Anticancer Activity and Molecular Targets of Piper cernuum Substances in Oral Squamous Cell Carcinoma Models.

Oral squamous cell carcinoma (OSCC) is a worldwide public health problem, with high morbidity and mortality rates. The development of new drugs to treat OSCC is paramount. Piper plant species have shown many biological activities. In the present study, we show that dichloromethane partition of Piper cernuum (PCLd) is nontoxic in chronic treatment in mice, reduces the amount of atypia in tongues of chemically induced OSCC, and significantly increases animal survival. To identify the main active compounds, chromatographic purification of PCLd was performed, where fractions 09.07 and 14.05 were the most active and selective. These fractions promoted cell death by apoptosis characterized by phosphatidyl serine exposition, DNA fragmentation, and activation of effector caspase-3/7 and were nonhemolytic. LC-DAD-MS/MS analysis did not propose matching spectra for the 09.07 fraction, suggesting compounds not yet known. However, aporphine alkaloids were annotated in fraction 14.05, which are being described for the first time in P. cernuum and corroborate the observed cytotoxic activity. Putative molecular targets were determined for these alkaloids, in silico, where the androgen receptor (AR), CHK1, CK2, DYRK1A, EHMT2, LXRß, and VEGFR2 were the most relevant. The results obtained from P. cernuum fractions point to promising compounds as new preclinical anticancer candidates.

Structural insights into the inhibition of the nsP2 protease from Chikungunya virus by molecular modeling approaches.

Chikungunya virus (CHIKV) is the etiological agent of the Chikungunya fever which has spread worldwide. Clinically, this disease may lead to prolonged incapacitating joint pain that can compromise remarkably the patients' quality of life. However, there are no licensed vaccines or specific drugs to fight this infection yet, making the search for novel therapies an imperative need. In this scenario, the CHIKV nsP2 protease emerged as an attractive therapeutic target once this protein plays a pivotal role in viral replication and pathogenesis. Hence, we investigated the structural basis for the inhibition of this enzyme by using molecular docking and dynamics simulations. Compounds with inhibitory activities against CHIKV nsP2 protease determined experimentally were selected from the literature. Docking studies with a set of stereoisomers showed that trans isomers, but not cis ones, bound close to the catalytic dyad which may explain isomerism requirements to the enzyme's inhibition. Further, binding mode analyses of other known inhibitors revealed highly conserved contacts between inhibitors and enzyme residues like N1011, C1013, A1046, Y1079, N1082, W1084, L1205, and M1242. Molecular dynamics simulations reinforced the importance of some of these interactions and pointed to nonpolar interactions as the main forces for inhibitors' binding. Finally, we observed that true inhibitors exhibited lower structural fluctuation, higher ligand efficiency and did not induce significant changes in protein correlated motions. Collectively, our findings might allow discerning true inhibitors from false ones and can guide drug development efforts targeting the nsP2 protease to fight CHIKV infections in the future.

Pro-Apoptotic Antitumoral Effect of Novel Acridine-Core Naphthoquinone Compounds against Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is a global public health problem with high incidence and mortality. The chemotherapeutic agents used in the clinic, alone or in combination, usually lead to important side effects. Thus, the discovery and development of new antineoplastic drugs are essential to improve disease prognosis and reduce toxicity. In the present study, acridine-core naphthoquinone compounds were synthesized and evaluated for their antitumor activity in OSCC cells. The mechanism of action, pharmacokinetics, and toxicity parameters of the most promising compound was further analyzed using in silico, in vitro, and in vivo methods. Among the derivatives, compound 4e was highly cytotoxic (29.99 µM) and selective (SI 2.9) at levels comparable and generally superior to chemotherapeutic controls. Besides, compound 4e proved to be non-hemolytic, stable, and well tolerated in animals at all doses tested. Mechanistically, compound 4e promoted cell death by apoptosis in the OSCC cell, and molecular docking studies suggested this compound possibly targets enzymes important for tumor progression, such as RSK2, PKM2, and topoisomerase IIα. Importantly, compound 4e presented a pharmacological profile within desirable parameters for drug development, showing promise for future preclinical trials.

Etiologia e epidemiologia da tinea capitis: relato de série de casos e revisão da literatura / Etiology and epidemiology of tinea capitis: case-serie report and literature review

Dermatofitose é uma micose superficial, causada por fungos filamentosos denominados dermatófitos, que são capazes de degradar estruturas queratinizadas. Os agentes dessas infecções em humanos pertencem a três gêneros: Microsporum, Trichophyton e Epidermophyton. O objetivo deste trabalho é revisar os estudos epidemiológicos e relatos de casos de tinea capitis, a partir de artigos publicados entre 2000 e 2018. Com base nos dados analisados, o gênero masculino foi o mais afetado pela tinea capitis e a faixa etária mais relatada foi a de indivíduos menores de 10 anos. As principais espécies isoladas foram: T. tonsurans e M. canis, sendo o primeiro mais encontrado nas regiões norte, nordeste e centro-oeste, e o segundo, nas regiões sudeste e sul do Brasil. Nos relatos de casos foram reportadas lesões com diferentes características, sendo algumas mais inflamatórias, eritematosas, com pústulas, placas de alopécia ou descamativas do que outras. Dor e prurido foram sintomas observados em alguns casos. A griseofulvina e os derivados azólicos foram os principais fármacos empregados na terapia, ainda que em associação em alguns casos. As avaliações dos tratamentos empregados nos casos de tinea capitis devem ser minuciosamente realizadas, visto que há relatos de casos em que a reposta terapêutica não é eficiente, agravando as lesões e prolongando o tempo de tratamento.

Dermatophytosis is a superficial mycosis, caused by filamentous fungi called dermatophytes, which are capable of degrading keratinized structures. The agents of these infections in humans belong to three genera: Microsporum, Trichophyton and Epidermophyton. The objective of this study is to review the epidemiological studies and reports of tinea capitis cases in Brazil, based on articles published between 2000 and 2018. Based on the data analyzed, the male gender was the most affected by Tinea capitis and the most reported age group was of individuals with less than 10 years. The main species isolated from the samples were: T. tonsurans and M. canis, being the first one most found in the north, northeast and center-west regions and the second one found in the southeastern and southern regions of Brazil. In the case reports, lesions with different characteristics were reported, being some more inflammatory, erythematous, with pustules, others with plaques of alopecia or desquamative than others. Pain and itching were symptoms observed in some cases. Griseofulvin and azole derivatives were the main drugs used in therapy, although in association in some cases. The evaluations of the treatment employed in the cases of Tinea capitis should be thoroughly done since there are reports of cases in which the therapeutic response is not efficient, aggravating the lesions and prolonging the treatment time

A divulgação de vídeos de anatomia do sistema nervoso central no Youtube / Dissemination of videos on the anatomy of the central nervous system by Youtube

O estudo visa avaliar os métodos de exposição de conteúdos de neuroanatomia utilizados nos vídeos compartilhados no YouTube, o impacto destes vídeos e a aceitação dos usuários. Trata-se de uma pesquisa quantitativa, com abordagem descritiva e analítica observacional, envolvendo a análise de vídeos de neuroanatomia divulgados em português no site do YouTube. A pesquisa foi realizada no Youtube utilizando as palavras-chave "telencéfalo", "diencéfalo" e "tronco encefálico". Os vídeos foram categorizados de acordo com o método de exposição do conteúdo de neuroanatomia como equipamentos multimídia (EM), peças plásticas (PPT), peças plastinadas (PPN), e peças cadavéricas formolizadas (PCF) para avaliação do número de visualizações e aceitação dos usuários (número de likes e dislikes). Foi observado que as PPT foram mais utilizadas nos vídeos de neuroanatomia. Porém, os vídeos que utilizaram EM tiveram mais visualizações diárias e maior aceitação pelos usuários do Youtube. Os resultados do presente estudo sugerem que os vídeos de neuroanatomia utilizando EM podem contribuir de forma complementar para o ensino-aprendizado destes conteúdos.

The aim of this work is to access the exposure methods of neuroanatomy used in YouTube-shared videos, their impact and acceptance by users, by a quantitative, descriptive and analytic research. Research was undertaken in YouTube with keywords "telencephalon", "diencephalon" and "brainstem". Videos were categorized according to the exposure method of the neuroanatomic contents, such as multimedia equipments (ME), plastic parts (PPT), plastinated parts (PPN), and cadaver pieces in formaldehyde (PCF), to evaluate the number of visualizations and acceptance by the users (number of likes and dislikes). The exposure method based on PPT was the most used one in neuroanatomy videos. However, ME videos had more daily visualizations and greater acceptance by the Youtube users. Results suggest that neuroanatomy videos with ME may contribute in a complementary manner towards the teaching-learning of these contents.

Design strategies of oxidosqualene cyclase inhibitors: Targeting the sterol biosynthetic pathway.

Targeting the sterol biosynthesis pathway has been explored for the development of new bioactive compounds. Among the enzymes of this pathway, oxidosqualene cyclase (OSC) which catalyzes lanosterol cyclization from 2,3-oxidosqualene has emerged as an attractive target. In this work, we reviewed the most promising OSC inhibitors from different organisms and their potential for the development of new antiparasitic, antifungal, hypocholesterolemic and anticancer drugs. Different strategies have been adopted for the discovery of new OSC inhibitors, such as structural modifications of the natural substrate or the reaction intermediates, the use of the enzyme's structural information to discover compounds with novel chemotypes, modifications of known inhibitors and the use of molecular modeling techniques such as docking and virtual screening to search for new inhibitors. This review brings new perspectives on structural insights of OSC from different organisms and reveals the broad structural diversity of OSC inhibitors which may help evidence lead compounds for further investigations with various therapeutic applications.