Abstract Background: Cystic fibrosis (CF) is one of the most common autosomal recessive disease, and the type of mutation is recognized as one of the most important factors determining the survival rate. Factors contributing to disease exacerbations, and survival rate are poor nutritional status, lung failure, and infection development by Pseudomonas Aeruginosa .The study aimed to evaluate the effect of the severity of mutation, nutritional status, lung function, and Pseudomonas aeruginosa infection on survival rate in adult patients with Cystic Fibrosis. Material and methods: A study of 124 (68 ♀ and 56 ♂) CF patients aged from 18 to 51 years were evaluated for: a) type of mutation in the CFTR gene, b) nutritional status (BMI), c) lung function (FEV1%), and d) Pseudomonas aeruginosa (PA) infection. For statistical calculations, Kaplan-Meier analysis of survival and Chi-squared test for multiple samples were used. Results: Both the type of mutation (Chi²=12.73, df= 3, p=0.005), lung function (Chi² = 15.20, df = 2, p = 0.0005), PA infection (Chi²= 11.48, df= 3, p= 0.009), and BMI (Chi²=31.08, df=4, p<0.000) significantly differentiated the probability of survival of CF patients. The shortest life expectancy was observed in patients with a severe type of mutation on both alleles, FEV1% between 40-70%, subjects in whom Pseudomonas culture was extensively drug-resistant or pandrug-resistant, and patients whose BMI was lower than 18.5 kg/m². The period from 30 to 40 years of age was of the most critical in CF adults’ lifespan. Furthermore, most exacerbations occurred between 20 and 35 years of age. Conclusions: All factors included in the study significantly influenced the survival rate of patients with cystic fibrosis. In the face of the growing population of CF patients, the research on factors affecting their life expectancy seems to take on greater importance.
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.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 (FEV1%), and (d) Pseudomonas aeruginosa prevalence. For statistical calculations, Kaplan-Meier analysis of survival, chi-squared test for multiple samples, and logistic regression were used.The type of mutation (χ2 = 12.73, df = 3, p = 0.005), FEV1% (χ2 = 15.20, df = 2, p = 0.0005), Pseudomonas aeruginosa prevalence (χ2 = 11.48, df = 3, p = 0.009), and BMI (χ2 = 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, FEV1% < 40, subjects in whom Pseudomonas culture was extensively drug-resistant or pandrug-resistant, and patients whose BMI was lower than 18.5 kg/m2. 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).All factors included in the study were significantly related to the survival rate of patients with cystic fibrosis.
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 β1-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 [3H]thymidine incorporation into DNA. The expression of of β1-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 β1-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 β1-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.
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.
Summary 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.
Trabectedin, also known as ecteinascidin 743 (Et-743), is a tetrahydroisoquinoline alkaloid that was originally isolated from the Caribbean sea squirt Ecteinascidia turbinata. Trabectedin is one of the first anticancer drugs of marine origin that has been approved in the European Union. The compound is used to treat patients with advanced soft tissue sarcoma in case of failure of conventional anthracyclines and ifosfamide therapy and in the treatment of recurrent platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin. The mechanism of action of trabectedin is based on interaction with the minor groove of DNA double helix. It triggers a cascade of events that interfere with several transcription factors, DNA binding proteins and DNA repair pathways, resulting in G2/M cell cycle arrest and ultimately apoptosis. Moreover, emerging evidence indicates that Et-743 has dual effects. In addition to induce direct growth inhibition, cell death and differentiation of malignant cells it also affects the tumor microenvironment by reducing the production of key inflammatory mediators. A multifaceted mechanism of action may explain positive results when trabectedin is used in the treatment of cancer that exhibits resistance to conventional chemotherapeutics. The widespread use of ecteinascidins in therapy as well as in clinical trials is, however, limited by the high price of these compounds. Therefore, intensive work is being carried out on the search for synthetic analogues of ecteinascidins with equally high activity against tumor cells.
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.
'/%3e%3c/g%3e%3cuse xlink:href='%23d' x='45.714'/%3e%3cuse xlink:href='%23e' transform='matrix(-1 0 0 1 479.792 0)'/%3e%3cg id='f' fill='%23fff'%3e%3cpath fill='%23039' d='M232.636 202.406v.005c0 2.212.85 4.227 2.212 5.69 1.365 1.466 3.245 2.377 5.302 2.377 2.067 0 3.944-.905 5.303-2.365 1.358-1.459 2.202-3.472 2.202-5.693v-10.768l-14.992-.013-.028 10.766'/%3e%3ccircle cx='236.074' cy='195.735' r='1.486'/%3e%3ccircle cx='244.392' cy='195.742' r='1.486'/%3e%3ccircle cx='240.225' cy='199.735' r='1.486'/%3e%3ccircle cx='236.074' cy='203.916' r='1.486'/%3e%3ccircle cx='244.383' cy='203.905' r='1.486'/%3e%3c/g%3e%3cuse xlink:href='%23f' y='-26.016'/%3e%3cuse xlink:href='%23f' x='-20.799'/%3e%3cuse xlink:href='%23f' x='20.745'/%3e%3cuse xlink:href='%23f' y='25.784'/%3e%3c/svg%3e)
