Effect of liraglutide on microcirculation in rat model with absolute insulin deficiency.

INTRODUCTION: The investigations of angiotropic effects of liraglutide are an issue of significant scientific and practical interest. The successful application of liraglutide has been shown in glycemic control in patients with the type 2 diabetes mellitus (DM), but the effect of liraglutide in patients with type 1 DM has not been completely studied yet in clinical practice. Therefore, the present study is aimed to investigate the effect of liraglutide which is agonist of glucagon-like peptide-1 receptors, on microcirculation in white outbred rats with the alloxan-induced diabetes. MATERIALS AND METHODS: The study was performed with 70 white outbred rats, divided into 4 groups: 1) control group (intact animals (Control)); 2) comparison group (diabetes mellitus (DM)) - animals with the alloxan-induced diabetes; 3) experimental group no. 1 (liraglutide low dose (LLD)) - animals with the alloxan-induced diabetes, which were injected by liraglutide at dosage of 0.2 mg/kg of animal weight per a day; 4) experimental group no. 2 (liraglutide high dose (LHD)) - animals with the alloxan-induced diabetes, which were injected by liraglutide at dosage of 0.4 mg/kg of animal weight per a day. The carbohydrate metabolism disorders, the microcirculation of posterior paw skin, as well as the concentration of catecholamines and markers of endothelial alteration in blood were estimated at the 42nd day of the experiment in the comparison and experimental groups. RESULTS: It was found that the correction of carbohydrate metabolism by liraglutide is succeeded by the normalization of skin perfusion of posterior paw skin of the experimental animals. Recovery of microcirculation is associated with a decrease in vascular tone and stimulation of endothelium-dependent vasodilation, caused by simultaneous decrease of catecholamines, endothelin-1 and asymmetric dimethylarginine (ADMA) concentrations in blood serum. At the same time, the administration of liraglutide on the background of insulin-deficiency results in decrease of endothelial cell alteration markers concentration in blood, such as sE-selectin, syndecan-1, and vascular endothelial growth factor (VEGF). CONCLUSION: Administration of liraglutide leads to the normalization of the carbohydrate metabolism simultaneously with the correction of microcirculation in rats with the absolute insulin deficiency. The demonstrated recovery of microcirculation by liraglutide, which represents an analogue of glucagon-like peptide-1, provides new prospects for its approval as a potential drug for pathogenetic correction of microcirculatory disorders in patients with the type 1 DM.

Current Principles, Challenges, and New Metrics in pH-Responsive Drug Delivery Systems for Systemic Cancer Therapy.

The paradigm of drug delivery via particulate formulations is one of the leading ideas that enable overcoming limitations of traditional chemotherapeutic agents. The trend toward more complex multifunctional drug carriers is well-traced in the literature. Nowadays, the prospectiveness of stimuli-responsive systems capable of controlled cargo release in the lesion nidus is widely accepted. Both endogenous and exogenous stimuli are employed for this purpose; however, endogenous pH is the most common trigger. Unfortunately, scientists encounter multiple challenges on the way to the implementation of this idea related to the vehicles' accumulation in off-target tissues, their immunogenicity, the complexity of drug delivery to intracellular targets, and finally, the difficulties in the fabrication of carriers matching all imposed requirements. Here, we discuss fundamental strategies for pH-responsive drug delivery, as well as limitations related to such carriers' application, and reveal the main problems, weaknesses, and reasons for poor clinical results. Moreover, we attempted to formulate the profiles of an "ideal" drug carrier in the frame of different strategies drawing on the example of metal-comprising materials and considered recently published studies through the lens of these profiles. We believe that this approach will facilitate the formulation of the main challenges facing researchers and the identification of the most promising trends in technology development.

Influence of the new formulation based on silver alginate microcapsules loaded with tannic acid on the microcirculation of the experimental periodontitis in rats.

The microvascular changes caused by disorders of host immune response to oral microorganisms resulting in long-lasting inflammation of gums play a critical role in the periodontal lesion in the pathogenesis of chronic periodontitis. Current strategies of non-surgical periodontal therapy are aimed at the attainment of anti-inflammatory effects. We hypothesized that the usage of the microencapsulated form of anti-inflammatory substances with vasoactive effects could enhance the efficiency of the therapy by the prolonged release of active components. The prepared suspension of silver-alginate microcapsules loaded with tannic acid in the hydrogel was applied in vivo to the experimental model of periodontitis in rats induced by a ligature. The effect of this formulation was assessed by monitoring changes in local microcirculation performed by the Laser Doppler Flowmetry (1 and 24 h after application of hydrogel on intact gums and 21-days after the start of periodontitis' modeling). Application of the hydrogel containing multicomponent microcapsules to the affected area of gums allows correction of inflammatory microcirculatory disorders in model periodontitis. Immobilization of tannic acid into microcapsules allows increasing the correction of the following parameters: perfusion disorders, neurogenic tone of arterioles, myogenic tone of precapillary sphincters, as well as a venous outflow in the microvasculature of the gums. The hydrogel containing multicomponent microcapsules reduces the vascular inflammatory response in the model of periodontitis. Loading of silver-alginate microcapsules with tannic acid enhances the efficiency of microvascular disorders' correction in the model of periodontitis that suggests the prospects for application of this drug delivery system for non-surgical treatment of periodontitis.

Osteogenic Capability of Vaterite-Coated Nonwoven Polycaprolactone Scaffolds for In Vivo Bone Tissue Regeneration.

In current orthopedic practice, bone implants used to-date often exhibit poor osteointegration, impaired osteogenesis, and, eventually, implant failure. Actively pursued strategies for tissue engineering could overcome these shortcomings by developing new hybrid materials with bioinspired structure and enhanced regenerative potential. In this study, the osteogenic and therapeutic potential of bioactive vaterite is investigated as a functional component of a fibrous polymeric scaffold for bone regeneration. Hybrid two-layered polycaprolactone scaffolds coated with vaterite (PCL/CaCO3 ) are studied during their 28-days implantation period in a rat femur defect. After this period, the study of tissue formation in the defected area is performed by the histological study of femur cross-sections. Immobilization of alkaline phosphatase (ALP) into PCL/CaCO3 scaffolds accelerates new bone tissue formation and defect repair. PCL/CaCO3 and PCL/CaCO3 /ALP scaffolds reveal 37.3% and 62.9% areas, respectively, filled with newly formed bone tissue in cross-sections compared to unmineralized PCL scaffold (17.5%). Bone turnover markers are monitored on the 7th and 28th days after implantation and reveal an increase of osteocalcin level for both PCL/CaCO3 and PCL/CaCO3 /ALP compared with PCL indicating the activation of osteogenesis. These findings indicate that vaterite, as an osteoconductive component of polymeric scaffolds, promotes osteogenesis, supports angiogenesis, and facilitates bone defect repair.

[The role of diabetes in the onset and development of endothelial dysfunction].

The vascular endothelium performs many functions. It is a key regulator of vascular homeostasis, maintains a balance between vasodilation and vasoconstriction, inhibition and stimulation of smooth muscle cell migration and proliferation, fibrinolysis and thrombosis, and is involved to regulation of platelet adhesion and aggregation. Endothelial dysfunction (ED) plays the critical role in pathogenesis of diabetes mellitus (DM) vascular complications. The purpose of this review was to consider the mechanisms leading to the occurrence of ED in DM. The paper discusses current literature data concerning the role of hyperglycemia, oxidative stress, advanced glycation end products in endothelial alteration. A separate section is devoted to the particularities of the functioning of the antioxidant system and their significance in the development of ED in DM. The analysis of the literature allows to conclude that pathological activation of glucose utilization pathways causes damage of endothelial cells, which is accompanied by disorders of all their basic functions. Metabolic disorders in DM cause a pronounced imbalance of free radical processes and antioxidant defense, accompanied by oxidative stress of endotheliocytes, which contributes to the progression of ED and the development of vascular complications. Many aspects of multicomponent regulatory reactions in the pathogenesis of the development of ED in DM have not been sufficiently studied.

Influence of the electrolyte's pH on the properties of electrochemically deposited hydroxyapatite coating on additively manufactured Ti64 alloy.

Properties of the hydroxyapatite obtained by electrochemical assisted deposition (ED) are dependent on several factors including deposition temperature, electrolyte pH and concentrations, applied potential. All of these factors directly influence the morphology, stoichiometry, crystallinity, electrochemical behaviour, and particularly the coating thickness. Coating structure together with surface micro- and nano-scale topography significantly influence early stages of the implant bio-integration. The aim of this study is to analyse the effect of pH modification on the morphology, corrosion behaviour and in vitro bioactivity and in vivo biocompatibility of hydroxyapatite prepared by ED on the additively manufactured Ti64 samples. The coatings prepared in the electrolytes with pH = 6 have predominantly needle like morphology with the dimensions in the nanometric scale (~30 nm). Samples coated at pH = 6 demonstrated higher protection efficiency against the corrosive attack as compared to the ones coated at pH = 5 (~93% against 89%). The in vitro bioactivity results indicated that both coatings have a greater capacity of biomineralization, compared to the uncoated Ti64. Somehow, the coating deposited at pH = 6 exhibited good corrosion behaviour and high biomineralization ability. In vivo subcutaneous implantation of the coated samples into the white rats for up to 21 days with following histological studies showed no serious inflammatory process.

A whole-cell amperometric herbicide biosensor based on magnetically functionalised microalgae and screen-printed electrodes.

We report the fabrication of an amperometric whole-cell herbicide biosensor based on magnetic retention of living cells functionalised with magnetic nanoparticles (MNPs) on the surface of a screen-printed electrode. We demonstrate that Chlorella pyrenoidosa microalgae cells coated with biocompatible MNPs and retained on the electrode with a permanent magnet act as a sensing element for the fast detection of herbicides. The magnetic functionalisation does not affect the viability and photosynthesis activity-mediated triazine herbicide recognition in microalgae. The current of ferricyanide ion was recorded during alternating illumination periods and biosensor fabricated was used to detect atrazine (from 0.9 to 74 µM) and propazine (from 0.6 to 120 µM) (the limits of detection 0.7 and 0.4 µM, respectively). We believe that the methodology presented here can be widely used in fabrication of a number of whole cell biosensors since it allows for efficient and reversible cells immobilisation and does not affect the cellular metabolism.