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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: Microbial dysbiosis has been linked to cystic fibrosis (CF); however, the composition of gut microbiota in adult CF patients in relation to severity of CF transmembrane conductance regulator (CFTR) gene mutation and nutritional status have not yet been explored. Study aimed to assess the gut microbiota composition in adults with CF, and its relationship with the severity of CFTR mutations, and BMI., Methods: Gut microbiota of 41 adults with CF, and 26 non-CF controls were compared using whole 16S rRNA gene sequencing. Differences in the microbial community between groups of patients classified according to the severity of CFTR mutations, and BMI were assessed. The alpha diversity, beta diversity, and taxa abundance were identified to reflect gut microbiota composition., Results: Results showed a significant decrease in alpha diversity of bacterial communities in CF compared to non-CF group, but no significant difference between the CF groups distinguished by the severity of CFTR mutations. However, more severe mutations were associated with the higher relative abundance of Bacteroides and Streptococcus and the lower relative abundance of Faecalibacterium and Blautia. Undernourished CF patients showed significantly lower alpha diversity compared to non-CF group and CF patients with BMI within the norm. Significant differences in the structure of the gut microbiota between CF and non-CF groups, as well as between BMI groups were also found., Conclusions: Our research indicates that CF is associated with alterations in gut microbiota in adults. Additionally, in adult CF patients, the composition of the gut microbiota is also related to BMI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

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).)

Objective: The aim of this study was to describe the relationship between the prevalence of Pseudomonas aeruginosa (PA) and lung function, as well as the nutritional status and type of gene mutation in adult patients with cystic fibrosis (CF)., Methods: This cross-sectional study evaluated 103 Polish adults with CF the following: • The occurrence of PA and the level of bacterial susceptibility to antibiotics; • Type of mutation in the CFTR gene; • Nutritional status assessed by body mass index (BMI), and • Lung function measured by forced expiratory volume in 1 s (FEV1%)., Results: The absence or presence of PA and the level of bacterial resistance were significantly related to the type of gene mutation (P < 0.001). In patients with a severe mutation, PA more often was extensively drug resistant or pandrug resistant compared with Pseudomonas culture-negative patients or patients with mild or unclassified mutations on both alleles. Associations were found between the presence of PA and lower values of BMI (P < 0.001), and FEV1% (P < 0.001). The risk for PA occurrence and the development of bacterial resistance increased twice in the case of severe mutation (odds ratio [OR], 2.51; 95% confidence interval [CI], 1.62-3.89), four times when BMI decreased <18.5 (OR, 4.15; 95% CI, 1.43-10.08). and six times when FEV1% fell <40 (OR, 6.75; 95% CI, 3.11-14.64)., Conclusions: The presence of PA is associated with lower FEV1% and BMI values. Deterioration of lung function, undernutrition, and severe type of gene mutation are linked to a higher probability of PA acquisition and resistance to antibiotic treatment., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective The aim of the current study was to examine the anticancer activity and the detailed mechanism of novel diisoquinoline derivatives in human gastric cancer cells (AGS). Methods The viability of AGS cells was measured by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Cell cycle analysis and apoptosis assay were performed by standard flow cytometric method. Confocal microscopy bioimaging was used to demonstrate the expression of pivotal proteins engaged in apoptosis (caspase-8, caspase-3, p53) and cell signaling (AKT, ERK1/2). Results All compounds decreased the number of viable cells in a dose-dependent manner after 24 and 48 h of incubation, although compound 2 was a more cytotoxic agent, with IC 50 values of 21 ± 2 and 6 ± 2 μM, compared to 80 ± 2 and 45 ± 2 μM for etoposide. The cytotoxic and antiproliferative effects of novel compounds were associated with the induction of apoptosis. The highest percentage of early and late apoptotic cells was observed after 48 h of incubation with compound 2 (89.9%). The value was higher compared to compound 1 (20.4%) and etoposide (24.1%). The novel diisoquinoline derivatives decreased the expression of AKT and ERK1/2. Their mechanism was associated with p53-mediated apoptosis, accumulation of cells in the G2/M phase of cell cycle and inhibition of topoisomerase II. Conclusion These data strongly support compound 2 as a promising molecule for treatment of gastric cancer.

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.

The aim of our study was to determine whether the use of cisplatin in the presence echistatin in MDA-MB-231 breast cancer cells leads to a reduction of toxic effects associated with the use of cisplatin. The expression of β 1 -integrin and insulin-like growth factor 1 receptor (IGF-IR), signaling pathway protein expression: protein kinase B (AKT), mitogen-activated protein kinases (ERK1/ERK2), nuclear factor kappa B (NFκB), and caspase-3 and -9 activity was measured after 24 h of incubation with tested compounds to explain detailed molecular mechanism of induction of apoptosis. The viability of MDA-MB-231 breast cancer cells was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Annexin V-FITC/propidium iodide staining assay was performed to detect the induction of apoptosis. Inhibition DNA biosynthesis was determined by [ 3 H]thymidine incorporation into DNA. The expression of of β 1 -integrin, IGF-IR, AKT, ERK1/ERK2, NFκB, caspase-3 and -9 was evaluated using Western blot. The results suggest that treatment of MDA-MB-231 breast cancer cells for 24 h cisplatin plus echistatin severely inhibits cell growth and activates apoptosis by upregulation of caspase-3 and -9 expressions. The effect was stronger than treatment cisplatin and echistatin alone. In this study, we have found that cisplatin plus echistatin treatment decreases collagen biosynthesis in MDA-MB-231 breast cancer cells stronger than the individual compounds. The inhibition was found to be dependent on the β 1 -integrin and IGF receptor activation. A significant reduction of ERK1/ERK2, AKT expression in cancer cells after cisplatin plus echistatin treatment was also found. The cancer cells treated by echistatin, cisplatin, and in particular the combination of both compounds drastically increased expression of NFκB transcription factor. Our results suggest that combined therapy cisplatin plus echistatin is a possible way to improve selectiveness of cisplatin. This mechanism probably is due to downregulation of expression of β 1 -integrin and IGF-IR receptors, and the signaling pathway proteins induced by these receptors. Our results suggest that therapy cisplatin plus echistatin is a possible way to improve selectiveness of cisplatin., Competing Interests: The authors declare that they have no conflict of interest.

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.