[Prospects for use of short peptides in pharmacotherapeutic correction of Alzheimer's disease.]

Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized by progressive cognitive decline. This review discusses current therapeutic strategies for the treatment of Alzheimer's disease, their limitations, and potential prospects. The feasibility of comprehensive approach for AD therapy is considered in contrast to the classical method in the development of therapeutic strategy. Leu-Ile, Glu-Trp, Lys-Glu, Gly-Pro, Glu-Asp-Arg, Lys-Glu-Asp, Met-Glu-His-Phe-Pro-Gly-Pro short peptides are described as multitarget agents with a wide range of activity.

Association of three single nucleotide polymorphisms in the LPIN1 gene with milk production traits in cows of the Yaroslavl breed.

Lipin-1 is a member of the evolutionarily conserved family of proteins and is expressed predominantly in adipose tissue and skeletal muscle. On the one hand, lipin-1 is an enzyme that catalyzes the dephosphorylation of phosphatidic acid to diacylglycerol (DAG) and thus participates in the metabolic pathways of biosynthesis of storage lipids in the cell, membrane phospholipids, and intracellular signaling molecules. On the other hand, lipin-1 is able to be transported from the cytoplasm to the nucleus and is a coactivator of lipid metabolism gene transcription. It was shown, using the analysis of single nucleotide polymorphism (SNP) associations, that the lipin-1 coding gene (LPIN1) is a promising candidate gene for milk production traits in Holstein and Brown Swiss cows. However, it is unclear how much of its effect depends on the breed. The Yaroslavl dairy cattle breed was created in the 18-19 centuries in Russia by breeding northern Great Russian cattle, which were short and poor productive, but well adapted to local climatic conditions and bad food base. It was shown by whole genome genotyping and sequencing that the Yaroslavl breed has unique genetics compared to Russian and other cattle breeds. The aim of the study was to assess the frequency of alleles and genotypes of three SNPs in the LPIN1 gene and to study the association of these SNPs with milk production traits in Yaroslavl cows. Blood samples from 142 cows of the Yaroslavl breed were obtained from two farms in the Yaroslavl region. Genotyping of SNPs was carried out by polymerase chain reaction-restriction fragment length polymorphism method. Associations of SNPs with 305-day milk yield, fat yield, fat percentages, protein yield, and protein percentages were studied from the first to the fourth lactation. Statistical tests were carried out using a mixed linear model, taking into account the relationship between individuals. We identified three SNPs - rs110871255, rs207681322 and rs109039955 with a frequency of a rare allele of 0.042-0.261 in Yaroslavl cows. SNP rs110871255 was associated with fat yield during the third and fourth lactations. SNP rs207681322 was associated with milk yield for the second, third and fourth lactations, as well as protein yield for the third lactation. Thus, we identified significant associations of SNPs rs207681322 and rs110871255 in the LPIN1 gene with a number of milk production traits during several lactations in Yaroslavl cows.

Neuroprotective properties of anti-apoptotic BCL-2 proteins in 5xFAD mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia. An early feature of the AD pathology is the dysregulation of intracellular Ca2+ signaling in neurons. In particular, increased Ca2+ release from endoplasmic reticulum-located Ca2+ channels, including inositol-1,4,5-trisphosphate type 1 receptors (IP3R1) and ryanodine receptors type 2 (RyR2), have been extensively reported. Known for its anti-apoptotic properties, Bcl-2 also has the ability to bind to and inhibit the Ca2+-flux properties of IP3Rs and RyRs. In this study, the hypothesis that the expression of Bcl-2 proteins can normalize dysregulated Ca2+ signaling in a mouse model of AD (5xFAD) and thereby prevent or slow the progression of AD was examined. Therefore, stereotactic injections of adeno-associated viral vectors expressing Bcl-2 proteins were performed in the CA1 region of the 5xFAD mouse hippocampus. In order to assess the importance of the association with IP3R1, the Bcl-2K17D mutant was also included in these experiments. This K17D mutation has been previously shown to decrease the association of Bcl-2 with IP3R1, thereby impairing its ability to inhibit IP3R1 while not affecting Bcl-2's ability to inhibit RyRs. Here, we demonstrate that Bcl-2 protein expression leads to synaptoprotective and amyloid-protective effects in the 5xFAD animal model. Several of these neuroprotective features are also observed by Bcl-2K17D protein expression, suggesting that these effects are not associated with Bcl-2-mediated inhibition of IP3R1. Potential mechanisms for this Bcl-2 synaptoprotective action may be related to its ability to inhibit RyR2 activity as Bcl-2 and Bcl-2K17D are equally potent in inhibiting RyR2-mediated Ca2+ fluxes. This work indicates that Bcl-2-based strategies hold neuroprotective potential in AD models, though the underlying mechanisms requires further investigation.

[AEDG peptide regulates human circadian rhythms genes expression during pineal gland accelerated aging.]

Night work provides biorhythms desynchronization, disorder of melatonin-producing function and accelerated pineal gland aging. One of the promising geroprotectors restoring the pineal melatonin synthesis is the AEDG (Ala-Glu-Asp-Gly) peptide. AEDG peptide increases in 1,7 times the 6-sulfatoxymelatonin (6-SOMT) excretion in the urine of middle-aged people. Moreover, AEDG peptide normalized circadian Clock and Csnk1e genes hyper expression in leukocytes in 1,9-2,1 times and increases the Cry2 gene hypo expression in peripheral blood lymphocytes in 2 times in people with reduced melatonin-producing epiphysis function. The geroprotective effect of the AEDG peptide is based on its ability to restore the epiphysis melatonin-producing function by means regulation of human circadian genes expression.

[Cys-Flanked Cationic Peptides For Cell Delivery of the Herpes Simplex Virus Thymidine Kinase Gene for Suicide Gene Therapy of Uterine Leiomyoma].

Uterine leiomyoma (UL) is the most common benign tumor in women of reproductive age. Gene therapy using suicidal genes appears to be a promising approach for UL treatment. One of key factors for success of gene therapy is the right choice of genetic construct carrier. A promising group of non-viral carriers for cell delivery of expression vectors is cationic Cys-flanked peptides which form tight complexes with DNA due to electrostatic interactions and the presence of interpeptide disulfide bonds. The paper reports a comparative study of the physico-chemical, toxic, and transfectional properties of the DNA-peptide complexes obtained by matrix polymerization or oxidative polycondensation of Cys-flanked peptides using the chain growth terminator 2-amino ethanethiol. We have demonstrated the therapeutic effect of the delivery of the pPTK-1 plasmid carrying the herpes simplex virus type 1 (HSV-1) thymidine kinase gene into PANC-1, and HEK-293T cell culture as well as into primary UL cells. It has been shown that the carriers obtained by oxidative polycondensation transform primary UL cells more efficiently than those produced by matrix polymerization. Treatment with ganciclovir resulted in the death of up to 40% of UL cells transfected with the pPTK-1 plasmid. The perspectives of use of the polyR6 carrier produced by oxidative polycondensation as a tool for the development of modular peptide carriers for the purposes of UL gene therapy were discussed.

Development of an electrochemical biosensor for the determination of triglycerides in serum samples based on a lipase/magnetite-chitosan/copper oxide nanoparticles/multiwalled carbon nanotubes/pectin composite.

A very sensitive electrochemical biosensor to determine totals triglycerides (TGs) in serum samples has been developed. It is based on the electrochemical oxidation of glycerol at glassy carbon electrodes modified with magnetic nanoparticles bonded to lipase enzyme and copper oxide nanoparticles, both supported on a multiwalled carbon nanotubes/pectin dispersion. Glycerol is produced by enzymatic reaction between the TGs present in samples and the lipase immobilized. The quantification of triglycerides was performed by amperometric measurements. The proposed electrochemical biosensor improves the performance of others methods developed for the TGs quantification. The determination of TGs does not need a pretreatment of serum samples. The PLS-1 algorithm was used for the quantification of TGs. According to this algorithm, the of detection and quantification limits were from 3.2 × 10-3 g L-1 to 3.6 × 10-3 g L-1, and from 9.6 × 10-3 to 1.1 × 10-2 g L-1, respectively. The sensitivity was 1.64 × 10-6 A L g-1. The proposed electrochemical biosensor exhibited a very good performance, a stability of 20 days, very good reproducibility and repeatability, and it is presented as a very good alternative for the determination of TGs in human serum clinical samples.