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

Unique Signatures of Natural Background Radiation on Human Y Chromosomes from Kerala, India

The most frequently observed major consequences of ionizing radiation are chromosomal lesions and cancers, although the entire genome may be affected. Owing to its haploid status and absence of recombination, the human Y chromosome is an ideal candidate to be assessed for possible genetic alterations induced by ionizing radiation. We studied the human Y chromosome in 390 males from the South Indian state of Kerala, where the level of natural background radiation (NBR) is ten-fold higher than the worldwide average, and that from 790 unexposed males as control.We observed random microdeletions in the Azoospermia factor (AZF) a, b and c regions in >90%, and tandem duplication and copy number polymorphism (CNP) of 11 different Y-linked genes in about 80% of males exposed to NBR. The autosomal homologues of Y-linked CDY genes largely remained unaffected. Multiple polymorphic copies of the Y-linked genes showing single Y-specific signals suggested their tandem duplication. Some exposed males showed unilocus duplication of DAZ genes resulting in six copies. Notably, in the AZFa region, approximately 25% of exposed males showed deletion of the DBY gene, whereas flanking genes USP9Y and UTY remained unaffected. All these alterations were detected in blood samples but not in the germline (sperm) samples.Exposure to high levels of NBR correlated with several interstitial polymorphisms of the human Y chromosome. CNPs and enhanced transcription of the SRY gene after duplication are envisaged to compensate for the loss of Y chromosome in some cells. The aforesaid changes, confined to peripheral blood lymphocytes, suggest a possible innate mechanism protecting the germline DNA from the NBR. Genome analysis of a larger population focusing on greater numbers of genes may provide new insights into the mechanisms and risks of the resultant genetic damages. The present work demonstrates unique signatures of NBR on human Y chromosomes from Kerala, India

Genetic instability in lung cancer: concurrent analysis of chromosomal, mini- and microsatellite instability and loss of heterozygosity

To investigate what kind of genetic instability plays important roles in lung carcinogenesis, we analyzed micro- and minisatellite instability, loss of heterozygosity (LOH) and chromosome instability in 55 cases of lung cancer, including, 10 squamous cell, 5 large cell, and 3 small cell carcinomas, and 37 adenocarcinomas. Analysis of minisatellite instability, the mechanism of which is different from microsatellite instability, has not been reported previously. Minisatellite instability was detected in only one case (1/55, 1.8%), and the frequency of microsatellite instability was low, being found only in three cases (3/55, 5.5%). In contrast, LOH, for at least in one locus, was observed in 27 cases (49.1%). In adenocarcinomas, the frequency of LOH was higher in poorly differentiated compared to more differentiated carcinomas. For chromosome instability, a similar correlation between differentiation grade and instability was observed in adenocarcinomas. And instability was more common in large cell and small cell carcinomas than in adenocarcinomas. Our analysis showed that chromosome instability and LOH, rather than mini- and microsatellite instability, play significant roles in the development of lung cancer

Dioxin Induces Genomic Instability in Mouse Embryonic Fibroblasts

Ionizing radiation and certain other exposures have been shown to induce genomic instability (GI), i.e., delayed genetic damage observed many cell generations later in the progeny of the exposed cells. The aim of this study was to investigate induction of GI by a nongenotoxic carcinogen, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Mouse embryonic fibroblasts (C3H10T1/2) were exposed to 1, 10 or 100 nM TCDD for 2 days. Micronuclei (MN) and expression of selected cancer-related genes were assayed both immediately and at a delayed point in time (8 days). For comparison, similar experiments were done with cadmium, a known genotoxic agent. TCDD treatment induced an elevated frequency of MN at 8 days, but not directly after the exposure. TCDD-induced alterations in gene expression were also mostly delayed, with more changes observed at 8 days than at 2 days. Exposure to cadmium produced an opposite pattern of responses, with pronounced effects immediately after exposure but no increase in MN and few gene expression changes at 8 days. Although all responses to TCDD alone were delayed, menadione-induced DNA damage (measured by the Comet assay), was found to be increased directly after a 2-day TCDD exposure, indicating that the stability of the genome was compromised already at this time point. The results suggested a flat dose-response relationship consistent with dose-response data reported for radiation-induced GI. These findings indicate that TCDD, although not directly genotoxic, induces GI, which is associated with impaired DNA damage response

Y-chromosomal diversity in Europe is clinal and influenced primarily by geography, rather than by language

Clinal patterns of autosomal genetic diversity within Europe have been interpreted in previous studies in terms of a Neolithic demic diffusion model for the spread of agriculture; in contrast, studies using mtDNA have traced many founding lineages to the Paleolithic and have not shown strongly clinal variation. We have used 11 human Y-chromosomal biallelic polymorphisms, defining 10 haplogroups, to analyze a sample of 3,616 Y chromosomes belonging to 47 European and circum-European populations. Patterns of geographic differentiation are highly nonrandom, and, when they are assessed using spatial autocorrelation analysis, they show significant dines for five of six haplogroups analyzed. Clines for two haplogroups, representing 45% of the chromosomes, are continentwide and consistent with the demic diffusion hypothesis. Clines for three other haplogroups each have different foci and are more regionally restricted and are likely to reflect distinct population movements, including one from north of the Black Sea. principal-components analysis suggests that populations are related primarily on the basis of geography, rather than on the basis of linguistic affinity. This is confirmed in Mantel tests, which show a strong and highly significant partial correlation between genetics and geography but a low nonsignificant partial correlation between genetics and language. Genetic-barrier analysis also indicates the primacy of geography in the shaping of patterns of variation. These patterns retain a strong signal of expansion from the Near East but also suggest that the demographic history of Europe has been complex and influenced by other major population movements, as well as by linguistic and geographic heterogeneities and the effects of drift

Computed tomography and magnetic resonance imaging in the diagnosis of the small and large intestine strictures in Crohn’s disease. Radiological semiotics and assessment of the inflammation activity

Rationale: Crohn's disease is characterized by continuous severe course, and in a half of the patients is associated with formation of strictures that are difcult to treat and significantly decrease quality of life. Difficulties during the differentiation between inflammation-related and fbrostenotic strictures and divergent approaches to their treatment in patients with Crohn's disease indicate the need in precise diagnostics and systematization of the radiological semiotics of strictures.Aim: To propose radiological semiotics of the small and large intestine strictures based on the results of multiaxial computed tomography (MACT) and magnetic resonance imaging (MRI).Materials and methods: MACT and MRI visualization was performed in 40 patients with a stenotic type of Crohn's disease.Results: The radiological signs of the strictures were classifed into two main groups: intestinal and extra-intestinal. They were systematized according to nine criteria, such as character of formation, etiology, number, inflammation grade, extension, shape, and location, presence of ileus and presence of other complications. The inflammation activity in the intestinal wall was evaluated during the postcontrast assessment: active inflammation in the arterial phase (at 25 seconds after administration of the contrast agent), chronic inflammation in the delayed phase (at 10 minutes). The MRI results were cross-checked with those of MACT. At the precontrast stage, MRI was more informative as per the width of the intestinal lumen, whereas MACT was preferential in the diagnosis of fat infltration of the intestinal wall. Post-contrast MACT and MRI were diagnostically equivalent. The most indicative for active inflammation were diffuse weighed MRI images, arterial phase MACT and MRI, whereas chronic inflammation and wall fbrosis were better diagnosed at the delayed phase (at 10 minutes) of MACT and MRI. Both methods (MACT and MRI) could not differentiate between the submucous and muscular layers of the intestinal wall. Mixed type of inflammation was seen in the walls of intestinal strictures: chronic inflammation dominated in the intermediate, most extensive part of a stricture and remained stable during the dynamic follow-up, whereas active inflammation was found in the marginal parts of the strictures, which were most susceptible to changes during the follow-up.Conclusion: Based on a set of certain signs obtained by radiological visualization, we propose a registry for stricture assessment based on evaluation of the inflammation activity