Unraveling the Mechanism of Platelet Aggregation Suppression by Thioterpenoids: Molecular Docking and In Vivo Antiaggregant Activity.

Natural monoterpenes and their derivatives are widely considered the effective ingredients for the design and production of novel biologically active compounds. In this study, by using the molecular docking technique, we examined the effects of two series of "sulfide-sulfoxide-sulfone" thioterpenoids containing different (e.g., bornane and pinane) monoterpene skeletons on the platelet's aggregation. Our data revealed that all the synthesized compounds exhibit inhibitory activities on platelet aggregation. For example, compound 1 effectively inhibited platelet activation and demonstrated direct binding with CD61 integrin, a well-known platelet GPIIb-IIIa receptor on platelets. We further examined the antiaggregant activity of the most active compound, 1, in vivo and compared its activity with that of acetylsalicylic acid and an oral GPIIb-IIIa blocker, orbofiban. We found that compound 1 demonstrates antiaggregant activity in rats when administered per os and its activity was comparable with that of acetylsalicylic acid and orbofiban. Moreover, similarly, tirofiban, a well-known GPIIb-IIIa blocker, compound 1, effectively decreased the expression of P-selectin to the values similar to those of the intact platelets. Collectively, here, we show, for the first time, the potent antiaggregant activity of compound 1 both in vitro and in vivo due to its ability to bind with the GPIIb-IIIa receptor on platelets.

The off-label use of drugs for parenteral nutrition as a solvent of substances slightly soluble in water in pharmacological research.

Because of the problem to evaluate biological activity in water-soluble substances in all phases of preclinical and clinical studies, the research work enabled to develop the original solvent for poorly soluble compounds based on substances for parenteral nutrition. The main aim is to examine the impact of the original solvent based on substances for parenteral nutrition on biological systems exemplified by the hemostatic system, characterized by sensitivity and variability of the effects in response to any impact, and its comparison with the solvents that are conventional in pharmacological research. Experimental work is performed according to the "guidance on preclinical research of new pharmacological substances" in vitro. The findings show that traditional solvents at low dosages affect all the researched indicators of the hemostasis system. The smallest effect in respect of the hemostatic system was characterized by ethanol, and the most apparent antiaggregational effect was registered with dioxane. 10% concentration of original blend of lipids made no effect on hemostasis system. Thus, according to their own findings and experience in application of lipid emulsions as substances of parenteral nutrition, they can be considered to be an adequate solvent in all phases of preclinical and clinical studies of new drugs.

Cytokine Profile of Patients with Allergic Rhinitis Caused by Pollen, Mite, and Microbial Allergen Sensitization.

Allergic rhinitis (AR) is especially prevalent among the population of large cities. Immunologically, the airway epithelium is a region where the population of allergen-presenting cells concentrates. These cells actively express a group of receptors of the innate immune system. A specific cytokine profile is its representation. The study was aimed at evaluating the cytokine profile in patients with seasonal and perennial allergic rhinitis. The cytokine profile of nasal secretion and blood serum of 44 patients with AR was studied. 24 of them had seasonal allergic rhinitis (SAR), and 20 patients suffered from perennial allergic rhinitis (PAR). The patients' age ranged from 4 to 60 years. It was determined in our study that the activation of the GM-CSF production retained in patients with PAR sensitized to mite allergen components (Dermatophagoides pteronyssinus). There was a higher production profile of TNF-α and TSLP in nasal secretion in the patients with perennial allergic rhinitis and additional high sensitization to SEs. Sensitization to mold fungal allergen components significantly increases in patients with seasonal allergic rhinitis. They demonstrated high level of sensitization to the Aspergillus fumigatus component m3. Thus, along with other clinical trials, the study performed would clarify some aspects of molecular pathogenesis of human allergic rhinitis.

Fibrosis biomarkers in workers exposed to MWCNTs.

Multi-walled carbon nanotubes (MWCNT) with their unique physico-chemical properties offer numerous technological advantages and are projected to drive the next generation of manufacturing growth. As MWCNT have already found utility in different industries including construction, engineering, energy production, space exploration and biomedicine, large quantities of MWCNT may reach the environment and inadvertently lead to human exposure. This necessitates the urgent assessment of their potential health effects in humans. The current study was carried out at NanotechCenter Ltd. Enterprise (Tambov, Russia) where large-scale manufacturing of MWCNT along with relatively high occupational exposure levels was reported. The goal of this small cross-sectional study was to evaluate potential biomarkers during occupational exposure to MWCNT. All air samples were collected at the workplaces from both specific areas and personal breathing zones using filter-based devices to quantitate elemental carbon and perform particle analysis by TEM. Biological fluids of nasal lavage, induced sputum and blood serum were obtained from MWCNT-exposed and non-exposed workers for assessment of inflammatory and fibrotic markers. It was found that exposure to MWCNTs caused significant increase in IL-1ß, IL6, TNF-α, inflammatory cytokines and KL-6, a serological biomarker for interstitial lung disease in collected sputum samples. Moreover, the level of TGF-ß1 was increased in serum obtained from young exposed workers. Overall, the results from this study revealed accumulation of inflammatory and fibrotic biomarkers in biofluids of workers manufacturing MWCNTs. Therefore, the biomarkers analyzed should be considered for the assessment of health effects of occupational exposure to MWCNT in cross-sectional epidemiological studies.

Circulating Microparticles Alter Formation, Structure, and Properties of Fibrin Clots.

Despite the importance of circulating microparticles in haemostasis and thrombosis, there is limited evidence for potential causative effects of naturally produced cell-derived microparticles on fibrin clot formation and its properties. We studied the significance of blood microparticles for fibrin formation, structure, and susceptibility to fibrinolysis by removing them from platelet-free plasma using filtration. Clots made in platelet-free and microparticle-depleted plasma samples from the same healthy donors were analyzed in parallel. Microparticles accelerate fibrin polymerisation and support formation of more compact clots that resist internal and external fibrinolysis. These variations correlate with faster thrombin generation, suggesting thrombin-mediated kinetic effects of microparticles on fibrin formation, structure, and properties. In addition, clots formed in the presence of microparticles, unlike clots from the microparticle-depleted plasma, contain 0.1-0.5-µm size granular and CD61-positive material on fibres, suggesting that platelet-derived microparticles attach to fibrin. Therefore, the blood of healthy individuals contains functional microparticles at the levels that have a procoagulant potential. They affect the structure and stability of fibrin clots indirectly through acceleration of thrombin generation and through direct physical incorporation into the fibrin network. Both mechanisms underlie a potential role of microparticles in haemostasis and thrombosis as modulators of fibrin formation, structure, and resistance to fibrinolysis.