Development Of Systemic Inflammation Research Articles

D-beta-hydroxybutyrate up-regulates Claudin-1 and alleviates the intestinal hyperpermeability in lipopolysaccharide-treated mice

The hyperpermeability of intestinal epithelium is a key contributor to the occurrence and development of systemic inflammation. Although D-beta-hydroxybutyrate (BHB) exhibits various protective effects, whether it affects the permeability of intestinal epithelium in systemic inflammation has not been clarified. In this study, we investigated the effects of BHB on the intestinal epithelial permeability, the epithelial marker E-cadherin and the tight junction protein Claudin-1 in colon in the lipopolysaccharide (LPS)-induced systemic inflammation mouse model. Intraperitoneal injection of LPS was used to induce systemic inflammation and BHB was given by oral administration. The permeability of intestinal epithelium, the morphological changes of colonic epithelium, the distribution and generation of colon E-cadherin, and the Claudin-1 generation and its epithelial distribution in colon were detected. The results confirmed the intestinal epithelial hyperpermeability and inflammatory changes in colonic epithelium, with disturbed E-cadherin distribution in LPS-treated mice. Besides, colon Claudin-1 generation was decreased and its epithelial distribution in colon was weakened in LPS-treated mice. However, BHB treatments alleviated the LPS-induced hyperpermeability of intestinal epithelium, attenuated the colonic epithelial morphological changes and promoted orderly distribution of E-cadherin in colon. Furthermore, BHB up-regulated colon Claudin-1 generation and promoted its colonic epithelial distribution and content in LPS-treated mice. In conclusion, BHB may alleviate the hyperpermeability of intestinal epithelium via up-regulation of Claudin-1 in colon in LPS-treated mice.

The role of the gastrointestinal barrier in obesity-associated systemic inflammation.

Systemic inflammation is a key contributor to the onset and progression of several obesity-associated diseases and is thought to predominantly arise from the hyperplasia and hypertrophy of white adipose tissue. However, a growing body of works suggests that early changes in the gastrointestinal (GI) barrier may contribute to both local, within the GI lining, and systemic inflammation in obesity. Intestinal barrier dysfunction is well-characterized in inflammatory GI disorders such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) and is known to contribute to systemic inflammation. Thus, drawing parallels between GI disorders, where intestinal permeability and systemic inflammation are prominent features, and obesity-induced GI manifestations may provide insights into the potential role of the intestinal barrier in systemic inflammation in obesity. This review summarizes the current literature surrounding intestinal barrier dysfunction in obesity and explores the potential role of intestinal hyperpermeability and intestinal barrier dysfunction in the development of systemic inflammation and GI dysfunction in obesity.

Role of the S1P Signaling Pathway in the Pathogenesis of Angioimmunoblastic T-Cell Lymphoma

Peripheral T cell lymphomas (PTCLs) are a group of aggressive lymphoid malignancies originating from mature T cells. Angioimmunoblastic T-cell lymphomas (AITL) represent 20% to 30% of all PTCL diagnoses and are associated with autoimmune features, poor response to chemotherapy, and dismal prognosis. Molecular profiling of AITL has identified T-follicular helper (TFH) cells as the cell of origin of AITL, while mutational analysis has identified frequent alterations in epigenetic regulators ( TET2, DNMT3A, and IDH2) and elements of the TCR pathway as drivers of AITL transformation. Our group identified the highly recurrent RHOA G17V mutation as a defining hallmark of AITL and other T-cell lymphomas of TFH-cell origin (Palomero et al., 2014). Using a novel conditional knockin mouse model, we demonstrated that expression of Rhoa G17V in CD4+ T-cells induces TFH cell specification and promotes AITL lymphomagenesis in the context of loss of Tet2 (Cortes et al., 2018). Recently, we have identified that Rhoa G17V regulates the expression of the sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) one of the five members of the receptor family of S1P, which plays an essential role in immune response and lymphocyte trafficking. During thymic T-cell development, expression of Rhoa G17V in CD4+ cells inhibited S1PR1 downregulation after the double positive stage leading to altered positive selection, reduced CD4+ single positive cell numbers and premature thymic egress of autorreactive T-cells which results in the development of systemic inflammation and autoimmunity. In our Tet2 −/− RHOA G17V AITL tumor model, constitutive activation of S1P receptors supported activation of the STAT3 and NFkB pathway and enhanced migration of malignant cells to peripheral organs. Mechanistically, expression of Rhoa G17V in mature CD4+ T-cells impaired re-phosphorylation of the Ezrin-Radoxin-Moesin (ERM) complex independently of ROCK signaling and led to the activation and increased migration of CD4+ T-cells. Importantly, blockade of S1PR1 signaling by fingolimod induced anti-tumor activity in Tet2 −/− RHOA G17V lymphoma-bearing mice in vivo with significant reductions in tumor burden associated with increased apoptosis and decreased STAT3 phosphorylation. Furthermore, analysis of a panel of primary tumors from AITL patients using a multiplexed staining panel and PhenoImager platform revealed significantly higher S1PR1 expression in AITL tumor cells than normal TFH cells from benign reactive lymph nodes. Our findings highlight the role of S1P signaling pathway in the pathogenesis of RHOA G17V-driven AITLs and the potential therapeutic benefit of targeting this pathway.

Distribution of polymorphic variants of the TNF-α and TNFRSF1α genes in miners with dust lung pathology

Introduction. Long-term exposure to coal-rock dust on the body causes the development of systemic inflammation, one of the development mechanisms of which is an increase in the production of pro-inflammatory cytokines as follows: TNF-α, IL-1β, IL-2, IL-6. The development and course of occupational pathology were shown to depend on the individual characteristics of the body of those who works in hazardous conditions. In this regard, it is necessary to establish the significance of the polymorphism of the TNF-α and TNFRSF1α genes in the development of dust lung pathology in workers of the main occupations of the mines in the South of Kuzbass. 
 The aim of the study was to investigate the prevalence of polymorphic variants of the TNF-α (rs1800629) and TNFRSF1α (rs4149584) genes in miners with dust lung pathology.
 Materials and methods. A survey of one hundred twenty seven miners working for a long time in the mines of the south of Kuzbass was carried out. Of these: 
 69 miners with prolonged exposure to high concentrations of coal-rock dust with a previously proven diagnosis of dust lung pathology, 58 miners without a proven diagnosis of dust lung pathology working in the same sanitary and hygienic conditions (control). The typing of the TNF-α (rs1800629) and TNFRSF1α (rs4149584) genes was carried out using the Real-Time method.
 Results. The GG rs1800629 TNF-α genotype were shown to be a potent molecular genetic marker of the risk of developing dust lung pathology, the chance of detecting it in the group of the miners with dust pathology is almost 4 times higher than in the control group. The carriage of the A allele and the heterozygous AG rs1800629 TNF-α genotype reduce the probability of developing dust lung pathology. It has been established that the GG rs4149584 TNFRSF1α genotype can be a molecular and genetic marker of the risk of developing dust lung pathology, the chance of detecting it in the group of the miners with dust pathology is 2.6 times higher than in the control group.
 Limitations. The study was limited by relatively small size of the groups under study.
 Conclusion. The carriage of homozygous GG genotypes of the rs1800629 and rs4149584 polymorphic loci of the TNF-α and TNFRSF1α genes, respectively, is associated with the risk of developing dust lung pathology in miners in the South of Kuzbass. The carriage of the A allele and the heterozygous AG rs1800629 TNF-α genotype reduce the probability of developing dust lung pathology.

NF-κB/NLRP3 inflammasome axis and risk of Parkinson's disease in Type 2 diabetes mellitus: A narrative review and new perspective.

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD). Genetic predisposition and immune dysfunction are involved in the pathogenesis of PD. Notably, peripheral inflammatory disorders and neuroinflammation are associated with PD neuropathology. Type 2 diabetes mellitus (T2DM) is associated with inflammatory disorders due to hyperglycaemia-induced oxidative stress and the release of pro-inflammatory cytokines. Particularly, insulin resistance (IR) in T2DM promotes the degeneration of dopaminergic neurons in the substantia nigra (SN). Thus, T2DM-induced inflammatory disorders predispose to the development and progression of PD, and their targeting may reduce PD risk in T2DM. Therefore, this narrative review aims to find the potential link between T2DM and PD by investigating the role of inflammatory signalling pathways, mainly the nuclear factor kappa B (NF-κB) and the nod-like receptor pyrin 3 (NLRP3) inflammasome. NF-κB is implicated in the pathogenesis of T2DM, and activation of NF-κB with induction of neuronal apoptosis was also confirmed in PD patients. Systemic activation of NLRP3 inflammasome promotes the accumulation of α-synuclein and degeneration of dopaminergic neurons in the SN. Increasing α-synuclein in PD patients enhances NLRP3 inflammasome activation and the release of interleukin (IL)-1β followed by the development of systemic inflammation and neuroinflammation. In conclusion, activation of the NF-κB/NLRP3 inflammasome axis in T2DM patients could be the causal pathway in the development of PD. The inflammatory mechanisms triggered by activated NLRP3 inflammasome lead to pancreatic β-cell dysfunction and the development of T2DM. Therefore, attenuation of inflammatory changes by inhibiting the NF-κB/NLRP3 inflammasome axis in the early T2DM may reduce future PD risk.

Hepatobiliary system and intestinal injury in new coronavirus infection (COVID-19): A retrospective study

An important area of effective control of the coronavirus disease 19 (COVID-19) pandemic is the study of the pathogenic features of severe acute respiratory syndrome coronavirus 2 infection, including those based on assessing the state of the intestinal microbiota and permeability. To study the clinical features of the new COVID-19 in patients with mild and moderate severity at the stage of hospitalization, to determine the role of hepatobiliary injury, intestinal permeability disorders, and changes in the qualitative and quantitative composition of the microbiota in the development of systemic inflammation in patients with COVID-19. The study was performed in 80 patients with COVID-19, with an average age of 45 years, 19 of whom had mild disease, and 61 had moderate disease severity. The scope of the examination included traditional clinical, laboratory, biochemical, instrumental, and radiation studies, as well as original methods for studying microbiota and intestinal permeability. The clinical course of COVID-19 was studied, and the clinical and biochemical features, manifestations of systemic inflammation, and intestinal microbiome changes in patients with mild and moderate severity were identified. Intestinal permeability characteristics against the background of COVID-19 were evaluated by measuring levels of proinflammatory cytokines, insulin, faecal calprotectin, and zonulin. This study highlights the role of intestinal permeability and microbiota as the main drivers of gastroenterological manifestations and increased COVID-19 severity.

Profiles of lipid, protein and microRNA expression in exosomes derived from intestinal epithelial cells after ischemia-reperfusion injury in a cellular hypoxia model.

Intestinal ischemia-reperfusion injury leads to proinflammatory responses via gut-derived mediators, and accumulating evidence suggests that exosomes secreted by intestinal epithelial cells are involved in the development of systemic inflammation. Studies have reported changes in protein, lipid, and microRNA (miRNA) expression; however, considering the different experimental conditions, information on the relationships among these biomolecules remains insufficient. The aim of this study was to elucidate the multiple changes that simultaneously occur in exosomes after ischemic stimulation. Here, differentiated human intestinal Caco-2 cells were exposed to 95% air (normoxia group) or 5% O2 (hypoxia group) for 6 h. Cells in each group were subsequently incubated for 24 h in an atmosphere of 5% CO2 plus 95% air. The conditioned medium of each group was collected for isolating intestinal epithelial cell-derived exosomes. Together with proteome analyses, lipid analyses, and miRNA quantification, biological functional assays were performed using monocytic NF-κB reporter cells. Lipid metabolism-related protein expression was upregulated, miRNA levels were slightly altered, and unsaturated fatty acid-containing lysophosphatidylcholine concentration increased after hypoxia and reoxygenation injury; this suggested that the changes in exosomal components associated with ischemia-reperfusion injury activates inflammation, including the NF-κB pathway. This study elucidated the multiple changes that co-occur in exosomes after ischemic stimulation and partially clarified the mechanism underlying exosome-mediated inflammation after intestinal ischemic recanalization.

The role of cytokines in the development of systemic inflammation in chronic obstructive pulmonary disease and obesity

Patients with chronic obstructive pulmonary disease (COPD) are characterized by a variety of comorbid conditions, including both somatic (arterial hypertension, atherosclerosis, coronary heart disease, bronchial asthma, malignant neoplasms, diabetes mellitus, obesity, etc.) and mental (depressive disorders, suicide attempts). Against the background of various chronic diseases of the respiratory system, endocrine, metabolic disorders, the risks of exacerbations of COPD increase. The leading unifying mechanism of these conditions is systemic subclinical inflammation. Its excessive activity leads to the loss of the physiological functions of inflammation, which is accompanied by an imbalance in the endocrine system and the release of high concentrations of hormones and neurotransmitters. The result of this response is the uncoupling of cytokine mechanisms, which leads to an imbalance in the system of pro- and anti-inflammatory cytokines. The article describes the role of the pro-inflammatory chemokine IL-8 (interleukin 8), which is responsible for the migration of neutrophils to the site of inflammation. This is how the neutrophilic type of inflammation is formed. IL-4 and IL-10 are considered, which occupy a leading position in the formation of CD4+ type of immunoreactivity, which is observed in bronchial asthma. Attention is focused on the significance of IL-6, because it is an integral component of local and systemic inflammation. An increase in its concentration and, as a result, a potential risk of damage to the respiratory epithelium is the remodeling of the bronchial tree, resulting in a decrease in the elasticity of the epithelium of the respiratory tract. This mechanism leads to the formation of pulmonary emphysema and further potentiation of pathophysiological processes in patients with COPD. Since IL-6 is a cytokine with anti-inflammatory properties, its molecular activity is achieved by interacting with a special receptor complex consisting of two subunits: IL-6R and gp130. The former mediates IL-6 binding, while the latter triggers the JAK/STAT or MAPK signaling cascade pathways. The result of the reaction of IL-6 with the effector cell directly depends on the type of signaling. The paper describes three mechanisms of signal transduction into the target cell: classical, cluster, and transsignaling. Thus, by studying the role of cytokines in the systemic inflammatory response, we have shown the cross-talk between adipose tissue and the lungs in obesity, highlighting the main inflammatory mediators, which may indicate new therapeutic targets for preventing pulmonary dysfunction.

Hepatitis C Virus Nonstructural Protein 3 Increases Secretion of Interleukin-lbeta in HEK293T Cells with a Reconstructed NLRP3 Inflammasome

The pathology of diseases arising from infections by viruses of Flaviviridae is largely determined by the development of systemic inflammation. The cytokines interleukin-1beta and interleukin-18 play a key role in triggering inflammation. Their secretion from cells, in its turn, is induced upon activation of inflammasomes. Activation of NLRP3 (NLR pyrin domain-containing family 3) inflammasomes was detected in cells infected with Flaviviridae. Some nonstructural proteins of these viruses have been shown to be able to activate or to inhibit the NLRP3 inflammasome, in particular, through interaction with its components. In this study, a functional NLRP3 inflammasome was reconstructed in human HEK293T cells and the effect of some nonstructural proteins of individual Flaviviridae viruses on it was studied. This model did not reveal any impact of nonstructural NS1 proteins of the West Nile virus, NS3 of hepatitis C virus, or NS5 of tick-borne encephalitis virus on the inflammasome components content. At the same time, in the presence of the NS1 of the West Nile virus and NS5 of the tick-borne encephalitis virus, the level of secretion of interleukin-1beta did not change, whereas in the presence of the NS3 protein of the hepatitis C virus, it increased by 1.5 times. Thus, NS3 can be considered as one of the factors of NLRP3 inflammasome activation and inflammatory pathogenesis in chronic hepatitis C virus infection.

Changes in immune status and cytoarchitectonics of neutrophil granulocytes during development of acute necrotic pancreatitis

The aim of the study is to study changes in immune status indicators and cytoarchitectonics of neutrophil granulocytes in patients with a severe course of acute necrotic pancreatitis. Materials and methods. The subject of the study was 32 patients aged 37 to 59 years, diagnosed with acute necrotizing pancreatitis, severe course, early phase. The control group was 30 donors, comparable by sex and age to the main group. Upon admission, atomic force microscopy of neurophilic granulocytes was performed to determine its shape, state of the membrane, geometric dimensions, and the immune status and chemical composition of the neutrophil were also evaluated. Results. During the development of severe acute pancreatitis in the early phase, immune inhibition along the cell link is recorded, a decrease in the concentration of immunoglobulins A and M. During atomic force microscopy, violations of the structural organization of the neutrophil granulocyte were found. Changes in the chemical state of the neutrophil were recorded, a significant decrease in the content of oxygen, sodium and calcium was revealed, which confirms the role of cellular hypoxia and apoptosis in the development of systemic inflammation. With an increase in the degree of severity of mechanical jaundice, the neutrophil acquired a convex shape, the number of nucleus segments increased, the cell membrane became not even, the neutrophil volume reached 61.58 ± 4.65 μm3. The value of neutrophil adhesion forces fell by 31% in severe pancreatitis. Conclusion. The severity of acute pancreatitis is due to the inhibition of the immune system and the functional capabilities of neutrophil granulocytes, leading to the generalization of the inflammatory reaction and the development of multi-organ insufficiency.

β-hydroxybutyrate enhances bovine neutrophil adhesion by inhibiting autophagy.

Subclinical ketosis (SCK) in dairy cows, a common metabolic disorder during the perinatal period, is accompanied by systemic inflammation and a high concentration of blood β-hydroxybutyrate (BHB). BHB induced adhesion of neutrophils may play a crucial role in the development of systemic inflammation in SCK cows. Autophagy, an intracellular degradation system, regulates the recycling of membrane adhesion molecules and may be involved in BHB regulating adhesion and pro-inflammatory activation of bovine neutrophils. Thus, the objective of this study was to determine the relationship between BHB, autophagy, and neutrophil adhesion. Here, elevated abundance of serum amyloid A, haptoglobin, C-reactive protein, interleukin-1β, interleukin-6, and tumor necrosis factor-α were found in SCK cows, and all these pro-inflammatory factors had a strong positive correlation with serum BHB. After BHB treatment, the number of adherent neutrophils and the adhesion associated protein abundance of both total and membrane CD11a, CD11b, and CD18 was greater, confirming that BHB promoted the adhesion of bovine neutrophils. However, the mRNA abundance of ITGAL (CD11a), ITGAM (CD11b), and ITGB2 (CD18) did not show a significant difference, suggesting that the degradation of adhesion molecules may be impaired. Transmission electron microscopy revealed a decreased number of autophagosomes and a decrease in mRNA abundance of SQSTM1 (p62) and MAP1LC3B (LC3) after BHB treatment. In parallel, protein abundance of p62 increased while the ratio of protein LC3 II to LC3 I decreased after BHB treatment, indicating that BHB inhibits autophagy of bovine neutrophils. To confirm the regulatory role of autophagy in BHB promoting neutrophil adhesion, we used an autophagy activator rapamycin (RAPA). Data showed that RAPA relieved the inhibitory effect on autophagy and the promotive effect on cell adhesion induced by BHB. Importantly, BHB inhibited the colocalization of LC3 and CD11b, which was relieved by RAPA, further confirming the regulatory role of autophagy in the recycling of the above adhesion molecules. Furthermore, BHB treatment increased the mRNA abundance and the release of pro-inflammatory factors IL-1B, IL-6, and TNF of bovine neutrophils, and these effects were attenuated by RAPA. Overall, the present study revealed that BHB promotes the adhesion of bovine neutrophils by inhibiting autophagy.

ЕКСПРЕСІЯ ГЕНІВ LRP1 ТА OLR1 У КРОВІ ХВОРИХ НА ОСТЕОАРТРИТПІСЛЯ SARS-CoV2-ІНФЕКЦІЇ

Background. Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infection was first reported in Wuhan, China in December 2019, and then spread rapidly worldwide, causing an estimated 771 million active cases with ~7 million deaths as of September 2023. The pandemic of the new coronavirus SARS-CoV-2 poses a great threat to the world in many aspects: medical, social, economic and other. A comprehensive understanding of the interaction of the virus with the body is fundamentally important in the fight against SARS-CoV-2. During the 2019 coronavirus disease (Coronavirus disease 2019, COVID-19), epithelial cells of the respiratory tract are affected, which is manifested by symptoms of a respiratory infection. The SARS-CoV-2 virus, as an infectious trigger, causes damage to other organ systems, in particular, the musculoskeletal system, and can also complicate the condition of patients with comorbid diseases. Мethods. The aim of the work was to determine the expression of LRP1 and OLR1 genes in the blood of patients with osteoarthritis after SARS-CoV2 infection. All study participants were divided into three groups. The first group (n = 10) is conditionally healthy people. The second group (n = 22) – patients with osteoarthritis of the knee joints II-III degree. The third group (n = 14) is patients with osteoarthritis of the knee joints II-III degree, who suffered a mild and moderate form of COVID-19 6–9 months ago. The expression of LRP1 and OLR1 genes was determined in the blood. RNA was obtained by the Chomczynski method. Synthesis of cDNA and quantitative polymerase chain reaction in real time (Real-time PCR, qPCR) using the commercial kit "Thermo Scientific Verso SYBR Green 1-Step qRT-PCR ROX Mix" ("Thermo Scientific, Lithuania). Processing of research results was carried out using generally accepted methods of variational statistics. Results. In the blood of patients with osteoarthritis, the expression of the LRP1 gene decreases and the expression of the OLR1 gene increases compared to a group of conditionally healthy people. In patients with osteoarthritis after infection with SARS-CoV-2, more significant violations of the expression of the studied genes are shown. Conclusions. The obtained data indicate a violation of the metabolism of lipoproteins in the body, the activation of free radical processes and the development of systemic inflammation, which leads to a decrease in vascular protection and endothelial dysfunction in patients with osteoarthritis, which increases under conditions of additional infectious load on the body under the influence of SARS-CoV2 infection.

Грудное вскармливание: первая ступень на пути к формированию сбалансированного состава кишечной микробиоты как один из способов профилактики некоторых социально значимых заболеваний

The non-systematic literature review describes the mechanisms by which breastfeeding prevents the development of the metabolic syndrome and socially significant diseases associated with it: obesity, diabetes type 2 and atopic diseases. One of the mechanisms of metabolic programming is the effect of breast milk on the development of the infant's intestinal microbiota. Human milk oligosaccharides can stimulate the growth of commensal bacteria. Cytokines, secretory immunoglobulins, leukocytes, lactoferrin and lysozyme can prevent colonization by pathogenic microorganisms and prevent an increase in the permeability of the intestinal barrier, the absorption of bacterial metabolic products, including lipopolysaccharide, and the development of systemic inflammation, including inflammation adipose tissue. Polyunsaturated fatty acids from breast milk prevent adipocyte hypertrophy at an early age and the development of obesity in the adults. Adiponectin prevents insulin resistance, other hormones that are part of breast milk influence the eating habits of children and prevent weight gain in adulthood. The inclusion of breast milk components in artificial mixtures has the potential to prevent the development of many socially significant diseases.

Associations Of Fatty Acid Composition In Leukocyte Membranes With Systemic Inflammation In Chronic Obstructive Pulmonary Disease Progression

Background — The development of systemic inflammation is a key pathogenetic mechanism in progression of chronic obstructive pulmonary disease (COPD). Fatty acids (FAs) and their oxidized derivatives serve as essential regulators of inflammation. The relationship between systemic inflammation and FA metabolism in COPD is poorly understood. In our research, we focused on examining the FA composition of the leukocyte membrane in COPD and the FA metabolism in association with systemic inflammation. Objective — We examined 137 patients with mild, moderate, or severe COPD. The control group comprised 32 healthy non-smokers. Methods — Blood cytokines and immune cell subpopulations were evaluated by flow cytometry. The FA composition of the leukocyte membranes was analyzed by gas chromatography. The concentrations of eicosanoids (thromboxane B2 (TXB2), leukotriene B4 (LTB4)) in plasma were measured by ELISA. Results — Our results implied systemic inflammation in all patients with COPD. The analysis of the FA composition of leukocyte membrane demonstrated increased level of saturated FAs and n-6 polyunsaturated fatty acids (PUFAs), along with reduced levels of monounsaturated FAs and n-3 PUFAs, in patients with COPD. The TXB2 and LTB4 content was increasing in COPD patients. We established a significant correlation with n-6 PUFAs, immune cells, and cytokines, which was indicative of an important role of FAs in the progress of systemic inflammation in COPD. Conclusion — Thus, FA modification of immune cells in patients with chronic pathologies of the bronchopulmonary system leads not only to disruption of the cell membrane structure, but also to the pathology of immune response regulation, and contributes to the development of the inflammatory process. The latter is a decisive factor in the pathogenesis of COPD.

Gut Dysbiosis in Children with Cystic Fibrosis: Development, Features and the Role of Gut-Lung Axis on Disease Progression.

Cystic fibrosis (CF) is the most common autosomal recessive disease among Caucasians. Over the last 20 years, culture-independent analysis, including next-generation sequencing, has paired with culture-based microbiology, offering deeper insight into CF lung and gut microbiota. The aim of this review is to analyse the features of gut microbiota in patients with CF and its possible role in the progression of the disease, establishing the basis for a potential role in microbe-based therapies. The literature analysis showed that the gut environment in CF patients has unique features due to the characteristics of the disease, such as decreased bicarbonate secretion, increased luminal viscosity, and an acidic small intestinal environment, which, due to the treatment, includes regular antibiotic use or a high-energy and fat-dense diet. As a result, the gut microbial composition appears altered, with reduced richness and diversity. Moreover, the population of pro-inflammatory bacteria is higher, while immunomodulatory genera, such as Bacteroides and Bifidobacterium, are scarcer. The imbalanced gut microbial population has a potential role in the development of systemic inflammation and may influence clinical outcomes, such as respiratory exacerbations, spirometry results, and overall growth. Although a better understanding of the pathophysiology behind the gut-lung axis is needed, these findings support the rationale for considering gut microbiota manipulation as a possible intervention to regulate the severity and progression of the disease.

Study of the Antioxidant Properties of Filipendula ulmaria and Alnus glutinosa.

The demographic situation of the last few decades is characterized by the increased numbers of elderly and senile people, i.e., by the aging of the population. In humans, ageing is closely associated with the enhanced production of reactive oxygen species (ROS), development of systemic inflammation and related vascular atherosclerotic alterations and metabolic disorders, like obesity, diabetes mellitus and neurodegenerative diseases. As these age-related alterations are directly associated with up-regulation of ROS production and development of chronic oxidative stress, their onset can be essentially delayed by continuous daily consumption of dietary antioxidants—natural products of plant origin. Such antioxidants (in the form of plant extracts, biologically active complexes or individual compounds) can be supplemented to functional foods, i.e., dietary supplementations for daily diet aiming prolongation of active life and delay of the senescence onset. Thereby, use of widely spread medicinal plants might essentially improve cost efficiency of this strategy and availability of antioxidant-rich functional foods. Therefore, here we addressed, to the best of our knowledge for the first time, the antioxidant activity of the extracts prepared from the aerial parts of Filipendula ulmaria and Alnus glutinosa growing in the Kaliningrad region of Russia, and assessed the contents of the biologically active substances underlying these properties. It was found that the extract prepared with the leaves of Filipendula ulmaria and female catkins of Alnus glutinosa demonstrated high antioxidant activity, although the former plant was featured with a higher antioxidant potential. The highest antioxidant activity detected in the methanol extracts of Alnus glutinosa reached 1094.02 ± 14.53 µmol TE/g, radical scavenging of activity was 584.45 ± 35.3 µmol TE/g, reducing capacity at interaction with iron complex—471.63 ± 7.06 µmol TE/g. For the methanol extracts of Filipendula ulmaria the antioxidant activity reached 759.78 ± 19.08 µmol TE/g, antioxidant activity for free radical removal was 451.08 ± 24.45 µmol TE/g and antioxidant activity for restorative ability with iron complex was 332.28 ± 10.93 µmol TE/g. These values are consistent with the total yields of the extracts and their content of ellagic acid. The ethyl acetate extracts of the both plants showed just minimal antioxidant activity. Thus, the considered extracts have an essential potential. This creates good prospects for the further use of herbal extracts of Filipendula ulmaria and Alnus glutinosa as a source of natural antioxidants.

Anti-inflammatory properties of the extract of maruna virgin (Tanacetum parthenium L.) on the model of chronic inflammation modeled by the Freund’ adjuvant in rats

Еhe aim of the study was to investigate the effectiveness of a thick extract of feverfew (Tanacetum parthenium L.) herb in chronic inflammation (adjuvant arthritis) in rats.
 The anti-inflammatory properties of the water-alcohol thick extract of feverfew (Tanacetum parthenium L.) herb (ETP) were studied in the model of adjuvant arthritis (ADA) (0.1 ml of Freund's adjuvant (PAF), once subcutaneously at the base of the tail of white nonlinear male rats (body weight 200–220 g). After 7 days, the introduction of PAF was repeated (subcutaneously in the right hind paw of rats). The animals were divided into 4 groups of 9 rats each, in the intact group – 6 animals. Distilled water (1 ml/100 g) was administered to positive control animals (PCs) on the background of pathology. An aqueous solution of ETP (50 mg/kg) and diclofenac sodium (1% starch suspension, 8 mg/kg) were administered from day 1 of the experiment and for four weeks daily intragastrically once daily. The volume of the affected foot (V) was measured using a LE7500 plethysmometer (PANLAB, Italy) in dynamics – at 1, 5, 10, 15, 20, 25 and 30 days after administration of a permissive dose of PAF. The intensity of inflammation in rats was assessed by peripheral blood parameters, biochemical indicators - markers of the inflammatory process. Statistical analysis of data was performed using the standard software package «Statistica v. 6.0». Differences between groups were considered statistically significant at p <0.05.
 The course of ADA was characterized by the development of systemic inflammation, as evidenced by an increase in the number of leukocytes, increased erythrocyte sedimentation rate (ESR) and the content of C-reactive protein (CRP). A statistically significant increase in the level of LF and sialic acids indicates membrane-destructive processes in connective tissue. Against the background of ETP significantly decreased the level of the main indicator of inflammation CRP 2 times, the content of markers of destruction of joint tissue – sialic acid and LF decreased by 1.9 times relative to PC animals, indicating a positive effect on local and systemic manifestations of inflammation in ADA. The effectiveness of ETP was not inferior to diclofenac sodium (DS).
 Based on the data obtained, it can be concluded that the studied ETP at a dose of 50 mg/kg in the ADA model in rats has a pronounced anti-inflammatory effect and is not inferior to diclofenac sodium, which makes it promising further research as an effective anti-inflammatory agent.

The Effect of Erythrocyte-Containing Donor Blood Components in the Priming of the Cardiopulmonary Bypass Circuit on the Development of Systemic Inflammation During Correction of Congenital Heart Defects in Children

Various pathological factors accompanying any cardiac surgery can cause intraoperative systemic inflammatory responses (SIR). As the number of cardiac surgical interventions grows worldwide, the issue of SIR prevention appears highly relevant.Aim of the study. To determine the effect of not using donor blood components in the priming of the cardiopulmonary bypass circuit in children with septal congenital heart defects, operated under cardiopulmonary bypass, on the severity of SIR.Material and methods. A prospective, randomized study included 40 children with a median age of 14 [12–22.5] months and weight of 8.8 [7.25–11] kg. All patients underwent radical correction of septal defect under cardiopulmonary bypass. The patients were divided into two groups depending on the use of donor blood components for priming the CPB. The severity of SIR was assessed using four specific serum biomarkers such as interleukin 1b (IL-1b), interleukin 6 (IL-6), interleukin 10 (IL-10), and tumor necrosis factor alpha (TNF-α), measured before the operation, after the CPB and 16 hours after the surgery. In addition, the intra- and postoperative periods were evaluated.Results. The safety of the proposed strategy of skipping the donor blood was confirmed by lack of any organ dysfunction in all patients, as well as a significant difference in the balance of oxygen delivery and consumption. In addition, the levels of systemic inflammation markers after CPB were significantly higher in patients who had transfusion: IL-1b was 3.3 [3.2–3.48] pg/mL vs 2.86 [2.7–3.11] pg/mL (P=0.003) and TNF-α reached 1.81 [1.37–3.3] pg/mL vs 1.33 [1.26–1.76] pg/mL (P=0.034). Meanwhile, 16 hours post surgery, IL-6 and IL-10 levels were significantly higher in the group using donor blood components with IL-6 being 48.91 [33.89–57.6] pg/mL vs 31.56 [26.83–48.89] pg/mL (P=0.087) and IL-10 reaching 0.8 [0.76–1.43] pg/mL vs 0.69 [0.6–0.83] pg/mL (P=0.005).Conclusion. The study demonstrates and confirms the safety and efficacy of cardiopulmonary bypass without using donor blood components to reduce the severity of the systemic inflammatory response in children undergoing correction of septal congenital heart defects.

Circular RNA Hecw1 Regulates the Inflammatory Imbalance in Spinal Cord Injury via miR-3551-3p/LRRTM1 Axis.

Spinal cord injury (SCI) is a neurological disease having devastating effect and results in the development of systemic inflammation. However, the molecular mechanisms of SCI remain not entirely elucidated. This study was directed toward exploring the circ Hecw1 involved in the mechanism of lipopolysaccharide (LPS)-triggered inflammation damage in neuronal cells. The in vitro model of SCI based on PC12 cells were established with lipopolysaccharide. The cell proliferation was determined by the use of cell counting kit-8 (CCK8). The expressions of circHecw1, miR-3551-3p, and inflammatory factors were measured by quantitative real-time PCR and ELISA assay. Flow cytometry was used to assess apoptosis. Western blot analysis was performed for the purpose of determining LRRTM1 and NF-kB signaling. The expression of circ Hecw1, TNF-α, IL-6, and IL-1β in LPS-triggered PC12 cells and the expression of miR-3551-3p and IL-10 were significantly decreased. Knockdown of circHecw1 promoted proliferation and inhibited apoptosis and reduction in the inflammatory cytokine expression. Our study revealed that circHecw1 regulates SCI neuronal cell inflammation imbalance by regulating the miR-3551-3p/LRRTM1 signaling.

Pivotal role of adipocyte‐Na/K‐ATPase Signaling in the pathogenesis of Experimental Uremic Cardiomyopathy by fat transplantation

ObjectiveMounting evidence highlights the role of adipose tissue in the development of systemic inflammation that contributes to various metabolic abnormalities. We have recently demonstrated that administration of NaKtide, antagonist of Na/K‐ATPase (NKA) signaling, coupled to adipocyte specific promoter can improve adipocyte phenotype and further attenuated experimental uremic cardiomyopathy. Studies have shown that transplanting brown adipose tissue from C57BL6 mice reduced obesity and improved whole energy metabolism. Therefore, the objective of the present study is to explore the specific role of adipocyte function in systemic inflammation and associated pathologies of uremic cardiomyopathy using adipose tissue transplantation studies.HypothesisIn the present study, we hypothesize that, the transplantation of NaKtide transfected subcutaneous fat into mice with partial nephrectomy (PNx) may help to provide a deeper understanding of adipocyte‐NKA signaling, that modulate the progression of uremic cardiomyopathy.MethodsFollowing 4 weeks of PNx or Sham surgery and lenti‐adiponectin‐Naktide in C57BL6 mice, 200 mg of subcutaneous fat pads were dissected and subcutaneously transplanted into the dorsal interscapular region of the recipient mice at the time of the PNx surgery. The tissues were harvested for morphological and molecular analyses after 8 weeks of transplantation. Statistical analysis of the data were performed by one‐way analysis of variance.ResultsThe immunofluorescence staining showed high expression of NaKtide in fat tissues of mice transplanted with NaKtide transfected fat. The pSrc protein expression in the fat tissue was significantly upregulated in PNx, which was significantly down‐regulated by PNx+NaKtide fat transplantation (p<0.01). The adipose tissue dysfunction during PNx was assessed by the level of protein carbonylation and mRNA expression of IL‐1β and Sirt2, which were significantly reversed by NaKtide transfected fat (p<0.01). The transplantation of NaKtide transfected adipose tissue significantly improved the systemic inflammation (p<0.01). The altered plasma miRNA expressions in PNx were also normalized by NaKtide transfected fat transplantation. PNx mice developed cardiomyopathy characterized by increased heart weight and decreased cardiac function, assessed by echocardiography measurements (p<0.01). These alterations were reversed by the transplantation of adipose tissues from PNx+NaKtide donor mice (p<0.01). The mice transplanted with the fat tissue of PNx+NaKtide showed significantly decreased cardiac fibrosis, when compared to PNx heart, which was further confirmed by the mRNA expression of major fibrotic genes in cardiac tissues.ConclusionThe study demonstrates that, the inhibition of adipocyte‐NKA signaling in uremic cardiomyopathy could modulate the adipocyte redox state that resulted in the manipulation of systemic inflammatory milieu and associated pathophysiological mechanisms, which can be used as a clinical target for therapeutic intervention of uremic cardiomyopathy.