Concentration-dependent Mode Research Articles

Novel pyridazinone derivatives bind to KSRP: Synthesis, anti-tumor biological evaluations and modelling insights

Pyridazinone derivatives have been extensively used as anticancer agents. IMB5036 is a structure specific pyridazinone compound with potential antitumor activity via targeting KSRP protein which controls gene expression at multiple levels. In this study, fifteen IMB5036 analogues were synthesized and preliminary structure-activity relationships were explored. Among them, compounds 8 and 10 exhibited remarkably anti-proliferation of various cancer cells and a good cancer cell selectivity (against human fetal hepatocyte L02 cells). More detailed investigation was included that both 8 and 10 inhibited colony formation and migration in concentration-dependent mode against MCF-7 cells. Additionally, 8 and 10 induced apoptosis and cell cycle arrest, decreased mitochondrial membrane potential, damaged DNA, and increased reactive oxygen species. Moreover, 8 displayed a potent antitumor efficacy (TGI = 74.2 %, at a dose of 30 mg/kg) in MCF-7 xenograft model by i.p. injection. Further, we synthesized a biotinylated probe 16 for identifying the detail domain of KSRP. Through pull down assay and molecular docking study, we validated that the KH23 domain functioned as the binding pocket for the compounds. Thus, compound 8 was identified as a novel targeting KSRP pyridazinone-based compound and exhibited excellent antitumor activity both in vitro and in vivo.

Comparative genomic and transcriptomic analyses reveal distinct response strategies to hypoxia by Vibrio parahaemolyticus isolates of clinical and aquatic animal origins

PurposeVibrio parahaemolyticus is a leading seafood borne pathogen worldwide. The aim of this study was to decipher the response mechanism of V. parahaemolyticus isolates of clinical and aquatic animal origins to the hypoxic condition, which challenges the bacterial survival in the host and in the environment.MethodsGrowth profiles of V. parahaemolyticus isolates (n = 5) of clinical and aquatic animal origins were examined at different stress conditions (osmolality, acid, temperature, and O2 concentrations). Draft genomes of the V. parahaemolyticus isolates were determined using the Illumina sequencing technique. Comparative genomic analysis were performed to identify and validate the hypoxic tolerance-related genes.ResultsThe V. parahaemolyticus isolates had an oxygen concentration-dependent growth mode, and the 10% O2 condition strongly inhibited the bacterial growth, when incubated in TSB medium (pH 8.5, 3% NaCl) at 37 °C. Unexpectedly, in marked contrast to the normal 21% O2 condition, the 10% O2 treatment for 24 h significantly increased biofilm formation of V. parahaemolyticus isolates (p < 0.05). Draft genome sequences of four V. parahaemolyticus isolates of aquatic animal origins were determined (4.914–5.3530 Mb), which carried mobile genetic elements (n = 12–29). Genome-wide gene expression changes triggered by the hypoxic condition were further examined. Comparative transcriptomic analyses unveiled multiple molecular strategies employed by the bacterium to mitigate the cell damage caused by the hypoxia. Of note, the pathogenic V. parahaemolyticus ATCC17802 down-regulated and/or shut down ten metabolic pathways to reduce cell viability and maintain cell structure under the hypoxic stress.ConclusionsThe results of this study fill prior gaps in the response mechanism of V. parahaemolyticus to the hypoxic condition. Different tolerance to hypoxia contributes to the persistence of pathogenic V. parahaemolyticus in the niches.

Isolation and identification of hyperin and naringenin from guava cultivated in Iraq and evaluation of cytotoxic activity of hyperin

The guava plant, Psidium guajava L., serves as proof of the abundant donations of nature, providing a delicious guava fruit; this plant is rich in groups of medicinal and nutritional benefits. Guava belonging to the Myrtaceae family, many previous studies reported many phytochemical constituents in its leaves that have many pharmacological activities and medicinal properties; this study focuses on the isolation, structural elucidation and calculation concentration of flavonoids, assessment of the cytotoxic activityof hyperin from Psidium guajava leaves newly cultivated in Iraq. The isolation process involved the use of thin-layer chromatography (TLC) and preparative high-performance liquid chromatography (PHPLC) and structural elucidation involved NMR (nuclear magnetic resonance spectroscopy) and FTIR (Fourier transform infrared spectrometer) for detailed structural insights into 2 isolated flavonoids. The isolation techniques proved effective in obtaining pure samples of hyperin and naringenin from the ethyl acetate and n.butanol fractions and structural elucidation techniques gives a good explanation for 2 isolated flavonoids. Evaluate cytotoxic activity of hyperin flavonoid against prostate cancer cell line (PC-3), human breast cancer cell line (MCF-7) and normal dermal fibroblast neonatal (HdFn), hyperin flavonoid exhibited a decrease in cell viability (%) with IC50 58.9 ?g /mL against the prostate cancer cell and IC50 90.58 ?g /mL against human breast cancer and noncytotoxic to HDFn, with an IC50 value substantially surpassing concentrations of 100 ?g/mL. These analytical approaches provided a comprehensive understanding of the chemical composition of the isolated flavonoids and interpreted that guava has cytotoxic activity against some cancers, depending on a concentration-dependent mode.

Investigation on the Efficacy of Two Food Supplements Containing a Fixed Combination of Selected Probiotics and β-Glucans or Elderberry Extract for the Immune System: Modulation on Cytokines Expression in Human THP-1 and PBMC

Several herbal and other natural products are used as ingredients in food supplements to strengthen immunity even if, very often, marketed products are proposed without a clear rationale or experimental evidence. In this study, we aimed to investigate the effect on human monocytes (THP-1) and on ex vivo human peripheral blood mononuclear cells (PBMC) of two formulations, one containing Bifidobacterium animalis subsp. lactis Bl-04® with β-glucans (for adults) and one containing Lactobacillus rhamnosus CRL1505 with elderberry extract (for children). We compared formulations with single ingredients, with bacterial lipopolysaccharide (LPS) and the drug pidotimod; cytokines expression level was evaluated testing different concentrations of samples at two exposure times. As expected, LPS caused a non-specific huge upregulation of cytokines expression both in THP-1 and in PBMC, whereas pidotimod mainly upregulated IL-2 in PBMC and IL-8 in THP-1. The two formulations showed a difference between a pro-inflammatory stimulus such as LPS, and also from an immunostimulant drug, such as pidotimod, as they mainly upregulated the expression of IL-6 and IL-10 in PBMC but not in THP-1, in a concentration-dependent mode. Probiotics were shown to play a major role, but β-glucans and elderberry extract exerted a synergistic activity. This work demonstrated that combining selected probiotics with other natural products having immunomodulatory properties is an interesting strategy to develop innovative formulations in the sector of food supplements.

Single Live Cell Imaging of Multidrug Resistance Using Silver Ultrasmall Nanoparticles as Biosensing Probes in Triple-Negative Breast Cancer Cells.

Silver ultrasmall nanoparticles (Ag UNPs) (size < 5 nm) were used as biosensing probes to analyze the efflux kinetics contributing to multidrug resistance (MDR) in single live triple-negative breast cancer (TNBC) cells by using dark-field optical microscopy to follow their size-dependent localized surface plasmon resonance. TNBC cells lack expression of estrogen (ER-), progesterone (PR-), and human epidermal growth factor 2 (HER2-) receptors and are more likely to acquire resistance to anticancer drugs due to their ability to transport harmful substances outside the cell. The TNBC cells displayed greater nuclear and cytoplasmic efflux, resulting in less toxicity of Ag UNPs in a concentration-independent manner. In contrast, more Ag UNPs and an increase in cytotoxic effects were observed in the receptor-positive breast cancer cells that have receptors for ER+, PR+, and HER2+ and are known to better respond to anticancer therapies. Ag UNPs accumulated in receptor-positive breast cancer cells in a time-and concentration-dependent mode and caused decreased cellular growth, whereas the TNBC cells due to the efflux were able to continue to grow. The TNBC cells demonstrated a marked increase in survival due to their ability to have MDR determined by efflux of Ag UNPs outside the nucleus and the cytoplasm of the cells. Further evaluation of the nuclear efflux kinetics of TNBC cells with Ag UNPs as biosensing probes is critical to gain a better understanding of MDR and potential for enhancement of cancer drug delivery.

Fruit Extract of Oil Palm (&lt;i&gt;Elaeis Guineensis&lt;/i&gt; (Jacq.)) Inhibits Uterine Contractility in &lt;i&gt;Ex-Vivo&lt;/i&gt; Mouse Models

Background: Different parts of Elaeis guineensis (EG) plants are used ethno-medicinally for treating numerous illnesses including abdominal contraction.&#x0D; Objectives: Thus, this study evaluated the inhibitory potential of the fruit-extract of EG on the uterine contractility in ex-vivo mouse models.&#x0D; Material and Methods: The effect of EG extract on spontaneous uterine contractions, oxytocin (OT)-induced uterine contractions, high potassium chloride induced uterine contractions and oxytocin-induced calcium free contraction were evaluated in adult non-pregnant female albino mice.&#x0D; Results: EG in a concentration dependent mode diminished spontaneous uterine contractions, while amplitude and frequency of contractions were inhibited significantly, but the frequency of contraction was at the highest concentration of EG. EG also produced a significant inhibition of the frequency of OT-induced contraction in calciumfree media.&#x0D; Conclusion: The aqueous fruit extracts of EG inhibited uterine contraction in the uterus through inhibition of intracellular calcium stores.

The antibiofilm potential of a heteropolysaccharide produced and characterized from the isolated marine bacterium Glutamicibacter nicotianae BPM30

Biofilms are the significant causes of 80% of chronic infections in the oral cavity, urinary tract, biliary tube, lungs, gastrointestinal tract, and so on to the general public. Treatment of pathogenic biofilm using bacterial exopolysaccharides (EPS) is an effective and promising strategy. In the present work, a marine bacterium was isolated, studied for exopolysaccharide production, and tested for its antibiofilm activity. Approximately 1.31 ± 0.07 g/L of a purified extracellular polysaccharide was produced and characterized from the isolated marine bacterium Glutamicibacter nicotianae BPM30. The hydrolyzed EPS contains multiple monosaccharides such as rhamnose, fructose, glucose, and galactose. The EPS demonstrated potential antibiofilm activity on four tested pathogens in a concentration-dependent mode. The antibiofilm activity of the purified EPS was studied by crystal violet assay and fluorescence staining method. Comparative inhibition results obtained for the tested strains are 93.25% ± 5.25 and 88.56% ± 2.25 for K. pneumoniae; 92.65% ± 7.6 and 98.33% ± 0.85 for P. aeruginosa; 90.36% ± 6.3 and 52.08% ± 7.74 for S. typhi; 84.62% ± 5.6 and 77.90% ± 5.90 for S. dysenteriae. The results of the present work demonstrated the antibiofilm potential of EPS, which could be helpful in the invention of novel curative approaches in battling bacterial biofilm-related medical complications.

Inhibitory Effects of Trans-Cinnamaldehyde Against Pseudomonas aeruginosa Biofilm Formation.

Pseudomonas aeruginosa biofilm formation has been considered to be an important determinant of its pathogenicity in most infections. The antibiofilm activity of trans-cinnamaldehyde (TC) against P. aeruginosa was investigated in this study. Results demonstrated that the minimum inhibitory concentration (MIC) of TC against P. aeruginosa was 0.8 mg/mL, and subinhibitory concentrations (SICs) was 0.2 mg/mL and below. Crystal violet staining showed that TC at 0.05-0.2 mg/mL reduced biofilm biomass in 48 h in a concentration-dependent mode. The formation area of TC-treated biofilms was significantly declined (p < 0.01) on the glass slides observed by light microscopy. Field-emission scanning electron microscopy further demonstrated that TC destroyed the biofilm morphology and structure. Confocal laser scanning microscopic observed the dispersion of biofilms and the reduction of exopolysaccharides after TC treatment stained with concanavalin A (Con-A)-fluorescein isothiocyanate conjugate and Hoechst 33258. Meanwhile, TC caused a significant decrease (p < 0.01) in the component of polysaccharides, proteins, and DNA in extracellular polymeric substance. The swimming and swarming motility and quorum sensing of P. aeruginosa was also found to be significantly inhibited (p < 0.01) by TC at SICs. Furthermore, SICs of TC repressed the several genes transcription associated with biofilm formation as determined by real-time quantitative polymerase chain reaction. Overall, our findings suggest that TC could be applied as natural and safe antibiofilm agent to inhibit the biofilm formation of P. aeruginosa.

Synthesis of nickel cobalt-codoped tin oxide nanoparticles from Psidium guajava with anticancer properties

Metal oxide nanoparticles have been found to selectively target the tumor cells while non-toxic to the normal cells. Leukemia is one of the widespread and deadly cancers in adults, as well as the most common cancer in children. Recently, the nanoparticles have evolved as a simple, economic, effective, and ecologically sound strategy among the known nanoparticle synthesis techniques. In the present study, the structural, optical, and antibacterial effects of nickel cobalt-codoped Tin oxide nanoparticles (SnNiCoO2 NPs) formulated by the green process and the anticancer potential of SnNiCoO2 NPs in Molt-4 cells have been studied. The cytotoxic potential of the NPs against Molt-4 cells was estimated by MTT assay. The ROS and MMP levels were measured using fluorescent dyes and the changes in morphology and nuclei were noted using AO/EB staining. CAT, SOD, MDA, and GSH), and Proinflammatory Cytokines (TNF-α and IL1β) were also studied. The activity of caspase-3, −9, and −8 levels was examined to analyze the apoptotic mechanism. The XRD patterns of SnNiCoO2 NPs revealed a tetragonal structure. The SnNiCoO2 NPs was revealed a diameter of 126 nm by the DLS study. The morphology and elemental composition were studied using FESEM and EDAX spectra. In the FT-IR study, the O-sn-O stretching band was found to be 615 and 542 cm-1. The antimicrobial potential of the SnNiCoO2 NPs was examined against S. aureus, E. coli, and C. Albicans strains. A tremendous reduction in the viability of MOLT-4 cells at concentration-dependent mode witnessed the cytotoxic potential of the formulated NPs. The augmented ROS accumulation, depletion of MMP status, depleted antioxidants, and increased proinflammatory cytokines (TNF-α and IL1β) were noted on the NPs exposed cells. Furthermore, the increased expressions of caspase-3, −9, and −8 was also noted in the NPs treated MOLT-4 cells. Hence, the outcomes suggest that the formulated SnNiCoO2 NPs had remarkably potent antimicrobial and anticancer properties and could potentially prove beneficial in cancer treatment. Induces mitochondrial oxidative stress with nickel–cobalt-codoped tin oxide nanoparticles from Psidium guajava, which is a potential drug candidate for the antibiotic, antifungal, and anticancer activities of plant-based nanoparticles.

Prenylated flavonoids and derivatives isolated from the root barks of Sophora flavescens as potent antibacterial agents against Staphylococcus aureus

Sophora flavescens Alt. is widely used in traditional medicine as a functional food ingredient for the treatment of diseases, used as antipyretics, pesticide, and antibacterial agents to treat pruritus and other skin infections. In this study, ten new prenylated flavonoids and analogs (1–10) including nine flavanones (1–6 and 8–9), one flavanol (7), and one chromone (10), along with thirteen known flavonoids (11–23), have been obtained from the root barks of Sophora flavescens. Their structures were elucidated through comprehensive spectroscopic analysis. Bioactive assay discovered that 2R-sophoflavonoid A (2) possessed an excellent ability to suppress the growth of Staphylococcus aureus (MIC = 2 µg/mL) and low cytotoxicity toward the LO2 cells. Furthermore, the time-kill curves showed compound 2 had the ability to kill S. aureus rapidly. The bactericidal rate of compound 2 was faster than that of ampicillin at the concentration of 10 times MIC, and the bactericidal time of compound 2 was 3 min while ampicillin for 90. Crystal violet assay showed that compound 2 not only inhibited the formation of biofilms but also eradicated mature biofilms in a concentration-dependent mode. Preliminary mechanistic studies revealed that 2 possessed grateful antibacterial effects through damaging the membrane integrity, stimulating ROS generation, and reducing bacterial metabolism. In summary, these results suggested that compound 2 was a potential lead compound against S. aureus and can also be a candidate for a disinfectant.

How to Use Respiratory Chain Inhibitors in Toxicology Studies-Whole-Cell Measurements.

Mitochondrial electron transport chain (ETC) inhibition is a phenomenon interesting in itself and serves as a tool for studying various cellular processes. Despite the fact that searching the term “rotenone” in PubMed returns more than 6900 results, there are many discrepancies regarding the directions of changes reported to be caused by this RTC inhibitor in the delicate redox balance of the cell. Here, we performed a multifaceted study of the popular ETC inhibitors rotenone and antimycin A, involving assessment of mitochondrial membrane potential and the production of hydrogen peroxide and superoxide anions at cellular and mitochondrial levels over a wide range of inhibitor concentrations (1 nmol/dm3–100 µmol/dm3). All measurements were performed with whole cells, with accompanying control of ATP levels. Antimycin A was more potent in hindering HepG2 cells’ abilities to produce ATP, decreasing ATP levels even at a 1 nmol/dm3 concentration, while in the case of rotenone, a 10,000-times greater concentration was needed to produce a statistically significant decrease. The amount of hydrogen peroxide produced in the course of antimycin A biological activity increased rapidly at low concentrations and decreased below control level at a high concentration of 100 µmol/dm3. While both inhibitors influenced cellular superoxide anion production in a comparable manner, rotenone caused a greater increase in mitochondrial superoxide anions compared to a modest impact for antimycin A. IC50 values for rotenone and antimycin A with respect to HepG2 cell survival were of the same order of magnitude, but the survival curve of cells treated with rotenone was clearly biphasic, suggesting a concentration-dependent mode of biological action. We propose a clear experimental setup allowing for complete and credible analysis of the redox state of cells under stress conditions which allows for better understanding of the effects of ETC inhibition.

Structural and Binding Properties of the Active Cell Wall Hydrolase RipA from M. tuberculosis, a Promising Biosensing Molecule for Early Warning Bacterial Detection.

Peptidoglycan is an essential component of the cell wall in all bacteria. In particular, the cell walls of Gram-positive bacteria are composed mostly of a thick layer of peptidoglycan. Its accessibility has important implications for their sensing in whole bacterial detection methodologies. Indeed, there is an urgent demand for rapid tests which can identify whole bacteria, e.g., directly at the point of care. The aim of this work is to explore the suitability of RipA, a key cell division protein of M. tuberculosis, for whole cell biosensing of Gram-positive bacteria. We here conducted Molecular Dynamics (MD) studies aimed at the understanding of the structural and dynamic features of active RipA and at the design of a suitable bioreceptor. Based on these studies, we engineered a RipA variant for covalent oriented immobilisation on golden surfaces and are able to bind peptidoglycan, albeit without degrading it. Surface Plasmon Resonance (SPR) was employed to check the ability of functionalized golden chips to recognize whole bacteria. MD analyses elucidated the structural details of the active form of RipA and suggested that this enzyme, once inactivated, presents a rigid and well-exposed peptidoglycan recognition cleft. We engineered RipA for proper oriented immobilisation on golden chips for SPR studies. Results show that once chemically coupled to a golden chip, the developed RipA-based bioreceptor is able to detect B. subtilis, used as a model in a concentration-dependent mode. Results highlight the potential of the engineered molecule to be integrated in the development of early warning biosensors for Gram-positive contamination in clinical diagnosis or food-borne infections.

A Novel Peptide Derived from Arca inflata Induces Apoptosis in Colorectal Cancer Cells through Mitochondria and the p38 MAPK Pathway.

Colorectal carcinoma (CRC) is one of the major causes of cancer-related incidence and deaths. Here, we identified a novel antitumor peptide, P6, with a molecular weight of 2794.8 Da from a marine Chinese medicine, Arca inflata Reeve. The full amino acid sequence and secondary structure of P6 were determined by tandem mass de novo sequencing and circular dichroism spectroscopy, respectively. P6 markedly inhibited cell proliferation and colony formation, and induced apoptosis in CRC cells. Mechanistically, transcriptomics analysis and a serial functional evaluation showed that P6 induced colon cancer cell apoptosis through the activation of the p38-MAPK signaling pathway. Moreover, it was demonstrated that P6 exhibited antitumor effects in a tumor xenograft model, and induced cell cycle arrest in CRC cells in a concentration-dependent mode. These findings provide the first line of indication that P6 could be a potential therapeutic agent for CRC treatment.

Interactive multiple binding of oleic acid, warfarin and ibuprofen with human serum albumin revealed by thermal and fluorescence studies

Human serum albumin binds a wide variety of drugs with different structure and affinity to two main binding sites, drug site 1 (DS1) and drug site 2 (DS2), which partially or totally overlap with fatty acid (FA) sites. Although multiple binding sites are available for endogenous compounds, FAs are the primary physiological ligands of albumin and their competition in the occupancy of DS1 and DS2 affects the binding of exogenous molecules, with a possible impact on drug delivery. In this work, we have investigated the simultaneous binding of oleic acid, warfarin and ibuprofen to albumin using differential scanning calorimetry and fluorescence to evaluate the impact on the conformational stability of the protein. The two drugs are widely used for their anticoagulant (warfarin) and anti-inflammatory (ibuprofen) properties, and can be also considered as site markers to probe DS1 and DS2, respectively. Oleic acid is one of the most important fatty acids from a physiological point of view for its role as a source of energy for cells, and also it binds albumin with the highest association constant. When complexed with oleic acid the calorimetric profile of albumin shows a biphasic trend whose line shape depends on the ligand concentration. The binding capacity of either warfarin or ibuprofen to albumin is modulated by oleate molecules in a concentration-dependent mode being synergic cooperative (warfarin) or competitive-like (ibuprofen). The overall results provide insights on the dynamics of albumin/ligands complex, which in turn may have important pharmacokinetic and pharmacodynamic implications.

Both Acidic pH Value and Binding Interactions of Tartaric Acid With α-Glucosidase Cause the Enzyme Inhibition: The Mechanism in α-Glucosidase Inhibition of Four Caffeic and Tartaric Acid Derivates.

The inhibition mechanism of four caffeic and tartaric acid derivates, including caffeic acid (CA), tartaric acid (TA), caftaric acid (CFA) and chicoric acid (CHA) against α-glucosidase was characterized by substrate depletion, fluorescence quenching, isothermal titration calorimetry (ITC) and molecular docking. TA and CA were found with the highest and no inhibition effect respectively, and caffeoyl substitution at 2 and/or 3-OH of TA significantly decreased its inhibition. The enzyme inhibition effects of organic acids were not in an inhibitor concentration-dependent mode, and there was a rush increase in inhibition at a respective acidic pH value, especially for CFA and CHA, suggesting the important role of acidic pH in the enzyme inhibition for both compounds. Besides, CA, CFA and CHA were shown with strong quenching effects on α-glucosidase fluorescence because of π-conjugations between aromatic ring of caffeoyl moiety and that of enzyme fluorescent residues. However, no fluorescence quenching effect was observed for TA due to lack of aromatic ring. Additionally, a direct binding interaction behavior was observed for TA with α-glucosidase according to the fitted independent binding model in ITC, but not for CFA and CHA. Therefore, both acidic pH and binding interactions of TA with α-glucosidase resulted in the enzyme inhibition.

Design, synthesis and antibacterial activity of chalcones against MSSA and MRSA planktonic cells and biofilms

Staphylococcus aureus is the one of the most successful modern pathogens. The same bacterium that lives as a skin and mucosal commensal can be transmitted in health-care and community-settings and causes severe infections. Thus, there is a great challenge for a discovery of novel anti-Staphylococcus aureus compounds, which should act against resistant strains. Herein, we designed and synthesized a series of 17 chalcones, substituted by amino group on ring A, which were evaluated against methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus MRSA planktonic cells. The antibacterial potency was improved by substituents on ring B, which were designed according to Topliss’ manual method. 4-bromo-3′-aminochalcone (5f) was the most active, demonstrating minimum inhibitory concentration (MIC) values of 1.9 μg mL−1 and 7.8 µg mL−1 against MSSA and MRSA, respectively. The association of 5f with vancomycin demonstrated synergistic effect against MSSA and MRSA, with Fractional Inhibitory Concentration Index (FICI) values of 0.4 and 0.3, respectively. Subinhibitory concentration of 5f inhibited the MSSA and MRSA adhesion to human keratinocytes. Chalcone 5f was able to reduce MSSA and MRSA biofilm formation, as well as acts on preformed biofilm in concentration-dependent mode. Scanning electron microscopy analyses confirmed severe perturbations caused by 5f on MSSA and MRSA biofilm architecture. The acute toxicity assay, using Galleria mellonella larvae, indicated a low toxic effect of 5f after 72 h, displaying lethality of 20% and 30% at 7.8 μg mL−1 and 78.0 μg mL−1, respectively. In addition, the antibacterial activity spectrum of 5f indicated action against planktonic cells of Enterococcus faecalis (MIC = 7.8 μg mL−1), Acinetobacter baumannii (MIC = 15.6 μg mL−1) and Mycobacterium tuberculosis (MIC = 5.7 μg mL−1). Altogether, these results open new avenues for 5f as an anti-Staphylococcus aureus agent, with potential applications as antibacterial drug, adjunct of antibiotics and medical devices coating.

Concentration-dependent mode of binding of drug oxatomide with DNA: multi-spectroscopic, voltammetric and metadynamics simulation analysis

The interaction between antihistaminic drug oxatomide (OXT) and calf-thymus DNA (CT-DNA) has been investigated in a physiological buffer (pH 7.4) using UV–Vis, fluorescence, 1H NMR and circular dichroism spectral techniques coupled with viscosity measurements, KI quenching, voltammetry and in silico molecular modeling studies. OXT binds with CT-DNA in a concentration-dependent manner. At a lower [Drug]/[CT-DNA] molar ratio (0.6–0.1), OXT intercalates into the base pairs of CT-DNA, while at a higher [Drug]/[CT-DNA] molar ratio (13–6), the drug binds in the minor grooves of CT-DNA. The binding constants for the interaction are found to be in the order of 103–105 M−1, and the groove binding mode of interaction exhibits a slightly higher binding constant than that of intercalative mode. Thermodynamic analysis of binding constants at three different temperatures suggests that both these modes of binding are mainly driven by hydrophobic interactions (ΔH o > 0 and ΔS o > 0). Voltammetric investigations indicate that the electro-reduction of OXT is an adsorption controlled process and shifts in reduction peak potentials reiterate the concentration-dependent mode of binding of the drug with CT-DNA. The free energy landscape obtained at the all-atom level, using metadynamics simulation studies, revealed two major binding forces: partial intercalation and minor groove binding, which corroborate well with the experimental results. Communicated by Ramaswamy H. Sarma

In vitro toxicity of fibrous glaucophane

The health hazard represented by the exposure to asbestos may also concern other minerals with asbestos-like crystal habit. One of these potentially hazardous minerals is fibrous glaucophane. Fibrous glaucophane is a major component of blueschist rocks of California (USA) currently mined for construction purposes. Dust generated by the excavation activities might potentially expose workers and the general public. The aim of this study was to determine whether fibrous glaucophane induces in vitro toxicity effects on lung cells by assessing the biological responses of cultured human pleural mesothelial cells (Met-5A) and THP-1 derived macrophages exposed for 24 h and 48 h to glaucophane fibres. Crocidolite asbestos was tested for comparison. The experimental configuration of the in vitro tests included a cell culture without fibres (i.e., control), cell cultures treated with 50 μg/mL (i.e., 15.6 μg/cm2) of crocidolite fibres and 25-50−100 μg/mL (i.e., 7.8−15.6–31.2 μg/cm2) of glaucophane fibres. Results showed that fibrous glaucophane may induce a decrease in cell viability and an increase in extra-cellular lactate dehydrogenase release in the tested cell cultures in a concentration dependent mode. Moreover, it was found that fibrous glaucophane has a potency to cause oxidative stress. The biological reactivity of fibrous glaucophane confirms that it is a toxic agent and, although it apparently induces lower toxic effects compared to crocidolite, exposure to this fibre may be responsible for the development of lung diseases in exposed unprotected workers and population.

In vitro DNA Binding, Anticancer and Molecular Docking Studies of New Sydnone Compounds

Sydnones have been a novel class of mesoionic compound due to versatility of their applications in various fields. Sydnone derivative have seen as an interesting structure grouped in the heterocyclic community, which is having regions of both positive and negative charges linked with a poly-heteroatomic system. This structural characteristic allows them to cross biological membranes and interact with biomolecules. Four sydnones namely 3-(4-decyloxybiphenyl-4′-yl) sydnone (MC-176), 3-(4-octyloxy-2,3-difluorobiphenyl-4′-yl) sydnone (MC-192), 3-(4-biphenyl-4′-yl) sydnone (MC-450) and 3-(4-butylbiphenyl-4′-yl) sydnone (MC-456) were evaluated for biophysical interactions between DNA and sydnones and antiproliferative activity. The UV-visible spectroscopic study indicates interaction between sydnone and dsDNA with a slight red and hypochromic shift in absorption spectra, which shows the intercalation mode of binding. The binding constant of DNA-Sydnone complexes were in the range from 1.4 × 104 M–1 to 7.1 × 104 M–1 for different sydnone compounds (MC-176, MC-192, MC-450, MC-456). FTIR spectra indicated that sydnone interaction with DNA occurs through base pairs and the phosphate backbone of the DNA. The cytotoxic and apoptotic effects of a sydnone derivatives on human cervical cancer (HeLa) and breast tumor (BT) 474 cancer cell lines were determined. The compounds possess antiproliferative activity in a concentration-dependent mode. The changes of morphological characteristic of cancer cells were determined by fluorescent staining techniques indicate the apoptotic cell death. The molecular docking studies of sydnone compounds with caspase 3 and EGF-TK showed better interactions (according to docking score) along with commercially available breast cancer drug molecule anastrozole. The docking score of sydnone molecules (MC-456, MC-450, MC-192 and MC-176) with EGF-TK enzyme were -6.44, -6.42, -5.46 and -4.53, respectively. The binding energy of anastrozole with EGF-TK was -6.41. As well Caspase 3 inhibition with sydnone compounds MC-456, MC-450, MC-192 and MC-176 were -6.09, -6.48, -5 and -3.49, respectively. The binding energy of anastrozole with caspase 3 was -6.24. All sydnone compounds were studied for ADME toxicity studies along with Lipinski rule of five to assess their drug likeness properties by in silico approach. MC-450 found to have good ADMET (absorption, distribution, metabolism, excretion and toxicology) properties among all the sydnone compounds. Thus, the present work indicates that these sydnone compounds would be a well prospective in developing anticancer medicines.

Determining the critical micelle concentrations of cationic surfactants based on the visible-light-induced oxidase-like activity of fluorescein

As the critical micelle concentration (CMC) is one of the essential parameters of surfactant, the determination of CMC value is of great significance. We explored a facile and novel strategy based on the visible-light-induced oxidase-like activity of fluorescein for determining the CMC value of cationic surfactants. Fluorescein as a visible-light-induced oxidase mimic can catalyze the change of 3,3′,5,5′-tetramethylbenzidine (TMB) from colorless to blue (oxidation state TMB) under visible light illumination. Nevertheless, it was worth noticed that cationic surfactant could significantly inhibit the catalytic activity of fluorescein with a concentration-dependent mode due to the electrostatic interaction between negatively charged fluorescein and cationic surfactant in aqueous solution. With the increased of surfactants concentrations, the absorbance of the oxidation state TMB was decreased. As the concentration of cationic surfactant reached CMC, the catalytic activity of fluorescence was almost inhibited completely. Therefore, this novel and convenient spectrometric method provides a new idea for the determination of CMC value and also broadens the application of small molecule mimic enzymes.