Mechanisms and pharmacology of diabetic neuropathy – experimental and clinical studies

Neuropathic pain is the most common chronic complication of diabetes mellitus. The mechanisms involved in the development of diabetic neuropathy include changes in the blood vessels that supply the peripheral nerves; metabolic disorders, such as the enhanced activation of the polyol pathway; myo-inositol depletion; and increased non-enzymatic glycation. Currently, much attention is focused on the changes in the interactions between the nervous system and the immune system that occur in parallel with glial cell activation; these interactions may also be responsible for the development of neuropathic pain accompanying diabetes. Animal models of diabetic peripheral neuropathy have been utilized to better understand the phenomenon of neuropathic pain in individuals with diabetes and to define therapeutic goals. The studies on the effects of antidepressants on diabetic neuropathic pain in streptozotocin (STZ)-induced type 1 diabetes have been conducted. In experimental models of diabetic neuropathy, the most effective antidepressants are tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors. Clinical studies of diabetic neuropathy indicate that the first line treatment should be tricyclic antidepressants, which are followed by anticonvulsants and then opioids. In this review, we will discuss the mechanisms of the development of diabetic neuropathy and the most common drugs used in experimental and clinical studies.     

Mechanisms of Anticancer Activity of a Fatty Acid Mixture Extracted from Hen Egg Yolks Enriched in Conjugated Linoleic Acid Diene (CLA) against WM793 Melanoma Cells

The conjugated linoleic acid (CLA) diene is a biologically active compound with proven health-promoting effects. In terms of anticancer properties, it has been shown that CLA reduces the proliferation of cancer cells. In this study, it has been demonstrated that a mixture of fatty acids, isolated from chicken egg yolk enriched in CLA isomers by biofortification, reduces (by 30.5%) the proliferation of human melanoma cancer cells line WM793 to a greater extent than a mixture of fatty acids not containing these isomers. At the same time, the tested fatty acid mixtures show no effect on human normal BJ fibroblast cells. For the first time, the genes with increased expression have been identified and the proteins have been activated by the fatty acid mixture of CLA-enriched egg yolk, mainly responsible for mitochondrial pathway-dependent apoptosis.     

Modulation of antioxidant enzyme gene expression by extremely low frequency electromagnetic field in post-stroke patients

Oxidative stress plays the most important role in the pathogenesis of stroke. Extremely low frequency electromagnetic field (ELF-EMF) therapy may be complementary in post-stroke therapy, as it modulates oxidative stress. The aim of this study was to evaluate the messenger ribonucleic acid (mRNA) levels of certain antioxidant genes in post-stroke patients given ELF-EMF therapy. Forty-eight post-stroke patients were divided into two groups: an ELF-EMF group and a non-ELF-EMF group. All patients underwent the same program of physical therapy, but the ELF-EMF group was additionally given ELF-EMF treatment. In order to determine the level of gene expression, we evaluated the level of mRNA expression of catalase, superoxide dismutase, and glutathione peroxidase. We observed that after ELF-EMF therapy, the mRNA expression of the studied genes (CAT, SOD1, SOD2, GPx1, and GPx4) significantly increased, which enhanced the antioxidant defence of the body. ELF-EMF therapy intensifies the endogenous antioxidant system by increasing the mRNA expression of genes encoding antioxidant enzymes and enhances the effectiveness of post-stroke patient therapy.     

Expression of PI(4,5)P2-binding proteins lowers the PI(4,5)P2level and inhibits FcgammaRIIA-mediated cell spreading and phagocytosis

We found that FcgammaRII-mediated cell spreading and phagocytosis were correlated with an increase of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P(2)] level in cells. During the spreading, a long-lasting elevation of PI(4,5)P(2) and concomitant actin polymerization occurred. Filopodia and lamellae of spreading cells were enriched in phosphatidylinositol 4-phosphate 5-kinase Ialpha (PIP5-kinase Ialpha) that colocalized with PI(4,5)P(2 )and actin filaments. Both spreading and phagocytosis were inhibited by expression of the C(374-440) fragment of PIP5-kinase Ialpha or the pleckstrin homology domain of phospholipase Cdelta(1 )(PLCdelta(1)-PH), two probes binding PI(4,5)P(2). These probes reduced the amount of PI(4,5)P(2) in the cells, evoked reorganization of the actin cytoskeleton and abolished PI(4,5)P(2) elevation during phagocytosis. Simultaneously, PLCdelta(1)-PH-GFP reduced the amount of PIP5-kinase Ialpha associated with the plasma membrane. In vitro studies demonstrated that PIP5-kinase Ialpha-GST bound PI(4,5)P(2), phosphatidylinositol 4-monophosphate, and less efficiently, phosphatidic acid. The data suggest that the PLCdelta(1)-PH domain, and possibly also the C(374-440) fragment, when expressed in cells, can compete with endogenous PIP5-kinase Ialpha for PI(4,5)P(2 )binding in the plasma membrane leading eventually to PI(4,5)P(2) depletion.     

The Latest Achievements in the Construction of Influenza Virus Detection Aptasensors

Aptamers are short fragments of nucleic acids, DNA or RNA that have the ability to bind selected proteins with high specificity and affinity. These properties allow them to be used as an element of biosensors for the detection of specific proteins, including viral ones, which makes it possible to design valuable diagnostic tools. The influenza virus causes a huge number of human and animal deaths worldwide every year, and contributes to remarkable economic losses. In addition, in 2020, a new threat appeared—the SARS-Cov-2 pandemic. Both disease entities, especially in the initial stage of infection, are almost identical in terms of signs and symptoms. Therefore, a diagnostic solution is needed that will allow distinguishing between both pathogens, with high sensitivity and specificity; it should be cheap, quick and possible to use in the field, for example, in a doctor’s office. All the mentioned properties are met by aptasensors in which the detection elements are specific aptamers. We present here the latest developments in the construction of various types of aptasensors for the detection of influenza virus. Aptasensor operation is based on the measurement of changes in electric impedance, fluorescence or electric signal (impedimetric, fluorescence and electrochemical aptasensors, respectively); it allows both qualitative and quantitative determinations. The particularly high advancement for detecting of influenza virus concerns impedimetric aptasensors.     

c-myc and bcl-2 modulate p53 function by altering p53 subcellular trafficking during the cell cycle.

We have studied the ability of c-myc and bcl-2 oncogenes to modulate p53 function. Our studies show that coincident expression of human Bcl-2 protein with p53 prolongs survival of murine erythroleukemia cells. This effect was associated with a loss of the G1 specificity of p53-mediated cell cycle arrest. Furthermore, we found that the c-myc and bcl-2 genes cooperate to inhibit p53 functions. Coexpression of bcl-2 and c-myc can totally overcome p53-induced apoptosis and cell cycle arrest by altering the subcellular trafficking of p53 during the cell cycle: the p53 remains in the cytoplasm of the cotransfected cells during a critical period in G1. This finding suggests a mechanism by which normal hematopoietic progenitors can survive and proliferate despite p53 expression and by which the inappropriate expression of bcl-2 and c-myc can cooperate in transformation.