Levosimendan inhibits disulfide tau oligomerization and ameliorates tau pathology in TauP301L-BiFC mice.

Tau oligomers play critical roles in tau pathology and are responsible for neuronal cell death and transmitting the disease in the brain. Accordingly, preventing tau oligomerization has become an important therapeutic strategy to treat tauopathies, including Alzheimer's disease. However, progress has been slow because detecting tau oligomers in the cellular context is difficult. Working toward tau-targeted drug discovery, our group has developed a tau-BiFC platform to monitor and quantify tau oligomerization. By using the tau-BiFC platform, we screened libraries with FDA-approved and passed phase I drugs and identified levosimendan as a potent anti-tau agent that inhibits tau oligomerization. 14C-isotope labeling of levosimendan revealed that levosimendan covalently bound to tau cysteines, directly inhibiting disulfide-linked tau oligomerization. In addition, levosimendan disassembles tau oligomers into monomers, rescuing neurons from aggregation states. In comparison, the well-known anti-tau agents methylene blue and LMTM failed to protect neurons from tau-mediated toxicity, generating high-molecular-weight tau oligomers. Levosimendan displayed robust potency against tau oligomerization and rescued cognitive declines induced by tauopathy in the TauP301L-BiFC mouse model. Our data present the potential of levosimendan as a disease-modifying drug for tauopathies.

Congenital malformations of the urinary system as visceral markers of undifferentiated connective tissue dysplasia.

OBJECTIVE: The relevance of this study is conditioned by the need for urgent search and implementation of effective methods of treatment of urinary system diseases in people of different ages, as well as addressing issues of quality treatment of connective tissue diseases in general and its dysplasia in particular. The aim of the article is to identify congenital defects as visceral markers of connective tissue dysplasia. METHODS: The methodology of this study includes a survey of a group of children with considerable problems in the development and functioning of the urinary system at the age of 2 weeks to 3 years, in order to qualitatively select and determine the most effective methods of treatment. Children who took part in this study had a set of phenotypic and clinical properties of undifferentiated connective tissue dysplasia. RESULTS: The considerable prevalence of undifferentiated connective tissue dysplasia in young children with congenital malformations of the urinary system, especially in children with abnormal development and functioning of kidney tissue, which substantially influences the course of the disease was determined. Also, treatment of undifferentiated connective tissue dysplasia was predicted. CONCLUSIONS: It was concluded that the presence of a malformation of the urinary system, which is acquired by a child from birth, can be considered as a visceral manifestation of undifferentiated connective tissue dysplasia.

Finding a molecular genetic marker for the incidence of recurrent episodes of acute obstructive bronchitis in children.

Over the last ten years, the incidence of the pathology of the bronchus-pulmonary system in children has increased 3.6 times, mainly due to acute and recurrent inflammatory diseases of the upper and lower respiratory tract. Thus, the problem of identifying children with recurrent episodes of acute obstructive bronchitis and an increased risk of developing asthma is relevant and promising. The goal of this study was to find molecular genetic markers associated with increased susceptibility of children to repeated episodes of acute obstructive bronchitis. The molecular genetic testing of the IL4 gene of a single nucleotide polymorphism C-33T was performed in 35 children with recurrent episodes of acute obstructive bronchitis and 35 children with acute bronchitis. The results were statistically processed on a personal computer with the calculation of values the arithmetic mean (M), of the errors arithmetic mean (m), Student criterion (t), the degree of probability (p), Pearson criterion (χ2), and the odds ratio (OR). Statistically significant differences were figured at p<0.01 and p<0.05. It has been proved that the presence of a child's genotype 33CT IL4 increases the risk of recurrent acute obstructive bronchitis four times.