The Determination of the Biocompatibility of New Compositional Materials, including Carbamide-Containing Heterocycles of Anti-Adhesion Agents for Abdominal Surgery.

Due to traumatic injuries, including those from surgical procedures, adhesions occur in over 50% of cases, necessitating exclusive surgical intervention for treatment. However, preventive measures can be implemented during abdominal organ surgeries. These measures involve creating a barrier around internal organs to forestall adhesion formation in the postoperative phase. Yet, the effectiveness of the artificial barrier relies on considerations of its biocompatibility and the avoidance of adverse effects on the body. This study explores the biocompatibility aspects, encompassing hemocompatibility, cytotoxicity, and antibacterial and antioxidant activities, as well as the adhesion of blood serum proteins and macrophages to the surface of new composite film materials. The materials, derived from the sodium salt of carboxymethylcellulose modified by glycoluril and allantoin, were investigated. The research reveals that film materials with a heterocyclic fragment exhibit biocompatibility comparable to commercially used samples in surgery. Notably, film samples developed with glycoluril outperform the effects of commercial samples in certain aspects.

Coal-Derived Humic Substances: Insight into Chemical Structure Parameters and Biomedical Properties.

An investigation was carried out on humic substances (HSs) isolated from the coal of the Kansk-Achinsk basin (Krasnoyarsk Territory, Russia). The coal HSs demonstrate the main parameters of molecular structure inherent to this class of natural compounds. An assessment was performed for the chemical, microbiological, and pharmacological safety parameters, as well as the biological efficacy. The HS sample meets the safety requirements in microbiological purity, toxic metals content (lead, cadmium, mercury, arsenic), and radionuclides. The presence of 11 essential elements was determined. The absence of general, systemic toxicity, cytotoxicity, and allergenic properties was demonstrated. The coal HS sample was classified as a Class V hazard (low danger substances). High antioxidant and antiradical activities and immunotropic and cytoprotective properties were identified. The ability of the HS to inhibit hydroxyl radicals and superoxide anion radicals was revealed. Pronounced actoprotective and nootropic activities were also demonstrated in vivo. Intragastric administration of the HS sample resulted in the improvement of physical parameters in mice as assessed by the "swim exhaustion" test. Furthermore, intragastric administration in mice with cholinergic dysfunction led to a higher ability of animals with scopolamine-induced amnesia to form conditioned reflexes. These findings suggest that the studied HS sample is a safe and effective natural substance, making it suitable for use as a dietary bioactive supplement.

pH-triggered delivery of magnetic nanoparticles depends on tumor volume.

Nowadays there is growing recognition of the fact that biological systems have a greater impact on nanoparticle target delivery in tumors than nanoparticle design. Here we investigate the targeted delivery of Fe3O4 magnetic nanoparticles conjugated with pH-low-insertion peptide (MNP-pHLIP) on orthotopically induced MDA-MB-231 human breast carcinoma xenografts of varying volumes as a model of cancer progression. Using in vivo magnetic resonance imaging and subsequent determination of iron content in tumor samples by inductively coupled plasma atomic emission spectroscopy we found that MNP-pHLIP accumulation depends on tumor volume. Transmission electron microscopy, histological analysis and immunohistochemical staining of tumor samples suggest that blood vessel distribution is the key factor in determining the success of the accumulation of nanoparticles in tumors.

A Novel Series of [1,2,4]Triazolo[4,3-a]Pyridine Sulfonamides as Potential Antimalarial Agents: In Silico Studies, Synthesis and In Vitro Evaluation.

For the development of new and potent antimalarial drugs, we designed the virtual library with three points of randomization of novel [1,2,4]triazolo[4,3-a]pyridines bearing a sulfonamide fragment. The library of 1561 compounds has been investigated by both virtual screening and molecular docking methods using falcipain-2 as a target enzyme. 25 chosen hits were synthesized and evaluated for their antimalarial activity in vitro against Plasmodium falciparum. 3-Ethyl-N-(3-fluorobenzyl)-N-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-6-sulfonamide and 2-(3-chlorobenzyl)-8-(piperidin-1-ylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one showed in vitro good antimalarial activity with inhibitory concentration IC50 = 2.24 and 4.98 µM, respectively. This new series of compounds may serve as a starting point for future antimalarial drug discovery programs.

Methylation of Methyl 4-Hydroxy-2-thioxo-1,2-dihydroquinoline-3-carboxylate: Synthetic, Crystallographic, and Molecular Docking Studies.

Consecutive alkylation of 4-hydroxy-2-thioxo-1,2-dihydroquinoline-3-carboxylate by CH3I has been investigated to establish regioselectivity of the reaction for reliable design and synthesis of combinatorial libraries. In the first stage, the product of S-methylation-methyl 4-hydroxy-2-(methylthio)quinoline-3-carboxylate was obtained. The subsequent alkylation with CH3I led to the formation of both O- and N-methylation products mixture-methyl 4-methoxy-2-(methylthio)quinoline-3-carboxylate and methyl 1-methyl-2-(methylthio)-4-oxo-1,4-dihydroquinoline-3-carboxylate with a predominance of O-methylated product. The structure of synthesized compounds was confirmed by means of elemental analysis, 1H-NMR, 13C-NMR, LC/MS, and single-crystal X-ray diffraction. The quantum chemical calculations of geometry and electron structure of methyl 4-hydroxy-2-(methylthio)quinoline-3-carboxylate's anion were carried out. According to molecular docking simulations, the studied compounds can be considered as potent inhibitors of Hepatitis B Virus replication. Experimental in vitro biological studies confirmed that studied compounds demonstrated high inhibition of HBV replication in 10 µM concentration.

Effect of alpha-lactalbumin and lactoferrin oleic acid complexes on chromatin structural organization.

This work focuses on the study of multimeric alpha-lactalbumin oleic acid and lactoferrin oleic acid complexes. The purpose of the research is to study possible mechanisms involved in their pro-apoptotic activities, as seen in some tumor cell cultures. Complexes featuring oleic acid (OA) with human alpha-lactalbumin (hAl) or with bovine alpha-lactalbumin (bAl), and human lactoferrin (hLf) were investigated using small-angle neutron scattering (SANS). It was shown that while alpha-lactalbumin protein complexes were formed on the surface of polydisperse OA micelles, the lactoferrin complexes comprised a monodisperse system of nanoscale particles. Both hAl and hLf complexes appeared to interact with the chromatin of isolated nuclei affecting chromatin structural organization. The possible roles of these processes in the specific anti-tumor activity of these complexes are discussed.

Impact of cold adaptation on cardiac tolerance to ischemia/reperfusion and glucocorticoid, thyroid hormone levels.

We have established that the continuous cold exposure (CCE, 4°C, 4 weeks) causes cold adaptation, increases systolic blood pressure, exerts infarct-limiting effect during coronary artery occlusion (45 min) and reperfusion (2 h). The CCE increases adrenal weight, heart weight and triiodothyronine (T3) level but does not change thymus, spleen weight, serum cortisol, corticosterone and thyroxin (T4) levels. The long-term (4°C, 8 h/day, 4 weeks) intermittent cold exposure (LICE) induces adaptation to the cold and increases T4 level. The brief (4°C, 1.5 h/day, 4 weeks) intermittent cold exposure (BICE) also evokes adaptation to the cold but had no effect on the blood pressure, the cardiac tolerance to ischemia/reperfusion, and does not change thymus, spleen weight, serum cortisol, corticosterone, T3 and T4 levels.

PMIDA-Modified Fe3O4 Magnetic Nanoparticles: Synthesis and Application for Liver MRI.

The surface modification of Fe3O4-based magnetic nanoparticles (MNPs) with N-(phosphonomethyl)iminodiacetic acid (PMIDA) was studied, and the possibility of their use as magnetic resonance imaging contrast agents was shown. The effect of the added PMIDA amount, the reaction temperature and time on the degree of immobilization of this reagent on MNPs, and the hydrodynamic characteristics of their aqueous colloidal solutions have been systematically investigated for the first time. It has been shown that the optimum condition for the modification of MNPs is the reaction at 40 °C with an equimolar amount of PMIDA for 3.5 h. The modified MNPs were characterized by X-ray diffraction, transmission electron microscopy, Fourier transform infrared spectroscopy, thermogravimetric, and CHN elemental analyses. The dependence of the hydrodynamic characteristics of the MNP colloidal solutions on the concentration and pH of the medium was studied by the dynamic light scattering method. On the basis of the obtained data, we can assume that the PMIDA molecules are fixed on the surface of the MNPs as a monomolecular layer. The modified MNPs had good colloidal stability and high magnetic properties. The calculated relaxivities r2 and r1 were 341 and 102 mmol-1 s-1, respectively. The possibility of using colloidal solutions of PMIDA-modified MNPs as a T2 contrast agent for liver studies in vivo (at a dose of 0.6 mg kg-1) was demonstrated for the first time.

Size-Dependent Ability of Liposomes to Accumulate in the Ischemic Myocardium and Protect the Heart.

Liposomes have the potential to be used for drug delivery. Meanwhile, liposome size may affect their accumulation in the target tissue. We investigated the myocardial accumulation of 2 populations of liposomes (∼70 and 110 nm diameter) during ischemia and their effect on ischemia/reperfusion injury. Isolated rat hearts were subjected to 30 minutes of low-flow ischemia with the liposomes, followed by 30 minutes of liposome-free reperfusion. The liposomes were loaded with the fluorescent dye Nile Red to assess their accumulation in the myocardium. The cardiac functional recovery during reperfusion was evaluated using force-velocity characteristics and coronary flow (CF). Reperfusion injury was evaluated by lactate dehydrogenase release. In addition, CF and contractility were assessed in hearts perfused normally with 70 nm liposomes. There was a 6- and 4-fold greater accumulation of the small liposomes in the myocardium and mitochondria, respectively, compared with the large liposomes. Importantly, even without any incorporated drugs, both populations of liposomes improved functional recovery and reduced lactate dehydrogenase release. However, the smaller liposomes showed significantly higher protective and vasodilatory effects during reperfusion than the larger particles. These liposomes also increased CF and contractility during normal perfusion. We suggest that the protective properties of the liposomes could be related to their membrane-stabilizing effect.

Partially Assembled Nucleosome Structures at Atomic Detail.

The evidence is now overwhelming that partially assembled nucleosome states (PANS) are as important as the canonical nucleosome structure for the understanding of how accessibility to genomic DNA is regulated in cells. We use a combination of molecular dynamics simulation and atomic force microscopy to deliver, in atomic detail, structural models of three key PANS: the hexasome (H2A·H2B)·(H3·H4)2, the tetrasome (H3·H4)2, and the disome (H3·H4). Despite fluctuations of the conformation of the free DNA in these structures, regions of protected DNA in close contact with the histone core remain stable, thus establishing the basis for the understanding of the role of PANS in DNA accessibility regulation. On average, the length of protected DNA in each structure is roughly 18 basepairs per histone protein. Atomistically detailed PANS are used to explain experimental observations; specifically, we discuss interpretation of atomic force microscopy, Förster resonance energy transfer, and small-angle x-ray scattering data obtained under conditions when PANS are expected to exist. Further, we suggest an alternative interpretation of a recent genome-wide study of DNA protection in active chromatin of fruit fly, leading to a conclusion that the three PANS are present in actively transcribing regions in a substantial amount. The presence of PANS may not only be a consequence, but also a prerequisite for fast transcription in vivo.

Discontinuities-free complete-active-space state-specific multi-reference coupled cluster theory for describing bond stretching and dissociation.

The earlier proposed multi-reference state-specific coupled-cluster theory with the complete active space reference [CASCC; Lyakh et al., J. Chem. Phys. 122, 024108 (2005)] suffered from a problem of energy discontinuities when the formal reference state was changing in the calculation of the potential energy curve (PEC). A simple remedy to the discontinuity problem is found and is presented in this work. It involves using natural complete active space self-consistent field active orbitals in the complete active space coupled-cluster calculations. The approach gives smooth PECs for different types of dissociation problems, as illustrated in the calculations of the dissociation of the single bond in the hydrogen fluorine molecule and of the symmetric double-bond dissociation in the water molecule.

Prevention of Metastasis by Suppression of Stemness Genes Using a Combination of microRNAs.

We propose an original strategy for metastasis prevention using a combination of three microRNAs that blocks the dedifferentiation of cancer cells in a metastatic niche owing to the downregulation of stemness genes. Transcriptome microarray analysis was applied to identify the effects of a mixture of microRNAs on the pattern of differentially expressed genes in human breast cancer cell lines. Treatment of differentiated CD44- cancer cells with the microRNA mixture inhibited their ability to form mammospheres in vitro. The combination of these three microRNAs encapsulated into lipid nanoparticles prevented lung metastasis in a mouse model of spontaneous metastasis. The mixture of three microRNAs (miR-195-5p/miR-520a/miR-630) holds promise for the development of an antimetastatic therapeutic that blocks tumor cell dedifferentiation, which occurs at secondary tumor sites and determines the transition of micrometastases to macrometastases.

Development of a Potent and Selective G2A (GPR132) Agonist.

G protein-coupled receptor G2A was postulated to be a promising target for the development of new therapeutics in neuropathic pain, acute myeloid leukemia, and inflammation. However, there is still a lack of potent, selective, and drug-like G2A agonists to be used as a chemical tool or as the starting matter for the development of drugs. In this work, we present the discovery and structure-activity relationship elucidation of a new potent and selective G2A agonist scaffold. Systematic optimization resulted in (3-(pyridin-3-ylmethoxy)benzoyl)-d-phenylalanine (T-10418) exhibiting higher potency than the reference and natural ligand 9-HODE and high selectivity among G protein-coupled receptors. With its favorable activity, a clean selectivity profile, excellent solubility, and high metabolic stability, T-10418 qualifies as a pharmacological tool to investigate the effects of G2A activation.

Synthesis, analysis of mol-ecular and crystal structures, estimation of inter-molecular inter-actions and biological properties of 1-benzyl-6-fluoro-3-[5-(4-methylcyclohexyl)-1,2,4-oxadiazol-3-yl]-7-(piperidin-1-yl)quinolin-4-one.

The title compound, C30H33N4O2F, can be obtained via a two-step synthetic scheme involving 1-benzyl-6-fluoro-4-oxo-7-(piperidin-1-yl)-1,4-di-hydro-quino-line-3-carbo-nitrile as a starting compound that undergoes substitution with hydroxyl-amine and subsequent cyclization with 4-methyl-cyclo-hexane-1-carb-oxy-lic acid. It crystallizes from 2-propanol in the triclinic space group P with a mol-ecule of the title compound and one of 2-propanol in the asymmetric unit. After the mol-ecular structure was clarified using NMR and LC/MS, the mol-ecular and crystalline arrangements were defined with SC-XRD. A Hirshfeld surface analysis was performed for a better understanding of the inter-molecular inter-actions. One strong (O-H⋯O) and three weak [C-H⋯F (intra-molecular) and two C-H⋯O] hydrogen bonds were found. The contributions of short contacts to the Hirshfeld surface were estimated using two-dimensional fingerprint plots showing that O⋯H/H⋯O, C⋯H/H⋯C and C⋯C contacts are the most significant for the title compound and O⋯H for the 2-propanol. The crystal structure appears to have isotropically packed tetra-mers containing two mol-ecules of the title compound and two mol-ecules of 2-propanol as the building unit according to analysis of the distribution of pairwise inter-action energies. A mol-ecular docking study was carried out to evaluate the inter-actions of the title compound with the active centers of macromolecules corresponding to viral targets, namely, anti-hepatitis B activity [HBV, capsid Y132A mutant (VCID 8772) PDB ID: 5E0I] and anti-COVID-19 main protease activity (PDB ID: 6LU7). The data obtained revealed a noticeable affinity towards them that exceeded that of the reference ligands.

Enhanced Antioxidant Activity and Reduced Cytotoxicity of Silver Nanoparticles Stabilized by Different Humic Materials.

The current article describes the biological activity of new biomaterials combining the "green" properties of humic substances (HSs) and silver nanoparticles. The aim is to investigate the antioxidant activity (AOA) of HS matrices (macroligands) and AgNPs stabilized with humic macroligands (HS-AgNPs). The unique chemical feature of HSs makes them very promising ligands (matrices) for AgNP stabilization. HSs have previously been shown to exert many pharmacological effects mediated by their AOA. AgNPs stabilized with HS showed a pronounced ability to bind to reactive oxygen species (ROS) in the test with ABTS. Also, higher AOA was observed for HS-AgNPs as compared to the HS matrices. In vitro cytotoxicity studies have shown that the stabilization of AgNPs with the HS matrices reduces the cytotoxicity of AgNPs. As a result of in vitro experiments with the use of 2,7-dichlorodihydrofluorescein diacetate (DCFDA), it was found that all HS materials tested and the HS-AgNPs did not exhibit prooxidant effects. Moreover, more pronounced AOA was shown for HS-AgNP samples as compared to the original HS matrices. Two putative mechanisms of the pronounced AOA of the tested compositions are proposed: firstly, the pronounced ability of HSs to inactivate ROS and, secondly, the large surface area and surface-to-volume ratio of HS-AgNPs, which facilitate electron transfer and mitigate kinetic barriers to the reduction reaction. As a result, the antioxidant properties of the tested HS-AgNPs might be of particular interest for biomedical applications aimed at inhibiting the growth of bacteria and viruses and the healing of purulent wounds.

Biosynthesis of Functional Silver Nanoparticles Using Callus and Hairy Root Cultures of Aristolochia manshuriensis.

This study delves into the novel utilization of Aristolochia manshuriensis cultured cells for extracellular silver nanoparticles (AgNPs) synthesis without the need for additional substances. The presence of elemental silver has been verified using energy-dispersive X-ray spectroscopy, while distinct surface plasmon resonance peaks were revealed by UV-Vis spectra. Transmission and scanning electron microscopy indicated that the AgNPs, ranging in size from 10 to 40 nm, exhibited a spherical morphology. Fourier-transform infrared analysis validated the abilty of A. manshuriensis extract components to serve as both reducing and capping agents for metal ions. In the context of cytotoxicity on embryonic fibroblast (NIH 3T3) and mouse neuroblastoma (N2A) cells, AgNPs demonstrated varying effects. Specifically, nanoparticles derived from callus cultures exhibited an IC50 of 2.8 µg/mL, effectively inhibiting N2A growth, whereas AgNPs sourced from hairy roots only achieved this only at concentrations of 50 µg/mL and above. Notably, all studied AgNPs' treatment-induced cytotoxicity in fibroblast cells, yielding IC50 values ranging from 7.2 to 36.3 µg/mL. Furthermore, the findings unveiled the efficacy of the synthesized AgNPs against pathogenic microorganisms impacting both plants and animals, including Agrobacterium rhizogenes, A. tumefaciens, Bacillus subtilis, and Escherichia coli. These findings underscore the effectiveness of biotechnological methodologies in offering advanced and enhanced green nanotechnology alternatives for generating nanoparticles with applications in combating cancer and infectious disorders.

Metabolic Homeostasis in Chronic Helminth Infection Is Sustained by Organ-Specific Metabolic Rewiring.

Opisthorchiasis, is a hepatobiliary disease caused by flukes of the trematode family Opisthorchiidae. A chronic form of the disease implies a prolonged coexistence of a host and the parasite. The pathological changes inflicted by the worm to the host's hepatobiliary system are well documented. Yet, the response to the infection also triggers a deep remodeling of the host systemic metabolism reaching a new homeostasis and affecting the organs beyond the worm location. Understanding the metabolic alternation in chronic opisthorchiasis, could help us to pinpoint pathways that underlie infection opening possibilities for the development of more selective treatment strategies. Here, with this report we apply an integrative, multicompartment metabolomics analysis, using multiple biofluids, stool samples and tissue extracts to describe metabolic changes in Opisthorchis felineus infected animals at the chronic stage. We show that the shift in lipid metabolism in the serum, a depletion of the amino acids pool, an alteration of the ketogenic pathways in the jejunum and a suppressed metabolic activity of the spleen are the key features of the metabolic host adaptation at the chronic stage of O. felineus infection. We describe this combination of the metabolic changes as a "metabolically mediated immunosuppressive status of organism" which develops during a chronic infection. This status in combination with other factors (e.g., parasite-derived immunomodulators) might increase risk of infection-related malignancy.

Crystal structure, Hirshfeld analysis and a mol-ecular docking study of a new inhibitor of the Hepatitis B virus (HBV): ethyl 5-methyl-1,1-dioxo-2-{[5-(pentan-3-yl)-1,2,4-oxa-diazol-3-yl]meth-yl}-2H-1,2,6-thia-diazine-4-carboxyl-ate.

The title compound, C15H22N4O5S, was prepared via alkyl-ation of 3-(chloro-meth-yl)-5-(pentan-3-yl)-1,2,4-oxa-diazole in anhydrous dioxane in the presence of tri-ethyl-amine. The thia-diazine ring has an envelope conformation with the S atom displaced by 0.4883 (6) Šfrom the mean plane through the other five atoms. The planar 1,2,4-oxa-diazole ring is inclined to the mean plane of the thia-diazine ring by 77.45 (11)°. In the crystal, mol-ecules are linked by C-H⋯N hydrogen bonds, forming chains propagating along the b-axis direction. Hirshfeld surface analysis and two-dimensional fingerprint plots have been used to analyse the inter-molecular contacts present in the crystal. Mol-ecular docking studies were use to evaluate the title compound as a potential system that inter-acts effectively with the capsid of the Hepatitis B virus (HBV), supported by an experimental in vitro HBV replication model.

Plasma metabolomics of the time resolved response to Opisthorchis felineus infection in an animal model (golden hamster, Mesocricetus auratus).

BACKGROUND: Opisthorchiasis is a hepatobiliary disease caused by flukes of the trematode family Opisthorchiidae. Opisthorchiasis can lead to severe hepatobiliary morbidity and is classified as a carcinogenic agent. Here we investigate the time-resolved metabolic response to Opisthorchis felineus infection in an animal model. METHODOLOGY: Thirty golden hamsters were divided in three groups: severe infection (50 metacercariae/hamster), mild infection (15 metacercariae/hamster) and uninfected (vehicle-PBS) groups. Each group consisted of equal number of male and female animals. Plasma samples were collected one day before the infection and then every two weeks up to week 22 after infection. The samples were subjected to 1H Nuclear Magnetic Resonance (NMR) spectroscopy and multivariate statistical modelling. PRINCIPAL FINDINGS: The time-resolved study of the metabolic response to Opisthorchis infection in plasma in the main lines agrees with our previous report on urine data. The response reaches its peak around the 4th week of infection and stabilizes after the 10th week. Yet, unlike the urinary data there is no strong effect of the gender in the data and the intensity of infection is presented in the first two principal components of the PCA model. The main trends of the metabolic response to the infection in blood plasma are the transient depletion of essential amino acids and an increase in lipoprotein and cholesterol concentrations. CONCLUSIONS: The time resolved metabolic signature of Opisthorchis infection in the hamster's plasma shows a coherent shift in amino acids and lipid metabolism. Our work provides insight into the metabolic basis of the host response on the helminth infection.

Is oxidative stress of adipocytes a cause or a consequence of the metabolic syndrome?

Metabolic syndrome is accompanied by oxidative stress in animals and humans. The main source of ROS in experimental metabolic syndrome is NADPH oxidase and possibly adipocyte mitochondria. It is now documented that oxidative stress induces insulin resistance of adipocytes and increases secretion of leptin, MCP-1, IL-6, and TNF-α by adipocytes. It was established that oxidative stress induces a decrease in adiponectin production by adipocytes. It has also been shown that obesity itself can induce oxidative stress. Oxidative stress can cause an alteration of intracellular signaling in adipocytes that apparently leads to the formation of insulin resistance of adipocytes. Chronic stress, glucocorticoids, mineralocorticoids, angiotensin-II, TNF-α also play an important role in the pathogenesis of oxidative stress of adipocytes. Oxidative stress is not only a consequence of metabolic syndrome, but also a reason and a foundational link in the pathogenesis of the metabolic syndrome.