Transition metal carbonyl complexes used as CO-releasing molecules (CORMs) for biological and therapeutic applications may exhibit interesting antimicrobial activity. However, understanding the ...chemical traits and mechanisms of action that rule this activity is required to establish a rationale for the development of CORMs into useful antibiotics. In this work the bactericidal activity, the toxicity to eukaryotic cells, and the ability of CORMs to deliver CO to bacterial and eukaryotic cells were analysed for a set of seven CORMs that differ in the transition metal, ancillary ligands and the CO release profile. Most of these CORMs exhibited bactericidal properties that decrease in the following order: CORM-2 > CORM-3 > ALF062 > ALF850 > ALF186 > ALF153 > Fe(SBPy
3
)(CO)(BF
4
)
2
. A similar yet not entirely coincident decreasing order was found for their induction of intracellular reactive oxygen species (ROS) in
E. coli.
In contrast, studies in model animal cells showed that for any given CORM, the level of intracellular ROS generated was negligible when compared with that measured inside bacteria. Importantly, these CORMs were in general not toxic to eukaryotic cells, namely murine macrophages, kidney LLC-PK1 epithelial cells, and liver cell line HepG2. CORM-2 and CORM-3 delivered CO to the intracellular space of both
E. coli
and the two types of tested eukaryotic cells, yet toxicity was only elicited in the case of
E. coli.
CO delivered by ALF186 into the intercellular space did not enter
E. coli
cells and the compound was not toxic to either bacteria or to eukaryotic cells. The Fe(
ii
) carbonyl complex Fe(SBPy
3
)(CO)
2+
had the reverse, undesirable toxicity profile, being unexpectedly toxic to eukaryotic cells and non-toxic to
E. coli
. ALF153, the most stable complex in the whole set, was essentially devoid of toxicity or ROS induction ability in all cells. These results suggest that CORMs have a relevant therapeutic potential as antimicrobial drugs since (i) they can show opposite toxicity profiles towards bacteria and eukaryotic cells; (ii) their activity can be modulated through manipulation of the ancillary ligands, as shown with the three {Ru(CO)
3
}
2+
and two zerovalent Mo based CORMs; and (iii) their toxicity to eukaryotic cells can be made acceptably low. With this new approach, this work contributes to the understanding of the roots of the bactericidal action of CORMs and helps in establishing strategies for their development into a new class of antibiotics.
Transition metal carbonyl complexes used as CO-releasing molecules (CORMs) for biological and therapeutic applications may exhibit interesting antimicrobial activity.
The work presented in this thesis aimed at unravelling novel modes of antimicrobial action through: i) the study of Staphylococcus aureus defences against nitric oxide, an antimicrobial weapon of the ...innate immune system, namely by performing the biochemical characterisation of S. aureus NO-detoxifying flavohaemoglobin and analysing the conditions under which the enzyme is operative; ii) the identification of the mechanisms beyond the antibacterial activity of azole antibiotics towards S. aureus that were shown to include the increase of endogenous reactive oxygen species triggered by the binding of imidazoles to flavohaemoglobin; and iii) the discovery of a novel type of bactericides, the carbon monoxide-releasing molecules, and identification of its potential cellular targets via analysis of the transcriptional response of Escherichia coli to CORM-2, a carbon monoxide-releasing molecule known to mimic the physiological function of carbon monoxide. (...)
To evaluate the temporal trend of bronchopulmonary dysplasia (BPD) in preterm infants who survived to at least 36 weeks' post-menstrual age (PMA) and BPD or death at 36 weeks' PMA, and to analyse ...variables associated with both outcomes.
Retrospective cohort with data retrieved from an ongoing national registry.
19 Brazilian university public hospitals.
Infants born between 2010 and 2019 with 23-31 weeks and birth weight 400-1499 g.
Temporal trend was evaluated by Prais-Winsten model and variables associated with BPD in survivors or BPD or death were analysed by logistic regression.
Of the 11 128 included infants, BPD in survivors occurred in 22%, being constant over time (annual per cent change (APC): -0.80%; 95% CI: -2.59%; 1.03%) and BPD or death in 45%, decreasing over time (APC: -1.05%; 95% CI: -1.67%; -0.43%). Being male, small for gestational age, presenting with respiratory distress syndrome, air leaks, needing longer duration of mechanical ventilation, presenting with treated patent ductus arteriosus and late-onset sepsis were associated with an increase in the chance of BPD. For the outcome BPD or death, maternal bleeding, multiple gestation, 5-minute Apgar <7, late-onset sepsis, necrotising enterocolitis and intraventricular haemorrhage were added to the variables reported above as increasing the chance of the outcome.
The frequency of BPD in survivors was constant and BPD or death decreased by 1.05% at each study year. These results show some improvement in perinatal care in Brazilian units which resulted in a reduction of BPD or death, but further improvements are still needed to reduce BPD in survivors.
Escherichia coli RIC (Repair of Iron Centers) is a diiron protein previously reported to be involved in the repair of iron-sulfur proteins damaged by oxidative or nitrosative stresses, and proposed ...to act as an iron donor. This possible role of RIC was now examined specifically by evaluating its ability to donate iron ions to apo-iron-sulfur proteins, determining the iron binding constants and assessing the lability of its iron ions. We show, by UV-visible, EPR and resonance Raman spectroscopies that RIC may participate in the synthesis of an iron-sulfur cluster in the apo-forms of the spinach ferredoxin and IscU when in the presence of the sulfide donating system IscS and L-cysteine. Iron binding assays allowed determining the as-isolated and fully reduced RIC dissociation constants for the ferric and ferrous iron of 10-27 M and 10-13 M, respectively. Mossbauer studies revealed that the RIC iron ions are labile, namely when the center is in the mixed-valence redox form as compared with the ( mu -oxo) diferric one. Altogether, these results suggest that RIC is capable of delivering iron for the formation of iron-sulfur clusters.
Helicobacter pylori is a pathogen that establishes long life infections responsible for chronic gastric ulcer diseases and a proved risk factor for gastric carcinoma. The therapeutic properties of ...carbon-monoxide releasing molecules (CORMs) led us to investigate their effect on H. pylori. We show that H. pylori 26695 is susceptible to two widely used CORMs, namely CORM-2 and CORM-3. Also, several H. pylori clinical isolates were killed by CORM-2, including those resistant to metronidazole. Moreover, sub-lethal doses of CORM-2 combined with metronidazole, amoxicillin and clarithromycin was found to potentiate the effect of the antibiotics. We further demonstrate that the mechanisms underpinning the antimicrobial effect of CORMs involve the inhibition of H. pylori respiration and urease activity. In vivo studies done in key cells of the innate immune system, such as macrophages, showed that CORM-2, either alone or when combined with metronidazole, strongly reduces the ability of H. pylori to infect animal cells. Hence, CORMs have the potential to kill antibiotic resistant strains of H. pylori.
•UNESCO estimates that the closure of educational institutions because of the pandemic is affecting half of the world's students – 890 million in 114 countries.•Although temporary school closures as ...a result of health crises and other emergencies are not new, the global scale and speed of the current educational disruption are unfortunately unmatched and, if prolonged, may cause psychological pain and suffering at different levels.•The outbreak has changed the schedule of conferences and sports events, and institutions are canceling classroom-based classes and converting them to online sessions. Colleges are being forced to consider large-scale preventive measures to keep students and professors healthy as well as to create plans for when infections materialize on campus.•By discussing online and distance education, the coronavirus opens an important and urgent issue that affects mental health – these are virtually unexplored topics, and their results have not been validated yet.
: According to UNESCO's monitoring, more than 160 countries implemented nationwide closures, which impacted over 87% of the world's student population. Several other countries implemented localized school closures; should these closures become nationwide, millions of additional learners will experience education disruption. Universities from around the world have been uncertain about how long the coronavirus crisis will last and how it might affect the mental health of students and faculty. The psychological impact has been a critical disruptor, creating anxiety and uncertainty.
: The data were cross-checked with information from the main international newspapers.
: By discussing online and distance education, the coronavirus opens an important and urgent issue that affects mental health – these are virtually unexplored topics, and their results have not been validated yet. Online education is not limited to distance education, as it regards a grouping of learning/teaching procedures completed in cyberspace. Blended learning was, thus, introduced as a tool in personalized learning to adjust to new realities. These are unprecedented circumstances, and we understand they create stress, favoring anguish and a fierce search for new knowledge acquisition.
: Current research highlights that anxiety and depression, exacerbated by uncertainties and intensification of the information flow, will grow extensively. Negative physiological consequences of stress will manifest. For instance, loneliness, which will increase under these circumstances, seems to have a negative impact on education and, therefore, on psychological pain and suffering.
The Sexual Inhibition and Sexual Excitation Scales (SIS/SES) were developed to assess individual propensities for sexual excitation and sexual inhibition in men and women. The objective of the ...present study was to validate the Portuguese version of the SIS/SES and to investigate the degree to which SIS/SES scores predict different dimensions of Portuguese men’s and women’s sexual functioning. Gender differences were also examined. A community sample of 370 Portuguese men and 373 women completed self-report measures of sexual function (IIEF, Rosen et al.,
1997
; FSFI, Rosen et al.,
2000
) and of the propensity for sexual inhibition and sexual excitation (SIS/SES, Janssen et al.,
2002a
). Exploratory factor analysis revealed a three-factor solution further supported by confirmatory factor analysis. The three factors identified resemble the original ones, and reliability analyses indicated they have both satisfactory internal consistency and stability over time. Age and Sexual Inhibition Due to the Threat of Performance Failure (SIS1) were both significant negative predictors of men’s sexual desire, erectile function, and orgasm. Sexual Excitation (SES) was a positive predictor of sexual desire in both men and women and of men’s erectile function and of women’s lubrication and orgasm. Age was also a significant and negative predictor of women’s sexual desire. Significant gender differences were found for all three SIS/SES scales with men having significantly higher excitation and lower inhibition scores as compared to women. The Portuguese version of the SIS/SES was shown to be suitable for use within the Portuguese population in both clinical and basic research. Our findings provide further cross-cultural validation of the Dual Control Model of Sexual Response and underscore the importance of the role of excitatory and inhibitory processes in women’s and men’s sexual functioning and response.
An increased commercial interest in fructo-oligosaccharides (FOS) has emerged in the last decade due to their prebiotic activity. At large scale, the FOS are produced by microbial enzymes from ...sucrose. A mixture of FOS and other saccharides is obtained in this process. The presence of such saccharides reduces the prebiotic, caloric, and cariogenic value of the final product. Therefore, many efforts have been conducted to obtain a product with increased FOS purity. This review comprises the most important technological and physicochemical aspects including FOS production and recovery processes; safety, dose and health claims concerning its intake; and commercially available FOS.
Microorganisms are exposed to harmful oxygen and nitrogen reactive species that are formed in the environment and produced by cells of the mammalian innate immunity. Iron-sulfur clusters, contained ...in proteins that largely sustain microbial life, are damaged by oxidative/nitrosative stresses causing the inactivation of the protein/enzyme. Depending on the extension of the damage, the functional recuperation of the Fe-S protein requires specialized machineries for repair or de novo assembly of the cluster. Repair of Iron Centres (RIC) are a family of di-iron proteins whose first member was identified in Escherichia coli (formely YtfE) as having an unprecedented role in the protection of Fe-S centres by delivering iron for the formation of Fe-S clusters1,2. We show that in human pathogens such as Staphylococcus aureus, Neisseria gonorrhoeae and Trichomonas vaginalis RIC confers protection against nitrogen and oxygen reactive species. Moreover, we demonstrate that RIC is required for full virulence of S. aureus upon infection of the wax moth larva Galleria mellonella3–5.
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