ABSTRACT
BACKGROUND: 6-Shogaol, one of the main bioactive constituents of Zingiber officinale has been shown to possess various therapeutic properties. Interaction of a therapeutic compound with plasma proteins greatly affects its pharmacokinetic and pharmacodynamic properties. PURPOSE: The present investigation was undertaken to characterize the interaction between 6-shogaol and the main in vivo transporter, human serum albumin (HSA). METHODS: Various binding characteristics of 6-shogaol-HSA interaction were studied using fluorescence spectroscopy. Thermal stability of 6-shogaol-HSA system was determined by circular dichroism (CD) and differential scanning calorimetric (DSC) techniques. Identification of the 6-shogaol binding site on HSA was made by competitive drug displacement and molecular docking experiments. RESULTS: Fluorescence quench titration results revealed the association constant, Ka of 6-shogaol-HSA interaction as 6.29 ± 0.33 × 10(4) M(-1) at 25 ºC. Values of the enthalpy change (-11.76 kJ mol(-1)) and the entropy change (52.52 J mol(-1) K(-1)), obtained for the binding reaction suggested involvement of hydrophobic and van der Waals forces along with hydrogen bonds in the complex formation. Higher thermal stability of HSA was noticed in the presence of 6-shogaol, as revealed by DSC and thermal denaturation profiles. Competitive ligand displacement experiments along with molecular docking results suggested the binding preference of 6-shogaol for Sudlow's site I of HSA. CONCLUSION: All these results suggest that 6-shogaol binds to Sudlow's site I of HSA through moderate binding affinity and involves hydrophobic and van der Waals forces along with hydrogen bonds.
Subject(s)
Catechols/chemistry , Serum Albumin/chemistry , Zingiber officinale/chemistry , Binding Sites , Calorimetry, Differential Scanning , Circular Dichroism , Hot Temperature , Humans , Molecular Docking Simulation , Molecular Structure , Spectrometry, Fluorescence , ThermodynamicsABSTRACT
We examined the induction of apoptosis by cytochalasin (cc) derivatives (1-14) isolated from the Japanese fungus Daldinia vernicosa to HCT116 human colon cancer cell line based on their cytotoxicity, DNA ladder and DNA fragmentation ratio in agarose gel electrophoresis, and morphological changes. Most cc derivatives tested here induced apoptosis. Particularly cytochalasin 1 (cc1), monoacetate of 1 (cc1Ac), and cc14 were the most potent apoptosis inducers. These apoptotic activities were stronger than that of cytochalasin D as a known apoptosis inducer in HCT116 cell. However, cc4 and cc12 induced necrosis. The structure-activity relationship including their cytotoxicity will be discussed.
Subject(s)
Apoptosis/drug effects , Cytochalasins/pharmacology , Fungi/chemistry , Cytochalasins/isolation & purification , Electrophoresis, Agar Gel , Humans , Tumor Cells, CulturedABSTRACT
Brefeldin A (BFA) can induce a wide variety of human cancer cells to differentiation and apoptosis and is in development as an anticancer agent. To elucidate structural requirements for cytotoxicity and induction of differentiation and apoptosis, BFA was structurally modified into various derivatives including 4-epi-BFA in this study. Their inducing activities of apoptosis were evaluated with their cytotoxicities, DNA fragmentation and morphological changes in human colon cancer cell HCT 116. The cytotoxicity of 4-epi-BFA (TX-1923) (IC50 = 60 microM) was 300 times lower than that of BFA (IC50 = 0.2 microM). Furthermore, 4-epi-BFA induced DNA fragmentation and apoptotic morphological changes at much higher concentrations (70 and 50 microM, respectively) than BFA (0.11 and 0.36 microM, respectively). These results indicated that the configuration of 4-hydroxyl group of brefeldin A plays a key role in the cytotoxicity and induction of apoptosis. On the other hand, 7-O-acetyl-BFA, 4-O-acetyl-BFA, and 4,7-di-O-acetyl-BFA exhibited potential activities in cytotoxicity and inducibility of apoptosis. We suggested that the structural determinants for BFA include the moiety of the Michael acceptor, the conformational rigidity of the 13-membered ring, and the configuration of 4-hydroxyl group.
Subject(s)
Apoptosis/drug effects , Brefeldin A/pharmacology , Cell Differentiation/drug effects , Brefeldin A/chemistry , Cell Line , Magnetic Resonance Spectroscopy , Mass Spectrometry , Structure-Activity Relationship , Tumor Cells, CulturedSubject(s)
Adenosine Diphosphate/metabolism , Antioxidants/pharmacology , Ferrous Compounds/metabolism , Lipid Peroxidation/drug effects , Methylglucosides/pharmacology , Mitochondria, Liver/drug effects , Animals , Antioxidants/metabolism , Free Radical Scavengers/metabolism , Male , Methylglucosides/chemistry , Methylglucosides/metabolism , Mitochondria, Liver/metabolism , Molecular Structure , Rats , Rats, WistarABSTRACT
The ability of hospitals to fulfil their roles--of information processing and dissemination, and of quality patient care provider--is influenced by the availability of supporting information systems. Using computers in wards, which is a change process, introduces new working practices accompanied by attitudinal and knowledge alterations in the users. This paper suggests that as a practical approach users need to be consulted and assessed prior to the introduction of computers in their work places. A questionnaire survey, the main purpose of which was to determine the potential users' responses and to measure their computer competencies, was sent to 183 nursing staff in several hospitals. Results show that the respondents have slightly positive attitudes towards computers even though 85% of them were computer illiterate. A training strategy is needed to increase competencies and to develop more favourable attitudes, which can be monitored using four training indicators.
