Effect of immersion in disinfectants on the color stability of denture base resins and artificial teeth obtained by 3D printing.

PURPOSE: To evaluate the effect of immersion in disinfecting solutions on the color stability of denture base resins and artificial teeth obtained by 3D printing. MATERIALS AND METHODS: Forty discs (15 × 3 mm) were obtained for each group: Lucitone 550 and Cosmos Denture 3D (denture base resins), Duralay and Cosmos TEMP 3D (artificial teeth resins). The discs were immersed in disinfectant solutions: Corega Tabs, 2% chlorhexidine digluconate, 0.25% sodium hypochlorite, and distilled water. Color measurements were obtained with a spectrophotometer before immersion in disinfectants and after the simulated periods of 6 and 12 months. Data (ΔE00 ) were submitted to mixed three-way ANOVA and Bonferroni post-test. RESULTS: For denture base resins, Cosmos Denture 3D showed greater color change regardless of the solution and immersion time. The immersion time of 6 months influenced the color change of the denture base resins regardless of the disinfectant solution. For the artificial teeth resins, the immersion time of 12 months showed a significant color change when compared to 6 months. Cosmos TEMP 3D showed greater color change for all solutions, except for 0.25% sodium hypochlorite. Duralay resin showed greater color change in 2% chlorhexidine, regardless of immersion time. CONCLUSIONS: For denture base resins, the immersion time significantly changed the color regardless of the solution. For artificial teeth resins, Cosmos TEMP 3D showed greater color changes in all solutions when compared to Duralay, except for 0.25% sodium hypochlorite. Chlorhexidine digluconate significantly changed the color of Duralay.

Microbial adhesion and biofilm formation by Candida albicans on 3D-printed denture base resins.

This study evaluated surface properties and adhesion/biofilm formation by Candida albicans on 3D printed denture base resins used in 3D printing. Disc-shaped specimens (15 mm x 3 mm) of two 3D-printed resins (NextDent Denture 3D+, NE, n = 64; and Cosmos Denture, CO, n = 64) and a heat-polymerized resin (Lucitone 550, LU, control, n = 64) were analyzed for surface roughness (Ra µm) and surface free energy (erg cm-2). Microbiologic assays (90-min adhesion and 48-h biofilm formation by C. albicans) were performed five times in triplicate, with the evaluation of the specimens' surface for: (i) colony forming units count (CFU/mL), (ii) cellular metabolism (XTT assay), and (iii) fluorescence and thickness of biofilm layers (confocal laser scanning microscopy). Data were analyzed using parametric and nonparametric tests (α = 0.05). LU presented higher surface roughness Ra (0.329±0.076 µm) than NE (0.295±0.056 µm) (p = 0.024), but both were similar to CO (0.315±0.058 µm) (p = 1.000 and p = 0.129, respectively). LU showed lower surface free energy (47.47±2.01 erg cm-2) than CO (49.61±1.88 erg cm-2) and NE (49.23±2.16 erg cm-2) (p<0.001 for both). The CO and NE resins showed greater cellular metabolism (p<0.001) and CO only, showed greater colonization (p = 0.015) by C. albicans than LU in the 90-min and 48-hour periods. It can be concluded that both 3D-printed denture base resins are more prone to colonization by C. albicans, and that their surface free energy may be more likely associated with that colonization than their surface roughness.

Antileishmanial activity of 2-amino-thiophene derivative SB-200.

Leishmaniasis, presenting the highest number of cases worldwide is one of the most serious Neglected Tropical Diseases (NTDs). Clinical manifestations are intrinsically related to the host's immune response making immunomodulatory substances the target of numerous studies on antileishmanial activity. The currently available drugs used for treatment present various problems including high toxicity, low efficacy, and associated drug resistance. The search for therapeutic alternatives is urgent, and in this context, thiophene derivatives appear to be a promising therapeutic alternative (many have shown promising anti-leishmanial activity). The objective of this study was to investigate the antileishmanial activity of the 2-amino-thiophenic derivative SB-200. The thiophenic derivative was effective in inhibiting the growth of Leishmania braziliensis, Leishmania major, and Leishmania infantum promastigotes, obtaining respective IC50 values of 4.25 µM, 4.65 µM, and 3.96 µM. For L. infantum, it was demonstrated that the antipromastigote effect of SB-200 is associated with cell membrane integrity losses, and with morphological changes observed during scanning and transmission electron microscopy. Cytotoxicity was performed for J774.A1 macrophages and VERO cells, to obtain a CC50 of 42.52 µM and a SI of 10.74 for macrophages and a CC50 of 39.2 µM and an SI of 9.89 for VERO cells. The anti-amastigote activity of SB-200 revealed an IC50 of 2.85 µM and an SI of 14.97 against macrophages and SI of 13.8 for VERO cells. The anti-amastigote activity of SB-200 is associated with in vitro immunomodulation. For acute toxicity, SB-200 against Zophobas morio larvae permitted 100% survival. We conclude that the 2-amino-thiophenic derivative SB-200 is a promising candidate for in vivo anti-leishmania drug tests to evaluate its activity, efficacy, and safety.

Effectiveness of disinfectant solutions associated or not with brushing on the biofilm control of a 3D printed-denture base resin.

BACKGROUND: The formation of biofilm on denture bases is a recurrent clinical problem that favors the development of denture stomatitis. The effectiveness of a hygiene protocol in a 3D-printed denture base resin is still uncertain. OBJECTIVE: To evaluate of the effectiveness of immersion, associated or not with brushing in a soap solution, on the biofilm control of a 3D-printed denture base resin. METHODOLOGY: Specimens of denture base resins [Cosmos Denture (COS) and Classico (CLA/control)] were contaminated in vitro with Candida albicans and immersed in sodium hypochlorite 0.25% (SH, alkaline peroxide) AP, chlorhexidine digluconate 2% (CD or PBS-Control), associated or not with brushing with 0.78% Lifebuoy soap. Roughness was evaluated before and after brushing and immersion. The effectiveness of the protocols was assessed by CFU/mL, cellular metabolism (XTT), scanning electron microscopy (SEM), and confocal scanning laser microscopy. Data were analyzed by T student, ANOVA/Welch, and Tukey/Gomes-Howell pos-hoc tests (α = 0.05). RESULTS: CLA showed greater roughness than COS. CFU/mL and XTT were higher in COS resin with a higher hyphae formation. Immersion in SH and CD eliminated CFU/mL and reduced XTT for both resins, associated or not with brushing. AP reduced CFU/mL only when associated with brushing. CONCLUSIONS: The biofilm on the 3D-printed resin was thicker and presumably more pathogenic, regardless of its smoother surface. Immersions in SH 0.25% and CD 2% are effective hygiene protocols for both resins, associated or not with brushing. AP should be recommended when associated with brushing with a Lifebuoy 0.78% solution.

Cytotoxic and Antileishmanial Effects of the Monoterpene ß-Ocimene.

Leishmaniasis is a group of infectious-parasitic diseases with high mortality rates, and endemic in many regions of the globe. The currently available drugs present serious problems such as high toxicity, costs, and the emergence of drug resistance. This has stimulated research into new antileishmania drugs based on natural products and their derivatives. ß-Ocimene is a monoterpene found naturally in the essential oils of many plant species which presents antileishmanial activity, and which has not yet been evaluated for its potential to inhibit the etiological agent of leishmaniasis. The aim of this work was to evaluate the activity of ß-ocimene against Leishmania amazonensis, its cytotoxicity, and potential mechanisms of action. ß-Ocimene presented direct activity against the parasite, with excellent growth inhibition of promastigotes (IC50 = 2.78 µM) and axenic amastigotes (EC50 = 1.12 µM) at concentrations non-toxic to RAW 264.7 macrophages (CC50 = 114.5 µM). The effect is related to changes in membrane permeability and resulting abnormalities in the parasitic cell shape. These were, respectively, observed in membrane integrity and atomic force microscopy assays. ß-Ocimene was also shown to act indirectly, with greater activity against intra-macrophagic amastigotes (EC50 = 0.89 µM), increasing TNF-α, nitric oxide (NO), and reactive oxygen species (ROS), with lysosomal effects, as well as promoting decreases in IL-10 and IL-6. Against intra-macrophagic amastigote forms the selectivity index was higher than the reference drugs, being 469.52 times more selective than meglumine antimoniate, and 42.88 times more selective than amphotericin B. Our results suggest that ß-ocimene possesses promising in vitro antileishmania activity and is a potential candidate for investigation in in vivo assays.

Selene-Ethylenelacticamides and N-Aryl-Propanamides as Broad-Spectrum Leishmanicidal Agents.

The World Health Organization classifies Leishmania as one of the 17 "neglected diseases" that burden tropical and sub-tropical climate regions with over half a million diagnosed cases each year. Despite this, currently available anti-leishmania drugs have high toxicity and the potential to be made obsolete by parasite drug resistance. We chose to analyze organoselenides for leishmanicidal potential given the reduced toxicity inherent to selenium and the displayed biological activity of organoselenides against Leishmania. Thus, the biological activities of 77 selenoesters and their N-aryl-propanamide derivatives were predicted using robust in silico models of Leishmania infantum, Leishmania amazonensis, Leishmania major, and Leishmania (Viannia) braziliensis. The models identified 28 compounds with >60% probability of demonstrating leishmanicidal activity against L. infantum, and likewise, 26 for L. amazonesis, 25 for L. braziliensis, and 23 for L. major. The in silico prediction of ADMET properties suggests high rates of oral absorption and good bioavailability for these compounds. In the in silico toxicity evaluation, only seven compounds showed signs of toxicity in up to one or two parameters. The methodology was corroborated with the ensuing experimental validation, which evaluated the inhibition of the Promastigote form of the Leishmania species under study. The activity of the molecules was determined by the IC50 value (µM); IC50 values < 20 µM indicated better inhibition profiles. Sixteen compounds were synthesized and tested for their activity. Eight molecules presented IC50 values < 20 µM for at least one of the Leishmania species under study, with compound NC34 presenting the strongest parasite inhibition profile. Furthermore, the methodology used was effective, as many of the compounds with the highest probability of activity were confirmed by the in vitro tests performed.

Evaluation of Shear Bond Strength Between Denture Teeth and 3D-Printed Denture Base Resin.

PURPOSE: The aim of this study was to evaluate the bond strength between two types of artificial teeth with a 3D-printed denture base resin using different bonding agents. MATERIALS AND METHODS: Two types of artificial teeth were evaluated: 3D-printed (Cosmos TEMP) and prefabricated polymethylmethacrylate (Biotone) bonded to cylinders (2.5 mm in height and 5 mm in diameter) of 3D-printed denture bases (Cosmos Denture designing by Meshmixer and printed by Flashforge Hunter DLP Resin 3D Printer). Two combinations between denture base and artificial teeth were eveluated: Cosmos Denture - Biotone, n = 30, and Cosmos Denture - Cosmos TEMP, n = 30. For each combination, the specimens were randomly distributed according to the bonding agent: (1) autopolymerized acrylic resin-Duralay, n = 10; (2) 3D-printed resin Cosmos TEMP, n = 10; and (3) methylmethacrylate monomer (MMA) + 3D-printed resin Cosmos TEMP, n = 10, totaling 60 specimens. The application of MMA was done conditioning the tooth surface for 180 seconds; the other agents were applied on the same surface. The virtual design of the 3D-printed resin teeth was obtained by scanning the first maxillary molar of the prefabricated teeth as the same protocol of cylinders. The control group (n = 10) was a conventional heat-polymerized denture base resin (Lucitone 550) bonded to the prefabricated resin teeth (Biotone). The shear bond tests were performed by applying a perpendicular force to the artificial tooth - denture base resin, through a chisel at 1 mm/min until failure. Two-way ANOVA and Bonferroni post hoc tests (α = 0.05) were used for multiple comparisons. RESULTS: For the Biotone tooth, the bond strength was significantly higher using MMA + Cosmos TEMP (10.04 MPa), and similar to the control (11.84 MPa, p = 0.484). For the 3D-printed tooth (Cosmos TEMP), the bond strength using the agents Cosmos TEMP (9.57 MPa) and MMA + Cosmos TEMP (12.72 MPa) were similar to the control (11.84 MPa, p = 0.169 and p = 1, respectively), but different from each other (p = 0.016). CONCLUSIONS: From the results, it is recommended to use: MMA + Cosmos TEMP bonding agent for the Biotone tooth; and Cosmos TEMP or MMA + Cosmos TEMP bonding agents for the Cosmos TEMP tooth, both attached to the 3D-printed denture resin Cosmos Denture.

Effectiveness of disinfectant solutions associated or not with brushing on the biofilm control of a 3D printed-denture base resin

Abstract The formation of biofilm on denture bases is a recurrent clinical problem that favors the development of denture stomatitis. The effectiveness of a hygiene protocol in a 3D-printed denture base resin is still uncertain. Objective To evaluate of the effectiveness of immersion, associated or not with brushing in a soap solution, on the biofilm control of a 3D-printed denture base resin. Methodology Specimens of denture base resins [Cosmos Denture (COS) and Classico (CLA/control)] were contaminated in vitro with Candida albicans and immersed in sodium hypochlorite 0.25% (SH, alkaline peroxide) AP, chlorhexidine digluconate 2% (CD or PBS-Control), associated or not with brushing with 0.78% Lifebuoy soap. Roughness was evaluated before and after brushing and immersion. The effectiveness of the protocols was assessed by CFU/mL, cellular metabolism (XTT), scanning electron microscopy (SEM), and confocal scanning laser microscopy. Data were analyzed by T student, ANOVA/Welch, and Tukey/Gomes-Howell pos-hoc tests (α = 0.05). Results CLA showed greater roughness than COS. CFU/mL and XTT were higher in COS resin with a higher hyphae formation. Immersion in SH and CD eliminated CFU/mL and reduced XTT for both resins, associated or not with brushing. AP reduced CFU/mL only when associated with brushing. Conclusions The biofilm on the 3D-printed resin was thicker and presumably more pathogenic, regardless of its smoother surface. Immersions in SH 0.25% and CD 2% are effective hygiene protocols for both resins, associated or not with brushing. AP should be recommended when associated with brushing with a Lifebuoy 0.78% solution.

Effect of repair methods and materials on the flexural strength of 3D-printed denture base resin.

PURPOSE: The aim of this study was to evaluate the flexural strength of a 3D-printed denture base resin (Cosmos Denture), after different immediate repair techniques with surface treatments and thermocycling. MATERIALS AND METHODS: Rectangular 3D-printed denture base resin (Cosmos Denture) specimens (N = 130) were thermocycled (5,000 cycles, 5℃ and 55℃) before and after the different repair techniques (n = 10 per group) using an autopolymerized acrylic resin (Jet, J) or a hard relining resin (Soft Confort, SC), and different surface treatments: Jet resin monomer for 180 s (MMA), blasting with aluminum oxide (JAT) or erbium: yttrium-aluminum-garnet laser (L). The control group were intact specimens. A three-point flexural strength test was performed, and data (MPa) were analyzed by ANOVA and Games-Howell post hoc test (α = 0.05). Each failure was observed and classified through stereomicroscope images and the surface treatments were viewed by scanning electron microscope (SEM). RESULTS: Control group showed the highest mean of flexural strength, statistically different from the other groups (P < .001), followed by MMA+J group. The groups with L treatment were statistically similar to the MMA groups (P > .05). The JAT+J group was better than the SC and JAT+SC groups (P < .05), but similar to the other groups (P > .05). Adhesive failures were most observed in JAT groups, especially when repaired with SC. The SEM images showed surface changes for all treatments, except JAT alone. CONCLUSION: Denture bases fabricated with 3D-printed resin should be preferably repaired with MMA+J. SC and JAT+SC showed the worst results. Blasting impaired the adhesion of the SC resin.

Diagnóstico e notificação de casos de violência contra crianças e adolescentes: conhecimento de estudantes de Odontologia / Diagnosis and reporting of cases of violence against children and adolescents: knowledge of dental students

O objetivo desse estudo foi avaliar o conhecimento de estudantes de Odontologia acerca do diagnóstico e da notificação em casos de violência contra crianças e adolescentes (VCA). Trata-se de um estudo transversal, descritivo e exploratório realizado com os estudantes (n=100) que cursavam oitavoe décimo períodos no semestre 2018.1, dos turnos diurno e noturno do curso de Odontologia do Nordeste brasileiro.Os dados foram coletados por meiodequestionárioautoaplicável, composto por 22 perguntas. Os dados foram tabulados e analisadossegundo estatística descritiva e teste de associação entre as variáveis, considerando p-valor <0,05 como significância estatística. A importância do tema foi reconhecida pela quase totalidade dos estudantes(99,0%), no entanto,menos da metade (45,0%) considerou que as informações recebidas na graduação foram suficientes. Destaca-se, porém, que os estudantes demonstraram conhecimento razoável do assunto,com percentual de acertos de 75,27%. Não houve diferença significativa entre o número de acertos dos alunos do oitavo e décimo períodos. Embora 85,0% dos estudantes afirmaram que a conduta correta em caso suspeito de VCA seja fazer denúncia ao Conselho Tutelar da localidade, menos da metade afirmou conhecer a ficha de notificação específica e apenas 10,0% conheciam que a pena para os profissionais que não notificarem é multa de 3 a 20 salários de referência. Conclui-se que os estudantes apresentaram conhecimento satisfatório no que diz respeito ao diagnóstico de VCA e domínio sobre os meios de denúncia para notificação específica (AU).

The aim of this study was to evaluate the knowledge of dental students about the diagnosis and notification in cases of violence against children and adolescents (VCA). This is a cross-sectional, descriptive and exploratory study conducted with dental students (n = 100) attending the eighth and tenth periods, between March and June 2018, at an undergraduate dental program in a northeastern Brazilian city. Data were collected through a self-administered questionnaire consisting of 22 questions. Data were tabulated and analyzed according to descriptive statistics and association test between variables, considering a p-value <0.05 as statistically significant. The importance of the topic was recognized by almost all students (99.0%); however, less than half (45.0%) considered that the information received during the undergraduate course was sufficient. It is noteworthy that the students demonstrated reasonable knowledge of the subject, with a percentage of correct answers of 75.27%. There was no significant difference regarding the number of correct answers between the eighth-and tenth-period students. Although 85.0% of students said that the correct conduct in case of suspected VCA is to report them to the local Guardianship Council, less than half said they knew the specific notification form and only 10.0% knew that the penalty for professionalswho do not notify these cases is a fine ranging from 3 to 20 minimum wages. It was concluded that the students demonstrated satisfactory knowledge regarding the diagnosis of VCA and knew about the means of reporting these cases (AU).

Curzerene antileishmania activity: Effects on Leishmania amazonensis and possible action mechanisms.

Leishmaniasis is a set of infectious diseases with high rates of morbidity and mortality, it affects millions of people around the world. Treatment, mainly with pentavalent antimonials, presents significant toxicity and many cases of resistance. In previous works we have demonstrated the effective and selective antileishmanial activity of Eugenia uniflora L. essential oil, being constituted (47.3%) by the sesquiterpene curzerene. Considering the high rate of parasite inhibition demonstrated for E. uniflora essential oil, and the significant presence of curzerene in the oil, this study aimed to evaluate its antileishmania activity and possible mechanisms of action. Curzerene was effective in inhibiting the growth of promastigotes (IC50 3.09 ± 0.14 µM) and axenic amastigotes (EC50 2.56 ± 0.12 µM), with low cytotoxicity to RAW 264.7 macrophages (CC50 83.87 ± 4.63 µM). It was observed that curzerene has direct effects on the parasite, inducing cell death by apoptosis with secondary necrotic effects (producing pores in the plasma membrane). Curzerene proved to be even more effective against intra-macrophage amastigote forms, with an EC50 of 0.46 ± 0.02 µM. The selectivity index demonstrated by curzerene on these parasite forms was 182.32, being respectively 44.15 and 8.47 times more selective than meglumine antimoniate and amphotericin B. The antiamastigote activity of curzerene was associated with immunomodulatory activity, as it increased TNF-α, IL-12, and NO levels, and lysosomal activity, and decreased IL-10 and IL-6 cytokine levels detected in macrophages infected and treated. In conclusion, our results demonstrate that curzerene is an effective and selective antileishmanial agent, a candidate for in vivo investigation in models of antileishmanial activity.

Eugenia piauhiensis Vellaff. essential oil and γ-elemene its major constituent exhibit antileishmanial activity, promoting cell membrane damage and in vitro immunomodulation.

Leishmaniasis is considered as one of the most Neglected Tropical Diseases (NTDs) in the world, caused by protozoan parasites of the genus Leishmania. Treatment of leishmaniasis by chemotherapy remains a challenge because of limited efficacy, toxic side effects, and drug resistance. The search for new therapeutic agents from natural sources has been a constant for the treatment of diseases such as leishmaniasis. The objective of this study was to evaluate the biological activity of Eugenia piauhiensis Vellaff. essential oil (EpEO) and its major constituent γ-elemene on promastigote and amastigote forms of Leishmania (Leishmania) amazonensis, its cytotoxicity, and possible mechanisms of action. EpEO was more active (IC50 6.43 ± 0.18 µg/mL) against promastigotes than γ-elemene [9.82 ± 0.15 µg/mL (48.05 ± 0.73 µM)] and the reference drug miltefosine [IC50 17.25 ± 0.26 µg/mL (42.32 ± 0.64 µM)]. EpEO and γ-elemene exhibited low cytotoxicity against J774.A1 macrophages, with CC50 225.8 ± 3.57 µg/mL and 213.21 ± 3.3 µg/mL (1043 ± 16.15 µM), respectively. Additionally, EpEO and γ-elemene present direct activity against the parasite, decreasing plasma membrane integrity. EpEO and γ-elemene also proved to be even more active against intracellular amastigotes of the parasite [IC50 4.59 ± 0.07 µg/mL and 8.06 ± 0.12 µg/mL (39.44 ± 0.59 µM)], respectively), presenting indirect effects through macrophage activity modulation. Anti-amastigote activity was associated with increased TNF-α, IL-12, NO, and ROS levels. In conclusion, our results suggest EpEO and γ-elemene as promising candidates for new drug development against leishmaniasis.

Antileishmanial activity of cordiaquinone E towards Leishmania (Leishmania) amazonensis.

Leishmaniasis is caused by several protozoan species of Leishmania, and being endemically present in 98 countries around the world, it is also a severe public-health problem. The available antileishmanial drugs are toxic and yet present risks of recurrent infection. Efforts to find new, effective, and safe oral agents for the treatment of leishmaniasis are continuing throughout the world. This work aimed to evaluate the antileishmania activity of cordiaquinone E (CORe), isolated from the roots of Cordia polycephala (Lam.) I. M. Johnston. Cytotoxicity, and possible mechanisms of action against promastigote and amastigote forms of Leishmania amazonensis were examined. CORe was effective in inhibiting promastigote (IC50 4.5 ± 0.3 µM) and axenic amastigote (IC50 2.89 ± 0.11 µM) growth in concentrations found non-toxic for the host cell (CC50 246.81 ± 14.5 µM). Our results revealed that CORe presents direct activity against the parasite, inducing cell death by apoptosis. CORe present greater activity against intracellular amastigotes (EC50 1.92 ± 0.2 µM), yet with much higher selectivity indexes than the reference drugs, being respectively more benign towards RAW 264.7 macrophages than meglumine antimoniate and amphotericin B, (respectively by 4.68 and 42.84 fold). The antiamastigote activity was associated with increased TNF-α, IL-12, NO, and ROS levels, as well as decreased IL-10 levels. These results encourage the progression of studies on this compound for the development of new leishmanicidal agents.

Fungistatic Action of N-Acetylcysteine on Candida albicans Biofilms and Its Interaction with Antifungal Agents.

Therapies targeted to fungal biofilms, mainly against the matrix, and therapies that do not induce microbial resistance are relevant. N-acetylcysteine (NAC), a mucolytic agent, has shown antimicrobial action. This study evaluated the effect of NAC against fluconazole-susceptible (CaS) and -resistant (CaR) Candida albicans. The susceptibility of planktonic cultures to NAC, the effect of NAC on biofilms and their matrix, the interaction of NAC with antifungal agents, and confocal microscopy were evaluated. Data were analyzed descriptively and by the ANOVA/Welch and Tukey/Gomes-Howell tests. The minimum inhibitory concentration (MIC) of NAC was 25 mg/mL for both strains. NAC significantly reduced the viability of both fungal strains. Concentrations higher than the MIC (100 and 50 mg/mL) reduced the viability and the biomass. NAC at 12.5 mg/mL increased the fungal viability. NAC also reduced the soluble components of the biofilm matrix, and showed synergism with caspofungin against planktonic cultures of CaS, but not against biofilms. Confocal images demonstrated that NAC reduced the biofilm thickness and the fluorescence intensity of most fluorochromes used. High concentrations of NAC had similar fungistatic effects against both strains, while a low concentration showed the opposite result. The antibiofilm action of NAC was due to its fungistatic action.

Computer-Assisted Design of Thiophene-Indole Hybrids as Leishmanial Agents.

BACKGROUND: Chemoinformatics has several applications in the field of drug design, helping to identify new compounds against a range of ailments. Among these are Leishmaniasis, effective treatments for which are currently limited. OBJECTIVE: To construct new indole 2-aminothiophene molecules using computational tools and to test their effectiveness against Leishmania amazonensis (sp.). METHODS: Based on the chemical structure of thiophene-indol hybrids, we built regression models and performed molecular docking, and used these data as bases for design of 92 new molecules with predicted pIC50 and molecular docking. Among these, six compounds were selected for the synthesis and to perform biological assays (leishmanicidal activity and cytotoxicity). RESULTS: The prediction models and docking allowed inference of characteristics that could have positive influences on the leishmanicidal activity of the planned compounds. Six compounds were synthesized, one-third of which showed promising antileishmanial activities, with IC50 ranging from 2.16 and 2.97 µM (against promastigote forms) and 0.9 and 1.71 µM (against amastigote forms), with selectivity indexes (SI) of 52 and 75. CONCLUSION: These results demonstrate the ability of Quantitative Structure-Activity Relationship (QSAR)-based rational drug design to predict molecules with promising leishmanicidal potential, and confirming the potential of thiophene-indole hybrids as potential new leishmanial agents.

Virtual Screening and the In Vitro Assessment of the Antileishmanial Activity of Lignans.

Leishmaniasis is endemic in at least 98 countries. Due to the high toxicity and resistance associated with the drugs, we chose lignans as an alternative, due to their favorable properties of absorption, distribution, metabolism, excretion, and toxicity (ADMET). To investigate their leishmanicidal potential, the biological activities of a set of 160 lignans were predicted using predictive models that were built using data for Leishmania major and L. (Viannia) braziliensis. A combined analysis, based on ligand and structure, and several other computational approaches were used. The results showed that the combined analysis was able to select 11 lignans with potential activity against L. major and 21 lignans against L. braziliensis, with multitargeting effects and low or no toxicity. Of these compounds, four were isolated from the species Justicia aequilabris (Nees) Lindau. All of the identified compounds were able to inhibit the growth of L. braziliensis promastigotes, with the most active compound, (159) epipinoresinol-4-O-ß-d-glucopyranoside, presenting an IC50 value of 5.39 µM and IC50 value of 36.51 µM for L. major. Our findings indicated the potential of computer-aided drug design and development and demonstrated that lignans represent promising prototype compounds for the development of multitarget drugs against leishmaniasis.

Methyl gallate: Selective antileishmanial activity correlates with host-cell directed effects.

Leishmaniasis is a widespread tropical infection caused by different species of Leishmania protozoa. Many of the available drugs against the disease are toxic and in certain cases parasite drug resistance is developed. The discovery of drugs for the treatment of leishmaniasis is a pressing concern. In the present work, we describe in vitro studies of the phenolic compound methyl gallate (MG) against Leishmania (Leishmania) amazonensis and its possible mechanisms of action. The in vitro activity of MG was assayed against L. amazonensis (promastigotes, axenic amastigotes, and intramacrophagic amastigotes). Cytotoxicity tests were performed with J774A.1 macrophages and THP-1 cell derived macrophages. To evaluate mechanisms of action, we analyzed cellular TNF-α, IL-12, IFN-γ, IL-10, IL-6, NO, ROS levels, arginase activity, and structural mechanisms (phagocytic and lysosomal activities) involving macrophage activation. Meglumine antimoniate and amphotericin B were used as reference drugs. It was observed that MG effectively inhibited the growth of both promastigote (IC50 5.71 µM) and amastigote-like forms (EC50 5.39 µM), with much higher selectivity indexes than the reference drugs, being more benign towards J774A.1 macrophages than meglumine antimoniate and amphotericin B, at 1631- and 70.92-fold respectively, with respect to the promastigote form. Additionally, MG proved to be even more active against intracellular amastigotes of the parasite (EC50 4.24 µM). Our results showed that antileishmania activity was associated with increased TNF-α, IL-12, NO and ROS levels, as well as decreased IL-6 and decreased arginase activity. In addition, MG induced increased phagocytic capability, and lysosomal volume in macrophages; structural parameters of microbicidal activity. Taken together, our results suggest that MG may be a promising candidate for new drug development against leishmaniasis.

Practical Implications of Myocardial Viability Studies.

Many non-invasive methods, such as imaging tests, have been developed aiming to add a contribution to existing studies in estimating patients' prognosis after myocardial injury. This prognosis is proportional to myocardial viability, which is evaluated in coronary artery disease and left ventricular dysfunction patients only. While myocardial viability represents the likelihood of a dysfunctional muscle (resulting from decreased oxygen supply for coronary artery obstruction), hibernation represents post-interventional functional recovery itself. This article proposes a review of pathophysiological basis of viability, diagnostic methods, prognosis and future perspectives of myocardial viability. An electronic bibliographic search for articles was performed in PubMed, Lilacs, Cochrane and Scielo databases, according to pre-established criteria. The studies showed the ability of many imaging techniques in detecting viable tissues in dysfunctional areas of left ventricle resulting from coronary artery injuries. These techniques can identify patients who may benefit from myocardial revascularization and indicate the most appropriate treatment.