Development of New Leishmanicidal Compounds via Bioconjugation of Antimicrobial Peptides and Antileishmanial Guanidines.

Leishmaniasis refers to a collection of diseases caused by protozoa from the Leishmania genus. These diseases, along with other parasitic afflictions, pose a significant public health issue, particularly given the escalating number of at-risk patients. This group includes immunocompromised individuals and those residing in impoverished conditions. The treatment of leishmaniasis is crucial, particularly in light of the mortality rate associated with nontreatment, which stands at 20-30,000 deaths per year globally. However, the therapeutic options currently available are limited, often ineffective, and potentially toxic. Consequently, the pursuit of new therapeutic alternatives is warranted. This study aims to design, synthesize, and evaluate the leishmanicidal activity of antimicrobial peptides functionalized with guanidine compounds and identify those with enhanced potency and selectivity against the parasite. Accordingly, three bioconjugates were obtained by using the solid-phase peptide synthesis protocol. Each proved to be more potent against intracellular amastigotes than their respective peptide or guanidine compounds alone and demonstrated higher selectivity to the parasites than to the host cells. Thus, the conjugation strategy employed with these compounds effectively contributes to the development of new molecules with leishmanicidal activity.

Leishmanicidal Activity of Guanidine Derivatives against Leishmania infantum.

Leishmaniasis is a neglected tropical infectious disease with thousands of cases annually; it is of great concern to global health, particularly the most severe form, visceral leishmaniasis. Visceral leishmaniasis treatments are minimal and have severe adverse effects. As guanidine-bearing compounds have shown antimicrobial activity, we analyzed the cytotoxic effects of several guanidine-bearing compounds on Leishmania infantum in their promastigote and amastigote forms in vitro, their cytotoxicity in human cells, and their impact on reactive nitrogen species production. LQOFG-2, LQOFG-6, and LQOFG-7 had IC50 values of 12.7, 24.4, and 23.6 µM, respectively, in promastigotes. These compounds exhibited cytotoxicity in axenic amastigotes at 26.1, 21.1, and 18.6 µM, respectively. The compounds showed no apparent cytotoxicity in cells from healthy donors. To identify mechanisms of action, we evaluated cell death processes by annexin V and propidium iodide staining and nitrite production. Guanidine-containing compounds caused a significant percentage of death by apoptosis in amastigotes. Independent of L. infantum infection, LQOFG-7 increased nitrite production in peripheral blood mononuclear cells, which suggests a potential mechanism of action for this compound. Therefore, these data suggest that guanidine derivatives are potential anti-microbial molecules, and further research is needed to fully understand their mechanism of action, especially in anti-leishmanial studies.

Novel Selective and Low-Toxic Inhibitor of LmCPB2.8ΔCTE (CPB) One Important Cysteine Protease for Leishmania Virulence.

Leishmaniasis is a highly prevalent, yet neglected disease caused by protozoan parasites of the genus Leishmania. In the search for newer, safer, and more effective antileishmanial compounds, we herein present a study of the mode of action in addition to a detailed structural and biological characterization of LQOF-G6 [N-benzoyl-N'-benzyl-N″-(4-tertbutylphenyl)guanidine]. X-ray crystallography and extensive NMR experiments revealed that LQOF-G6 nearly exclusively adopts the Z conformation stabilized by an intramolecular hydrogen bond. The investigated guanidine showed selective inhibitory activity on Leishmania major cysteine protease LmCPB2.8ΔCTE (CPB) with ~73% inhibition and an IC50-CPB of 6.0 µM. This compound did not show any activity against the mammalian homologues cathepsin L and B. LQOF-G6 has been found to be nontoxic toward both organs and several cell lines, and no signs of hepatotoxicity or nephrotoxicity were observed from the analysis of biochemical clinical plasma markers in the treated mice. Docking simulations and experimental NMR measurements showed a clear contribution of the conformational parameters to the strength of the binding in the active site of the enzyme, and thus fit the differences in the inhibition values of LQOF-G6 compared to the other guanidines. Furthermore, the resulting data render LQOF-G6 suitable for further development as an antileishmanial drug.

Novel Biobased Epoxy Thermosets and Coatings from Poly(limonene carbonate) Oxide and Synthetic Hardeners.

In the area of coating development, it is extremely difficult to find a substitute for bisphenol A diglycidyl ether (DGEBA), the classical petroleum-based raw material used for the formulation of epoxy thermosets. This epoxy resin offers fast curing reaction with several hardeners and the best thermal and chemical resistance properties for applications in coatings and adhesive technologies. In this work, a new biobased epoxy, derived from poly(limonene carbonate) oxide (PLCO), was combined with polyetheramine and polyamineamide curing agents, offering a spectrum of thermal and mechanical properties, superior to DGEBA-based thermosets. The best formulation was found to be a combination of PLCO and a commercial curing agent (Jeffamine) in a stoichiometric 1:1 ratio. Although PLCO is a solid due to its high molecular weight, it was possible to create a two-component partially biobased epoxy paint without the need of volatile organic compounds (i.e., solvent-free formulation), intended for use in coating technology to partially replace DGEBA-based thermosets.

A Biosourced Epoxy Resin for Adhesive Thermoset Applications.

Biobased epoxy-derived raw materials will be essential for future coating and adhesive designs in industry. Here, a facile approach is reported towards the incorporation of limonene into an epoxy-functionalized polycarbonate and its crosslinking with a polyamine curing agent to obtain a thermoset material. For the first time, a solvent-borne adhesive with excellent film-forming, mechanical and adhesion strength properties is described.

Individual-based Creatine Kinase Reference Values in Response to Soccer Match-play.

The aim of the present study was to determine the creatine kinase reference limits for professional soccer players based on their own normal post-match response. The creatine kinase concentration was analyzed in response to official matches in 25 players throughout a 3-year period. Samples were obtained between 36-43 hours following 70 professional soccer matches and corresponded to 19.1±12.1 [range: 6-49] samples per player. Absolute reference limits were calculated as 2.5th and 97.5th percentile of the samples collected. Creatine kinase values were also represented as a percentage change from the individual's season mean and represented by 90th, 95th and 97.5th percentiles. The absolute reference limits for creatine kinase concentration calculated as 97.5th and 2.5th percentiles were 1480 U.L-1 and 115.8 U.L-1, respectively. The percentage change from the individual's season mean was 97.45±35.92% and players were in the 90th, 95th and 97.5th percentiles when the percentages of these differences were 50.01, 66.7, and 71.34% higher than player's season mean response, respectively. The data allowed us to determine whether the creatine kinase response is typical or if it is indicative of a higher than normal creatine kinase elevation and could be used as a practical guide for detection of muscle overload, following professional soccer match-play.

Green Nanocoatings Based on the Deposition of Zirconium Oxide: The Role of the Substrate.

Herein, the influence of the substrate in the formation of zirconium oxide monolayer, from an aqueous hexafluorozirconic acid solution, by chemical conversion and by electro-assisted deposition, has been approached. The nanoscale dimensions of the ZrO2 film is affected by the substrate nature and roughness. This study evidenced that the mechanism of Zr-EAD is dependent on the potential applied and on the substrate composition, whereas conversion coating is uniquely dependent on the adsorption reaction time. The zirconium oxide based nanofilms were more homogenous in AA2024 substrates if compared to pure Al grade (AA1100). It was justified by the high content of Cu alloying element present in the grain boundaries of the latter. Such intermetallic active sites favor the obtaining of ZrO2 films, as demonstrated by XPS and AFM results. From a mechanistic point of view, the electrochemical reactions take place simultaneously with the conventional chemical conversion process driven by ions diffusion. Such findings will bring new perspectives for the generation of controlled oxide coatings in modified electrodes used, as for example, in the construction of battery cells; in automotive and in aerospace industries, to replace micrometric layers of zinc phosphate by light-weight zirconium oxide nanometric ones. This study is particularly addressed for the reduction of industrial waste by applying green bath solutions without the need of auxiliary compounds and using lightweight ceramic materials.

Effects of Plyometric Versus Optimum Power Load Training on Components of Physical Fitness in Young Male Soccer Players.

PURPOSE: The current study aimed to compare the effects of plyometric (PT) versus optimum power load (OPL) training on physical performance of young high-level soccer players. METHODS: Athletes were randomly divided into PT (horizontal and vertical drills) and OPL (squat + hip thrust exercises at the load of maximum power output) interventions, applied over 7 weeks during the in-season period. Squat and countermovement jumps, maximal sprint (10 and 30 m), and change of direction (COD; agility t test) were the pretraining and posttraining measured performance variables. Magnitude-based inference was used for within- and between-group comparisons. RESULTS: OPL training induced moderate improvements in vertical squat jump (effect size [ES]: 0.97; 90% confidence interval [CI], 0.32-1.61) and countermovement jump (ES: 1.02; 90% CI, 0.46-1.57), 30-m sprint speed (ES: 1.02; 90% CI, 0.09-1.95), and COD performance (ES: 0.93; 90% CI, 0.50-1.36). After PT training method, vertical squat jump (ES: 1.08; 90% CI, 0.66-1.51) and countermovement jump (ES: 0.62; 90% CI, 0.18-1.06) were moderately increased, while small enhancements were noticed for 30-m sprint speed (ES: 0.21; 90% CI, -0.02 to 0.45) and COD performance (ES: 0.53; 90% CI, 0.24-0.81). The 10-m sprint speed possibly increased after PT intervention (small ES: 0.25; 90% CI, -0.05 to 0.54), but no substantial change (small ES: 0.36; 90% CI, -0.40 to 1.13) was noticed in OPL. For between-group analyses, the COD ability and 30-m sprint performances were possibly (small ES: 0.30; 90% CI, -0.20 to 0.81; Δ = +1.88%) and likely (moderate ES: 0.81; 90% CI, -0.16 to 1.78; Δ = +2.38%) more improved in the OPL than in the PT intervention, respectively. CONCLUSIONS: The 2 different training programs improved physical performance outcomes during the in-season period. However, the combination of vertically and horizontally based training exercises (squat + hip thrust) at optimum power zone led to superior gains in COD and 30-m linear sprint performances.

Tos psicógena: una rara causa de la tos crónica / Psychogenic cough: A rare cause of chronic cough

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Antinociception induced by chronic glucocorticoid treatment is correlated to local modulation of spinal neurotransmitter content.

BACKGROUND: While acute effects of stress on pain are well described, those produced by chronic stress are still a matter of dispute. Previously we demonstrated that chronic unpredictable stress results in antinociception in the tail-flick test, an effect that is mediated by increased levels of corticosteroids. In the present study, we evaluated nociception in rats after chronic treatment with corticosterone (CORT) and dexamethasone (DEX) in order to discriminate the role of each type of corticosteroid receptors in antinociception. RESULTS: Both experimental groups exhibited a pronounced antinociceptive effect after three weeks of treatment when compared to controls (CONT); however, at four weeks the pain threshold in CORT-treated animals returned to basal levels whereas in DEX-treated rats antinociception was maintained. In order to assess if these differences are associated with altered expression of neuropeptides involved in nociceptive transmission we evaluated the density of substance P (SP), calcitonin gene-related peptide (CGRP), somatostatin (SS) and B2-gamma-aminobutiric acid receptors (GABAB2) expression in the spinal dorsal horn using light density measurements and stereological techniques. After three weeks of treatment the expression of CGRP in the superficial dorsal horn was significantly decreased in both CORT and DEX groups, while GABAB2 was significantly increased; the levels of SP for both experimental groups remained unchanged at this point. At 4 weeks, CGRP and SP are reduced in DEX-treated animals and GABAB2 unchanged, but all changes were restored to CONT levels in CORT-treated animals. The expression of SS remained unaltered throughout the experimental period. CONCLUSION: These data indicate that corticosteroids modulate nociception since chronic corticosteroid treatment alters the expression of neuropeptides involved in nociceptive transmission at the spinal cord level. As previously observed in some supraspinal areas, the exclusive GR activation resulted in more profound and sustained behavioural and neurochemical changes, than the one observed with a mixed ligand of corticosteroid receptors. These results might be of relevance for the pharmacological management of certain types of chronic pain, in which corticosteroids are used as adjuvant analgesics.

[Ankle sprains: from diagnosis to management. the physiatric view]. / Entorses do tornozelo: do diagnóstico ao tratamento perspectiva fisiátrica.

Ankle injuries are the most frequently encountered injuries in clinical practice. They are often managed by general practicians, and not only by orthopaedic or physiatric physicians. This injury is usually non-complicated, but some care should be taken to assure an adequate management and to exclude severe lesions. The stability of the ankle is necessary for functional activity of lower extremity, allowing walking and participation in other high demanding activities like running or jumping. There is a constant concern in adopting the best diagnostic and treatment procedures to enhance the recovery and to prevent the chronic joint instability. According to this, there should be proposed comprehensive strategies focusing the rehabilitation view. The ankle is a complex articular structure with contributions from the talocrural, subtalar, and inferior tibiofibular joints. The full understanding of the functional anatomy and biomechanics is the first step for the evaluation of the etiologic factors. The recognition of the mechanism of injury, and the risk factors, should be carefully addressed to make an accurate diagnosis, proper management and to implement prophylactic measures, knowing that the lateral ligamentous complex is the most commonly injured. As always, diagnosis can be made taking an adequate history, performing a thorough physical examination, and when necessary, requesting complementary studies. The priority in initial assessment it's to clear out some severe complications, like fractures, that can mimic or that can be associated with ankle sprains. Although the conventional radiology is suitable for most cases, that has been greatly improved through the institution of the Ottawa Rules, in selected patients the severity of the damage is best evaluated with other imaging resources. Treatment of acute ankle sprains depends on the severity of the injury. Most acute lateral ligament injuries are best treated nonsurgically and will regain satisfactory ankle stability after functional treatment. The conservative approach has been found to be equally effective in treating grade I and II ankle sprains. Some controversy still exists regarding the appropriate treatment of grade III injuries. General belief is that the majority of these patients may also be treated well with conservative management. Surgical reconstruction may be necessary, in cases that develop chronic functional instability, and especially in athletes with high demands on ankle joint stability. The purpose of this article is to review the biomechanics, clinical examination, diagnosis, management and secondary prevention of ankle sprains. We discuss the use and benefit of different modalities and outline a three-phase intervention program of rehabilitation based on recent guidelines.

Hydrotherapy study in patients with failed back surgery syndrome: a therapeutic option / Estudo da hidroterapia em pacientes com síndrome pós-laminectomia: uma opção terapêutica

The study was carried out to evaluate the efficacy of hydrotherapy on ?failed back surgery syndrome?. Eight participants were assigned to an aquatic exercise group. The analgesic medication was withdrawn during the study. Evaluation parameters included the results of the Visual Analogue Scale (VAS) score and spine mobility. The patients were assessed at baseline and at the end of the 6-week follow-up period. The results showed that hydrotherapy had a positive impact on the outcome of chronic post-surgical low back pain. After 6 weeks of hydrotherapy, without analgesic medication, the overall mobility of the spine improved and back pain decreased. We conclude that aquatic exercises may positively impact the outcome of ?failed back surgery syndrome?, probably remaining one of the few successful measures in the management of this kind of patient.

O presente estudo foi realizado para avaliar a eficácia da hidroterapia na ?síndrome pós-laminectomia?. Oito participantes foram designados para um grupo de exercícios aquáticos. A medicação analgésica foi descontinuada durante o estudo. Os parâmetros de avaliação incluíram o escore da Escala Visual Analógica (EVA) e a mobilidade da coluna vertebral. Os pacientes foram avaliados em condições basais e ao final do período de seguimento de seis semanas. Os resultados mostraram que a hidroterapia teve um impacto positivo nos resultados da dor lombar crônica pós-cirúrgica. Após seis semanas de hidroterapia, sem medicação analgésica, a mobilidade geral da coluna melhorou e a dor lombar diminuiu. Concluímos que exercícios na água podem ter um impacto positivo no resultado da síndrome da falência da cirurgia lombar, provavelmente sendo uma das poucas medidas bem sucedidas no tratamento desse tipo de paciente.

Efeitos da microinjeção de agonistas de receptores opióides na matéria cinzenta periaquedutal dorsal de ratos submetidos ao teste do labirinto em cruz elevado

Este trabalho verificou os efeitos ansiolítico e ansiogênico obtidos após a microinjeção de agonistas mu e capa, respectivamente. Foi também verificado que estes efeitos foram bloqueados pelos respectivos antagonistas maltrexona e u50,488-h (AU)

Modulação opióide do substrato neural do comportamento defensivo na matéria cinzenta periaquedutal dorsal de ratos

Este trabalho analisou o envolvimento de mecanismos opióides na geração e elaboração de estados aversivos na matéria cinzenta periaquedutal dorsal (mcpd). Para isto, ratos implantados com quimitrodos nesta região foram submetidos ao teste do labirinto em cruz elevado. Os resultados obtidos mostraram que a morfina, em doses baixas, apresenta claros efeitos aversivos neste teste; enquanto que doses altas produzem efeitos pró-aversivos. As evidências obtidas sugerem que os efeitos anti-aversivos da morfina podem ser mediados por receptores opióides 'MI' e que os efeitos pró-aversivos podem ser mediados por receptores opióides do tipo k (AU)