Cheminformatics-driven discovery of hit compounds against Paracoccidioides spp.

Aims: The development of safe and effective therapies for treating paracoccidioidomycosis using computational strategies were employed to discover anti-Paracoccidioides compounds. Materials & methods: We 1) collected, curated and integrated the largest library of compounds tested against Paracoccidioides spp.; 2) employed a similarity search to virtually screen the ChemBridge database and select nine compounds for experimental evaluation; 3) performed an experimental evaluation to determine the minimum inhibitory concentration and minimum fungicidal concentration as well as cytotoxicity; and 4) employed computational tools to identify potential targets for the most active compounds. Seven compounds presented activity against Paracoccidioides spp. Conclusion: These compounds are new hits with a predicted mechanisms of action, making them potentially attractive to develop new compounds.

Neurosurgery societies around the world: A study and discussion about its importance.

Background: Harvey Cushing and collaborators created the first society of neurosurgeons in 1920, in the United States of America, the Society of Neurological Surgeons. In 1955, the World Federation of Neurosurgical Societies (WFNS) was created in Switzerland to improve neurosurgical care globally through the scientific cooperation of members. The performance of neurosurgical associations today is fundamental to discuss diagnostic methods and therapeutic approaches, transforming modern medicine. Although most neurosurgical associations are recognized worldwide, there are some societies that are not recognized internationally due to a lack of regulatory bodies and lack of official digital channels, among other reasons. The main objective of the article is to list the neurosurgical societies and to provide a more integrated view of the interactions between neurosurgical societies in different countries. Methods: We developed a table summarizing the countries recognized by the United Nations, the continents, capitals, name of the present societies, and social networks. We utilized "Country AND (Neurosurgery OR Neurological Surgery) AND (Society OR Association)," in English, and in the native language of the country. Our search included: PubMed, Scopus, Google, Google Scholar, and the WFNS website, without filters. Results: We found 189 neurosurgery associations, from 131 countries and territories; 77 countries did not have their own neurosurgical societies. Conclusion: There is a difference between the number of internationally recognized societies, and the number of societies found in this study. In the future, we should better organize neurosurgical societies in countries that have neurosurgical activity with those without such resources.

Influence of different ethylene-vinyl acetate brands used for custom-fitted mouthguard fabrication on the stress and strain during an impact.

BACKGROUND/AIM: The use of custom-fitted mouthguards can effectively prevent dentoalveolar trauma during sports practice. The aims of this study were to (1) Evaluate the elastic modulus of different EVA commercial brands used for custom-fitted mouthguards, and (2) Evaluate whether the different EVA brands can influence the stress and strain generated during an impact simulated by three-dimensional finite element analysis. METHODS: The elastic modulus of five EVA commercial brands (Essence® , Bio-Art® , Proform® , PolyShok® , and Erkodent® ) were calculated through uniaxial tensile tests. The obtained values were evaluated statistically by Kruskal-Wallis and Dunn's test. A three-dimensional model of the anterior maxilla was created using the Rhinoceros 5.0. A 3 mm custom-fitted mouthguard was simulated. The three-dimensional volumetric mesh was generated using the Patran software (MSC.Software) with isoparametrics, 4-noded tetrahedral elements, and exported to Marc/Mentat (MSC.Software) as element number 134. A non-linear dynamic impact analysis was performed in which a rigid object struck the central incisor at a speed of 5 m/s. The stresses were evaluated by the modified von Mises criteria, and the strains were also recorded. RESULTS: Statistically significant differences were observed for elastic modulus values (p < .001). Median values and the results of the Dunn's test were Essence® (38.1 A), Bio-Art® (34.9 AB), Proform® (20.8 BC), PolyShok® (17.4 CD), and Erkodent® (15.0 D) (different capital letters mean statistical differences among the groups). Stresses and strains generated in the model with mouthguards were significantly lower than the model without a mouthguard regardless of the commercial brand. There was no significant difference in the stress and strain on the enamel and dentin with the different EVA brands. The shock absorption ability was high for all the brands (more than 80%). CONCLUSION: The custom-fitted mouthguards, independently of the commercial brand, reduced stresses and strains during the impact.

In vitro and in silico analysis reveals antifungal activity and potential targets of curcumin on Paracoccidioides spp.

The search for new compounds with activity against Paracoccidioides, etiologic agents of Paracoccidioidomycosis (PCM), is extremely necessary due to the current scenario of the available therapeutic arsenal. Treatment is restricted to three classes of antifungals with side effects. Curcumin is a polyphenol with antifungal effects that is extracted from Curcuma longa. The present work aimed to evaluate the activity of curcumin in different species of Paracoccidioides and to evaluate the potential molecular targets of curcumin using computational strategies. In addition, interactions with classic antifungals used in the treatment of PCM were evaluated. Curcumin inhibits the growth of Paracoccidioides spp. exerting a fungicidal effect. The combination of curcumin with amphotericin B, co-trimoxazole, and itraconazole showed a synergistic or additive interaction. Molecular targets as superoxide dismutase, catalase, and isocitrate lyase were proposed based on in silico approaches. Curcumin affects the fungal plasma membrane and increases the production of reactive oxygen species. Therefore, curcumin is a good alternative for the treatment of PCM.

Overview of Antifungal Drugs against Paracoccidioidomycosis: How Do We Start, Where Are We, and Where Are We Going?

Paracoccidioidomycosis is a neglected disease that causes economic and social impacts, mainly affecting people of certain social segments, such as rural workers. The limitations of antifungals, such as toxicity, drug interactions, restricted routes of administration, and the reduced bioavailability in target tissues, have become evident in clinical settings. These factors, added to the fact that Paracoccidioidomycosis (PCM) therapy is a long process, lasting from months to years, emphasize the need for the research and development of new molecules. Researchers have concentrated efforts on the identification of new compounds using numerous tools and targeting important proteins from Paracoccidioides, with the emphasis on enzymatic pathways absent in humans. This review aims to discuss the aspects related to the identification of compounds, methodologies, and perspectives when proposing new antifungal agents against PCM.

Investigation of thiosemicarbazide free or within chitosan nanoparticles in a murine model of vulvovaginal candidiasis.

Vulvovaginal candidiasis is a serious health problem affecting numerous women around the world. Its treatment is based on antifungals which may not provide an effective cure because of the resistance presented by its etiological pathogens Candida spp. Candida albicans is the most prevalent species related to vulvovaginal candidiasis. Here, we evaluated the in vivo antifungal potential of thiosemicarbazide and thiosemicarbazide encapsulated within chitosan nanoparticles in a murine model of vulvovaginal candidiasis. The results demonstrated the antifungal capacity of free or nanoencapsulated thiosemicarbazide within chitosan to reduce the fungal load in the vaginal tissue of infected mice. In addition, histological analyses indicated the absence or a mild to moderate infection in thiosemicarbazide-treated groups. Statistical tests confirmed the existence of significant differences between the treated and the control groups. Therefore, our results suggest a potential application of thiosemicarbazide and encapsulated thiosemicarbazide as an alternative vulvovaginal candidiasis therapy.

Drug Repurposing for Paracoccidioidomycosis Through a Computational Chemogenomics Framework.

Paracoccidioidomycosis (PCM) is the most prevalent endemic mycosis in Latin America. The disease is caused by fungi of the genus Paracoccidioides and mainly affects low-income rural workers after inhalation of fungal conidia suspended in the air. The current arsenal of chemotherapeutic agents requires long-term administration protocols. In addition, chemotherapy is related to a significantly increased frequency of disease relapse, high toxicity, and incomplete elimination of the fungus. Due to the limitations of current anti-PCM drugs, we developed a computational drug repurposing-chemogenomics approach to identify approved drugs or drug candidates in clinical trials with anti-PCM activity. In contrast to the one-drug-one-target paradigm, our chemogenomics approach attempts to predict interactions between drugs, and Paracoccidioides protein targets. To achieve this goal, we designed a workflow with the following steps: (a) compilation and preparation of Paracoccidioides spp. genome data; (b) identification of orthologous proteins among the isolates; (c) identification of homologous proteins in publicly available drug-target databases; (d) selection of Paracoccidioides essential targets using validated genes from Saccharomyces cerevisiae; (e) homology modeling and molecular docking studies; and (f) experimental validation of selected candidates. We prioritized 14 compounds. Two antineoplastic drug candidates (vistusertib and BGT-226) predicted to be inhibitors of phosphatidylinositol 3-kinase TOR2 showed antifungal activity at low micromolar concentrations (<10 µM). Four antifungal azole drugs (bifonazole, luliconazole, butoconazole, and sertaconazole) showed antifungal activity at low nanomolar concentrations, validating our methodology. The results suggest our strategy for predicting new anti-PCM drugs is useful. Finally, we could recommend hit-to-lead optimization studies to improve potency and selectivity, as well as pharmaceutical formulations to improve oral bioavailability of the antifungal azoles identified.