Novel hybrids of sclareol and 1,2,4-triazolo[1,5-a]pyrimidine show collateral sensitivity in multidrug-resistant glioblastoma cells.

The synthesis of 24 hybrid molecules, consisting of naturally occurring sclareol (SCL) and synthetic 1,2,4-triazolo[1,5-a]pyrimidines (TPs), is described. New compounds were designed with the aim of improving the cytotoxic properties, activity, and selectivity of the parent compounds. Six analogs (12a-f) contained 4-benzylpiperazine linkage, while 4-benzyldiamine linkage was present in eighteen derivatives (12g-r and 13a-f). Hybrids 13a-f consist of two TP units. After purification, all hybrids (12a-r and 13a-f), as well as their precursors (9a-e and 11a-c), were tested on human glioblastoma U87 cells. More than half of the tested synthesized molecules, 16 out of 31, caused a significant reduction of U87 cell viability (more than 75% reduction) at 30 µM. The concentration-dependent cytotoxicity of these 16 compounds was also examined on U87 cells, corresponding multidrug-resistant (MDR) U87-TxR cells with increased P-glycoprotein (P-gp) expression and activity, and normal lung fibroblasts MRC-5. Importantly, 12l and 12r were active in the nanomolar range, while seven compounds (11b, 11c, 12i, 12l, 12n, 12q, and 12r) were more selective towards glioblastoma cells than SCL. All compounds except 12r evaded MDR, showing even better cytotoxicity in U87-TxR cells. In particular, 11c, 12a, 12g, 12j, 12k, 12m, 12n, and SCL showed collateral sensitivity. Hybrid compounds 12l, 12q, and 12r decreased P-gp activity to the same extent as a well-known P-gp inhibitor - tariquidar (TQ). Hybrid compound 12l and its precursor 11c affected different cellular processes including the cell cycle, cell death, and mitochondrial membrane potential, and changed the levels of reactive oxygen and nitrogen species (ROS/RNS) in glioblastoma cells. Collateral sensitivity towards MDR glioblastoma cells was caused by the modulation of oxidative stress accompanied by inhibition of mitochondria.

Unraveling the anti-virulence potential and antifungal efficacy of 5-aminotetrazoles using the zebrafish model of disseminated candidiasis.

Candida albicans remains the main causal agent of candidiasis, the most common fungal infection with disturbingly high mortality rates worldwide. The limited diversity and efficacy of clinical antifungal drugs, exacerbated by emerging drug resistance, have resulted in the failure of current antifungal therapies. This imposes an urgent demand for the development of innovative strategies for effective eradication of candidal infections. While the existing clinical drugs display fungicidal or fungistatic activity, the strategy specifically targeting C. albicans filamentation, as the most important virulence trait, represents an attractive approach for overcoming the drawbacks related to clinical antifungals. The results acquired in this study revealed the significant potential of 5-aminotetrazoles as a new class of effective and safe anti-virulence agents. Moreover, these novel agents were active when applied both alone and in combination with clinically approved polyenes. Complete prevention of C. albicans morphogenetic yeast-to-hyphae transition was achieved at doses as low as 1.3 µM under conditions mimicking various filamentation-responsive stimuli in the human body, while no cardio- or hepatotoxicity was observed at doses as high as 200 µM. The treatment of C. albicans-infected zebrafish embryos with nystatin alone had low efficacy, while the combination of nystatin and selected 5-aminotetrazoles prevented fungal filamentation, successfully eliminating the infection and rescuing the infected embryos from lethal disseminated candidiasis. In addition, the most potent anti-virulence 5-aminotetrazole prevented C. albicans in developing the resistance to nystatin when applied in combination, keeping the fungus sensitive to the antifungal drug.

A Retrospective Comparative Study of Serbian Underground Coalmining Injuries.

BACKGROUND: During 2011, a study was undertaken to assess safety conditions in Serbian underground coalmines by analysis of injury data. The study covered all Serbian coalmines, identified week spots from the aspect of safety, and recommended possible courses of action. Since then, Serbia has made changes to safety and health legislation; all coalmines introduced new preventive measures, adopted international standards, and made procedures for risk management. After 10 years a new study has been performed to analyze the impact of these changes. MATERIALS AND METHODS: In this study, the injuries that have occurred in the Serbian underground coal mines over the last 20 years were analyzed. Statistical data analysis was performed by IBM SPSS Statistics v23. The injuries that occurred in the last ten years were compared with the results of the previous study (2000-2009). The average values of injury rates for both periods were compared for each of the categories (severity, age, body part, qualification), and the results were presented as absolute difference or percentile difference. RESULTS: The results showed reduction in the number of injuries in the category of 20-30 years old workers, where the new training procedures for workers, which were set by mandatory legal regulations, certainly contributed. They also showed an increase in the number of injuries in the category of old workers, which indicates that the law did not have a positive effect on this category. CONCLUSION: The total number of injuries is still high; therefore, it is necessary to introduce mechanization and automation in mines and have a better policy for older workers who retire later nowadays.

Analysis of fatal injuries in Serbian underground coal mines - 50 years review.

The study presented here analyzes mining accidents and fatal injuries in Serbian underground coal mines over a period of 50 years, in order to assess the effectiveness of legislation changes in the overall safety of work environment. Two distinct periods, prior to 2000 and after 2000 were compared. The data from the period after 2000 were further analyzed to provide better understanding of the results. In order to assess the overall state of safety in Serbian mines, the data on fatal injuries were also compared to the international data. It was found that the legislative changes are more easily accepted by the common workers than by the mine management. Consequently, the key recommendation for the safety of coal mine companies in Serbia is the investment in the new technology. Additionally, mine management should be in the focus of the mining inspection with a stronger penal policy regarding mine safety neglect.