Agency in urgency and uncertainty. Vaccines and vaccination in European media discourses.

Although Covid-19 was not the first pandemic, it was unique in the scale and intensity with which societies responded. Countries reacted differently to the threat posed by the new virus. The public health crisis affected European societies in many ways. It also influenced the way the media portrayed vaccines and discussed factors related to vaccine hesitancy. Europeans differed in their risk perceptions, attitudes towards vaccines and vaccine uptake. In European countries, Covid-19-related discourses were at the centre of media attention for many months. This paper reports on a media analysis which revealed significant differences as well as some similarities in the media debates in different countries. The study focused on seven European countries and considered two dimensions of comparison: between the pre-Covid period and the beginning of the Covid pandemic period, and between countries. The rich methodological approach, including linguistics, semantic field analysis and discourse analysis of mainstream news media, allowed the authors to explore the set of meanings related to vaccination that might influence actors' agency. This approach led the authors to redefine vaccine hesitancy in terms of characteristics of the "society in the situation" rather than the psychological profile of individuals. We argue that vaccine hesitancy can be understood in terms of agency and temporality. This dilemma of choice that transforms the present into an irreversible past and must be taken in relation to an uncertain future, is particularly acute under the pressure of urgency and when someone's health is at stake. As such, it is linked to how vaccine meaning is co-produced within public discourses.

Trust matters: The Addressing Vaccine Hesitancy in Europe Study.

This article presents the design of a seven-country study focusing on childhood vaccines, Addressing Vaccine Hesitancy in Europe (VAX-TRUST), developed during the COVID-19 pandemic. The study consists of (a) situation analysis of vaccine hesitancy (examination of individual, socio-demographic and macro-level factors of vaccine hesitancy and analysis of media coverage on vaccines and vaccination and (b) participant observation and in-depth interviews of healthcare professionals and vaccine-hesitant parents. These analyses were used to design interventions aimed at increasing awareness on the complexity of vaccine hesitancy among healthcare professionals involved in discussing childhood vaccines with parents. We present the selection of countries and regions, the conceptual basis of the study, details of the data collection and the process of designing and evaluating the interventions, as well as the potential impact of the study. Laying out our research design serves as an example of how to translate complex public health issues into social scientific study and methods.

Flavonoid Derivatives as New Potent Inhibitors of Cysteine Proteases: An Important Step toward the Design of New Compounds for the Treatment of Leishmaniasis.

Leishmaniasis is a neglected tropical disease, affecting more than 350 million people globally. However, there is currently no vaccine available against human leishmaniasis, and current treatment is hampered by high cost, side-effects, and painful administration routes. It has become a United Nations goal to end leishmaniasis epidemics by 2030, and multitarget drug strategy emerges as a promising alternative. Among the multitarget compounds, flavonoids are a renowned class of natural products, and a structurally diverse library can be prepared through organic synthesis, which can be tested for biological effectiveness. In this study, we synthesised 17 flavonoid analogues using a scalable, easy-to-reproduce, and inexpensive method. All synthesised compounds presented an impressive inhibition capacity against rCPB2.8, rCPB3, and rH84Y enzymes, which are highly expressed in the amastigote stage, the target form of the parasite. Compounds 3c, f12a, and f12b were found to be effective against all isoforms. Furthermore, their intermolecular interactions were also investigated through a molecular modelling study. These compounds were highly potent against the parasite and demonstrated low cytotoxic action against mammalian cells. These results are pioneering, representing an advance in the investigation of the mechanisms behind the antileishmanial action of flavonoid derivatives. Moreover, compounds have been shown to be promising leads for the design of other cysteine protease inhibitors for the treatment of leishmaniasis diseases.

Semysinthetic biflavonoid Morelloflavone-7,4',7″,3‴,4‴-penta-O-butanoyl is a more potent inhibitor of Proprotein Convertases Subtilisin/Kexin PC1/3 than Kex2 and Furin.

BACKGROUND: Garcinia brasiliensis is a species native to the Amazon forest. The white mucilaginous pulp is used in folk medicine as a wound healing agent and for peptic ulcer, urinary, and tumor disease treatments. The activity of the proprotein convertases (PCs) Subtilisin/Kex is associated with the development of viral, bacterial and fungal infections, osteoporosis, hyperglycemia, atherosclerosis, cardiovascular, neurodegenerative and neoplastic diseases. METHODS: Morelloflavone (BF1) and semisynthetic biflavonoid (BF2, 3 and 4) from Garcinia brasiliensis were tested as inhibitor of PCs Kex2, PC1/3 and Furin, and determined IC50, Ki, human proinflammatory cytokines secretion in Caco-2 cells, mechanism of inhibition, and performed molecular docking studies. RESULTS: Biflavonoids were more effective in the inhibition of neuroendocrine PC1/3 than mammalian Furin and fungal Kex2. BF1 presented a mixed inhibition mechanism for Kex2 and PC1, and competitive inhibition for Furin. BF4 has no good interaction with Kex2 and Furin since carboxypropyl groups results in steric hindrance to ligand-protein interactions. Carboxypropyl groups of BF4 promote steric hindrance with Kex2 and Furin, but effective in the affinity of PC1/3. BF4 was more efficient at inhibiting PCl/3 (IC50 = 1.13 µM and Ki = 0,59 µM, simple linear competitive mechanism of inhibition) than Kex2, Furin. Also, our results strongly suggested that BF4 also inhibits the endogenous cellular PC1/3 activity in Caco-2 cells, since PC1/3 inhibition by BF4 causes a large increase in IL-8 and IL-1ß secretion in Caco-2 cells. CONCLUSIONS: BF4 is a potent and selective inhibitor of PC1/3. GENERAL SIGNIFICANCE: BF4 is the best candidate for further clinical studies on inhibition of PC1/3.

Cysteine proteases as potential targets for anti-trypanosomatid drug discovery.

Leishmaniasis and trypanosomiasis are endemic neglected disease in South America and Africa and considered a significant public health problem, mainly in poor communities. The limitations of the current available therapeutic options, including the lack of specificity, relatively high toxicity, and the drug resistance acquiring, drive the constant search for new targets and therapeutic options. Advances in knowledge of parasite biology have revealed essential enzymes involved in the replication, survival, and pathogenicity of Leishmania and Trypanosoma species. In this scenario, cysteine proteases have drawn the attention of researchers and they are being proposed as promising targets for drug discovery of antiprotozoal drugs. In this systematic review, we will provide an update on drug discovery strategies targeting the cysteine proteases as potential targets for chemotherapy against protozoal neglected diseases.

Cytotoxicity of 4-substituted quinoline derivatives: Anticancer and antileishmanial potential.

Chemical modifications of quinoline moiety have been recognized as a useful strategy to development of new drugs. Here, the cytotoxicity of a set of twenty-four 4-substituted quinolines (named HTI) was screened for their antitumor and antileishmanial potential in vitro, and the underlying mechanisms investigated. HTI 21 and HTI 22 exhibited the highest cytotoxicity, being selected to the subsequent studies. Both derivatives induced caspase-dependent apoptosis associated to the dissipation of the mitochondrial transmembrane potential (ΔΨ) and ROS generation. HTI-induced cell death was calcium dependent, associated to thiol oxidation and cysteine proteases activation. In isolated mitochondria, HTI derivatives promoted mitochondrial permeabilization by different mechanisms. The inhibition of BCL-2 by venetoclax enhanced the HTI-induced cytotoxicity. Regarding the inhibition of cysteine proteases type B of Leishmania mexicana, HTI 15 exhibited the most potent inhibitory activity through a linear non-competitive mechanism. These data highlight the therapeutic potential of 4-substituted quinolines as antitumor and antileishmanial drugs.