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Krzysztof Bielawski,1 Katarzyna Leszczyńska,2 Zbigniew Kałuża,3 Anna Bielawska,4 Olga Michalak,3 Tamara Daniluk,2 Olga Staszewska-Krajewska,3 Anna Czajkowska,4 Natalia Pawłowska,1 Agnieszka Gornowicz4 1Department of Synthesis and Technology of Drugs, 2Department of Microbiology, Medical University of Bialystok, Bialystok, 3Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, 4Department of Biotechnology, Medical University of Bialystok, Bialystok, Poland Abstract: A new class of highly functionalized tetrahydroisoquinolines with a quaternary carbon stereocenter was synthesized starting from an easily accessible l-tartaric acid. Nine strains of bacteria (Staphylococcus aureus, Streptococcus pyogenes, Streptococcus mutans, Streptococcus salivarius, Bacillus subtilis, Enterococcus faecalis, Moraxella catarrhalis, Escherichia coli, Campylobacter jejuni) were used for the determination of minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of synthesized compounds. The influence of analyzed compounds on viability and induction of apoptosis in human skin fibroblasts was determined. A majority of the synthesized compounds showed the strongest antibacterial properties toward some gram-negative bacteria (M. catarrhalis and C. jejuni) with a high level of selectivity. High antibacterial compounds have bactericidal activity ratio MBC/MIC =4. Our studies also proved that the novel compounds do not possess cytotoxic and proapoptotic potential in normal cells. Keywords: quaternary ammonium compounds, tetrahydroisoquinolines, antimicrobial activity, antibiotic resistance

Background: Cystic fibrosis (CF) is one of the most common autosomal recessive diseases. Factors contributing to disease exacerbations and survival rate of CF patients are type of mutation in the CFTR gene, poor nutritional status, lung failure, and infection development by Pseudomonas aeruginosa. The study aimed to evaluate the relationship between the severity of mutation, nutritional status, lung function, and Pseudomonas aeruginosa prevalence and survival rate in adult patients with cystic fibrosis., Methods: A study of 124 (68 ♀ and 56 ♂) adults with CF aged 18-51 years were evaluated for (a) type of mutation in the CFTR gene, (b) nutritional status (BMI), (c) lung function (FEV 1 %), and (d) Pseudomonas aeruginosa prevalence. For statistical calculations, Kaplan-Meier analysis of survival, chi-squared test for multiple samples, and logistic regression were used., Results: The type of mutation (χ 2 = 12.73, df = 3, p = 0.005), FEV 1 % (χ 2 = 15.20, df = 2, p = 0.0005), Pseudomonas aeruginosa prevalence (χ 2 = 11.48, df = 3, p = 0.009), and BMI (χ 2 = 31.08, df = 4, p < 0.000) significantly differentiated the probability of survival of patients with CF. The shortest life expectancy was observed in patients with a severe type of mutation on both alleles, FEV 1 % < 40, subjects in whom Pseudomonas culture was extensively drug-resistant or pandrug-resistant, and patients whose BMI was lower than 18.5 kg/m 2 . The period from 30 to 40 years of age was the most critical in CF adults' lifespan. The risk of adults with CF death doubled with Pseudomonas aeruginosa prevalence (OR = 2.06, 95% CI 1.29; 2.28) and eightfold when the bacteria acquired antibiotic resistance (OR = 8.11, 95% CI 1.67; 38.15)., Conclusions: All factors included in the study were significantly related to the survival rate of patients with cystic fibrosis., (© 2021. The Author(s).)

In this study, we evaluated the cytotoxic activity and antiproliferative potency of novel octahydropyrazin[2,1-a:5,4-a']diisoquinoline derivatives (1-7) in MCF-7 and MDA-MB-231 breast cancer cell lines. Annexin V binding assay and disruption of the mitochondrial potential were performed to determine apoptosis. The activity of caspases 3, 8, 9, and 10 was measured after 24 h of incubation with tested compounds to explain detailed molecular mechanism of induction of apoptosis. The results from experiments were compared with effects obtained after incubation in the presence of camptothecin and etoposide. Our study demonstrated that the most active compounds in both analyzed breast cancer cell lines were compounds 3 and 4. We also observed that all compounds induced apoptosis. We demonstrated the higher activity of caspases 3, 8, 9, and 10, which confirmed that induction of apoptosis is associated with external and internal cell death pathway. Our study revealed that the novel compounds in group of diisoquinoline derivatives are promising candidates in anticancer treatment by activation of both extrinsic and intrinsic apoptotic pathways.

Many studies have shown that naturally occurring compounds may support prevention and treatment of various diseases, including cancer. Pharmacological investigations revealed a wide spectrum of Nigella sativa biological activities. Combining natural compounds together with synthetic drugs may increase the anticancer activity and limit severe side effects of such a treatment and may be an alternative to monotherapy. The aim of the study was to evaluate the cytotoxic and proapoptotic effects of a novel octahydropyrazino[2,1-a:5,4-a']diisoquinoline derivative and its effect in combination with Nigella sativa seed oil or extract in human gastric cancer cells (AGS). Etoposide was used as a reference. Our studies proved that combination strategy based on novel octahydropyrazino[2,1-a:5,4-a']diisoquinoline derivative (OM-90) with Nigella sativa seed oil or extract represents the strongest efficacy in AGS cancer cells as compared to monotherapy and combined treatment with Nigella sativa seed oil or extract together with etoposide. Such a combination also leads to the activation of mitochondrial pathway, which plays a significant role in molecular mechanism of induction of apoptosis by these compounds.

Objectives: The following study has been conducted to evaluate the efficacy of computer-controlled bipolar vessel sealing system (ThermoStapler, EMED), as an alternative to sutures, in order to achieve haemostasis during vaginal hysterectomy., Material and Methods: One hundred and twenty patients have undergone vaginal hysterectomy, half of them with the use of ThermoStapler vessel sealing system (n = 60) and the other half with standard surgical technique (n = 60). Data compared in this retrospective study included the time of surgery, hemoglobin loss after the surgery, postoperative need for pain medication, duration of the hospital stay and intra/post-operative complications., Results: The time of surgery proved to be shorter, although not significantly, in the group of vaginal hysterectomy with sutures when compared to the other group. The intra-operative blood loss, confirmed by pre- and postoperative hemoglobin measurements, appeared to be slightly lower in the ThermoStapler group. However, postoperative need for pain medication was significantly less frequent in the bipolar forceps group (P < 0.05). Complications and the duration of the hospital stay were similar in case of both groups., Conclusion: ThermoStapler bipolar vessel sealing system (EMED) proves to be a valuable alternative to traditional technique using surgical sutures, and an effective and safe method of achieving haemostasis during vaginal hysterectomy, resulting in significantly reduced need for pain medication during hospitalization.