The molecular mechanisms underlying the observed anticancer effects of flavonoids remain unclear. Increasing evidence shows that the aryl hydrocarbon receptor (AHR) plays a crucial role in neoplastic disease progression, establishing it as a potential drug target. This study evaluated the potential of hydroxy flavonoids, known for their anticancer properties, to interact with AHR, both in silico and in vitro, aiming to understand the mechanisms of action and identify selective AHR modulators. A PAS-B domain homology model was constructed to evaluate in silico interactions of chrysin, naringenin, quercetin apigenin and agathisflavone. The EROD activity assay measured the effects of flavonoids on AHR’s activity in human breast cancer cells (MCF7). Simulations showed that chrysin, apigenin, naringenin, and quercetin have the highest AHR binding affinity scores (−13.14 to −15.31), while agathisflavone showed low scores (−0.57 and −5.14). All tested flavonoids had the potential to inhibit AHR activity in a dose-dependent manner in the presence of an agonist (TCDD) in vitro. This study elucidates the distinct modulatory effects of flavonoids on AHR, emphasizing naringenin’s newly described antagonistic potential. It underscores the importance of understanding flavonoid’s molecular mechanisms, which is crucial for developing novel cancer therapies based on these molecules.

The primary purpose of this study was to evaluate the participants' reports and knowledge about side effects promoted using hormonal contraception methods. To this end, a remote questionnaire was applied with questions directed to the knowledge of sociodemographic data, the purpose and side effects after the use of these methods of contraception. A total of 306 women with a mean age of 25 years participated in this study. The results showed that they recognize that there was reduced libido (51%); mood swings (47%); headache (37%) fatigue or discomfort in the legs (22%); increased body weight (33%) and other side effects and/or adverse effects after using hormonal contraception methods. The use of hormonal contraceptives has been widely associated with the emergence of several unwanted effects, corroborating the findings in the present study. It is also noteworthy that the presence of risk factors can also influence the emergence of such effects, so it is necessary that contraceptive users are aware of risk factors such as smoking, obesity, migraines, hypertension and family history of stroke and cardiovascular disease. These risk factors combined with the use of these methods can have serious consequences on the female physiology. In this context, it is reasonable to consider that the dissemination of such information is necessary, because many women seek non-scientific information in social networks and other means of information. Thus, the dissemination of scientific information is essential to achieve a healthier and well-oriented population.

Tuberculose é uma doença infecciosa causada pelo Mycobacterium tuberculosis que continua sendo uma das principais causas de morte por doença infecciosa. Este estudo teve como objetivo a identificação de potenciais inibidores da pantotenato sintetase, enzima essencial para a bactéria, através de triagem virtual hierárquica. Modelos baseados na forma e volume moleculares foram construídos e validados para filtrar um banco de dados com estruturas químicas produtos naturais. As moléculas selecionadas foram acopladas na estrutura do alvo molecular, obtido junto ao Protein Data Bank sob o código 3IUB com o programa FRED. O composto ZINC000012489800 foi a mais bem ranqueada. As interações intermoleculares mostraram interações hidrofóbicas, ligações de hidrogênio (aceptoras e doadoras) e iônicas, entre o composto identificado e aminoácidos importantes para o reconhecimento molecular já descritas na literatura. A molécula possui parâmetros farmacocinéticos razoáveis e bom índice de segurança toxicológico. Este estudo demonstra a eficácia dos métodos in silico na identificação de um composto promissor para o tratamento da tuberculose multirresistente, representando um passo importante na busca por novas terapias. Referências Bloom B, et al. Tuberculosis. Major Infect Dis. 2017;6(3):233-313. DOI: 10.1596/978-1-4648-0524-0_ch11. Moreira AD, Kritsk AL, Carvalho AC. Social determinants of health and catastrophic costs associated with the diagnosis and treatment of tuberculosis. J. Bras. de Pneumol. 23 fev 2020; 46(5): e20200015. DOI: 10.36416/1806-3756/e20200015. World Health Organization. Tuberculosis [Internet]; [citado 19 out 2023]. Available from: https://www.who.int/health-topics/tuberculosis#tab=tab_1. World Health Organization. Global Tuberculosis Report [Internet]. Geneva: WHO [citado 19 out 2023]. 68p. 2022. Available from: https://iris.who.int/bitstream/handle/10665/363752/9789240061729-eng.pdf?sequence=1. Ministério da Saúde (BR). Tuberculose [Internet]. Brasília: [editor desconhecido]; mar 2023 [citado 11 out 2023]. 64p. Boletim epidemiológico 2023. Available from: https://www.gov.br/saude/pt-br/centrais-de-conteudo/publicacoes/boletins/epidemiologicos/especiais/2023/boletim-epidemiologico-de-tuberculose-numero-especial-mar.2023. World Health Organization. TB BR profile [Internet]. [citado 19 out 2023]. Available from: https://worldhealthorg.shinyapps.io/tb_profiles/?_inputs_&entity_type="country"&lan="EN"&iso2="BR". Lee M, et al. Delamanid, linezolid, levofloxacin, and pyrazinamide for the treatment of patients with fluoroquinolone-sensitive multidrug-resistant tuberculosis (Treatment Shortening of MDR-TB Using Existing and New Drugs, MDR-END): study protocol for a phase II/III, multicenter, randomized, open-label clinical trial. Trials. 2019;20(1). DOI: 10.1186/s13063-018-3053-1. Brasil. Ministério da Saúde. Nota técnica sobre as mudanças no tratamento da tuberculose no Brasil para adultos e adolescentes – Versão 2 [internet]. [citado 15 dez 2023] Available from: http://www1.saude.rs.gov.br/dados/1293729099101nota%20t%e9cnica%20-%202%aa%20vers%e3o%20%28corrigida%20em%2022-10%29.pdf Borisov, S et al. “Surveillance of adverse events in the treatment of drug-resistant tuberculosis: first global report.” The Europ. Respirat. Jour. vol. 54,6 1901522. 19 Dec. 2019 [citado 15 dez 2023.]. DOI:10.1183/13993003.01522-2019 Tiberi S, et al. Drug resistant TB – latest developments in epidemiology, diagnostics and management. Int J Infect Dis. Mar 2022 [citado 19 out 2023]. DOI: 10.1016/j.ijid.2022.03.026. Dias FSS, Lima CCM. Interruption of the treatment of pulmonary tuberculosis: Risks for the individual and for public health. Braz. J. Develop. 2020 Sep. 21 [citado 11 out 2023.];6(9):70186-95. DOI: 10.34117/bjdv6n9-463. Silva GM. Planejamento computacional e avaliação biológica de inibidores alostéricos de glicogênio sintase cinase 3-β com interesse na doença de Alzheimer [Dissertação de doutorado]. Ribeirão Preto: Universidade de São Paulo; 2023 [citado 26 out 2023]. 143p. Wang S, Eisenberg D. Crystal structures of a pantothenate synthetase from M. tuberculosis and its complexes with substrates and a reaction intermediate. Protein Sci. Maio 2003 [citado 15 out 2023];12(5):1097-108. DOI: 10.1110/ps.0241803. Cusinato M. Estudos químicos e atividade antimicrobiana de bactérias associadas à abelha sem ferrão Scaptotrigona depilis [Dissertação de mestrado]. Ribeirão Preto: Universidade de São Paulo; 2020 [citado 20 out 2023]. 23p. Hopkins AL, Groom CR, Alex A. Ligand efficiency: a useful metric for lead selection. Drug Disc. Today. 2004 May 1 [cited 2023 Dec 15];9(10):430–1. DOI: 10.1016/S1359-6446(04)03069-7. Mendez D, et al. ChEMBL: towards direct deposition of bioassay data. Nucleic Acids Res. 2019; 47(D1): D930-D940. DOI:10.1093/nar/gky1075. vROCS 3.6.0.1. OpenEye, Cadence Molecular Sciences, Santa Fe, NM. http://www.eyesopen.com. Samala G, et al. Identification and development of 2-methylimidazo[1,2-a] pyridine-3-carboxamides as Mycobacterium tuberculosis pantothenate synthetase inhibitors. Bioorg. & Med. Chem. 2014 Aug. 22(15):4223–32. DOI:10.1016/j.bmc.2014.05.038. Yang Y, et al. A discovery of novel Mycobacterium tuberculosis pantothenate synthetase inhibitors based on the molecular mechanism of actinomycin D inhibition. Bioorg. & Med. Chem. Let. 2011 Jul; 21(13):3943–6. DOI: 10.1016/j.bmcl.2011.05.021. Mysinger MM, Carchia M, Irwin JJ, Shoichet BK. Directory of Useful Decoys, Enhanced (DUD-E): Better Ligands and Decoys for Better Benchmarking. J Med Chem. 5 jul 2012 [citado 10 out 2023];55(14):6582-94. DOI: 10.1021/jm300687e. SigmaPlot...

Introdução: A diabetes mellitus (DM) é uma doença crônica que se manifesta a partir da inatividade ou redução dos níveis de insulina no organismo, com consequente elevação da glicemia sérica. Isso permite a ativação da via poliol através das enzimas Aldose Redutase ALR1 que degrada aldeídos tóxicos e ALR2 responsável por converter a glicose em sorbitol. O subsequente acúmulo de sorbitol intracelular gera estresse oxidativo e danos teciduais, resultando em complicações como retinopatia, nefropatia e neuropatia, tornando o ALR2 um alvo relevante para o estudo. Objetivo: Identificar potenciais inibidores frente a ALR2 através de estudos computacionais. Metodologia: Inicialmente, a estrutura tridimensional da ALR2 foi obtida no banco de dados Protein Data Bank (PDB) e devidamente preparada no software PyMOL. Em seguida, os potenciais candidatos a fármacos foram selecionados a partir de moléculas naturais, seleção randomizada e estruturas conhecidas com potencial para reposicionamento de fármacos, sendo analisados os parâmetros físico-químicos e toxicológicos, posteriormente foram submetidos ao acoplamento molecular frente ao alvo. Resultados e Discussões: O composto ZINC18185774 foi classificado como melhor candidato para o estudo por apresentar o melhor perfil farmacocinético para biodisponibilidade oral e energia de afinidade de -11,8 kcal/mol, além disso, apresentou interações hidrofóbicas e ligações de hidrogênio frente a ALR2, segundo a análise topológica no servidor PoseView. Conclusão: Com isso, esse estudo mostra a eficiência das técnicas computacionais na identificação de potenciais candidatos que são capazes de inibir a ALR2, servindo como viés no desenvolvimento de novos fármacos para as complicações da diabetes. Referências 1. American Diabetes Association. Standards of Care in Diabetes—2024. Diabetes Care. 2024;47(Suppl 1):S1–S350. 2. Zakir M. et al. Cardiovascular Complications of Diabetes: From Microvascular to Macrovascular Pathways. Cureus [Internet]. 2023 Sep 24 [citado 2024 jan 10];15(9):e45835. Disponível em: https://doi.org/10.7759/cureus.45835. 3. Tehseen I. et al. Antidiabetic and hepato-renal protective effects of medicinal plants in STZ induced diabetic rats. Braz J Biol [Internet]. 2022 [citado 2024 jan 10];84. Disponível em: https://doi.org/10.1590/1519-6984.260189. 4. Kumar M. et al. Addressing Selectivity Issues of Aldose Reductase 2 Inhibitors for the Management of Diabetic Complications. Future Med Chem. 2020 Jul;12(14):1327–58. https://doi.org/10.4155/fmc-2020-0032. 5. Galgani G. et al. In Vitro Models of Diabetes: Focus on Diabetic Retinopathy. Cells. 2024 Nov 11;13(22):1864. https://doi.org/10.3390/cells13221864 6. Goto Y. et al. Effects of an aldose reductase inhibitor, epalrestat, on diabetic neuropathy. Clinical benefit and indication for the drug assessed from the results of a placebo-controlled double-blind study. Biomed Pharmacother. 1995;49(6):269–77. 7. Obrosova I.G., Chung S.S. Oxidative stress and diabetic complications: reactive species and target tissues. Dis Model Mech. 2010 Mar-Apr;3(3-4):94–8. doi:10.1242/dmm.040584. 8. Grewal A. et al. Updates on Aldose Reductase Inhibitors for Management of Diabetic Complications and Non-Diabetic Diseases. Mini Rev Med Chem. 2016;16(2):120–62. https://doi.org/10.2174/1389557515666150909143737. 9. Pushpakom S. et al. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov. 2019 Jan;18(1):41-58. doi:10.1038/nrd.2018.168. 10. Balestri F. et al. In search of differential inhibitors of aldose reductase. Biomolecules. 2022 Mar;12(4):485. doi:10.3390/biom12040485. 11. Sorokina M. et al. COCONUT online: Collection of Open Natural Products database. J Cheminform. 2021;13(1):2. doi:10.1186/s13321-020-00478-9. 12. Kim S. et al. PubChem 2025 update. Nucleic Acids Res. 2024;53(D1):D1516–25. doi:10.1093/nar/gkae1059. 13. Lipinski C.A. et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001 Mar;46(1-3):3–26. doi:10.1016/s0169-409x(00)00129-0. 14. Veber D.F et al. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem. 2002 Jun;45(12):2615–23. doi:10.1021/jm020017n. 15. Wichard D. In silico prediction of genotoxicity. Food Chem Toxicol. 2017 Aug;106:595–9. doi:10.1016/j.fct.2016.12.013. 16. Pires D.E.V., Blundell T.L., Ascher D.B. pkCSM: predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J Med Chem. 2015 Apr 22;58(9):4066–72. doi:10.1021/acs.jmedchem.5b00104. 17. Lins I. et al. Discovery of Thiopyrimidinone Derivatives as a New Class of Human Aldose Reductase Inhibitors. J Braz Chem Soc. 2022;33(9):1086–97. doi:10.21577/0103-5053.20220027. 18. MarvinSketch version 12.6.6. ChemAxon; 2013. 19. Stierand K, Rarey M. Molecular complexes at a glance: automated generation of two-dimensional complex diagrams. Bioinformatics. 2006 Jul;22(14):1710–6. 20. Howard EI, Sanishvili R, Cachau RE, Mitschler A, Barth P, Lamour V, et al. Ultrahigh resolution drug design I: Details of interactions in human aldose reductase-inhibitor complex at 0.66 Å. Proteins. 2004 Apr 2;55(4):792–804. doi:10.1002/prot.20015. 21. Fokoue H.H. et al. Há algo novo no reconhecimento molecular aplicado à química medicinal? Quim Nova. 2020;43(3):370–80. doi:10.21577/0100-4042.20170474. 22. Yasir M. et al. Investigating the inhibitory potential of flavonoids against aldose reductase: insights from molecular docking, dynamics simulations, and gmx_MMPBSA analysis. Curr Issues Mol Biol....