Abstract Thiosemicarbazones are promising classes of compounds with antitumor activity. For this study, six 2,4-dihydroxy-benzylidene-thiosemicarbazones compounds were synthesized. These compounds were submitted to different assays in silico, in vitro and in vivo to evaluate the toxicological, antioxidant and antitumor effects. The in silico results were evaluated by the SwissADME and pkCSM platforms and showed that all compounds had good oral bioavailability profiles. The in vitro and in vivo toxicity assays showed that the compounds showed low cytotoxicity against different normal cells and did not promote hemolytic effects. The single dose acute toxicity test (2000 mg/kg) showed that none of the compounds were toxic to mice. In in vitro antioxidant activity assays, the compounds showed moderate to low activity, with PB17 standing out for the ABTS radical capture assay. The in vivo antioxidant activity highlighted the compounds 1, 6 and 8 that promoted a significant increase in the concentration of liver antioxidant enzymes. Finally, all compounds showed promising antitumor activity against different cell lines, especially MCF-7 and DU145 lines, in addition, they inhibited the growth of sarcoma 180 at concentrations lower than 50 mg/kg. These results showed that the evaluated compounds can be considered as potential antitumor agents. study 2,4dihydroxybenzylidenethiosemicarbazones 24dihydroxybenzylidenethiosemicarbazones dihydroxybenzylidenethiosemicarbazones 2,4 dihydroxy benzylidene thiosemicarbazones 2 4 synthesized toxicological effects profiles 2000 (200 mg/kg mgkg mg kg mice PB PB1 assay 1 enzymes Finally lines MCF7 MCF 7 MCF- DU DU14 addition 18 5 agents 4dihydroxybenzylidenethiosemicarbazones 24 2, 200 (20 DU1 20 (2 (

Abstract Carbapenem-resistant P. aeruginosa (CRPA) has become a serious public health problem and the biofilm formation aggravates this problem. The study aimed to evaluate the occurrence of β-lactamases and quorum sensing (QS) genes in CRPA isolates, analyze production of biofilm, evaluate the response against meropenem (MPM) and∕or polymyxin B (POL B) and its association with azythromicin (AZT) using quantum dots (QDs) and proteomic analysis. Six CRPA isolates were analyzed. β-lactamases and QS genes were search using specific PCRs and were tested for biofilm production by quantitative technique. A CRPA isolate, containing blaKPC gene and biofilm-producing, was selected to assess its response to therapy using QDs and the MALDI-TOF. The β-lactamase detected was blaKPC in 66.7% of the isolates. All isolates were biofilm producers and carriers of the QS genes. QDs-MPM conjugates triggered the formation of biofilm and the association with AZT inhibited this effect. Proteomics analysis showed that treatments with MPM or POL B suppressed the expression of the transglycosylase protein, while combined therapy with AZT induced expression of the RpoN protein. Thus, this study shows that the use of fluorescence combined with the proteomics analysis was promising to understand how a CRPA strain reacts to antimicrobial treatment.

RESUMO Os escorpiões de interesse médico no Brasil pertencem ao gênero Tityus. Dentre eles, Tityus stigmurus é o principal responsável por picadas de escorpião na região Nordeste. Após uma picada, a peçonha de escorpião se distribui rapidamente para os órgãos, atingindo os rins depressa. Entretanto, há poucos trabalhos sobre fisiopatologia renal do envenenamento por escorpiões. Neste trabalho, avaliamos os efeitos da peçonha de T. stigmurus (TsV) sobre parâmetros renais em rins de ratos isolados. Ratos Wistar (n = 6), pesando 250-300 g, foram perfundidos com solução de Krebs-Henseleit contendo 6 g/100 mL de albumina de soro bovino. TsV nas concentrações de 0,3 e 1,0 μg/mL foi testado e os efeitos sobre a pressão de perfusão (PP), resistência vascular renal (RVR), fluxo urinário (FU), taxa de filtração glomerular (TFG) e excreção de eletrólitos foram analisados. Apenas na concentração de 1,0 μg/mL de TsV foram observados efeitos que aumentaram PP (controlePP40' = 92,7 ± 1,95; TsVPP40' = 182,0 ± 4,70 mmHg*, *p < 0,05), RVR (controleRVR40' = 3,28 ± 0,23 mmHg; TstRVR40' = 6,76 ± 0,45 mmHg*, *p < 0,05), FU (controleFU50' = 0,16 ± 0,04; TstFU50' = 0,60 ± 0,10 mL/g/min*, *p < 0,05), a TFG e excreção de eletrólitos, com alterações histológicas que indicam de lesão renal tubular. Em conclusão, peçonha de T. stigmurus induz um aumento transiente da PP com lesão tubular, ambos os quais conduzem a uma excreção elevada de eletrólitos.

ABSTRACT Scorpions belonging to the Tityus genus are of medical interest in Brazil. Among them, Tityus stigmurus is the main scorpion responsible for stings in the Northeast region. After a sting, the scorpion venom distributes rapidly to the organs, reaching the kidneys quickly. However, there are few studies concerning the renal pathophysiology of scorpion poisoning. In this study, we evaluated the effects of T. stigmurus venom (TsV) on renal parameters in isolated rat kidneys. Wistar rats (n = 6), weighing 250-300 g, were perfused with Krebs-Henseleit solution containing 6 g/100 mL bovine serum albumin. TsV at 0.3 and 1.0 μg/mL was tested, and the effects on perfusion pressure (PP), renal vascular resistance (RVR), urinary flow (UF), glomerular filtration rate (GFR), and electrolyte excretion were analyzed. Effects were observed only at TsV concentration of 1.0 μg/mL, which increased PP (controlPP40' = 92.7 ± 1.95; TsVPP40' = 182.0 ± 4.70* mmHg, *p < 0.05), RVR (controlRVR40' = 3.28 ± 0.23 mmHg; TstRVR40' = 6.76 ± 0.45* mmHg, *p < 0.05), UF (controlUF50' = 0.16 ± 0.04; TstUF50' = 0.60 ± 0.10* mL/g/min,*p < 0.05), GFR and electrolyte excretion, with histological changes that indicate renal tubular injury. In conclusion, T. stigmurus venom induces a transient increase in PP with tubular injury, both of which lead to an augmented electrolyte excretion.

Background : Apis mellifera stings are a problem for public health worldwide, particularly in Latin America due to the aggressiveness of its Africanized honeybees. Massive poisoning by A. mellifera venom (AmV) affects mainly the cardiovascular system, and several works have described its actions on heart muscle. Nevertheless, no work on the pharmacological action mechanisms of the AmV in isolated aorta has been reported. Thus, the present work aimed to investigate the actions of AmV and its main fractions, phospholipase A2 (PLA2) and melittin, on isolated aorta rings and a probable action mechanism. Results : AmV and the complex PLA2 + melittin (0.1-50 μg/mL) caused contraction in endothelium-containing aorta rings, but neither isolated PLA2 nor melittin were able to reproduce the effect. Endothelium removal did not change the maximum vasoconstrictor effect elicited by AmV. Ca2+-free medium, as well as treatment with phentolamine (5 μM), verapamil (10 μM), losartan (100 μM), and U-73122 (10 μM, a phospholipase C inhibitor), eliminated the AmV-induced contractile effects. Conclusions : In conclusion, AmV caused contractile effect in aorta rings probably through the involvement of voltage-operated calcium channels, AT1 and α-adrenergic receptors via the downstream activation of phospholipase C. The protein complex, PLA2 + melittin, was also able to induce vasoconstriction, whereas the isolated proteins were not.