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Neurovascular dysfunction is a central process in the pathogenesis of the stroke and most neurodegenerative diseases, including Alzheimer's disease. The multi-cell neurovascular unit (NVU) combines the components of the neural, vascular... more
Neurovascular dysfunction is a central process in the pathogenesis of the stroke and most neurodegenerative diseases, including Alzheimer's disease. The multi-cell neurovascular unit (NVU) combines the components of the neural, vascular and extracellular matrix (ECM) into an important interface whose proper function is critical to maintaining brain health. Tissue engineering now offers new tools and information to promote understanding of NVU's operation. A promising area for the development of NVU models is their bio-production through 3D bio-printing to produce a multi-layered NVU in which the contribution of the different cell types to neurovascular function and dysfunction can be studied at molecular and cellular levels. Nerve and vascular cells are encapsulated in a construct suitable for their viability and growth. This construct, called "bioink", is a pre-gelled biomaterial, usually with encapsulated cells, which can be bio-printed and gelled to successfully form a solid construct. Bio-printing allows accurate placement of the neural and vascular cells to form appropriate interactions mimicking the in vivo state. Individual NVU cell types interact with the other cellular components of NVU through biochemical and physical markers, with direct and indirect interactions between neural and vascular components. The cell line sources, either derived from AD patients or healthy individuals, can be developed with the IPSCs technology. IPSCs can be obtained by different somatic cells via reprogramming strategies and further on differentiated into various cell lines that can be used to model disease, to discover new drugs and to treat cell replacement. Last but not least, the availability of 3D NVU models can also facilitate screening of drugs to correct neural dysfunction due to stroke, Alzheimer's disease and other dementia.
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During growth on medium-chain length (mcl) polyhydroxyalkanoates (PHAs), or on sodium octanoate Thermus thermophilus HB8 produces an extracellular mcl-PHA depolymerase. This enzyme was purified from the culture medium of sodium... more
During growth on medium-chain length (mcl) polyhydroxyalkanoates (PHAs), or on sodium octanoate Thermus thermophilus HB8 produces an extracellular mcl-PHA depolymerase. This enzyme was purified from the culture medium of sodium octanoate-grown cells to electrophoretic homogeneity by hydrophobic interaction chromatography using Octyl-Sepharose CL-4B and gel permeation chromatography using Sephadex G-150. The molecular mass of the purified enzyme was approximately 28 kDa. A part of the gene TTHA1605 encoding a 24.17 kDa protein was demonstrated to encode the mcl-PHA depolymerase of T. thermophilus. The primary amino-acid sequence of purified enzyme reveals similarity to all reported so far extracellular mcl-PHA depolymerases. The purified enzyme could hydrolyze mcl – PHAs and p-nitrophenyl (pNP) esters but not short chain length (scl) – PHAs. The optimum pH range was 7.5–9 and the optimum temperature was 70 °C for pNP-octanoate (pNPO) hydrolysis. The Km value for pNPO was 53.2 μM. The enzyme was strongly inhibited by phenylmethylsulfonyl fluoride (PMSF) and non-ionic detergents (Tween 20, Tween 80 and Triton X-100). The results demonstrated in this study revealed that the mcl-PHA depolymerase from T. thermophilus is a distinct enzyme, which is different from those of other mcl-PHA-degrading bacteria.
Research Interests: Materials Engineering, Chemical Engineering, Biochemistry, Chemistry, POlymer degradation and stability, and 11 moreBiological Sciences, Gel Permeation Chromatography, Enzyme, Medium chain length-PHA, Polyhydroxyalkanoates, Molecular Mass, Amino Acid Sequence, Extracellular, culture medium, Polyhydroxyalkanoate, and Medical and Health Sciences
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Abstract The constantly changing bacterial resistance to antibiotics is a well-known problem and the scientific community is seeking to exploit new approaches through nanotechnology. The potential of copper as an antimicrobial agent has... more
Abstract The constantly changing bacterial resistance to antibiotics is a well-known problem and the scientific community is seeking to exploit new approaches through nanotechnology. The potential of copper as an antimicrobial agent has long been recognized and thus metallic copper as well as cupric oxide (CuO) or cuprous oxide (Cu2O) nanoparticles, called copper-based nanoparticles (Cu-based NPs), have attracted the attention of biomedical applications. Indeed, from a number of studies it is illustrated that Cu-based NPs display particular characteristics that can be properly handled to offer an attractive alternative, since they have higher retention times and can penetrate the microbial cells. In this chapter we focus on the antibacterial activity of CuO, Cu2O NPs, and copper composites Cu/Cu2O covered by polymers or embedded into matrices, since the composition of the NPs results in different mechanisms of action. The size- and shape-dependent effects are highlighted as well as the synthetic conditions that have been applied for the preparation of the NPs. Special attention is given to the antifungal activity of Cu-based NPs, since fungal cells are among the eukaryotic cells that are most similar to animal cells.
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Objective: Although Mediterranean diet is connected with longevity and lower rate of many disorders including Alzheimer's disease (AD), the effect of olive oil, which is the principal component of the Mediterranean diet, on fibrinolytic... more
Objective: Although Mediterranean diet is connected with longevity and lower rate of many disorders including Alzheimer's disease (AD), the effect of olive oil, which is the principal component of the Mediterranean diet, on fibrinolytic system related to AD and especially on plasminogen activator inhibitor-1 (PAI-1) and a2-antiplasmin in aged participants are not yet examined. This study was performed on 108 aged participants allocated into 5 groups: Mild Cognitive Impairment (MCI) (36) patients subjected to 1-year therapy with extra virgin olive oil (EVOO), MCI without therapy patients (26), MCI without therapy 1-year later patients (11), AD patients (30) and healthy individuals (16). Hypothesis/Purpose: To examine the effect of EVOO therapy on the fibrinolytic factors PAI-1 and a2-antiplasmin, on hallmarks of AD, tau and Aβ amyloid fragments and on an oxidative stress biomarker, MDA in the serum of MCI patients aiming to be exploited as a future preventive therapy. Results: Using ELISA method, the levels of both fibrinolytic factors PAI-1 and a2- antiplasmin in the serum of MCI patients were reduced notably in the EVOO treated patients versus the control group and were lower than those of all other groups. For better determination of AD from other pathological conditions the ratio Aβ1-42/Aβ1-40 was measured in serum of all participants. The more lessened the ratio is, the more cognitive impairment is observed in patients. The MCI group with one-year EVOO therapy displayed a ratio similar to this of healthy individuals. Moreover, patients with EVOO therapy showed decreased tau protein levels in comparison with all the other groups. The levels of the oxidative stress's biomarker, malondialdehyde (MDA) showed a significant decrease in MCI patients subjected to EVOO therapy revealing the involvement of the beneficial antioxidative properties of EVOO in the progression of AD. Conclusion: We demonstrated that EVOO therapy may prevent the risk of patients with MCI to progress to AD via decreasing fibrinolytic factors PAI-1 and a2 antiplasmin that reflecting in the diminution of the hallmarks proteins of AD, tau and Aβ amyloid as well and in a biomarker of oxidative stress, MDA.
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As an antioxidant, Vit C is involved in a number of biological processes such as cancer resistance, reduction of DNA damage and chromosomal breakage caused by several carcinogens and other agents (Odin, 1997; Konopacka et al., 2002;... more
As an antioxidant, Vit C is involved in a number of biological processes such as cancer resistance, reduction of DNA damage and chromosomal breakage caused by several carcinogens and other agents (Odin, 1997; Konopacka et al., 2002; Dusinska et al., 2003). However, in experimental studies (Odin, 1997), administration of large amounts of Vit C had a genotoxic effect. More specifically, Vit C has been reported to induce sister chromatid exchanges (SCEs) in CHO cells and human lymphocytes (Weitberg & Weitzman, 1985; Lialiaris et al., 1987), chromosomal aberrations, unscheduled DNA synthesis, DNA fragmentation (Rosin et al., 1980) and site-specific DNA cleavage (Kazakov et al., 1988; Wang & Van Ness, 1989). Other studies have also reported that mitomycin C, doxorubicin, cisplatin and hyperoxia, induced chromosomal aberrations and furthermore micronuclei pretreated with certain Vit C concentrations exhibited either protection or induction of chromosomal damage (Gille et al., 1991; Greggi...
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Copper based nanoparticles (Cu-based NPs) of different compositions and sizes have been hydrothermally synthesized by varying the reaction time in the presence of the biocompatible surfactants polyoxyethylene (20) sorbitan laurate (Tween... more
Copper based nanoparticles (Cu-based NPs) of different compositions and sizes have been hydrothermally synthesized by varying the reaction time in the presence of the biocompatible surfactants polyoxyethylene (20) sorbitan laurate (Tween 20) and polyethylene glycol 8000 (PEG 8000). Effective control of the above synthetic parameters gave rise to Cu, Cu2O and Cu/Cu2O NPs of 10-44 nm. The antibacterial activity of the NPs was screened against Gram-positive (Bacillus subtilis, Bacillus cereus, Staphylococcus aureus) and Gram-negative (Xanthomonas campestris, Escherichia coli) bacteria. The Cu-based NPs induce pDNA degradation in a dose-dependent manner as well as extensive ds CT-DNA degradation. Cu2O NPs of 16 nm and 12 nm exhibit the lowest IC50 values (2.13 μg/mL and 3.7 μg/mL) against B. cereus and B. subtilis, respectively. The agarose gel electrophoresis of ds CT-DNA treated with Cu2O NPs demonstrated degradation at high concentration. In lower concentrations, viscosity measurements indicated groove binding. In regard to the enhanced antibacterial effect and specificity of Cu2O NPs against the Gram-positive strains, the activity pathway was further explored and ROS production and lipid peroxidation verified. The released copper ions 5.15 mg/L in distilled water and 16.32 mg/L in nutrient medium, found below the critical value to inhibit bacterial growth and thus nanosized composition effect is predominant.
Research Interests: Chemistry, Inorganic Chemistry, Transmission Electron Microscopy, Medicine, Nuclear Chemistry, and 14 moreMetal Nanoparticles, DNA, Copper, Escherichia coli, Staphylococcus aureus, Lipid peroxidation, Agarose Gel Electrophoresis, Antibacterial activity, Anti-Bacterial Agents, Polyethylene Glycol, Bacillus subtilis, Microbial Sensitivity Tests, Bacillus Cereus, and Inorganic Biochemistry
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Oxidative/nitrative stress that results from the unbalance of the overproduction/clearance of reactive oxygen/nitrogen species (ROS/NOS), originated from a variety of endo- and/or exo-genous sources, can have detrimental effects on DNA... more
Oxidative/nitrative stress that results from the unbalance of the overproduction/clearance of reactive oxygen/nitrogen species (ROS/NOS), originated from a variety of endo- and/or exo-genous sources, can have detrimental effects on DNA and is involved in Alzheimer's disease (AD) pathology. An excellent marker of oxidative DNA lesions is 8-hydroxy-2'-deoxyguanosine (8-OHdG) while of nitrative stress the enzyme NOS2 (Nitric oxide synthase 2). Under massive oxidative stress, poly(ADP-ribose)polymerase 1 (PARP-1) enzyme activity, responsible for restoration of DNA damage, is augmented, DNA repair enzymes are recruited, and cell survival/or death is ensued through PARP-1 activation, which is correlated positively with neurodegenerative diseases. In this biochemical study the levels of PARP-1, 8-oxo-dG, and NOS2, Aβ1-42, and p-tau in their sera determined using Enzyme-Linked Immunosorbent Assay (ELISA). Patients diagnosed with Mild Cognitive Impairment participated in MICOIL clinical trial, were daily administered with 50 ml Extra Virgin Olive Oil (EVOO) for one year. All MCI patients' biomarkers that had consumed EVOO were tantamount to those of healthy participants, contrary to MCI patients who were not administered. EVOO administration in MCI patients resulted in the restoration of DNA damage and of the well-established "hallmarks" AD biomarkers, thanks probably to its antioxidant properties exhibiting a therapeutic potentiality against AD. Molecular docking simulations of the EVOO constituents on the crystal structure of PARP-1 and NOS-2 target enzymes were also employed, to study in silico the ability of the compounds to bind to these enzymes and explain the observed in vitro activity. In silico analysis has proved the binding of EVOO constituents on PARP-1and NOS-2 enzymes and their interaction with crucial amino acids of the active sites. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT03362996. MICOIL GOV IDENTIFIER: NCT03362996.
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Research Interests: Pharmacology, Chemistry, Biology, In Vitro, Caffeine, and 4 moreMutation, In Vivo, Chlorpromazine, and Nucleic Acid
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Journal URL: http://www.springer.at/amino_acidsAbstractPhosphate transport in bacteria occurs via a phosphate specific transporter system (PSTS) that belongs to the ABC family of transporters a multisubunit system containing an alkaline... more
Journal URL: http://www.springer.at/amino_acidsAbstractPhosphate transport in bacteria occurs via a phosphate specific transporter system (PSTS) that belongs to the ABC family of transporters a multisubunit system containing an alkaline phosphatase. DING proteins were characterized due to the N-terminal amino acid sequence DINGGGATL which is highly conserved in animal and plant isolates but more variable in microbes. Most prokaryotic homologues of the DING proteins often have some structural homology to phosphatases or periplasmic phos- 10th International Congress on Amino Acids and Proteins LXIX phate-binding proteins. In E. coli the product of the inducible gene DinG possesses ATP hydrolyzing helicase enzymic activity. An alkaline phosphorolytic enzyme of the PSTS system was purified to homogeneity from the thermophilic bacterium Thermus thermophilus. N-terminal sequence analysis of this protein revealed the same high degree of similarity to DING proteins especially to the human synovial stimulatory protein P205 the steroidogenesis-inducing protein and to the phosphate ABC transporter periplasmic phosphate-binding protein putative [P. fluorescens Pf-5]. The enzyme had a molecular mass of 40 kDa on SDS=PAGE exhibiting optimal phosphatase activity at pH 12.3 and 70 _C. The enzyme possessed characteristics of a DING protein such as ATPase ds endonuclease and 30phosphodiesterase (30-exonuclease) activities and binding to linear dsDNA displaying helicase activity on supercoiled DNA. In this work the purification and biochemical characterization of a T. thermophilus DING protein was achieved. The biochemical properties N-terminal sequence similarities of this protein implied that the enzyme belongs to the PSTS family and might be involved in the DNA repair mechanism of this microorganism
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Lipopolysaccharides (LPS) of Gram-negative bacteria are mediators of neuroinflammation and neurodegeneration that have been detected in close association with aggregations of brain amyloid beta (Aβ) and microtubule-associated protein tau... more
Lipopolysaccharides (LPS) of Gram-negative bacteria are mediators of neuroinflammation and neurodegeneration that have been detected in close association with aggregations of brain amyloid beta (Aβ) and microtubule-associated protein tau (MAPT). LPS induce the release of cytokines by microglia, the residing immune cells of the brain, and mediate the upregulation of inducible nitric oxide synthase (iNOS) – a mechanism associated with amyloidosis and MAPT destabilization. Curcumin is a natural product possessing several medicinal effects; however, its pharmaceutical exploitation is hindered by low bioavailability. V-Cur, a novel hemocompatible Vanadium (IV)-curcumin complex with higher solubility and pharmaceutical activity than curcumin, has been employed in the present study. Mixed cultures of primary rat brain neurons and microglia stimulated LPS presented increased levels of amyloid precursor protein (APP), an effect inhibited by either curcumin or V-Cur. V-Cur was also proved a m...
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An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely... more
An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
In this work, novel chrysin-loaded poly(ε-caprolactone) and poly(3-hydroxybutyrate) microcarriers were synthesized according to a modified oil-in-water single emulsion/solvent evaporation method, utilizing poly(vinyl alcohol) surfactant... more
In this work, novel chrysin-loaded poly(ε-caprolactone) and poly(3-hydroxybutyrate) microcarriers were synthesized according to a modified oil-in-water single emulsion/solvent evaporation method, utilizing poly(vinyl alcohol) surfactant as stabilizer and dispersing agent for the emulsification, and were evaluated for their physico-chemical and morphological properties, loading capacity and entrapment efficiency and in vitro release of their load. The findings suggest that the novel micro-formulations possess a spherical and relatively wrinkled structure with sizes ranging between 2.4 and 24.7 µm and a highly negative surface charge with z-potential values between (−18.1)–(−14.1) mV. The entrapment efficiency of chrysin in the poly(ε-caprolactone) and poly(3-hydroxybutyrate) microcarriers was estimated to be 58.10% and 43.63%, whereas the loading capacity was found to be 3.79% and 15.85%, respectively. The average release percentage of chrysin was estimated to be 23.10% and 18.01%, r...
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The daily consumption of Extra Virgin Olive Oil (EVOO) in Mediterranean nutrition is tightly associated with lower frequency of many diseases' appearance, including Alzheimer's disease (AD). Fibrinolytic system is already assumed... more
The daily consumption of Extra Virgin Olive Oil (EVOO) in Mediterranean nutrition is tightly associated with lower frequency of many diseases' appearance, including Alzheimer's disease (AD). Fibrinolytic system is already assumed to be involved in AD pathophysiology through various factors, especially plasminogen activator inhibitor-1 (PAI-1), a2-antiplasmin (α2ΑP) and tissue plasminogen activator (tPA). We, here, present a biochemical study, as a continuation of a clinical trial of a cohort of 84 participants, focusing on the pleiotropic effect of the annual EVOO consumption on the fibrinolytic factors of Mild Cognitive Impairment (MCI) patients. The levels of all these fibrinolytic factors, measured by Enzyme-linked Immunosorbent Assay (ELISA) method, were reduced in the serum of MCI patients annually administered with EVOO, versus not treated MCI patients, as well as AD patients. The well-established AD hallmarks (Aβ1-40 and Aβ1-42 species, tau, and p-tau) of MCI patients' group, annually administered with EVOO, were restored to levels equal to those of the cognitively-healthy group; in contrast to those patients not being administered, and their AD hallmarks levels increased at the end of the year. Moreover, one of the EVOO consumption multimodal effects on the MCI patients focused on the levels of an oxidative stress trademark, malondialdehyde (MDA) levels, displayed also a visible quenching of the MDA levels; On the other hand, an increase of the MDA levels exhibited in the MCI patients not consuming EVOO one year after, was attributed on the EVOO anti-oxidative properties exhibited after one year, in the MCI patients who had not consumed EVOO, attributing this difference on the EVOO anti-oxidative properties. These outcomes are exploitable towards the establishment of natural products like EVOO, as a preventive remedy fighting this neurodegenerative disorder, AD. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT03362996 MICOIL gov Identifier: NCT03362996.
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Quinones are of significant interest due to their important role in specific cellular functions. Quinoproteins are a big class of oxyreductive agents occurring in bacteria and other organisms. In this investigation derivatives of... more
Quinones are of significant interest due to their important role in specific cellular functions. Quinoproteins are a big class of oxyreductive agents occurring in bacteria and other organisms. In this investigation derivatives of 2-amino-1,4-benzoquinone, 2-amino-1,4-naphthoquinone and 2-amino-5,8-dihydroxy-1,4-naphthoquinone with a di- and a tripeptide were prepared for first time. The effect of the synthesized compounds on sister chomatid exchange (SCE) rates and human lymphocyte proliferation kinetics on a molar basis was studied. Among these coupled products the most effective in inducing SCEs and depressing proliferation rate indices is the coupling product of 2-amino-1,4-naphthoquinone with the tripeptide GHK (10). Next in order of magnitude in inducing cytogenetic effects is 2-amino-1,4-naphthoquinone (2) and its coupling products with glycine and serine (4 and 5), while the rest displayed marginal activity.
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Phosphate transport in bacteria occurs via a phosphate specific transporter system (PSTS) that belongs to the ABC family of transporters, a multisubunit system, containing an alkaline phosphatase. DING proteins were characterized due to... more
Phosphate transport in bacteria occurs via a phosphate specific transporter system (PSTS) that belongs to the ABC family of transporters, a multisubunit system, containing an alkaline phosphatase. DING proteins were characterized due to the N-terminal amino acid sequence DINGG GATL, which is highly conserved in animal and plant isolates, but more variable in microbes. Most prokaryotic homologues of the DING proteins often have some structural homology to phosphatases or periplasmic phosphate-binding proteins. In E. coli, the product of the inducible gene DinG, possesses ATP hydrolyzing helicase enzymic activity. An alkaline phosphorolytic enzyme of the PSTS system was purified to homogeneity from the thermophilic bacterium Thermus thermophilus. N-terminal sequence analysis of this protein revealed the same high degree of similarity to DING proteins especially to the human synovial stimulatory protein P205, the steroidogenesis-inducing protein and to the phosphate ABC transporter, periplasmic phosphate-binding protein, putative (P. fluorescens Pf-5). The enzyme had a molecular mass of 40 kDa on SDS/PAGE, exhibiting optimal phosphatase activity at pH 12.3 and 70 degrees C. The enzyme possessed characteristics of a DING protein, such as ATPase, ds endonuclease and 3' phosphodiesterase (3'-exonuclease) activities and binding to linear dsDNA, displaying helicase activity on supercoiled DNA. Purification and biochemical characterization of a T. thermophilus DING protein was achieved. The biochemical properties, N-terminal sequence similarities of this protein implied that the enzyme belongs to the PSTS family and might be involved in the DNA repair mechanism of this microorganism.
Research Interests: Biochemistry, Kinetics, Biology, Enzyme Inhibitors, DNA repair, and 15 moreMedicine, DNA, Fatty acids, Animals, Alkaline phosphatase, Enzyme, Cattle, Amino Acids, Helicase, Enzyme activity, Molecular Mass, Amino Acid Sequence, Cations, Adenosine Triphosphate, and Medical biochemistry and metabolomics
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Summary Ornithine decarboxylase (ODC) ofThermus thermophilus is associated with the nucleoid protein fraction. Analysis of this fraction by agarose gel electrophoresis and immunostaining revealed that ODC was bound to two groups of... more
Summary Ornithine decarboxylase (ODC) ofThermus thermophilus is associated with the nucleoid protein fraction. Analysis of this fraction by agarose gel electrophoresis and immunostaining revealed that ODC was bound to two groups of RNA-protein complexes. These two complexes of 1.5 and 0.6 kb in size disappeared from the gel by RNase A treatment or migrated to small molecular weight complexes by
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A numerical simulation of the direct zonal liquid chromatographic method is described for studying the binding of a ligand to a macromolecule by quantification of the interacting species present in a sample at equilibrium. The algorithm... more
A numerical simulation of the direct zonal liquid chromatographic method is described for studying the binding of a ligand to a macromolecule by quantification of the interacting species present in a sample at equilibrium. The algorithm accounts for both the kinetic exchanges in solution and the dispersion effects depicted by the Fick law. Dimensionless variables are used for the concentrations
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The binding of an anticancer drug (actinomycin D or ACTD) to double-stranded DNA (dsDNA) was studied by means of high-performance liquid chromatography (HPLC). ACTD is an antitumor antibiotic containing one chromophore group and two... more
The binding of an anticancer drug (actinomycin D or ACTD) to double-stranded DNA (dsDNA) was studied by means of high-performance liquid chromatography (HPLC). ACTD is an antitumor antibiotic containing one chromophore group and two pentapeptidic lactone cycles that binds dsDNA. Incubations of ACTD with DNA were performed at physiological pH. The complexed and free ligand concentrations of the mixture were