27 and 5.83 ± 1.2 µM against LTB0016, PH8, Josefa and LV78 strains) whilst having low toxicity in the host macrophages (CC50 = 170.30 µM). We detected by flow cytometry that there is a greater expression of subtilisin in the amastigote form; however, PF-429242 had a low effect against this intracellular form with an IC50 of >100 µM for intracellular amastigotes, as well as against axenic amastigotes (94.12 ± 2.8 µM for the LV78 strain). In conclusion, even though PF-429242 does not affect the intracellular forms, this drug will serve as a tool to explore pharmacological and potentially leishmanicidal targets.

Experimental evaluation of microplastic consumption by using a size-fractionation approach in the planktonic communities.

The increasing amount of plastic particles introduced into continental aquatic environments has drawn the attention of researchers around the globe. These particles can be assimilated by a wide range of aquatic organisms, from microorganisms to fish, causing detrimental effects on trophic webs. Using an experimental approach, we investigated the effect of microplastic particles of different sizes on the planktonic trophic chain by sampling natural plankton communities from a lake located in the Upper Paraná River floodplain, Brazil. Zooplankton samples were collected at the beginning of the experiment and after 36 h of incubation. Microplastic particles (MP) samples were taken every 12 h. The effect of MP particle consumption from the control and treatment groups indicates significant effects by all plankton size fractions (p < 0.05). We demonstrated that the presence of MP particles can significantly affect the trophic web, furthermore, we detected the effect of higher consumption effect of smaller size MP particles. This study suggest that the largest MP consumption effects come from the lower trophic levels of the trophic chain, such as protists. The competitive effect of large predators is a crucial factor in controlling the abundance of populations, and although they did not directly consume MP particles, they ingest them indirectly through prey capable of absorbing these compounds in the environment. Our findings warn that MP particles enter the food webs of tropical regions when exposed to these pollutants, and that the presence of these particles should not be neglected when studying freshwater ecosystems.

Effectiveness of the use of xylitol chewing gum in prevention of dental caries: A systematic review.

This systematic review of the literature assessed the effectiveness of using chewing gum containing only xylitol compared to prevention strategies or placebo in reducing the incidence of carious lesions in children using data obtained from randomized controlled trials. Electronic search was carried out in PubMed MEDLINE, Latin American and Caribbean Literature on the Health Science, Web of Science, Scopus, Science Direct, and Scientific Electronic Library Online through the period between 2000 and 2020. Included clinical studies were done in children when the xylitol was dispensed in gum and the preventive effect of xylitol on tooth decay was compared to other preventive strategies or control groups. The studies were evaluated for their quality to obtain the level of evidence. The preventive fraction of each study was extracted. Two hundred studies were found. After analyzing the inclusion and removal of duplicates, only five studies were analyzed for the quality of evidence. With the analysis through the Grading of Recommendations Assessment, Development, and Evaluation system, it was possible to verify the very low level of scientific evidence on the effectiveness of gums containing only xylitol for the prevention of caries in children. The preventive fraction obtained varied between - 0.31 and 0.57 depending on the compared prevention strategy. The conflicting results, limitations, and inconsistencies of the studies allow us to establish that there is insufficient evidence to support the use of gums containing only xylitol for the prevention of caries in children. Other properly designed clinical trials need to be carried out.

Effects of caffeine supplementation on muscle endurance, maximum strength, and perceived exertion in adults submitted to strength training: a systematic review and meta-analyses.

This study aimed to determine the effects of caffeine supplementation on muscle endurance, maximum strength, and ratings of perceived exertion (RPE) in individuals undergoing strength training with external resistance exercises. A search of three databases (PubMed, LiLACS, and CENTRAL) and gray literature was carried out to find randomized controlled trials, with a double-blind design, which investigated the effects of caffeine supplementation in healthy adults. Meta-analyses of weighted mean differences (WMD) and standardized mean differences (SMD) between caffeine and placebo groups from individual studies were performed using a random-effects model. Nineteen studies were included in the quantitative synthesis. Only the bench press and the leg press exercises were assessed in a sufficient number of studies to be included in meta-analyses. In the bench press exercise, caffeine supplementation improved strength resistance (WMD 0.87 (95% confidence interval (CI): 0.33, 1.41) repetitions, P = 0.001; 15 studies), and maximum strength (WMD 2.01 (95% CI: 0.20, 3.80) kg, P = 0.02; 7 studies), but showed no effect in RPE (SMD -0.45 (95% CI: -1.40, 0.48), P = 0.34, 7 studies) In the leg press exercise, no significant improvement were observed in muscle endurance (WMD: 1.24 (95% CI: -0.21, 2.70) repetitions, P = 0.09, 8 studies), maximum strength (WMD 8.49 (95% CI: -11.91, 28.90) kg, P = 0.415, 3 studies), and in RPE (SMD -0.17 (95% CI: -1.62, 1.27), P = 0.812, 3 studies). Caffeine supplementation showed a significant ergogenic effect on muscle endurance and maximum strength in the bench press exercise. More investigations are needed to clarify the contradictions in its effects regarding lower-body exercises.

Dendrimers in the context of nanomedicine.

Dendrimers are globular structures, presenting an initiator core, repetitive layers starting radially from the core and terminal groups on the surface, resembling tree architecture. These structures have been studied in many biological applications, as drug, DNA, RNA and proteins delivery, as well as imaging and radiocontrast agents. With reference to that, this review focused in providing examples of dendrimers used in nanomedicine. Although most studies emphasize cancer, there are others which reveal action in the neurosystem, reducing either neuroinflammation or protein aggregation. Dendrimers can carry bioactive compounds by covalent bond (dendrimer prodrug), or by ionic interaction or adsortion in the internal space of the nanostructure. Additionally, dendrimers can be associated with other polymers, as PEG (polyethylene glycol), and with targeting structures as aptamers, antibodies, folic acid and carbohydrates. Their products in preclinical/clinical trial and those in the market are also discussed, with a total of six derivatives in clinical trials and seven products available in the market.

Lipases obtained from orange wastes: Commercialization potential and biochemical properties of different varieties and fractions.

Brazil is the world's leading orange supplier for juice production purposes. However, the production process generates high amount of wastes, which leads to disposal problems. Orange wastes can be used for lipases production, incorporating the biorefinery concept into juice industries. Thus, the aim of the present study was to investigate the wastes of orange production chain as source of lipases based on different varieties (Pera, Hamlin, Valencia, and Natal), as well as on different fractions of wastes. The mass balance of the juice/wastes (2007-2016 crops) was evaluated, and lipases from different varieties and fraction were biochemically characterized. Overall, the wastes corresponded to approximately 43% of the fruit mass. All the fractions of all varieties showed lipase activity in emulsified olive oil and in p-nitrophenyl substrates. The highest lipase activities were obtained by Natal pulp in emulsified olive oil, Natal frit, and Hamlin peel in p-NPB and Hamlin frit in p-NPL and p-NPP. The bagasse, peel, and frit lipases from the different orange varieties showed optimum pH from 6.0 to 8.0 and optimal temperature from 30 °C to 60 °C. Thus, it is possible concluding that the orange processing for juice production purposes generates a large amount of wastes, which can be destined to profitable purposes as lipases production. Lipases produced by different fractions and varieties are biochemically diverse, enabling the application a wide range of processes. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 35: e2734, 2019.

Targeting Groups Employed in Selective Dendrons and Dendrimers.

The design of compounds with directed action to a defined organ or tissue is a very promising approach, since it can decrease considerably the toxicity of the drug/bioactive compound. For this reason, this kind of strategy has been greatly important in the scientific community. Dendrimers, on the other hand, comprise extremely organized macromolecules with many peripheral functionalities, stepwise controlled synthesis, and defined size. These nanocomposites present several biological applications, demonstrating their efficiency to act in the pharmaceutical field. Considering that, the main purpose of this review was describing the potential of dendrons and dendrimers as drug targeting, applying different targeting groups. This application has been demonstrated through interesting examples from the literature considering the last ten years of publications.