Search Results (115)

In modern dentistry, the problem of the prevention and treatment of peri-implantitis is relevant. Proposed methods of treating patients with peri-implantitis do not stop the pathological process with the possibility of achieving long-term remission. Liposomal complexes with dihydroquercetin make it possible to influence the pathogenetic links of the inflammatory process in periodontal tissues with the prospect of normalizing blood circulation and regeneration processes in the affected area. It has been established that the complex simultaneous effect of low-intensity laser radiation and a pharmaceutical (laserophoresis) provides the possibility of more significant penetration of the drug components into periodontal tissues. The study of the laserophoresis of the liposomal complex with dihydroquercetin in the treatment of patients with peri-implantitis is relevant. However, in the modern literature, there is a lack of studies on the effect of low-intensity laser radiation on the pharmaceutical structure of drugs based on the above-mentioned basis. Full article

Beta-caryophyllene (BCP) is a natural bicyclic sesquiterpene with high biological activity. Potentially, it can be used in the treatment of a wide range of neurological diseases. However, to date, there are practically no data on the interaction of BCP with biological membranes. In the present work, we studied for the first time the interaction of BCP with model membranes—liposomes based on egg yolk phosphatidylcholine (Egg PC) with a variable cholesterol content (from 0 to 25 w.%). Using ATR-FTIR spectroscopy, we have shown that the membrane rigidity and cholesterol content dramatically affect the nature of the interaction of BCP with the bilayer both at room temperature and at physiological temperatures. The incorporation of BCP into the thickness of the bilayer leads to changes in the subpolar region of the bilayer, and at a high cholesterol content, it can provoke the formation of defects in the membrane. Full article

The Oropouche virus is an orthobunyavirus responsible for causing Oropouche fever, a disease that primarily affects thousands of people in South and Central America. Currently, no specific antiviral treatments or vaccines are available against this virus, highlighting the urgent need for safe, affordable, and effective therapies. Natural products serve as an important source of bioactive compounds, and there is growing interest in identifying natural bioactive molecules that could be used for treating viral diseases. Quercetin hydrate is a compound classified as a flavonoid, which has garnered scientific attention due to its potential health benefits and its presence in various plant-based foods. In this study, we aim to evaluate the in vitro antiviral activity of quercetin hydrate against the Oropouche virus (OROV). Furthermore, we intend to explore its mode of action through in silico approaches. The cytotoxicity and antiviral activity of the compound were assessed using Vero cells. In addition, in silico studies were also performed through molecular docking, molecular dynamics simulations, Molecular Mechanics Poisson–Boltzmann surface area (MM/PBSA), and quantum-mechanical analysis in order to evaluate the interaction with the Gc protein of OROV. The assay revealed that the compound was highly active against the virus, inhibiting OROV with an EC50 value of 53.5 ± 26.5 µM under post-infection treatment conditions. The present study demonstrates that the compound is a promising antiviral agent; however, the mechanisms of action proposed in this study need to be experimentally verified by future assays. Full article

We studied the dynamic behavior of a single semiflexible ring in linear chain matrix based on a coarse-grained model using the molecular dynamics simulation approach. We found that that ring chains’ hollow centers are frequently filled with linear chains. However, as the rigidity of the linear chains increases, the linear chains arranged parallel to each other and the ring chain are temporary caged. As a result, the swing movement in the normal direction of the ring is significantly limited, and the relaxation time in the normal direction increases significantly. Our findings can help to understand the physical mechanism of the movement of the ring chain in ring–linear polymer blends at the microscopic level. Full article

Understanding the connection between local and global dynamics can provide valuable insights into enzymatic function and may contribute to the development of novel strategies for enzyme modulation. In this work, we investigated the dynamics at both the global and local (active site) levels of Shikimate Kinase (SK) through microsecond time-scale molecular dynamics (MD) simulations of the holoenzyme in the product state. Our focus was on the wild-type (WT) enzyme and two mutants (R116A and R116K) which are known for their reduced catalytic activity. Through exploring the dynamics of these variants, we gained insights into the role of residue R116 and its contribution to overall SK dynamics. We argue that the connection between local and global dynamics can be attributed to local frustration near the mutated residue which perturbs the global protein dynamics. Full article

Cancer resistance to chemotherapy and radiation therapies presents significant challenges, necessitating the exploration of alternative approaches. Targeting specific proteins at the molecular level, particularly their active sites, holds promise in addressing this issue. We investigated the potential of 4′-methoxy-2-nitrochalcone (MNC) as an MCL-1 inhibitor, examining its chemical and structural characteristics to elucidate its biological activity and guide the selection of potential candidates. We conducted a docking study, followed by synthesis, structural characterization, theoretical calculations, and in vitro experiments to comprehensively evaluate MNC. The docking results revealed MNC’s excellent binding within the active site of MCL-1. At 50 µM, MNC demonstrated 99% inhibition of HCT116 cell proliferation, with an IC50 value of 15.18 µM after 24 h. Treatment with MNC at 30.36 and 15.18 µM resulted in reduced cell density. Notably, MNC exhibited marked cytotoxicity at concentrations of 15.58 µM and 7.79 µM, inducing high frequencies of plasma membrane rupture and apoptosis, respectively. Our findings highlight the significant biological potential of MNC as an MCL-1 inhibitor. Furthermore, we propose exploring chalcones with hydrogen bond acceptor substituents as promising candidates for studying inhibitors targeting this protein. In conclusion, our study addresses the challenge of cancer resistance by investigating MNC as an MCL-1 inhibitor. Through detailed characterization and experimental validation, we establish the efficacof MNC in inhibiting cell proliferation and inducing cytotoxic effects. These results underscore the potential of MNC as a valuable therapeutic agent and suggest the use of chalcones with hydrogen bond acceptor substituents as a basis for developing novel MCL-1 inhibitors. Full article

In this study, secondary metabolites, toxicology and antioxidant properties of chloroform fractions from leaves (FCFMh), branches (FCGMh), and roots (FCRMh) of Mansoa hirsuta were investigated. The phytochemical screening detected flavonoids, especially chalcones. Through Liquid chromatography with mass spectrometry—LC–MS analysis, the flavonoids (isoorientin-2″-O-arabinoside), triterpenes (oleanolic acid and ursolic acid) and ceramide (phytosphingosine) were identified. From the Artemia salina assay, the fraction FCGMh was the most toxic (LC₅₀ = 64.21 µg·mL⁻¹), followed by FCRMh (LC₅₀ = 87.61 µg·mL⁻¹) and FCFMh (LC₅₀ = 421.9 µg·mL⁻¹). Concerning the cytotoxic potential, the root fraction (IC₅₀ 16.48 μg mL⁻¹) displayed the highest cytotoxicity against the breast cancer cell line (4T1), followed by leaves (IC₅₀ 33.13 μg mL⁻¹) and branches (IC₅₀ of 47.13 μg mL⁻¹). In conclusion, all the fractions of M. hirsuta showed cytotoxicity at the highest concentrations; however, remarkable biological properties were found for the root fractions. Computational analysis was performed using a molecular docking and pharmacophore approach to understand the antioxidant activity of its major metabolites. Full article

Fibronectin is a multi-domain, extracellular matrix protein that plays a number of biological roles. As the adsorption of fibronectin onto the surface of implanted devices can lead to an inflammatory response or bacterial colonisation, understanding the interaction of fibronectin with material surfaces is important in the design of materials for biomedical applications. This, however, relies on having knowledge of the molecular-scale behaviour of proteins, which is difficult to investigate experimentally. In this paper, we used molecular dynamics simulations to investigate the adsorption of heparin-binding fibronectin domains onto hydrophobic surfaces. Despite the high similarity between these, their adsorption differs both in terms of the strength and the specificity of this, indicating that relatively small changes in protein structure can lead to significant changes in adsorption behaviour. This suggests that the interplay between protein structure and surface chemistry is vital for understanding the protein adsorption process and the design of novel biomaterials. Full article

This paper outlines the methodology and results for a two-species finite volume scalar computational drug transport model developed for simulating the mass transport of Poly(lactic-co-glycolic acid (PLGA)) from a half-embedded single strut implanted in a coronary arterial vessel wall. The mathematical drug transport model incorporates the convection-diffusion equation in scalar form (dimensionless) with a two-species (free-drug and bound-drug) mass transport setup, including reversible equilibrium reaction source terms for the free and bound-drug states to account for the pharmaco-kinetic reactions in the arterial wall. The relative reaction rates of the added source terms control the interconversion of the drug between the free and bound-drug states. The model is solved by a 2D finite-volume method for discretizing and solving the free and bound drug transport equations with anisotropic vascular drug diffusivities. This model is an improvement over previously developed models using the finite-difference and finite element method. A dimensionless characteristic scaling pre-analysis was conducted a priori to evaluate the significance of implementing the reaction source terms in the transport equations. This paper reports the findings of an investigation of the interstitial flow profile into the arterial wall and the free and bound drug diffusion profiles with a parametric study of varying the polymer drug concentration (low and high), tortuosity, porosity, and Peclet and DamKöhler numbers over the course of 400 h (16.67 days). The results also reveal how a single species drug delivery model that neglects both a reversible binding reaction source term and the porosity and tortuosity of the arterial wall cannot accurately predict the distribution of both the free and bound drug. Full article

We report the results of computational studies of the guanosine triphosphate (GTP) hydrolysis in the active site of the KRas-NF1 protein complex, where KRas stands for the K-isoform of the Ras (ras sarcoma) protein and NF1 (neurofbromin-1) is the activating protein. The model system was constructed using coordinates of heavy atoms from the crystal structure PDB ID 6OB2 with the GTP analog GMPPNP. Large-scale classical molecular dynamics (MD) calculations were performed to analyze conformations of the enzyme-substrate complexes. The Gibbs energy profiles for the hydrolysis reaction were computed using MD simulations with quantum mechanics/molecular mechanics (QM/MM) interaction potentials. The density functional theory DFT(ωB97X-D3/6-31G**) approach was applied in QM and the CHARMM36 force field parameters in MM. The most likely scenario of the chemical step of the GTP hydrolysis in KRas-NF1 corresponds to the water-assisted mechanism of the formation of the inorganic phosphate coupled with the dissociation of GTP to GDP. Full article

In the drug design process, a frequent task is the decomposition of small molecules into fragments. There exist a number of approaches and methods to break molecules into fragments. However, a method that allows the decomposition of molecules into non-overlapping fragments that is meaningful in terms of medicinal chemistry is absent, and in this work, we present a new simple approach for the decomposition of molecules—MedChemFrag. It aims to break drug-like molecules into a set of rings and linkers, which are close to the perception of “fragments” by medicinal chemists. In contrast to most previous efforts aimed at breaking molecules using retrosynthetic feasible rules, our approach strives to preserve the functional groups, which may reveal the specific interaction pattern, e.g., the amide groups. Full article

Various forms of pesticides have been reported to be among the environmental toxicants, which are detrimental to human health. The active ingredients of these formulations can enter the human body through air, food, or water. Epidemiological studies suggest that these compounds strongly affect the developing brain in fetal and infant stages due to their ability to breach the underdeveloped blood–brain barrier. Since neural progenitor stem cells (NPCs) in the developing brain are the most vulnerable to these compounds, the mechanisms by which NPCs experience toxicity upon exposure to these chemicals must be investigated. Here, we assessed the viability of human fetal NPCs in 2D cultures in the presence of the active ingredients of six widely used pesticides using Live/Dead^® and Hoechst staining. The IC₅₀ values ranged from 4.1–201 μM. A significant drop in cell viability with increasing toxicant concentration (p < 0.01) was noted, with the order of toxicity being malathion < 4-aminopyridine < methoprene < prallethrin < temephos < pyriproxyfen. Changes in cellular biomechanical characteristics (Young’s modulus, tether force, membrane tension, and tether radius) were quantified using atomic force microscopy, whereas cell migration was elucidated over 48 h using a customized wound-healing assay. The Young’s modulus of fetal NPCs exposed to IC₅₀/2 doses of these compounds was reduced by 38–70% and that of those exposed to IC₅₀ doses was reduced by 71–80% (p < 0.001 vs. controls for both; p < 0.01 for IC₅₀ vs. IC₅₀/2 for each compound). Similar patterns were noted for tether forces and membrane tension in fetal NPCs. NPC migration was found to be compound type- and dose-dependent. These results attest to the significant detrimental effects of these compounds on various aspects of the human fetal NPC phenotype, and the utility of cell mechanics as a marker to assess developmental neurotoxicity. Full article

During the last few decades, developmental pattern formation has evolved from being a descriptive discipline to a quantitative one. That process has been possible due to the implementation of multidisciplinary approaches where biophysicists and mathematicians have played a key role. In this review, we highlight relevant Spanish contributions and stress their biophysical approaches, as well as provide some historical context. Finally, this work also aimed at bridging the concepts from biology to physics/math (and back) and at shedding light on some directions for future research. Full article

Deep eutectic solvents (DESs) and ionic liquids (ILs) are highly tailorable solvents that have shown a lot of promise for a variety of applications including cryopreservation, drug delivery, and protein stabilisation. However, to date, there is very limited information on the detailed interactions of these solvents with mammalian cells. In this work, we studied six DESs and one IL that show promise as cryoprotective agents, applying synchrotron macro–ATR–FTIR to examine their effects on key biochemical components of HaCat mammalian cells. These data were paired with resazurin metabolic assays and neutron reflectivity experiments to correlate cellular interactions with cellular toxicity. Stark differences were observed even between solvents that shared similar components. In particular, it was found that solvents that are effective cryoprotective agents consistently showed interactions with cellular membranes, while high toxicity correlated with strong interactions of the DES/IL with nucleic acids and proteins. This work sheds new light on the interactions between novel solvents and cells that may underpin future biomedical applications. Full article

X-ray photoelectron emission spectra of thermally reduced graphene oxide samples and carbon nanotubes (CNTs) with various oxidation degrees are presented in this paper. A method for the reconstruction of differential electron inelastic scattering cross sections from the energy loss spectra of photoelectrons is described and discussed. The analysis of the part of the characteristic photoelectron energy loss spectrum adjacent to the C1 peak indicated a considerable influence of the thermal reduction of graphene oxide on the electron properties of the samples obtained. On the contrary, the oxidation of CNTs by refluxing in a concentrated HNO₃ solution does not change the free electron excitation spectrum. Full article