(E)-1-(3-Benzoyl-4-phenyl-1H-pyrrol-1-yl)-3-phenylprop-2-en-1-one

Over the last decade, there has been an increasing effort to fight inflammatory conditions establishing new multitarget approaches. Chronic inflammation is implicated in many multifactorial diseases, constituting a great economic burden and a chronic health problem. In an attempt to develop new potent multifunctional anti-inflammatory agents, a cinnamic-pyrrole hybrid (6) was synthesized and screened for its antioxidant and anti-Lipoxygenase potential. The new compound, in comparison with its pyrrole precursor (4), showed improved biological activities. In silico calculations were performed to predict its drug-likeness. The examined derivative is considered orally bioavailable according to Lipinski’s rule of five. Compound 6 could be used as a lead for the synthesis of more effective hybrids.

Guidelines for genetic testing of healthy adults who deposit samples and related data in bioresource collections and biobanks

Currently, a significant part of research in the fields of human and medical genetics is carried out using tissue samples, genealogical, population, medical and personal data. Their use is of particular relevance in the “genome era”, since only joint analysis of genomic data and health status of the population is crucial for understanding how genes are associated with health and disease. Genetic studies of adults without symptoms of diseases are carried out to obtain data on a possible predisposition to multifactorial diseases, to establish the carrier status of autosomal recessive mutations as part of preconception care and to assess individual sensitivity to drugs. In addition, healthy individuals can be tested to detect an inherited disease at presymptomatic stage. This situation increasingly emphasizes the importance of storing data on genome sequencing or any other patient tests for subsequent data reanalysis, as well as their safety, including biosamples from an individual and one’s family. The review article, based on international experience, summarizes guidelines for genetic testing of healthy individuals. The options for storing biological samples and related data are considered.

The role of genes of the second phase of detoxification of xenobiotics in the pathogenesis of multifactorial diseases

The genetic status of a person is currently assigned a major role in the pathogenesis, diagnosis and treatment of various diseases. The most important genetic factors that have been attached great importance to are the genes of the glutathione-S-transferase family (GSTs). The genes of the glutathione-S-transferase family belong to the second phase of detoxification of xenobiotics and their altered activity leads to the development of many pathological conditions. GSTM, GSTT, GSTP are considered to be the most polymorphic. The issues of the participation of polymorphic GSTs in the development of infectious, allergic and oncological diseases, disorders of the reproductive system, as well as in the development of Alzheimer's disease are discussed in the article.

Associations of rs4244285 in the CYP2C19 gene with multifactorial diseases

Xenobiotic metabolism system in the current populations is involved in the biotransformation of a wide range of endogenous substrates and various xenobiotics, which can contribute to developing the diseases of various organ systems, and, in some cases, comorbid conditions where increased biotransformation system activity is observed. In this regard, it is of great interest to study the involvement of polymorphism in xenobiotic metabolism genes in the development of both isolated pathology and various comorbid conditions.Aim. The goal of study was to investigate the involvement of rs4244285 in the CYP2C19 gene in the development of isolated pathology and comorbidities.Material and Methods. The frequencies of alleles and genotypes were studied in groups of patients with comorbid conditions including groups of coronary artery disease (CAD) with hypertension (HTN) (CAD_HTN, n = 133) and bronchial asthma (BA) with HTN (BA_HTN, n = 178), in group of isolated BA (n = 135), and in the population sample of the city of Tomsk (n = 377). Association analysis covered three initial groups of patients (CAD, BA, and BA_HTN) and subgroups assigned based on the presence of absence of HTN diagnosis taking into account comorbid conditions both in patient samples and in population control.Results and Discussion. The study demonstrated the predisposing eff ect of GA genotype on the development of comorbid BA and HTN (OR = 1.94, p = 0.038) and comorbid CAD and HTN (OR = 2.26, p = 0.009) compared to isolated BA. The AA genotype was observed 3.98 times less often in HTN patients than in normotensive individuals. However, the diff erences did not reach the level of statistical signifi cance due to the low occurrence of this genotype.Conclusion. The obtained results may be explained by the involvement of CYP2C19-metabolites of arachidonic acid in the regulation of vascular tone, which requires further study.

Genomics and predictive medicine

Progress in understanding of structural and functional human genome organization and deciphering primary DNA sequence in human cells allowed for hitherto unreachable new capabilities of medical genetics in identifying the causes and mechanisms of inherited and inborn pathology. Implementation of genetics into medicine is progressively advancing along with improvement of molecular analysis of genome. Knowledge of genome and its functions allows to provide more accurate diagnosis, predict, to a considerable extent, the presence of genetic predisposition of a person to pathology, and to assess the chances for developing one or another disease. This approach became the basis for a new area of medical genetics named predictive medicine. The progress of predictive medicine refl ects success in tremendous upgrowth of molecular genetic methods and new capabilities of studying structure and functions of genome. Within less than 15 years after deciphering genome, medical genetics has travelled a long way from a single gene analysis to whole genome studies, from screening of genetic associations to systems genetics of multifactorial diseases, from translational to high-precision genetics, and from genetic passport idea to electronic genetic health records. The development of a genetic passport, prognostic genetic testing, and genomic chart of reproductive health is especially relevant for current practical medicine.

Sodium-Glucose Cotransporter 2 Inhibitors and Heart Failure: A Bedside-to-Bench Journey

Type 2 diabetes mellitus (T2DM) and heart failure (HF) are multifactorial diseases sharing common risk factors, such as obesity, hyperinsulinemia, and inflammation, with underlying mechanisms including endothelial dysfunction, inflammation, oxidative stress, and metabolic alterations. Cardiovascular benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors observed in diabetic and non-diabetic patients are also related to their cardiac-specific, SGLT-independent mechanisms, in addition to the metabolic and hemodynamic effects. In search of the possible underlying mechanisms, a research campaign has been launched proposing varied mechanisms of action that include intracellular ion homeostasis, autophagy, cell death, and inflammatory processes. Moreover, the research focus was widened toward cellular targets other than cardiomyocytes. At the moment, intracellular sodium level reduction is the most explored mechanism of direct cardiac effects of SGLT2 inhibitors that mediate the benefits in heart failure in addition to glucose excretion and diuresis. The restoration of cardiac Na+ levels with consequent positive effects on Ca2+ handling can directly translate into improved contractility and relaxation of cardiomyocytes and have antiarrhythmic effects. In this review, we summarize clinical trials, studies on human cells, and animal models, that provide a vast array of data in support of repurposing this class of antidiabetic drugs.

Hypoxic Processes Induce Complement Activation via Classical Pathway in Porcine Neuroretinas

Considering the fact that many retinal diseases are yet to be cured, the pathomechanisms of these multifactorial diseases need to be investigated in more detail. Among others, oxidative stress and hypoxia are pathomechanisms that take place in retinal diseases, such as glaucoma, age-related macular degeneration, or diabetic retinopathy. In consideration of these diseases, it is also evidenced that the immune system, including the complement system and its activation, plays an important role. Suitable models to investigate neuroretinal diseases are organ cultures of porcine retina. Based on an established model, the role of the complement system was studied after the induction of oxidative stress or hypoxia. Both stressors led to a loss of retinal ganglion cells (RGCs) accompanied by apoptosis. Hypoxia activated the complement system as noted by higher C3+ and MAC+ cell numbers. In this model, activation of the complement cascade occurred via the classical pathway and the number of C1q+ microglia was increased. In oxidative stressed retinas, the complement system had no consideration, but strong inflammation took place, with elevated TNF, IL6, and IL8 mRNA expression levels. Together, this study shows that hypoxia and oxidative stress induce different mechanisms in the porcine retina inducing either the immune response or an inflammation. Our findings support the thesis that the immune system is involved in the development of retinal diseases. Furthermore, this study is evidence that both approaches seem suitable models to investigate undergoing pathomechanisms of several neuroretinal diseases.

INTERACTOMICS AND PERSONALIZED PHARMACOTHERAPY - PRESENT AND LOOKING INTO THE FUTURE

The review highlights the advances in natural science that form the basis of the concept of personalized and precision medicine (PPM). The provisions of PPM (prediction, prevention, personalization) are disclosed and modern molecular genetic tools are shown, which are used in leading scientific and practical biomedical centers to improve the quality of treatment of patients with multifactorial diseases (MFD). The main principles of molecular genetic biomarking of MFDs, as well as gene technologies (CRISPR, non-coding RNA, etc.) used in medical practice and at the stage of clinical trials are highlighted. Particular attention is paid to molecular genetic methods of targeted therapy for cancer, including antitumor vaccines. Scientific developments in the field of prediction and preventive treatment of MFD are considered - precision healing technologies of tomorrow. The main provisions of interactomics as an interdisciplinary field of natural science are highlighted, as well as the applied aspects of this section of fundamental science for the creation of diagnostic and treatment-and-prophylactic technologies of a new generation.

Identification of an ASC oligomerization inhibitor for the treatment of inflammatory diseases

The ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD)) protein is an scaffold component of different inflammasomes, intracellular multiprotein platforms of the innate immune system that are activated in response to pathogens or intracellular damage. The formation of ASC specks, initiated by different inflammasome receptors, promotes the recruitment and activation of procaspase-1, thereby triggering pyroptotic inflammatory cell death and pro-inflammatory cytokine release. Here we describe MM01 as the first-in-class small-molecule inhibitor of ASC that interferes with ASC speck formation. MM01 inhibition of ASC oligomerization prevents activation of procaspase-1 in vitro and inhibits the activation of different ASC-dependent inflammasomes in cell lines and primary cultures. Furthermore, MM01 inhibits inflammation in vivo in a mouse model of inflammasome-induced peritonitis. Overall, we highlight MM01 as a novel broad-spectrum inflammasome inhibitor for the potential treatment of multifactorial diseases involving the dysregulation of multiple inflammasomes.

Molecular Modeling Techniques Applied to the Design of Multitarget Drugs: Methods and Applications

: Multifactorial diseases, such as cancer and diabetes present a challenge for the traditional “one-target, one disease” paradigm due to their complex pathogenic mechanisms. Although a combination of drugs can be used, a multitarget drug may be a better choice face of its efficacy, lower adverse effects and lower chance of resistance development. The computer-based design of these multitarget drugs can explore the same techniques used for single-target drug design, but the difficulties associated to the obtention of drugs that are capable of modulating two or more targets with similar efficacy impose new challenges, whose solutions involve the adaptation of known techniques and also to the development of new ones, including machine-learning approaches. In this review, some SBDD and LBDD techniques for the multitarget drug design are discussed, together with some cases where the application of such techniques led to effective multitarget ligands.