To obtain modulators for reducing mitochondrial damage by the inhibition of AI2 oligomer formation, 2-phenylbenzofuran derivatives were designed and prepared. Their inhibitory activity against AI2 ...fibril formation was screened using ThT fluorescence assay, and the effect of derivatives on mitochondrial function was evaluated using JC-1 and MTT assay. 2-Phenylbenzofuran derivatives with dimethylamino group at p-position had an excellent inhibitory activity against AI2 fibril formation. Particularly, compound 19m alleviated mitochondrial damage remarkably and possessed protective effects against AI2-induced cytotoxicity.
The cytotoxic activities of sesquilignans, (7S,8S,7a2R,8a2R)- and (7R,8R,7a2S,8a2S)-morinol A and (7S,8S,7a2S,8a2S)- and (7R,8R,7a2R,8a2R)-morinol B were compared, showing no significant difference ...between stereoisomers (IC50 = 24a35 mu M). As a next stage, the effect of substituents at 7, 7a2, and 7a3-aromatic ring on the activity was evaluated to find out the higher activity of (7S,8S,7a2R,8a2R)-7,7a2,7a3-phenyl derivative 18 (IC50 = 6a7 mu M). In the research on the structure-activity relationship of 7a3-position of (7S,8S,7a2R,8a2R)-7,7a2,7a3-phenyl derivative 18, the most potent compounds were 7,7a2,7a3-phenyl derivative 18 (IC50 = 6 mu M) against HeLa cells. Against HL-60 cells, 7a3-(4-nitrophenyl)-7,7a2-phenyl derivative 33 and 7a3-hexyl-7,7a2-phenyl derivative 37 (IC50 = 5 mu M) showed highest activity. We discovered the compounds showed four to sevenfold potent activity than that of natural (7S,8S,7a2R,8a2R)-morinol A. It was also confirmed that the 7a2-benzylic hydroxy group have an important role for exhibiting activity, on the other hand, the resonance system of cinnamyl structure is not crucial for the potent activity.
Objective
As the development and progression of colorectal cancer (CRC) are known to be affected by the immune system, cell subsets such as T cells, natural killer (NK) cells, and natural killer T ...(NKT) cells are considered interesting targets for immunotherapy and clinical biomarker research. Until now, the role of systemic immune profiles in tumor progression remains unclear. In this study, we aimed to characterize the immunophenotype of circulating T cells, NK cells, and NKT-like cells in patients with CRC, and to subsequently correlate these immunophenotypes to clinical follow-up data.
Methods
Using multiparameter flow cytometry, the subset distribution and immunophenotype of T cells (CD3
+
CD56
−
), CD56
dim
NK cells (CD3
−
CD56
dim
), CD56
bright
NK cells (CD3
−
CD56
bright
), and NKT-like (CD3
+
CD56
+
) cells were investigated in peripheral blood mononuclear cell (PBMC) samples from 71 CRC patients and 19 healthy donors.
Results
CRC patients showed profound differences in immune cell subset distribution and their immunophenotype compared to healthy donors, as characterized by increased percentage of regulatory T cells, and reduced expression level of the natural cytotoxicity receptors NKp44 and NKp46 on both CD56
dim
NK cells and NKT-like cells. Finally, we showed in a multivariate analysis that above-median percentage of CD16
+
NKT-like cells was independently associated with shorter disease-free survival in CRC patients.
Conclusion
The altered phenotype of circulating immune cell subsets in CRC and its association with clinical outcome highlight the potential use of PBMC subsets as prognostic biomarkers in CRC, thereby contributing to better insight into the role of systemic immune profiles in tumor progression.
Trifolium L. species with a rich isoflavone content have been used as expectorant, analgesic, antiseptic, tonic, and wound-healer in folk medicine. The aim of the study is to evaluate pharmacological ...properties of the extracts and isolated compounds of T. tricocephalum. Phytochemical investigation of the aerial parts of T. trichocephalum led to the isolation of daidzein, genistein, quercetin, and daidzein 4'-O-β-glucoside for the first time from this species. Isolated compounds along with the methanol extract, water, ethyl acetate and chloroform subextracts were tested for their radical scavenging and cytotoxic activity which was evaluated by MTT assay. According to the results of activity tests, extracts showed a concentration-dependent radical scavenging activity as well as cytotoxic effect on HepG2 cells at 400 μg/mL, whereas the compounds did not exert any obvious cytotoxic effect at tested concentrations.
Here, we use single-molecule techniques to study the aggregation of alpha-synuclein, the protein whose misfolding and deposition is associated with Parkinson's disease. We identify a conformational ...change from the initially formed oligomers to stable, more compact proteinase-K-resistant oligomers as the key step that leads ultimately to fibril formation. The oligomers formed as a result of the structural conversion generate much higher levels of oxidative stress in rat primary neurons than do the oligomers formed initially, showing that they are more damaging to cells. The structural conversion is remarkably slow, indicating a high kinetic barrier for the conversion and suggesting that there is a significant period of time for the cellular protective machinery to operate and potentially for therapeutic intervention, prior to the onset of cellular damage. In the absence of added soluble protein, the assembly process is reversed and fibrils disaggregate to form stable oligomers, hence acting as a source of cytotoxic species.
Natural killer (NK) cells are central players in the vertebrate immune system that rapidly eliminate malignantly transformed or infected cells. The natural cytotoxicity receptors (NCRs) NKp30, NKp44, ...and NKp46 are important mediators of NK cell cytotoxicity, which trigger an immune response on recognition of cognate cellular and viral ligands. Tumour and viral immune escape strategies targeting these receptor–ligand systems impair NK cell cytotoxicity and promote disease. Therefore, a molecular understanding of the function of the NCRs in immunosurveillance is instrumental to discovering novel access points to combat infections and cancer.
BackgroundLong term exposure to cytotoxic substances can lead to serious side effects. In reaction to a constant increase in activity in our oncology department, we decided to organise a campaign of ...surface tests to evaluate the environmental contamination and staff exposure to cytotoxics.PurposeTo measure contamination in different areas of our preparation unit, corresponding to different stages of the preparation. We then proposed adapted corrective measures.Material and methodsWe identified 7 sensitive areas to be tested: gloves of the technician’s helper, transfer airlock, telephone, two keyboards from the desk where the preparations were controlled, the case used to carry the preparations and the handle of the preparation unit’s door. Samples were collected by rubbing a sterile compress soaked with 0.1 mL of sterile water for injection onto a surface of 10 cm² of each zone. A quantitative analysis by ultraperformance liquid chromatography combined with mass spectrometry was used to measure contamination in each sample by 10 different cytotoxics. We tested the following drugs: cytarabine, cyclophosphamide, ganciclovir, gemcitabine, ifosfamide, irinotecan, methotrexate, dacarbazine, doxorubicin (detection limit 1 ng) and fluorouracil (detection limit 10 ng).ResultsNone of these molecules was found on the different areas tested, with the exception of the technician helper’s gloves, which were contaminated with 462.4 ng of cyclophosphamide, 180.1 ng of doxorubicin and 1.8 ng of ifosphamide.ConclusionThis study revealed contamination of the technician helper’s gloves by cytotoxics. Because the technician’s helper is required to pack the preparations, he may be responsible for contamination of the whole transportation network from the pharmacy to the oncology department. To avoid this contamination, corrective measures were implemented: cytotoxic drug preparations are now labelled and packed directly inside the isolator and the outer packaging is made on the way out of the isolator, using a reversible plastic bag. Thus there is no contact between the technician helper’s gloves and the preparation. Another campaign of tests will be carried out to evaluate the impact of these corrective measures on environmental contamination.No conflict of interest
The precise definition of the structural requirements for effective topoisomerase II poisoning by drug molecules is still an elusive issue. In the attempt to better define a pharmacophoric pattern, ...we prepared several conjugates combining the chemical features of two well-known topoisomerase II poisons, amsacrine and ametantrone. Indeed, an appropriate fusion geometry, which entails the anthracenedione moiety of ametantrone appropriately connected to the methanesulfonamidoaniline side chain of amsacrine, elicits DNA-intercalating properties, the capacity to inhibit the human topoisomerase IIbeta isoform, and cytotoxic activity resembling that of the parent compounds. In addition, the properties of the lateral groups linked to the anthracenedione group play an important role in modulating DNA binding and cell cytotoxicity. Among the compounds tested, 10, 11, and 19 appear to be promising for further development. PUBLICATION ABSTRACT
Based on the anti-hepatitis C activity of 2\'-C-methyl-adenosine and 2\'-C-methyl-guanosine, a series of new modified purine 2\'-C-methyl nucleosides was prepared as potential anti-hepatitis C virus ...agents. Herein, we report the synthesis of both 6-modified and 2-modified purine 2\'-C-methyl-nucleosides along with their anti-HCV replication activity and cytotoxicity in different cells.
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