Surveillance of human leptospirosis infections in Ukraine between 2018 and 2023.

Leptospirosis is a bacterial disease that affects both humans and animals worldwide. Currently, a positional war is ongoing in Ukraine, and the military is encountering a significant number of rodents in trenches and dugouts, which are known reservoirs for Leptospira, the causative agent of leptospirosis-a potentially dangerous infectious disease with a high mortality rate. The civilian population is also at potential risk of leptospirosis. The destruction of the Kakhovka Dam on June 6, 2023, has led to widespread devastation and human suffering. In the short term, there is a significant risk of rodent-borne diseases such as leptospirosis. We utilized data from the Ukrainian Centre for Disease Prevention Control and observed a substantial increase in prevalence in 2023. The notification rate in Ukraine in 2023 was 1.06 per 100,000 persons, which is higher than that of other countries in the European Union. Particular attention is being given to Zakarpattia Oblast, located on the western border of Ukraine, which shares boundaries with Romania, Hungary, Poland, and Slovakia, with an extremely high incidence rate of 12.08 per 100,000 persons. Based on these findings, we recommend education and awareness campaigns, vaccination, personal protective measures, and improved surveillance to address the increasing incidence of leptospirosis in Ukraine.

Modulatory Roles of AHR, FFAR2, FXR, and TGR5 Gene Expression in Metabolic-Associated Fatty Liver Disease and COVID-19 Outcomes.

Metabolic-associated fatty liver disease (MAFLD) is a risk factor for severe COVID-19. This study explores the potential influence of gut hormone receptor and immune response gene expression on COVID-19 outcomes in MAFLD patients. METHODS: We investigated gene expression levels of AHR, FFAR2, FXR, and TGR5 in patients with MAFLD and COVID-19 compared to controls. We examined associations between gene expression and clinical outcomes. RESULTS: COVID-19 patients displayed altered AHR expression, potentially impacting immune response and recovery. Downregulated AHR in patients with MAFLD correlated with increased coagulation parameters. Elevated FFAR2 expression in patients with MAFLD was linked to specific immune cell populations and hospital stay duration. A significantly lower FXR expression was observed in both MAFLD and severe COVID-19. CONCLUSION: Our findings suggest potential modulatory roles for AHR, FFAR2, and FXR in COVID-19 and MAFLD.

Communicable diseases in Ukraine during the period of 2018-2023: Impact of the COVID-19 pandemic and war.

BACKGROUND: By examining 2018-2023 data, this study explored the intricate impact of the Russian invasion, ongoing COVID-19 pandemic, and environmental disruptions on communicable diseases in Ukraine. This conflict exacerbates challenges in disease surveillance and healthcare, compounding stress among the population. METHODS: Leveraging the Centers for Disease Prevention Control's surveillance system, the study employs active and passive surveillance, utilizing medical records and laboratory reports. Notification rates gauge the incidence of communicable diseases, offering insights into trends during the study period. RESULTS: While salmonellosis, shigellosis, and rotavirus incidence are decreasing overall, there is a surge in viral hepatitis A, chronic hepatitis B, and C. This conflict hampers hepatitis C management, as evidenced by decreased numbers of treatment centers and patient enrollment. The prevalence of cough cases will increase in 2023, emphasizing the importance of sustained vaccination. The incidence of tuberculosis will increase in 2023 despite a general decrease. CONCLUSION: This study underscores the urgent need for sustained efforts and adequate resources, infrastructure, and international support to mitigate public health challenges in conflict-ridden Ukraine. Prioritizing vaccination programmes and enhancing healthcare accessibility in affected regions are crucial.

Comprehensive Analysis of Antiphage Defense Mechanisms: Serovar-Specific Patterns.

Leptospirosis is a major zoonotic disease caused by pathogenic spirochetes in the genus Leptospira, affecting over a million people annually and causing approximately 60,000 deaths. Leptospira interrogans, a key causative agent, likely possesses defense systems against bacteriophages (leptophages), yet these systems are not well understood. We analyzed 402 genomes of L. interrogans using the DefenseFinder tool to identify and characterize the antiphage defense systems. We detected 24 unique systems, with CRISPR-Cas (Clustered Regularly Interspaced Short Palindromic Repeats and CRISPR-associated proteins), PrrC, Borvo, and Restriction-Modification (R-M) being the most prevalent. Notably, Cas were identified in all strains, indicating their central role in phage defense. Furthermore, there were variations in the antiphage system distribution across different serovars, suggesting unique evolutionary adaptations. For instance, Retron was found exclusively in the Canicola serovar, while prokaryotic Argonaute proteins (pAgo) were only detected in the Grippotyphosa serovar. These findings significantly enhance our understanding of Leptospira's antiphage defense mechanisms. They reveal the potential for the development of serovar-specific phage-based therapies and underscore the importance of further exploring these defense systems.

COVID-19-associated encephalopathy: connection between neuroinflammation and microbiota-gut-brain axis.

While neurological complications of COVID-19, such as encephalopathy, are relatively rare, their potential significant impact on long-term morbidity is substantial, especially given the large number of infected patients. Two proposed hypotheses for the pathogenesis of this condition are hypoxia and the uncontrolled release of proinflammatory cytokines. The gut microbiota plays an important role in regulating immune homeostasis and overall gut health, including its effects on brain health through various pathways collectively termed the gut-brain axis. Recent studies have shown that COVID-19 patients exhibit gut dysbiosis, but how this dysbiosis can affect inflammation in the central nervous system (CNS) remains unclear. In this context, we discuss how dysbiosis could contribute to neuroinflammation and provide recent data on the features of neuroinflammation in COVID-19 patients.

Molecular mechanisms and therapeutic possibilities of short-chain fatty acids in posttraumatic stress disorder patients: a mini-review.

This mini-review explores the role of short-chain fatty acids (SCFAs) in posttraumatic stress disorder (PTSD). Highlighting the microbiota-gut-brain axis, this study investigated the bidirectional communication between the gut microbiome and mental health. SCFAs, byproducts of gut microbial fermentation, have been examined for their potential impact on PTSD, with a focus on molecular mechanisms and therapeutic interventions. This review discusses changes in SCFA levels and bacterial profiles in individuals with PTSD, emphasizing the need for further research. Promising outcomes from clinical trials using probiotics and fermented formulations suggest potential avenues for PTSD management. Future directions involve establishing comprehensive human cohorts, integrating multiomics data, and employing advanced computational methods, with the goal of deepening our understanding of the role of SCFAs in PTSD and exploring microbiota-targeted interventions.

Modulating Nitric Oxide: Implications for Cytotoxicity and Cytoprotection.

Despite the significant progress in the fields of biology, physiology, molecular medicine, and pharmacology; the designation of the properties of nitrogen monoxide in the regulation of life-supporting functions of the organism; and numerous works devoted to this molecule, there are still many open questions in this field. It is widely accepted that nitric oxide (•NO) is a unique molecule that, despite its extremely simple structure, has a wide range of functions in the body, including the cardiovascular system, the central nervous system (CNS), reproduction, the endocrine system, respiration, digestion, etc. Here, we systematize the properties of •NO, contributing in conditions of physiological norms, as well as in various pathological processes, to the mechanisms of cytoprotection and cytodestruction. Current experimental and clinical studies are contradictory in describing the role of •NO in the pathogenesis of many diseases of the cardiovascular system and CNS. We describe the mechanisms of cytoprotective action of •NO associated with the regulation of the expression of antiapoptotic and chaperone proteins and the regulation of mitochondrial function. The most prominent mechanisms of cytodestruction-the initiation of nitrosative and oxidative stresses, the production of reactive oxygen and nitrogen species, and participation in apoptosis and mitosis. The role of •NO in the formation of endothelial and mitochondrial dysfunction is also considered. Moreover, we focus on the various ways of pharmacological modulation in the nitroxidergic system that allow for a decrease in the cytodestructive mechanisms of •NO and increase cytoprotective ones.

Current treatment options for leptospirosis: a mini-review.

Leptospirosis, one of the most common global zoonotic infections, significantly impacts global human health, infecting more than a million people and causing approximately 60,000 deaths annually. This mini-review explores effective treatment strategies for leptospirosis, considering its epidemiology, clinical manifestations, and current therapeutic approaches. Emphasis is placed on antibiotic therapy, including recommendations for mild and severe cases, as well as the role of probiotics in modulating the gut microbiota. Furthermore, novel treatment options, such as bacteriophages and newly synthesized/natural compounds, are discussed, and the findings are expected to provide insights into promising approaches for combating leptospirosis.

AMR mechanisms in L. interrogans serovars: a comprehensive study.

Antimicrobial resistance (AMR) is one of the global health challenges of the 21st century. Data regarding AMR mechanisms in Leptospira interrogans, the causative agents of leptospirosis, have been relatively limited. Therefore, our study aimed to identify resistance genes and explore potential resistance mechanisms specific to particular serovars. We conducted a comprehensive analysis of 98 Leptospira strains, representing 10 common serovars, using whole-genome sequencing (WGS) FASTA files. Employing the PATRIC tool from the Bacterial and Viral Bioinformatics Resource Center (BV-BRC), we scrutinized the genomes for AMR genes. Our investigation revealed 32 genes associated with AMR, with 20 key genes consistently prevalent across most strains. Notably, we identified unique efflux pump systems in serovar Pomona, indicating distinctive resistance mechanisms in this serovar. In summary, our findings shed light on the genetic landscape of AMR in Leptospira, uncovering both common and serovar-specific resistance elements. The presence of unique efflux pump systems in serovar Pomona introduces a novel dimension to our understanding of resistance mechanisms. These insights underscore the importance of tailored intervention strategies and collaborative efforts between human and veterinary healthcare professionals, as well as environmental scientists, to address the complex dynamics of leptospirosis and its implications for antibiotic resistance.

Combined Pharmacological Modulation of Translational and Transcriptional Activity Signaling Pathways as a Promising Therapeutic Approach in Children with Myocardial Changes.

Myocardial hypertrophy is the most common condition that accompanies heart development in children. Transcriptional gene expression regulating pathways play a critical role both in cardiac embryogenesis and in the pathogenesis of congenital hypertrophic cardiomyopathy, neonatal posthypoxic myocardial hypertrophy, and congenital heart diseases. This paper describes the state of cardiac gene expression and potential pharmacological modulators at different transcriptional levels. An experimental model of perinatal cardiac hypoxia showed the downregulated expression of genes responsible for cardiac muscle integrity and overexpressed genes associated with energy metabolism and apoptosis, which may provide a basis for a therapeutic approach. Current evidence suggests that RNA drugs, theaflavin, neuraminidase, proton pumps, and histone deacetylase inhibitors are promising pharmacological agents in progressive cardiac hypertrophy. The different points of application of the above drugs make combined use possible, potentiating the effects of inhibition in specific signaling pathways. The special role of N-acetyl cysteine in both the inhibition of several signaling pathways and the reduction of oxidative stress was emphasized.

Exploring the complex interplay: gut microbiome, stress, and leptospirosis.

Leptospirosis, a re-emerging zoonotic disease, remains a significant global health concern, especially amid floods and disasters such as the Kakhovka Dam destruction. As is known, the stress that occurs in the conditions of military conflicts among civilian and military personnel significantly affects susceptibility to infectious diseases and possibly even influences their course. This review aims to explore how the gut microbiome and stress mediators (such as catecholamines and corticosteroids) might impact the leptospirosis disease course. The review opens new horizons for research by elucidating the connections between the gut microbiome, stress, and leptospirosis.

Exploring Leptospira interrogans FDAARGOS_203: Insights into AMR and Anti-Phage Defense.

Leptospira, which are known to be important disease-causing agents transmitted between animals and humans, result in significant illness and, in some cases, significant death in human populations. This purpose of this study was to examine the genomic structure of Leptospira interrogans serovar Copenhageni strain FDAARGOS_203 to identify the specific genetic factors that contribute to antimicrobial resistance (AMR) and defense against phages. The genome, consisting of two contigs totaling 4,630,574 base pairs, underwent thorough examination for protein-coding sequences, transfer RNA genes, and ribosomal RNA genes. A total of twenty-two antibiotic resistance genes that specifically target essential cellular processes such as cell wall synthesis, DNA replication, and protein synthesis have been identified. Significant among these were gidB, gdpD, and ggsA, each involved in separate aspects of antibiotic resistance. In addition, the investigation explored the defense mechanisms of bacteriophages, revealing the presence of defense islands that contain a range of anti-phage systems, including RM_Type_IV, PrrC, Borvo, CAS_Class1-Subtype-IC, and CAS_Class1-Subtype-IB. This comprehensive genomic analysis enhances our understanding of the molecular mechanisms that determine Leptospira's ability to adapt to various environments. The identified genetic factors linked to AMR and defense against phages not only enhance our scientific comprehension, but also provide a basis for focused interventions to reduce the impact of leptospirosis.

Exploring the interplay between posttraumatic stress disorder, gut microbiota, and inflammatory biomarkers: a comprehensive meta-analysis.

Introduction: Posttraumatic stress disorder (PTSD) is the most common mental health disorder to develop following exposure to trauma. Studies have reported conflicting results regarding changes in immune biomarkers and alterations in the abundance of bacterial taxa and microbial diversity in patients with PTSD. Aim: The purpose of this meta-analysis is to summarize existing studies examining gut microbiota characteristics and changes in immune biomarkers in patients with PTSD. Methods: Relevant studies were systematically searched in PubMed, Scopus, and Embase, published in English between January 1, 1960, and December 1, 2023. The outcomes included changes in abundance and diversity in gut microbiota (gut microbiota part) and changes in immune biomarkers (immune part). Results: The meta-analysis included a total of 15 studies, with 9 focusing on changes in inflammatory biomarkers and 6 focusing on changes in gut microbiota composition in patients with PTSD. No differences were observed between groups for all inflammatory biomarkers (P≥0.05). Two of the six studies found that people with PTSD had less alpha diversity. However, the overall Standardized Mean Difference (SMD) for the Shannon Diversity Index was not significant (SMD 0.27, 95% CI -0.62-0.609, p = 0.110). Regarding changes in abundance, in two of the studies, a significant decrease in Lachnospiraceae bacteria was observed. Conclusion: This meta-analysis provides a comprehensive overview of gut microbiota characteristics in PTSD, suggesting potential associations with immune dysregulation. Future research should address study limitations, explore causal relationships, and consider additional factors influencing immune function in individuals with PTSD. Systematic review registration: https://www.crd.york.ac.uk, identifier CRD42023476590.

Metformin Alters mRNA Expression of FOXP3, RORC, and TBX21 and Modulates Gut Microbiota in COVID-19 Patients with Type 2 Diabetes.

COVID-19 remains a significant global concern, particularly for individuals with type 2 diabetes who face an elevated risk of hospitalization and mortality. Metformin, a primary treatment for type 2 diabetes, demonstrates promising pleiotropic properties that may substantially mitigate disease severity and expedite recovery. Our study of the gut microbiota and the mRNA expression of pro-inflammatory and anti-inflammatory T-lymphocyte subpopulations showed that metformin increases bacterial diversity while modulating gene expression related to T-lymphocytes. This study found that people who did not take metformin had a downregulated expression of FOXP3 by 6.62-fold, upregulated expression of RORC by 29.0-fold, and upregulated TBX21 by 1.78-fold, compared to the control group. On the other hand, metformin patients showed a 1.96-fold upregulation in FOXP3 expression compared to the control group, along with a 1.84-fold downregulation in RORC expression and an 11.4-fold downregulation in TBX21 expression. Additionally, we found a correlation with gut microbiota (F/B ratio and alpha-diversity index) and pro-inflammatory biomarkers. This novel observation of metformin's impact on T-cells and gut microbiota opens new horizons for further exploration through clinical trials to validate and confirm our data. The potential of metformin to modulate immune responses and enhance gut microbiota diversity suggests a promising avenue for therapeutic interventions in individuals with type 2 diabetes facing an increased risk of severe outcomes from COVID-19.

Exploring Paxlovid Efficacy in COVID-19 Patients with MAFLD: Insights from a Single-Center Prospective Cohort Study.

This study investigates the intricate interplay between Metabolic-associated Fatty Liver Disease (MAFLD) and COVID-19, exploring the impact of MAFLD on disease severity, outcomes, and the efficacy of the antiviral agent Paxlovid (nirmatrelvir/ritonavir). MAFLD, affecting a quarter of the global population, emerges as a potential risk factor for severe COVID-19, yet the underlying pathophysiological mechanisms remain elusive. This study focuses on the clinical significance of Paxlovid, the first orally bioavailable antiviral agent granted Emergency Use Authorization in the United States. Notably, outcomes from phase II/III trials exhibit an 88% relative risk reduction in COVID-19-associated hospitalization or mortality among high-risk patients. Despite conflicting data on the association between MAFLD and COVID-19 severity, this research strives to bridge the gap by evaluating the effectiveness of Paxlovid in MAFLD patients with COVID-19, addressing the scarcity of relevant studies.

GHRL, LEP, LEPR genes polymorphism and their association with the metabolic syndrome in the Ukrainian population.

Objective. Many conflicting results have been obtained in the study of leptin (LEP) and leptin receptor (LEPR) gene variants that are associated with the obesity and diabetes possibly due to differences in the study populations. The aim of this study was to evaluate changes in the metabolic hormones (leptin, ghrelin, adiponectin, resistin) levels in the blood of obese patients in relation to the GHRL (rs696217), LEP (rs7799039), LEPR (rs1137100, rs1137101, rs1805094) polymorphism in Ukrainian population. Methods. The study involved 53 obesity cases and 48 non-obesity subjects (controls). The GHRL, LEP, and LEPR genes polymorphism (rs696217, rs7799039, rs1137100, rs1137101, rs1805094) was genotyped using a TaqMan real-time polymerase chain reaction method. Blood hormones (leptin, ghrelin, adiponectin, resistin) were determined with commercially available kits using a Multiskan FC analyzer. Results. The study of the effect of genotypes of the GHRL (rs696217), LEP (rs7799039), and LEPR (rs1137100, rs1805094) polymorphisms on the level of metabolic hormones (leptin, ghrelin, adiponectin, resistin) in the blood of obese patients did not show reliably significant results. Thus, the presence of the LEPR genes (rs1137101) polymorphism in the Ukrainian population indicates an increased risk of the metabolic syndrome development regardless of the homozygous or heterozygous genotype (genotypes AA, AG, GG). Conclusions. We established a significant effect of the presence of the A allele and G allele of the LEPR gene polymorphism (rs1137101) on the level of leptin, ghrelin, adiponectin, and resistin in the serum of patients diagnosed with the metabolic syndrome in the Ukrainian population.

The Relationship between COVID-19 Severity in Children and Immunoregulatory Gene Polymorphism.

Coronavirus disease (COVID-19) and its outcomes remain one of the most challenging problems today. COVID-19 in children could be asymptomatic, but can result in a fatal outcome; therefore, predictions of the disease severity are important. The goal was to investigate the human genetic factors that could be associated with COVID-19 severity in children. Single-nucleotide polymorphisms of the following genes were studied: ACE2 (rs2074192), IFNAR2 (rs2236757), TYK2 (rs2304256), OAS1 (rs10774671), OAS3 (rs10735079), CD40 (rs4813003), FCGR2A (rs1801274) and CASP3 (rs113420705). In the case-control study were 30 children with mild or moderate course of the disease; 30 with severe COVID-19 symptoms and multisystem inflammatory syndrome in children (MIS-C) and 15 who were healthy, and who did not have SARS-CoV-2 (PCR negative, Ig G negative). The study revealed that ACE2 rs2074192 (allele T), IFNAR2 rs2236757 (allele A), OAS1 rs10774671 (allele A), CD40 rs4813003 (allele C), CASP3 rs113420705 (allele C) and male sex contribute to severe COVID-19 course and MIS-C in 85.6% of cases. The World Health Organization reported that new SARS-CoV-2 variants may cause previously unseen symptoms in children. Although the study has limitations due to cohort size, the findings can help provide a better understanding of SARS-CoV-2 infection and proactive pediatric patient management.

Effect of the GHRL gene (rs696217) polymorphism on the metabolic disorders in patients with obesity in the Ukrainian population.

Objective. Over the past four decades, the prevalence of obesity has tripled and limited genetic studies with specific SNPs have been conducted, but no investigations using ghrelin and obestatin prepropeptide (GHRL) gene have been reported in the Ukrainians population. The aim of this study was to evaluate changes in the level of metabolic hormones in the blood of obese patients in relation to the GHRL (rs696217) polymorphism. Methods. The study involved 53 obesity cases and 48 non-obesity subjects (controls). The GHRL (rs696217) polymorphism was genotyped using a TaqMan real-time polymerase chain reaction method. Blood hormones were determined with commercially available kits using a Multi-skan FC analyzer. Results. Carriers of the T allele of the GHRL (rs696217) polymorphism were statistically significantly more in patients diagnosed with obesity compared to controls indicating a genetically determined cause of obesity. We also established a significant effect of the presence of the T allele of the GHRL (rs696217) polymorphism on the decrease in the adiponectin level and the increase of resistin level in obese patients. The study of the effect of genotypes (TT, GT, GG) of the GHRL (rs696217) polymorphism on the metabolic hormone levels in the blood of obese patients did not show reliably significant differences. Conclusions. The presence of the T allele of the GHRL (rs696217) polymorphism in Ukrainian population indicates an increased risk of the obesity development regardless on the homozygous or heterozygous genotype.

Transcription regulatory factor expression in T-helper cell differentiation pathway in eutopic endometrial tissue samples of women with endometriosis associated with infertility.

Endometriosis is a disease of epidemiological gravity of unknown primary reason. A complex of constitutional factors including the immune system has been considered as its background. The aim of the study was to identify Th1 and Th2 cells as well as the T-regulatory subset in the endometrium of women with endometriosis associated with infertility upon transcription factors expression. Expression of T-bet, GATA3, and Foxp3 genes was examined using a method of polymerase chain reaction (PCR) in the eutopic endometrial samples of 20 women with endometriosis associated with infertility and 20 women with infertility of tubal origin. An increase in mRNA expression for T-bet and GATA3 with prevailing mRNA level for T-bet and a decrease in Foxp3 expression were observed. In conclusion, the revealed changes in expression of transcription factors may indicate the imbalance between T-helper cells of the Th1 and Th2 type and elimination of regulatory function of T-cells, which can be one of the causes of endometriosis predisposing to the development of infertility associated with this disease.

2-Heteroaryl-[1,2,4]triazolo[1,5-c]quinazoline-5(6 H)-thiones and Their S-Substituted Derivatives: Synthesis, Spectroscopic Data, and Biological Activity.

In the continuing search for novel, biologically effective heterocyclic agents, several methods for the synthesis of 2-heteroaryl-[1,2,4]triazolo[1,5-c]quinazoline-5(6 H)-thiones have been developed: thiolation of oxo derivatives, [5+1] cyclocondensation of [2-(3-heteroaryl-[1,2,4]triazol-5-yl)phenyl]amines with carbon disulfide, potassium ethyl xanthogenate, or aryl isothiocyanates, and in situ reaction of 2-isothiocyanatobenzonitrile with hydrazides. A series of N-R-2-[(2-heteroaryl-[1,2,4]triazole-[1,5-c]quinazoline-5-yl)thio]acetamides were obtained by aminolysis of the corresponding acetic acids and alkylation of potassium thiolates with N-R-2-chloroacetamides. It was established that some potassium thiolates, 4 a-4 d, 4 h, and 4 i, had high antibacterial activity against Staphylococcus aureus with a minimum inhibitory concentration of 12.5 µg mL-1 and minimum bactericidal concentration of 25 µg mL-1 , which exceeded the values for trimethoprim. In addition, {2-[3-(1 H-indole-2-yl)-1 H-1,2,4-triazol-5-yl]phenyl}amine 2 i was investigated in the concentration range 100-0.01 µM at 59 lines of nine cancer cell types, and showed a mean effective concentration at 3.12-7.03 µM and cytotoxic effect at 15.56-67.38 µM. The possible mechanisms of activity were predicted by molecular docking studies to S. aureus dihydrofolate reductase and epidermal growth factor receptor kinase.