Simulated Physiological Conditions Research Articles

The Enhancement Effects of Forsythoside E on Serum Albumin Fluorescence Under Simulated Physiological Conditions

This study examines the fluorescence enhancement effects of forsythoside E, one of metabolites of Forsythia suspensa, on human serum albumin (HSA) and bovine serum albumin (BSA) under simulated physiological conditions. The increase in protein fluorescence induced by forsythoside E are approximately the same in slightly acidic and neutral solutions, whereas the protein fluorescence intensities barely change in the alkaline solution after adding forsythoside E. The fluorescence increase of proteins caused by forsythoside E are significantly bigger in ethanol than in the other two solvents. The enhancement effects of forsythoside E on protein fluorescence were weakened when Cu2+ and Fe3+ were pre-added to the solution. Forsythoside E had little effect on the fluorescence of glycosylated BSA (gBSA) but increased the fluorescence of glycosylated HSA (gHSA) in a concentration-dependent manner because BSA was significantly more glycosylated than HSA. These findings can help us to understand the delivering efficiency, absorption, toxicity, and the metabolic process of forsythoside E in vivo.

Molecular insights into the binding model and response mechanisms of triclosan with lysozyme

Triclosan is an emerging pollutant, which belongs to Pharmaceutical and Personal Care Products (PPCPs). The high exposure risk of triclosan is triggered by its high persistence and accumulation levels. Accordingly, we investigated the interaction mechanism of triclosan with lysozyme by biophysical methods, including multiple spectroscopic techniques, enzyme activity measurements, isothermal titration calorimetry (ITC) and molecular docking. The results indicated that the binding of triclosan and lysozyme contributed to the fluorescence sensitization and repositioned the fluorophore, such as Trp108, in a weaker polar microenvironment. Meanwhile, the binding of lysozyme and triclosan broke the secondary structure of lysozyme, as well as induced a small amount of α-Helix structure. The local surrounding of amide bond (CO) in lysozyme was altered and the content of α-Helix structure increased, suggesting that the protein scaffold and polypeptide chain of lysozyme were stretched and a lysozyme agglomerated with a larger particle size. In addition, the thermodynamic results indicated that triclosan docked to lysozyme at relatively moderate affinity, relying on hydrophobic forces, which was an endothermic reaction. The LysozymeTriclosan system became more disordered, indicating that the conformation of lysozyme was broken. Molecular simulations demonstrated that the docking pocket of lysozyme and triclosan contained 8 residues, consisting of Ala 107, Arg 112, Trp 108, Asn 59, Ile 98, Gln 57, Val 109 and Asp 52, which was core residues of lysozyme activity. Triclosan at high concentrations could occupy the native binding site of substrate and disturb Asp 52 residue, showing the antagonism with natural substrate, which inhibited the activity of lysozyme. In summary, this study elucidated the structural and functional responses of lysozyme after triclosan exposure simulated physiological conditions in vitro, as well as the interaction mode between triclosan and lysozyme.

Trapping of reactive carbonyl species by fiber-bound polyphenols from whole grains under simulated physiological conditions

The carbonyl trapping activity of bound-polyphenol rich insoluble dietary fiber (BP-IDF) from different whole grains and underlying mechanism of these BP-IDF actions were studied under simulated physiological conditions. We found that the black highland barley BP-IDF exhibited the most pronounced effect in scavenging carbonyls by trapping 88.7%, 72.2%, 95.7%, and 31.4% for methylglyoxal, glyoxal, acrolein, and malondialdehyde within 24 h, respectively. After vitro gastrointestinal digestion, the black highland barley BP-IDF still retained considerable trapping activity for carbonyls. The carbonyl scavenging capacity was reduced by up to 93% after removing bound polyphenols from the black highland barley BP-IDF, which was consistent with the reduction in its total phenolic content. Moreover, the formation of adducts between reactive carbonyl species (RCS) and polyphenols bound to insoluble dietary fiber (IDF) was also detected. Overall, these findings confirmed that IDF-bound polyphenols were still active to trap RCS, indicating the potential benefits of BP-IDF from whole grains as functional ingredients to limit carbonyl stress across the gastrointestinal tract.

Discovery of novel microtubule stabilizers targeting taxane binding site by applying molecular docking, molecular dynamics simulation, and anticancer activity testing

Disruption of the dynamic equilibrium of microtubules can induce cell cycle arrest in G2/M phase and apoptosis. Hence, discovery of novel tubulin polymerization inhibitors is very necessary and an important task in drug research and development for treatment of various tumors. In this investigation, 50 compounds were screened as microtubule stabilizers targeting the taxane site by combination of molecular docking methods. Among these hits, hits 19 and 38 with novel scaffolds exhibited the highest anti-proliferative activity with IC50 ranging from 9.50 to 13.81 μM in four cancer cell lines. The molecular dynamics simulations confirmed that tubulin and two hits could form stable systems. Meanwhile, the mechanism of the interactions between tubulin and two hits at simulated physiological conditions were probed. The in vitro tubulin polymerization assay revealed hits 19 and 38 were able to promote tubulin polymerization in a dose-dependent manner. Further, the immunofluorescence assay suggested that hits 19 and 38 could accelerate microtubule assembly in A549 and HeLa cells. Finally, studies on antitumor activity indicated that hits 19 and 38 induced G2/M phase cell cycle arrest and apoptosis, and inhibited cancer cell motility and migration in A549 and HeLa cells. Importantly, hit38 exhibited better anti-tubulin and anti-cancer activity than hit19 in A549 and HeLa cells. Therefore, these results suggest that hit38 represents a promising microtubule stabilizer for treating cancer and deserves further investigation.

Effect of Caffeine and Flavonoids on the Binding of Tigecycline to Human Serum Albumin: A Spectroscopic Study and Molecular Docking.

Human serum albumin (HSA) has a very significant role in the transport of drugs, in their pharmacokinetic and pharmacodynamic properties, as well as the unbound concentration of drugs in circulating plasma. The aim of this study was to look into the competition between tigecycline (TGC) and alkaloid (ALK) (caffeine (CAF)), and flavonoids (FLAVs) (catechin (CAT), quercetin (QUE), and diosmin (DIO)) in binding to HSA in simulated physiological conditions using multiple spectroscopic measurements and docking simulations. Fluorescence analysis was used to find the binding and quenching properties of double HSA-TGC and triple HSA-TGC-CAF/FLAV systems. The conformational change of the HSA was analyzed using synchronous fluorescence spectroscopy, Fourier transform infrared spectroscopy, and circular dichroism. Obtained results of spectroscopic analyses indicate that triple complexes of HSA-TGC-CAF/FLAVs are formed without problems and have higher binding affinities than double HSA-TGC. In addition, TGC does not change the microenvironments around the tryptophan (Trp) and tyrosine (Tyr) residues in the presence of ALK and FLAVs. Ultimately, the binding affinity, competition, and interaction nature were explored by docking modeling. Computational outcomes are in good accordance with experimentally obtained results. Accordingly, concluding remarks may be very useful for potential interactions between common food components and drugs.

Thiophenes-Naturally Occurring Plant Metabolites: Biological Activities and In Silico Evaluation of Their Potential as Cathepsin D Inhibitors.

Naturally, thiophenes represent a small family of natural metabolites featured by one to five thiophene rings. Numerous plant species belonging to the family Asteraceae commonly produce thiophenes. These metabolites possessed remarkable bioactivities, including antimicrobial, antiviral, anti-inflammatory, larvicidal, antioxidant, insecticidal, cytotoxic, and nematicidal properties. The current review provides an update over the past seven years for the reported natural thiophene derivatives, including their sources, biosynthesis, spectral data, and bioactivities since the last review published in 2015. Additionally, with the help of the SuperPred webserver, an AI (artificial intelligence) tool, the potential drug target for the compounds was predicted. In silico studies were conducted for Cathepsin D with thiophene derivatives, including ADMET (drug absorption/distribution/metabolism/excretion/and toxicity) properties prediction, molecular docking for the binding interaction, and molecular dynamics to evaluate the ligand–target interaction stability under simulated physiological conditions.

A new HClO-activated “turn-off” mitochondria-targetable NIR fluorescent probe for imaging of osteoarthritis in vivo

Hypochlorous acid (HClO) as a biomarker of inflammation has been implicated in redox signaling and combating microbial infection. Therefore, it is of great significance to develop an efficient method for detection and analysis of HClO in osteoarthritis. Herein, a new“turn-off” mitochondria-targetable NIR fluorescent probe, NIR-ClO, was reported for specific analysis and imaging of osteoarthritis response-related HOCl levels in vitro and in vivo. In the presence of HClO, due to the specific HOCl-triggered C = C bond cleavage reaction, NIR-ClO obtained a high sensitive and selective fluorescence “On-Off” response toward HClO with a good limit of detection(LOD) as low as 28.3 nM, and showed a fast response time (<60 s) , which allow it to be used for detection of HClO under a simulated physiological condition. In addition, NIR-ClO was successfully used to imaging of HClO in living RAW264.7 cells and osteoarthritis model rat. The results suggest that NIR-ClO is a robust tool for future studies on diagnosis osteoarthritis.

Dual anticancer drug delivery of D-galactose-functionalized stimuli-responsive nanogels for targeted therapy of the liver hepatocellular carcinoma

In the current research work for the first time, we designed and fabricated a new double-responsive (pH and temperature) and photoluminescent nanogels capped with D-galactose (D-Gal) moieties (CQDs/β-CD/NIPAM@AA-Gal) in three steps and then evaluated its potential as a targeted drug carrier. The used common characterization techniques approved the success in fabrication of the CQDs/β-CD/NIPAM@AA-Gal nanogels. CQDs/β-CD/NIPAM@AA-Gal nanogels demonstrated homogeneous size distribution with an average hydrodynamic diameter of about 657 nm. About 47.8% and 72% of loading capacity respectively were observed respectively for methotrexate (MTX) and doxorubicin (DOX) anticancer drugs (MTX@DOX@CQDs/β-CD/NIPAM@AA-Gal). The controlled drug release ability of the MTX@DOX@CQDs/β-CD/NIPAM@AA-Gal was verified through a comparison of the drug release profiles at the simulated tumor and physiological conditions. In vitro cytotoxicity, 4′,6-diamidino-2-phenylindole (DAPI) staining, and cell cycle assays displayed the good biocompatibility of CQDs/β-CD/NIPAM@AA-Gal. Furthermore, fluorescent imaging approved its bioimaging potential. Overall summation of the achieved results proposes that the CQDs/β-CD/NIPAM@AA-Gal can be generally tested as a medical nanovehicle with a wide range of applicability potential for cancer cells monitoring and co-drug delivery.

Fluorescent probe based on coumarin derivative for the selective detection of cysteine in living cells

Cysteine (Cys), an organic small molecule containing a sulfhydryl group, plays key roles in human physiology and disease. The detection of Cys in vitro and in vivo is essential for further elucidating its many biological functions. Herein, we designed and synthesized a coumarin-based fluorescent probe for Cys detection. This probe was successfully applied to the monitoring of Cys in living HeLa cells, indicating that this probe can penetrate viable cell membranes and selectively detect Cys in the presence of other analytes such as homocysteine and glutathione. The linear relationship of Cys was in the range of 0-50 µM and the limit of detection (LOD) of the probe 1 was 1.3 μM. It provides a potential possibility for the quantitative study of intracellular Cys. The probe 1 was designed and synthesized for the detection of intracellular Cys level in simulated physiological conditions and living cells. It was found that probe 1 could be used to detect Cys concentration in living cells with high selectivity.

Modification of indwelling PVC catheters by ionizing radiation with temperature- and pH-responsive polymers for antibiotic delivery

Gamma rays were evaluated as energy source to generate reactive points onto polyvinyl chloride (PVC) catheters, allowing the grafting of stimuli-responsive vinyl monomers that may endow the catheters with the ability to load and release vancomycin. Dual temperature- and pH- responsiveness was achieved in PVC catheters in a two-step route using the “grafting from” method. First N-isopropyl acrylamide (NIPAAm) was grafted onto the pre-irradiated PVC catheter, and then 4-vinyl pyridine (4VP) was grafted onto the PVC-g-NIPAAm catheter. The effects of reaction conditions, such as solvent, monomer concentration, and radiation dose, were studied. Grafted catheters were characterized by infrared spectroscopy (FTIR-ATR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), contact angle measurement, scanning electron microscopy (SEM), and swelling tests. Binary grafted catheters exhibited affinity for vancomycin, and the vancomycin-loaded catheters sustained the release under simulated physiological conditions of temperature and pH. Vancomycin-loaded catheters inhibited Staphylococcus aureus growth in a highly contaminated in vitro environment. It is to forecast that these modified catheters may be employed to prevent nosocomial infections or applied as antimicrobial therapy.

Preparation and characterization of magnetic nanohydrogel based on chitosan for 5-fluorouracil drug delivery and kinetic study

Chemotherapy is currently used for most cancer treatments, but one of the significant problems of this treatment is that it affects the healthy tissues of the body. Therefore, designing new systems for the intelligent and controlled release of these drugs in cancer tissues is one of the major challenges in the world. Hence, today, huge costs are spent designing appropriate new drug delivery systems (DDS) with controlled drug release. In this study, chitosan-polyacrylic acid encapsulated Fe3O4 magnetic nanogelic core-shell (Fe3O4@CS-PAA) was synthesized in the presence of glutaraldehyde used for loaded anticancer 5-fluorouracil (5-FU) drug. Also, the prepared Fe3O4@CS-PAA was characterized by using FT-IR, SEM, XRD, and VSM analysis. Then, drug delivery tests were carried out in the in-vitro conditions that are the simulated physiological environment and tumor tissue conditions. The drug release tests indicated that the Fe3O4@CS-PAA upgraded the rate of 5-FU release from nanogelic core-shell under tumor tissue conditions (pH 4.5) than physiological environments (pH 7.4). In addition, various models were used to investigate the drug release mechanism. Results of modeling studies of drug release showed the mechanism of 5-FU release from Fe3O4@CS-PAA controlled by Fickian diffusion.

Polyphosphazene-Based Nanocarriers for the Release of Camptothecin and Epirubicin.

The design and study of efficient polymer-based drug delivery systems for the controlled release of anticancer drugs is one of the pillars of nanomedicine. The fight against metastatic and invasive cancers demands therapeutic candidates with increased and selective toxicity towards malignant cells, long-term activity and reduced side effects. In this sense, polyphosphazene nanocarriers were synthesized for the sustained release of the anticancer drugs camptothecin (CPT) and epirubicin (EPI). Linear poly(dichloro)phosphazene was modified with lipophilic tocopherol or testosterone glycinate, with antioxidant and antitumor activity, and with hydrophilic Jeffamine M1000 to obtain different polyphosphazene nanocarriers. It allowed us to encapsulate the lipophilic CPT and the more hydrophilic EPI. The encapsulation process was carried out via solvent exchange/precipitation, attaining a 9.2–13.6 wt% of CPT and 0.3–2.4 wt% of EPI. CPT-loaded polyphosphazenes formed 140–200 nm aggregates in simulated body physiological conditions (PBS, pH 7.4), resulting in an 80–100-fold increase of CPT solubility. EPI-loaded polyphosphazenes formed 250 nm aggregates in an aqueous medium. CPT and EPI release (PBS, pH 7.4, 37 °C) was monitored for 202 h, being almost linear during the first 8 h. The slow release of testosterone and tocopherol was also sustained for 150 h in PBS (pH 7.4 and 6.0) at 37 °C. The co-delivery of testosterone or tocopherol and the anticancer drugs from the nanocarriers was expected. Cells of the human breast cancer cell line MCF-7 demonstrated good uptake of anticancer-drug-loaded nanocarriers after 6 h. Similarly, MCF-7 spheroids showed good uptake of the anticancer-drug-loaded aggregates after 72 h. Almost all anticancer-drug-loaded polyphosphazenes exhibited similar or superior toxicity against MCF-7 cells and spheroids when compared to raw anticancer drugs. Additionally, cell-cycle arrest in the G2/M phase was increased in response to the drug-loaded nanocarriers. Almost no toxicity of anticancer-drug-loaded aggregates against primary human lung fibroblasts was observed. Furthermore, the aggregates displayed no hemolytic activity, which is in contrast to the parent anticancer drugs. Consequently, synthesized polyphosphazene-based nanocarriers might be potential nanomedicines for chemotherapy.

Binding affinity of p-PD-based schiff-bases towards human serum albumin; in-vitro and in-silico assessment

The Schiff-bases {N,N′-Bis(2-hydroxybenzylidene)-benzene-1,4-diamine (L1), N,N′-Bis(5‑bromo-2-hydroxybenzylidene) -benzene-1,4-diamine (L2), N,N′-Bis(2‑hydroxy-3‑methoxy-benzylidene)-benzene-1,4-diamine (L3), and N,N′-Bis(2-hydroxynaphthylidene)-benzene-1,4-diamine (L4)} have been synthesised by the reaction of 1,4-phenylenediamine (p-PD) with the necessary aldehydes and characterised by UV–Vis, FT-IR, 1H NMR, and mass spectroscopy. Their solubilities, at room temperature, were determined according to the USP and BP classification. Quantum chemical calculations of the compounds L1 to L4 have been carried out by DFT at the B3LYP/6–311++G(d,p) level; these show the results of the calculations to be in accordance with the experimental ones. A comparative analysis of the experimental and calculated vibrational frequencies was performed and significant bands were identified.The binding affinity between our Schiff-bases and human serum albumin (hsa) was studied under simulated physiological conditions, using absorbance titration experiments, fluorescence spectroscopy, circular dichroism (CD), and molecular docking (MD). Interaction results revealed one molecule of synthesised Schiff-bases to bind to the protein. MD results suggested that the binding site of L1 and L3 was site IA and that of L2 and L4 were sites IIIB and IIA, respectively. In vitro anticancer activity of the synthesised compounds was evaluated against the human hepatocellular carcinoma (HepG2) and human breast (MCF-7) cancer cells using MTT assays. Among the compounds, L4 (containing a naphthyl substituents) exhibited the highest anticancer activity with IC50 values of 12.90 ± 8.91 and 13.90 ± 7.88 against the HepG2 and MCF-7 cell lines after an incubation of 24 h.

Selective detection of sulfasalazine antibiotic and its controllable photodegradation into 5-aminosalicylic acid by visible-light-responsive metal-organic framework.

The extensive use of sulfasalazine (SSZ) antibiotics has brought potential threats to aquatic ecosystems and human health. Thus, necessary measures for the removal of SSZ must be taken to prevent arbitrary antibiotic exposure to the aquatic environment. However, not all the recent photocatalysts that have been used for the degradation of SSZ could not achieve the controlled release of SSZ and hence are losing their medicinal values. Herein, by utilizing an Eosin Y moiety as an efficient light-harvesting and emission site, an Eosin Y-based visible-light-responsive metal-organic framework has been synthesized and characterized, which exhibits high selectivity for detecting the antibiotic SSZ in water and simulated physiological conditions, with a detection limit of below 1 μM (0.4 μg mL-1). It also represents the first example of a MOF-based photocatalyst for the controllable degradation of SSZ into 5-aminosalicylic acid with excellent catalytic activity and recyclability.

Injectable polyelectrolyte complex-nascent HAP biodegradable antibiotic delivery system for the treatment of osteomyelitis

An injectable osteoconductive polyelectrolyte complex (PEC)–hydroxyapatite (HAP) formulation capable of controlled delivery of ciprofloxacin has been developed from a novel biodegradable PEC and antibiotic loaded nascent hydroxyapatite (n-HAP) for the treatment of osteomyelitis. A single source (chitosan) derived polyelectrolytes were complexed in situ in the presence of n-HAP, pre-loaded with ciprofloxacin. The PEC-(n-HAP) nanoformulation (HPEC) was characterized by FT-IR, XRD, TGA and TEM analyses. HPEC combines functionalities of n-HAP (crystallinity and osteoconductivity) as well as PEC (biodegradable hydrophilic electrostatically bound macromolecular network) imparting better control over swelling and degradation kinetics favourable for drug release and transport of micronutrients. MTT assay and cytoskeleton staining (MG-63 cells) established cytocompatibility of HPEC. Early biomimetic mineralization of apatite was manifested under simulated physiological condition with a Ca/P of 1.23 (day 3) and 1.55 (day 6) complimented by in vitro biomineralization of MG-63 and human osteosarcoma (HOS) cells in a week (Alizarin Red S staining), which was further validated by calcium quantification. Antibacterial efficacy of HPEC has been evaluated by delivery kinetics of ciprofloxacin and by disc diffusion method against S. aureus and E. coli. The injectable system therefore possesses unique combination of functionalities: osteoconduction enriched with early biomineralization, antibacterial activity and is biodegradable; hence highly suitable for osteomyelitis treatment.

A comprehensive in silico investigation into the nsSNPs of Drd2 gene predicts significant functional consequences in dopamine signaling and pharmacotherapy

DRD2 is a neuronal cell surface protein involved in brain development and function. Variations in the Drd2 gene have clinical significance since DRD2 is a pharmacotherapeutic target for treating psychiatric disorders like ADHD and schizophrenia. Despite numerous studies on the disease association of single nucleotide polymorphisms (SNPs) in the intronic regions, investigation into the coding regions is surprisingly limited. In this study, we aimed at identifying potential functionally and pharmaco-therapeutically deleterious non-synonymous SNPs of Drd2. A wide array of bioinformatics tools was used to evaluate the impact of nsSNPs on protein structure and functionality. Out of 260 nsSNPs retrieved from the dbSNP database, initially 9 were predicted as deleterious by 15 tools. Upon further assessment of their domain association, conservation profile, homology models and inter-atomic interaction, the mutant F389V was considered as the most impactful. In-depth analysis of F389V through Molecular Docking and Dynamics Simulation revealed a decline in affinity for its native agonist dopamine and an increase in affinity for the antipsychotic drug risperidone. Remarkable alterations in binding interactions and stability of the protein–ligand complex in simulated physiological conditions were also noted. These findings will improve our understanding of the consequence of nsSNPs in disease-susceptibility and therapeutic efficacy.

Reevaluating a non-conventional procedure to microencapsulate beneficial lactobacilli: assessments on yield and bacterial viability under simulated technological and physiological conditions.

Maintaining viability of beneficial microorganisms applied to foods still constitutes an industrial challenge. Many microencapsulation methodologies have been studied to protect probiotic microorganisms and ensure their resistance from manufacturing through to consumption. However, in many Latin-American countries such as Argentina there are still no marketed food products containing microencapsulated beneficial bacteria. The objectives of this work were: (i) to obtain microcapsules containing Lactobacillus fermentum L23 and L. rhamnosus L60 in a milk protein matrix; and (ii) to evaluate the viability of microencapsulated lactobacilli exposed to long-term refrigerated storage, mid-high temperatures and simulated gastrointestinal conditions. The method of emulsification/rennet-catalyzed gelation of milk proteins used in this study led to high encapsulation yields for both strains (98.2-99%). Microencapsulated lactobacilli remained viable for 120 days at 4°C, while free lactobacilli gradually lost their viability under the same conditions. Microencapsulation increased the resistance of lactobacilli to mid-high temperatures, since they showed survival rates of 95-99.3% at 50 °C, and of 72.5-74.4% at 65 °C. Under simulated gastric conditions, the microencapsulated lactobacilli counts were higher than 8.5 log CFU mL-1 and showed survival rates between 96.61% and 97.74%. Furthermore, in the presence of bile (0.5-2% w/v) the survival of microencapsulated strains was higher than 96%. The microencapsulation process together with the matrix of milk proteins used in this study protected beneficial Lactobacillus strains against these first simulated technological and physiological conditions. These findings suggest that this microencapsulation method could contribute to secure optimal amounts of living lactobacilli cells able to reach the intestine. © 2021 Society of Chemical Industry.

Synthesis and biological evaluation of novel tetranuclear cyclopalladated complex bearing thiosemicarbazone scaffold ligand: Interactions with double‐strand DNA, coronavirus, and molecular modeling studies

AbstractThreading intercalators are a novel class of materials that carry two substituents along the diagonal positions of an aromatic ring. When bound to DNA, these substituents project out in DNA grooves. Tetranuclear complexes appear to be promising threading intercalators for developing therapeutics against cancer and viral infections that require high nucleic acid binding affinity. The objective of this work was to prepare the thiosemicarbazone scaffold ligand [4‐ClC6H4CHN=NC(S)NHPh] and tetranuclear cyclopalladated complex [Pd(4‐ClC6H4CHN=NC(S)NHPh)4] and to characterize the compounds by elemental analysis, 1D and 2D NMR, HRMS, and IR spectroscopy. The calf thymus DNA (CT‐DNA) binding properties of the compounds were investigated in vitro under simulated physiological conditions using UV–vis spectroscopy, emission spectral titration, methylene blue competitive binding, circular dichroism, DNA thermal denaturation, DNA binding, and coronavirus interactions using molecular simulation. The compounds showed cytotoxic effect against both human breast (MCF‐7) and colorectal (HCT116) cancer cells in a dose‐dependent manner. We demonstrated that the compounds are promising for DNA threading intercalation binders with large DNA binding constants on the order of 107 M−1 magnitude.

Ventriculoperitoneal Shunt Drainage Increases With Gravity and Cerebrospinal Fluid Pressure Pulsations: Benchtop Model.

There have been few improvements in cerebrospinal fluid (CSF) shunt technology since John Holter introduced the silicon valve, with overdrainage remaining a major source of complications. To better understand why valves are afflicted by supra-normal CSF flow rates. We present in Vitro benchtop analyses of flow through a differential pressure valve under simulated physiological conditions. The pseudo-ventricle benchtop valve testing platform that comprises a rigid pseudo-ventricle, compliance chamber, pulsation generator, and pressure sensors was used to measure flow rates through a differential pressure shunt valve under the following simulated physiological conditions: orientation (horizontal/vertical), compliance (low/medium/high), and pulsation generator force (low/medium/high). Our data show that pulse pressures are faithfully transmitted from the ventricle to the valve, that lower compliance and higher pulse generator forces lead to higher pulse pressures in the pseudo-ventricle, and that both gravity and higher pulse pressure lead to higher flow rates. The presence of a valve mitigates but does not eliminate these higher flow rates. Shunt valves are prone to gravity-dependent overdrainage, which has motivated the development of gravitational valves and antisiphon devices. This study shows that overdrainage is not limited to the vertical position but that pulse pressures that simulate rhythmic (eg, cardiac) and provoked (eg, Valsalva) physiological CSF pulsations increase outflow in both the horizontal and vertical positions and are dependent on compliance. A deeper understanding of the physiological parameters that affect intracranial pressure and flow through shunt systems is prerequisite to the development of novel valves.

Grain refinement effect on the Ti-45Nb alloy electrochemical behavior in simulated physiological solution

In this study, the influence of microstructural refinement induced by the high-pressure torsion (HPT) on the corrosion resistance of the Ti-45Nb (mass%) alloy was investigated. The alloy characteristics before and after the HPT deformation were analyzed by electron backscatter diffraction (EBSD), scanning transmission electron microscopy (STEM), x-ray diffraction (XRD), and Vickers microhardness measurements, while the alloy corrosion behavior in simulated physiological conditions was examined by potentiodynamic polarization measurements and electrochemical impedance spectroscopy (EIS) analysis. Detailed microstructural analyses revealed that the HPT deformation led to significant grain refinement of the Ti-45Nb alloy exhibiting an ultra-fine grained (UFG) microstructure along with a substantial increase of hardness. Results also indicated that the grain refinement did not affect the alloy phase composition since β-Ti and Ti4Nb phases were present in the microstructure before and after the HPT deformation. Even though the Ti-45Nb alloy in both, coarse-grained (CG) and UFG, conditions shows high corrosion resistance in Ringer's solution at 37 °C, it was observed that the HPT treatment additionally improved the alloy corrosion properties. Namely, more rapid formation of the passivating layer with better barrier properties on the UFG alloy surface was recorded and resulted in better corrosion resistance of the alloy after HPT deformation. An increase of the grain contact area in the refined microstructure caused an increase of the diffusive transfer along the grain boundaries, accelerated the formation of a less defective protective barrier surface layer, and promoted the alloy surface passivation in the simulated physiological conditions.