The Roles Of MicroRNAs On Tuberculosis Infection: Meaning Or Myth?

The central proteins for protection against tuberculosis are attributed to interferon-γ, tumor necrosis factor-α, interleukin (IL)-6 and IL-1β, while IL-10 primarily suppresses anti-mycobacterial responses. Several studies found alteration of expression profile of genes involved in anti-mycobacterial responses in macrophages and natural killer (NK) cells from active and latent tuberculosis and from tuberculosis and healthy controls. This alteration of cellular composition might be regulated by microRNAs (miRNAs). Albeit only 1% of the genomic transcripts in mammalian cells encode miRNA, they are predicted to control the activity of more than 60% of all protein-coding genes and they have a huge influence in pathogenesis theory, diagnosis and treatment approach to some diseases. Several miRNAs have been found to regulate T cell differentiation and function and have critical role in regulating the innate function of macrophages, dendritic cells and NK cells. Here, we have reviewed the role of miRNAs implicated in tuberculosis infection, especially related to their new roles in the molecular pathology of tuberculosis immunology and as new targets for future tuberculosis diagnostics

Gastric Carcinoma

Gastric cancer is one of the most common tumors worldwide. It has a heterogeneous milieu, where the genetic background, tumor immunology, oxidative stress, and microbial infections are key players in the multiple stages of tumorigenesis. These diverse factors are linked to the prognosis of the gastric cancer and the survival of gastric cancer patients. This book is appropriate for scientists and students in the field of oncology, gastroenterology, molecular biology, immunology, cell biology, biology, biochemistry, and pathology. This authoritative text carefully explains the fundamentals, providing a general overview of the principles followed by more detailed explanations of these recent topics efficiently. The topics presented herein contain the most recent knowledge in gastric cancer concerning the oncogenic signaling, genetic instability, the epigenetic aspect, molecular features and their clinical implications, miRNAs, integrin and E-cadherin, carbohydrate-associated-transferases, free radicals, immune cell responses, mucins, Helicobacter-pylori, neoadjuvant and adjuvant therapy, prophylactic strategy for peritoneal recurrence, and hepatic metastasis

Epigenetic Mediated Antimicrobial Resistance:Host versus Pathogen Epigenetic Alterations

Since the discovery of antibiotics, humans have been benefiting from them by decreasing the morbidity and mortality associated with bacterial infections. However, in the past few decades, misuse of antibiotics has led to the emergence of bacterial infections resistant to multiple drugs, a significant health concern. Bacteria exposed to inappropriate levels of antibiotics lead to several genetic changes, enabling them to survive in the host and become more resistant. Despite the understanding and targeting of genetic-based biochemical changes in the bacteria, the increasing levels of antibiotic resistance are not under control. Many reports hint at the role of epigenetic modifications in the bacterial genome and host epigenetic reprogramming due to interaction with resistant pathogens. Epigenetic changes, such as the DNA-methylation-based regulation of bacterial mutation rates or bacteria-induced histone modification in human epithelial cells, facilitate its long-term survival. In this review article, epigenetic changes leading to the development of antibiotic resistance in clinically relevant bacteria are discussed. Additionally, recent lines of evidence focusing on human host epigenetic changes due to the human–pathogen interactions are presented. As genetic mechanisms cannot explain the transient nature of antimicrobial resistance, we believe that epigenetics may provide new frontiers in antimicrobial discovery

Monotsüütide, monotsüütidest pä rinevate makrofaagide ja dendriitrakkude epigeneetilised profiilid

Väitekirja elektrooniline versioon ei sisalda publikatsioone.Immuunsüsteemi peamiseks ülesandeks on kaitsta organismi nakkushaiguste eest vältides samal ajal oma kudede kahjustamist. See tagatakse immuunrakkude mitmetasandilise reguleeritud koostöö tulemusena. Käesolev uurimus keskendub dendriitrakkudele, mis on immuunsüsteemi peamised antigeeni esitlevad rakud. Dendriitrakkudel on oluline roll nii immuunvastuse esilekutsumises kui ka kahjulike reaktsioonide mahasurumises. Nad töötlevad võõrast materjali ning presenteerivad seda oma raku pinnal teistele immunrakkudele, juhtides seeläbi teiste immuunrakkude tegevust. Koostöös monotsüütide, makrofaagide ja teiste immuunrakkudega, tagavad dendriitrakud organismi immuuntasakaalu. Katseklaasis, aga ka põletikukoldes, saadakse dendriitrakke veres tsirkuleerivatest monotsüütidest. Monotsüütidest pärinevaid dendriitrakke uuritakse jätkuvalt väga põhjalikult ning nad on praegusel hetkel ühed kõige lootustandvamad rakud vähi ja mitmete autoimmuunsete haiguste immuunteraapias. Selle töö eesmärgiks oli uurida geeniregulatsiooni muutusi, mis toimuvad monotsüütides nende diferentseerumisel dendriitrakkudeks ning tuvastada erinevusi monotsüütides noortel ning vanadel inimestel. Uurisime geenide avaldumise regulatsiooni epigeneetilisi muutuste abil monotsüütide diferentseerumisel. Epigeneetika on teadus, mis proovib selgitada, kuidas väga piiratud arve geene saab aluse panna erinevatele rakutüüpidele mõjutamata sealjuures DNA järjestust. Monotsüüdi diferentseerumisel makrofaagiks ja dendriitrakuks leiavad aset mitmed epigeneetilised muutused. Kirjeldasime monotsüütide, monotsüütidest pärinevatel makrofaagide ja dendriitrakkude geeniekspressioone, histoonide modifikatsioone ja mikroRNA profiile. Näitasime, et geenide aktiivsus ja histooni modifikatsioonide muster on väga hästi korreleeritav. Kirjeldasime dendriitrakkude ja makrofaagide mikroRNA ekspressiooni profiile, millest leidsime mitmeid ülesreguleeritud mikroRNAsid, sealhulgas ka varem kirjeldamata miR-511. Lisaks diferentseerumisele, kirjeldasime ka mitmeid erinevalt metüleeritud alasid vananemisel noorte ja vanade indiviidide monotsüütides, mis võivad osutuda kasulikuks mõistmaks paremini epigeneetika rolli vananemisel ning pakkumaks tulevikus uusi lähenemisi põletikuliste protsesside kontrolliks.The purpose of the immune system is to protect the body against diseases meanwhile avoiding damaging of tissues. This is provided by tightly regulated multilevel cooperation of the immune cells. This thesis focuses on dendritic cells; main antigen presenting cells in immune system. Dendritic cells are important both in inducing immune responses and in suppressing harmful reactions. They process foreign material and present it on their cell surface to other immune cells, thereby mediate the action of other immune cells. In cooperation with monocytes, macrophages and other immune cells, dendritic cells help to maintain the immune homeostasis in organisms. In vitro, but also in case of an infection, dendritic cells are rapidly generated in large numbers from monocytes. These monocyte-derived dendritic cells are under going extensive study and are currently the most promising cell type to be used in immunotherapy for cancer and various autoimmune diseases. The aim of this thesis is to study the changes in gene regulation in monocyte differentiation to dendritic cells and to identify differences in monocytes in young and elderly individuals. We studied gene expression regulation through epigenetic changes in monocyte differentiation. Epigenetics is a study that tries to clarify how limited number of genes can define different cell types without affecting the DNA sequence. In the differentiation of monocytes into macrophages and dendritic cells, several epigenetic changes take place. We described gene expression profiles, histone modifications and microRNA profiles in monocytes, monocyte-derived macrophages and dendritic cells. We showed that gene activity and histone modifications are in good correlation. We also described updated microRNAs expression profiles of dendritic cells and macrophages that revealed several upregulated miRNAs, among others novel miR-511. In addition to differentiation, we also described several differentially methylated CpG sites in monocytes of young and elderly individuals during ageing process that may be useful to better understand the role of epigenetics in ageing and provide new approaches to control inflammatory processes in future

Biomarkers in the Light of the Etiopathology of IC/BPS

In this review, we focused on putatively interesting biomarkers of interstitial cystitis/bladder pain syndrome (IC/BPS) in relation to the etiopathology of this disease. Since its etiopathology is still under discussion, the development of novel biomarkers is critical for the correct classification of the patients in order to open personalized treatment options, on the one hand, and to separate true IC/BPS from the numerous confusable diseases with comparable symptom spectra on the other hand. There is growing evidence supporting the notion that the classical or Hunner-type IC (HIC) and the non-Hunner-type IC (NHIC) are different diseases with different etiopathologies and different pathophysiology at the full-blown state. While genetic alterations indicate close relationship to allergic and autoimmune diseases, at present, the genetic origin of IC/BPS could be identified. Disturbed angiogenesis and impairment of the microvessels could be linked to altered humoral signaling cascades leading to enhanced VEGF levels which in turn could enhance leucocyte and mast cell invasion. Recurrent or chronic urinary tract infection has been speculated to promote IC/BPS. New findings show that occult virus infections occurred in most IC/BPS patients and that the urinary microbiome was altered, supporting the hypothesis of infections as major players in IC/BPS. Environmental and nutritional factors may also influence IC/BPS, at least at a late state (e.g., cigarette smoking can enhance IC/BPS symptoms). The damage of the urothelial barrier could possibly be the result of many different causality chains and mark the final state of IC/BPS, the causes of this development having been introduced years ago. We conclude that the etiopathology of IC/BPS is complex, involving regulatory mechanisms at various levels. However, using novel molecular biologic techniques promise more sophisticated analysis of this pathophysiological network, resulting in a constantly improvement of our understanding of IC/BPS and related diseases

The glycosyltransferase ST3GAL2 is regulated by miR-615-3p in the intestinal tract of Campylobacter jejuni infected mice

Background Campylobacter jejuni (C. jejuni) infections are of increasing importance worldwide. As a typical mucosal pathogen, the interaction of C. jejuni with mucins is a prominent step in the colonisation of mucosal surfaces. Despite recent advances in understanding the interaction between bacterial pathogens and host mucins, the mechanisms of mucin glycosylation during intestinal C. jejuni infection remain largely unclear. This prompted us to identify relevant regulatory networks that are concerted by miRNAs and could play a role in the mucin modification and interaction. Results We firstly used a human intestinal in vitro model, in which we observed altered transcription of MUC2 and TFF3 upon C. jejuni NCTC 11168 infection. Using a combined approach consisting of in silico analysis together with in vitro expression analysis, we identified the conserved miRNAs miR-125a-5p and miR-615-3p associated with MUC2 and TFF3. Further pathway analyses showed that both miRNAs appear to regulate glycosyltransferases, which are related to the KEGG pathway ‘Mucin type O-glycan biosynthesis’. To validate the proposed interactions, we applied an in vivo approach utilising a well-established secondary abiotic IL-10−/− mouse model for infection with C. jejuni 81-176. In colonic tissue samples, we confirmed infection-dependent aberrant transcription of MUC2 and TFF3. Moreover, two predicted glycosyltransferases, the sialyltransferases ST3GAL1 and ST3GAL2, exhibited inversely correlated transcriptional levels compared to the expression of the identified miRNAs miR-125a-5p and miR-615-3p, respectively. In this study, we mainly focused on the interaction between miR-615-3p and ST3GAL2 and were able to demonstrate their molecular interaction using luciferase reporter assays and RNAi. Detection of ST3GAL2 in murine colonic tissue by immunofluorescence demonstrated reduced intensity after C. jejuni 81-176 infection and was thus consistent with the observations made above. Conclusions We report here for the first time the regulation of glycosyltransferases by miRNAs during murine infection with C. jejuni 81-176. Our data suggest that mucin type O-glycan biosynthesis is concerted by the interplay of miRNAs and glycosyltransferases, which could determine the shape of intestinal glycosylated proteins during infection