Sisters in structure but different in character, some benzaldehyde and cinnamaldehyde derivatives differentially tune Aspergillus flavus secondary metabolism

Great are the expectations for a new generation of antimicrobials, and strenuous are the research efforts towards the exploration of diverse molecular scaffolds—possibly of natural origin – aimed at the synthesis of new compounds against the spread of hazardous fungi. Also high but winding are the paths leading to the definition of biological targets specifically fitting the drug’s structural characteristics. The present study is addressed to inspect differential biological behaviours of cinnamaldehyde and benzaldehyde thiosemicarbazone scaffolds, exploiting the secondary metabolism of the mycotoxigenic phytopathogen Aspergillus flavus. Interestingly, owing to modifications on the parent chemical scaffold, some thiosemicarbazones displayed an increased specificity against one or more developmental processes (conidia germination, aflatoxin biosynthesis, sclerotia production) of A. flavus biology. Through the comparative analysis of results, the ligand-based screening strategy here described has allowed us to delineate which modifications are more promising for distinct purposes: from the control of mycotoxins contamination in food and feed commodities, to the environmental management of microbial pathogens, to the investigation of specific structure–activity features for new generation drug discovery

Mechanistic insights on the mode of action of an antiproliferative thiosemicarbazone-nickel complex revealed by an integrated chemogenomic profiling study

Thiosemicarbazones (TSC) and their metal complexes display diverse biological activities and are active against multiple pathological conditions ranging from microbial infections to abnormal cell proliferation. Ribonucleotide reductase (RNR) is considered one of the main targets of TSCs, yet, the existence of additional targets, differently responsible for the multifaceted activities of TSCs and their metal complexes has been proposed. To set the basis for a more comprehensive delineation of their mode of action, we chemogenomically profiled the cellular effects of bis(citronellalthiosemicarbazonato)nickel(II) [Ni(S-tcitr)2] using the unicellular eukaryote Saccharomyces cerevisiae as a model organism. Two complementary genomic phenotyping screens led to the identification of 269 sensitive and 56 tolerant deletion mutant strains and of 14 genes that when overexpressed make yeast cells resistant to an otherwise lethal concentration of Ni(S-tcitr)2. Chromatin remodeling, cytoskeleton organization, mitochondrial function and iron metabolism were identified as lead cellular processes responsible for Ni(S-tcitr)2 toxicity. The latter process, and particularly glutaredoxin-mediated iron loading of RNR, was found to be affected by Ni(S-tcitr)2. Given the multiple pathways regulated by glutaredoxins, targeting of these proteins by Ni(S-tcitr)2 can negatively affect various core cellular processes that may critically contribute to Ni(S-tcitr)2 cytotoxicity

Folfiri versus xeliri in untreated advanced colorectal cancer: A phase II randomised trial of the Gruppo Oncologico dell' Italia Meridionale (prot. GOIM 2405)

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Which route of antibiotic administration should be used for third molar surgery? A split-mouth study to compare intramuscular and oral intake

Objectives. To compare the effectiveness of two different routes of antibiotic administration in preventing septic complications in patients undergoing third molar extraction. Materials and Methods. Twenty-four healthy patients requiring bilateral surgical removal of impacted mandibular third molars were successfully enrolled for this study. Depth of impaction, angulation, and relationship of the lower third molars with the mandibular branch had to be overlapping on both sides. A split-mouth design was chosen, so each patient underwent both the first and second surgeries, having for each extraction a different antibiotic route of administration. The second extraction was carried out 1 month later. To compare the effects of the two routes of antibiotic administration, inflammatory parameters, such as edema, trismus, pain, fever, dysphagia and lymphadenopathy were evaluated 2 and 7 days after surgery. Side effects of each therapy were evaluated 48h after surgery. Results. oral and intramuscular antibiotic therapies overlap in preventing post-operative complications in dental surgery (p>0.05), even if the oral intake, seems to promote the onset of significant gastrointestinal disorders (p=0.003). Conclusions. This study could help dentists in their ordinary practice to choose the right route of antibiotic administration in the third molar surgery. At the same effectiveness, the higher cost and the minor compliance of the patient seem not to justify a routine antibiotic intramuscular therapy, reserving it for patients with gastrointestinal disorders

Double gamers—can modified natural regulators of higher plants act as antagonists against phytopathogens? The case of jasmonic acid derivatives

As key players in biotic stress response of plants, jasmonic acid (JA) and its derivatives cover a specific and prominent role in pathogens-mediated signaling and hence are promising candidates for a sustainable management of phytopathogenic fungi. Recently, JA directed antimicrobial effects on plant pathogens has been suggested, supporting the theory of oxylipins as double gamers in plant-pathogen interaction. Based on these premises, six derivatives (dihydrojasmone and cis-jasmone, two thiosemicarbazonic derivatives and their corresponding complexes with copper) have been evaluated against 13 fungal species affecting various economically important herbaceous and woody crops, such as cereals, grapes and horticultural crops: Phaeoacremonium minimum, Neofusicoccum parvum, Phaeomoniella chlamydospora, Fomitiporia mediterranea, Fusarium poae, F. culmorum, F. graminearum, F. oxysporum f. sp. lactucae, F. sporotrichioides, Aspergillus flavus, Rhizoctonia solani, Sclerotinia spp. and Verticillium dahliae. The biological activity of these compounds was assessed in terms of growth inhibition and, for the two mycotoxigenic species A. flavus and F. sporotrichioides, also in terms of toxin containment. As expected, the inhibitory effect of molecules greatly varied amongst both genera and species; cis-jasmone thiosemicarbazone in particular has shown the wider range of effectiveness. However, our results show that thiosemicarbazones derivatives are more effective than the parent ketones in limiting fungal growth and mycotoxins production, supporting possible applications for the control of pathogenic fungi

The aflatox® project: Approaching the development of new generation, natural‐based compounds for the containment of the mycotoxigenic phytopathogen Aspergillus flavus and aflatoxin contamination

The control of the fungal contamination on crops is considered a priority by the sanitary authorities of an increasing number of countries, and this is also due to the fact that the geographic areas interested in mycotoxin outbreaks are widening. Among the different pre‐ and post‐harvest strategies that may be applied to prevent fungal and/or aflatoxin contamination, fungicides still play a prominent role; however, despite of countless efforts, to date the problem of food and feed contamination remains unsolved, since the essential factors that affect aflatoxins production are various and hardly to handle as a whole. In this scenario, the exploitation of bioactive natural sources to obtain new agents presenting novel mechanisms of action may represent a successful strategy to minimize, at the same time, aflatoxin contamination and the use of toxic pesticides. The Aflatox® Project was aimed at the development of new‐generation inhibitors of aflatoxigenic Aspergillus spp. proliferation and toxin production, through the modification of naturally occurring molecules: a panel of 177 compounds, belonging to the thiosemicarbazones class, have been synthesized and screened for their antifungal and anti‐aflatoxigenic potential. The most effective compounds, selected as the best candidates as aflatoxin containment agents, were also evaluated in terms of cytotoxicity, genotoxicity and epi‐genotoxicity to exclude potential harmful effect on the human health, the plants on which fungi grow and the whole ecosystem

Peritonitis in children on peritoneal dialysis in Cape Town, South Africa: epidemiology and risks

Peritonitis is a frequent complication of peritoneal dialysis (PD) in children as well in adults. Data on PD and peritonitis in pediatric patients are very scarce in developing countries. A retrospective cohort study was performed between 2000 and 2008 with the aim to evaluate PD treatment and peritonitis epidemiology in pediatric patients in South Africa and identify risk factors for peritonitis. Baseline characteristics and potential risk factors of peritonitis were recorded, including housing, socio-economic circumstances, distance to PD center, type of PD, mode of catheter placement, race, presence of gastrostomy tube, weight, and height. Outcome indices for peritonitis were peritonitis rate, time to first peritonitis, and number of peritonitis-free patients. The patient cohort comprised 67 patients who were on PD for a total of 544 months. The total number of peritonitis episodes was 129. Median peritonitis rate was one episode every 4.3 patient months (2.8 episodes/patient-year, range 0–21.2). Median time to first infection was 2.03 months (range 0.1–21.5 months), and 28.4% of patients remained free from peritonitis. Patients with good housing and good socio-economic circumstances had a significantly lower peritonitis rate and a longer time to first peritonitis episode. Peritonitis rate was high in this cohort, compared to numbers reported for the developed world; the characteristics of causative organisms are comparable. The most important risk factors for the development of peritonitis were poor housing and poor socio-economic circumstances. More intensive counseling may be beneficial, but improvement of general socio-economic circumstances will have the greatest influence on PD success

Insights into the molecular determinants involved in cap recognition by the vaccinia virus D10 decapping enzyme

Decapping enzymes are required for the removal of the 5′-end m7GpppN cap of mRNAs to allow their decay in cells. While many cap-binding proteins recognize the cap structure via the stacking of the methylated guanosine ring between two aromatic residues, the precise mechanism of cap recognition by decapping enzymes has yet to be determined. In order to get insights into the interaction of decapping enzymes with the cap structure, we studied the vaccinia virus D10 decapping enzyme as a model to investigate the important features for substrate recognition by the enzyme. We demonstrate that a number of chemically modified purines can competitively inhibit the decapping reaction, highlighting the molecular features of the cap structure that are required for recognition by the enzyme, such as the nature of the moiety at positions 2 and 6 of the guanine base. A 3D structural model of the D10 protein was generated which suggests amino acids implicated in cap binding. Consequently, we expressed 17 mutant proteins with amino acid substitutions in the active site of D10 and found that eight are critical for the decapping activity. These data underscore the functional features involved in the non-canonical cap-recognition by the vaccinia virus D10 decapping enzyme