Molecular mechanisms of complications development of nephrolithiasis associated with diabetes type 2

BACKGROUND. Until recently there is no understanding of the clinical features and the reasons for the progression of complications of diabetes-associated nephrolithiasis (NLT) which limits the development of effective treatment for patients with this kidney pathology.THE AIM was to investigate the molecular mechanisms of hematuria and leukocyturia in the comorbidity of nephrolithiasis with type 2 diabetes. PATIENTS AND METHODS. The study analyzed the clinical, instrumental, and laboratory data of 196 patients with NLT; the study included 48 (24.5 %) patients with comorbidity of NLT with type 2 diabetes. All patients at the stage of hospitalization underwent a comprehensive clinical and laboratory examination according to the traditional scheme adopted for the diagnosis of NLT. ATP, PAF, and collagen (Sigma) agonists at EC50 concentrations causing aggregation at the 50 % level in healthy individuals were used to analyze the functional activity of platelet (PLT) receptors. PLT aggregation was assessed by the turbidimetric method using a ChronoLog analyzer (USA). RESULTS. Microhematuria occurred in 27 (56.2 %) patients and gross hematuria in 21 (43.8 %) patients out of 48 patients with type 2 diabetes-associated NLT. Microscopy of urine in patients with comorbidity of NLT revealed a greater number of erythrocytes (P = 0.014); gross hematuria (P = 0.034) and leukocyturia (р=0,003) were more common in this cohort of patients. NLT complications occurred against the background of increased reactivity of P2X receptors, PAF receptor, and GPVI receptor (p <0.001) of PLT compared with that in patients with NLT without DM. The progression of leukocyturia was accompanied by increased severity of hematuria and was manifested by increased activity of GPVI receptors (p <0.001). CONCLUSION. The influence of diabetes on the pathogenesis of NLT complications is associated with increased ischemia of kidney tissue, systemic inflammatory response, and vascular wall remodeling. The activity of P2X, PAF, and GPVI platelet receptors could be considered as a system of potential biomarkers and prognostic factors of complications in the comorbidity of NLT with type 2 diabetes.

New Insights Into the Pathologic Roles of the Platelet-Activating Factor System

Described almost 50 years ago, the glycerophosphocholine lipid mediator Platelet-activating factor (PAF) has been implicated in many pathologic processes. Indeed, elevated levels of PAF can be measured in response to almost every type of pathology involving inflammation and cell damage/death. In this review, we provide evidence for PAF involvement in pathologic processes, with focus on cancer, the nervous system, and in photobiology. Importantly, recent insights into how PAF can generate and travel via bioactive extracellular vesicles such as microvesicle particles (MVP) are presented. What appears to be emerging from diverse pathologies in different organ systems is a common theme where pro-oxidative stressors generate oxidized glycerophosphocholines with PAF agonistic effects, which then trigger more enzymatic PAF synthesis via the PAF receptor. A downstream consequence of PAF receptor activation is the generation and release of MVP which provide a mechanism to transmit PAF as well as other bioactive agents. The knowledge gaps which when addressed could result in novel therapeutic strategies are also discussed. Taken together, an enhanced understanding of the PAF family of lipid mediators is essential in our improved comprehension of the relationship amongst the diverse cutaneous, cancerous, neurologic and systemic pathologic processes.

Rupatadine – a panacea for allergies? A literature review

Allergic diseases are one of the most common chronic diseases. The incidence of allergies is constantly increasing, and it is currently estimated that around 40% of the population suffers from at least one allergy. Current guidelines for the treatment of allergic rhinoconjunctivitis and urticaria recommend modern second-generation antihistamines. Rupatadine is the first hybrid molecule with high affinity for the H1 receptor resulting from remarkably strong binding to this receptor. It exhibits significant H1 receptor binding selectivity, greater in the lungs than in the cerebellum. It has antihistamine effect that is about 25 and 75 times stronger than that of cetirizine and loratadine, respectively. The second mechanism of its action is a strong antagonism of the platelet-activating factor (PAF) receptor. Rupatadine is rapidly absorbed, which correlates with the onset of anti-H1 and anti-PAF activity. Rupatadine is approximately 99% bound to plasma proteins, but at the same time it is very well distributed to other tissues. It undergoes metabolism in the liver through oxidative processes and glucuronide conjugation. Many studies indicate that rupatadine (10 mg) was at least as effective as desloratadine, cetirizine, loratadine and ebastine in reducing allergic symptoms in allergic rhinitis and urticaria. It has also been confirmed to be effective in relieving the symptoms of insect bite response. Rupatadine has a positive effect on the daily functioning of patients with allergic rhinitis and urticaria, and improves the quality of life of these people. At the same time, many cross-sectional studies have shown that rupatadine has a good safety and tolerability profile in adults and children and has not shown adverse cardiovascular effects.

Chemical Constituents and Biological Activities of Mitrella Kentii (Blume) Miq. Leaf Oil

Chemical constituents and biological activities of the Mitrella kentii leaf oil were investigated in this study. Gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS) were used to determine the chemical constituents of the oil. The oil was evaluated for its ability to inhibit prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) productions in human whole blood using a radioimmunoassay technique. Its inhibitory effect on platelet-activating factor (PAF) receptor binding with rabbit platelets using 3H-PAF as a ligand and its free radical scavenging effect on DPPH were also investigated. Caryophyllene oxide (33.8%), E,Z-farnesol (6.9%), benzyl benzoate (6.5%) and viridiflorol (6.5%) were among the major components of the oil. Even though weak inhibitory activities were observed in both PGE2 and TXB2 assays, significant results were obtained in both PAF receptor binding inhibition and 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging effect with IC50 value of 6.6 µg/mL and 155.6 µg/mL respectively. These promising activities warrant the development of the oil as an anti-inflammatory agent.

Bitis arietans Snake Venom Induces an Inflammatory Response Which Is Partially Dependent on Lipid Mediators

Bitis arietans is a snake of medical importance, as it is responsible for more accidents in humans and domestic animals than all other African snakes put together. The accidents are characterized by local and systemic alterations, such as inflammation, cardiovascular and hemostatic disturbances, which can lead victims to death or permanent disability. However, little is known about the envenomation mechanism, especially regarding the inflammatory response, which is related to severe clinical conditions triggered by the venom. Therefore, the aim of the present study was to evaluate the inflammatory response related to the B. arietans envenomation using a peritonitis mice model. By pharmacological interventions and use of mice genetically deficient of the 5-lipoxygenase enzyme (5-LO−/−) or platelet-activating factor (PAF) receptor (PAFR−/− the participation of eicosanoids and PAF in this response was also investigated. The obtained results demonstrated that the venom induces an in vivo inflammatory response, characterized by an early increased vascular permeability, followed by an accumulation of polymorphonuclear (PMN) cells in the peritoneal cavity, accompanied by the production of the eicosanoids LTB4, LTC4, TXB2 and PGE2, as well as the local and systemic production of IL-6 and MCP-1. These inflammatory events were attenuated by the pre-treatment with anti-inflammatory drugs that interfere in lipid mediators’ functions. However, 5-LO−/− mice did not show a reduction of inflammatory response induced by the venom, while PAFR−/− mice showed a reduction in both the PMN leukocytes number and the local and systemic production of IL-6 and MCP-1. This study demonstrated that the Bitis arietans venom contains toxins that trigger an inflammatory process, which is partially dependent on lipid mediators, and may contribute to the envenomation pathology.