Генетические особенности, связанные с обменом интерлейкинов у пациентов с гепатоцеллюлярной карциномой вследствие вирусного гепатита С

ГЕПАТИТ C /ПАТОФИЗИОЛПАРЕНТЕРАЛЬНО-ПЕРЕДАВАЕМЫЙ ГЕПАТИТ НИ-A, НИ-B /ПАТОФИЗИОЛПЕЧЕНИ НОВООБРАЗОВАНИЯРАК ПЕЧЕНИГЕПАТОЦЕЛЛЮЛЯРНАЯ КАРЦИНОМА /ГЕНЕТИНТЕРЛЕЙКИНЫМеханизмы образования гепатоцеллюлярной карциномы (ГЦК) остаются не до конца изученными. Имеются определенные генетические особенности, связанные с развитием ГЦК. Целью исследования являлось установить генетические особенности, связанные с интерлейкиновой стимуляцией и ассоциированные с развитием гепатоцеллюлярной карциномы у пациентов с вирусным гепатитом С (ВГС). Материал и методы. Генетические особенности пациентов с заболеваниями печени определялись путем сравнительного анализа экспрессии генов в тканях печени на основании результатов секвенирования, размещенных в открытых базах данных у 72 пациентов с гепатоцеллюлярной карциномой, вследствие гепатита С и 24 пациентов без поражения печени. Результаты. У пациентов с ГЦК-ВГС наблюдается повышенная экспрессия 4330 (7,93%) генов и сниженная экспрессия 693 (1,27%) генов по сравнению со здоровыми лицами. Среди сигнальных путей, связанных с активностью интерлейкинов так же, как и у пациентов с ГЦК-ВГС наибольшее число генов вовлечено в сигнальный путь интерлейкина-11, IL-1, IL-4 и IL-13, IL-10. Заключение. Установлена повышенная выработка провоспалительных цитокинов IL-1, 4, 6, 8, 13, обеспечивающих преимущественно гиперэкспрессии генов, связанных с JAK/STAT сигнальным путем. В то же время наблюдается выработка противовоспалительных цитокинов, таких как IL-10, 11, обеспечивающих рост и пролиферацию клеток, ангиогенез, регуляцию процессов апоптоза

EFFECT OF TOLL-LIKE RECEPTOR INHIBITOR IMIQUIMOD ON IL1R1 INTERACTION WITH IL-1RA AND ITS SNP VARIANT-AN IN SILICO APPROACH

Objective: Interleukin 1 receptor antagonist (IL1Ra) acts as an antagonist to Interleukin 1 beta (IL1β) signalling in maintaining homeostasis. A loss of function due to Single Nucleotide Polymorphism (SNP) occurrence in IL1Ra can lead to dysregulated state as seen in autoimmune disease pathogenesis. The current study aims at achieving conformational stability in the IL1R1-IL1Ra_SNP complex by introducing a ligand into the region apart from the active site of Interleukin 1 receptor type1 (IL1R1).Methods: Protein-protein docking was performed using ClusPro, for IL1R1 with IL1β, IL1Ra and IL1Ra_SNP variant to study the difference in the interaction between the complexes. A known inhibitor, Imiquimod was docked using Glide, to the Il1R1-IL1Ra_SNP complex using flexible docking and the change in surface energy was calculated.Results: Binding Interactions show that IL1Ra binds more avidly to IL1R1 than IL1β. Conformational instability was seen in the IL1R1-IL1Ra_SNP complex. The difference in the amino acid interactions between the IL1R1 with IL1Ra and IL1Ra_SNP variant further illustrated the change in binding residues and hydrogen bond formation. Upon docking of an appropriate ligand to the IL1R1-IL1Ra_SNP complex, the conformational stability of the IL1R1-IL1Ra_SNP complex enhanced considerably suggesting a possible mechanism for treating SNP-induced conformational instability.Conclusion: Toll-like receptors like IL1R1 have many binding pockets apart from its active site. No strategies have yet been reported in targeting them for correcting conformational instability induced by SNP. Through our study, it was observed that the conformational instability of IL1R1-IL1Ra_SNP complex decreased upon introducing an appropriate small molecule.Keywords: IL1β, IL1R1, IL1Ra, SN

Colorectal Cancer Biology

Colorectal cancer is a common disease, affecting millions worldwide and represents a global health problem. Effective therapeutic solutions and control measures for the disease will come from the collective research efforts of clinicians and scientists worldwide. This book presents the current status of the strides being made to understand the fundamental scientific basis of colorectal cancer. It provides contributions from scientists, clinicians and investigators from 20 different countries. The four sections of this volume examine the evidence and data in relation to genes and various polymorphisms, tumor microenvironment and infections associated with colorectal cancer. An increasingly better appreciation of the complex inter-connected basic biology of colorectal cancer will translate into effective measures for management and treatment of the disease. Research scientists and investigators as well as clinicians searching for a good understanding of the disease will find this book useful

THE ASSOCIATION BETWEEN TRAUMATIC BRAIN INJURY AND GLIOMAGENESIS AND ITS SPECIAL ROLE IN GLIOBLASTOMA MULTIFORME PATHOGENESIS: A REVIEW

Gliomas are the most common primary and aggressive intracranial tumors, represent 80% of malignant brain tumors, and despite the fact that are relatively rare tumors are responsible for significant mortality and morbidity. Glioblastoma multiforme (GBM) or diffuse astrocytoma, WHO grade IV, is the most common and aggressive primary central nervous system malignancy, represents 45% of all gliomas, shows an average incidence of 3.19/100,000 individuals, its median age of diagnosis is 64 years, and the median survival is 15 months as the 5-year relative survival is 5%. Previous studies have investigated the possible role of genetic and environmental factors in GBM pathogenesis; however, the majority of GBM cases were sporadic and certain risk factors have not been detected. GBM is divided into primary and secondary subtypes which develop through different genetic pathways, affect patients at different ages, and have differences in clinical outcomes, as show a great morphological and genetic heterogeneity. The role of traumatic brain injury (TBI) in GBM formation has been investigated in many previous reports which have hypothesized that TBI may predispose to gliomagenesis; however, the outcomes were highly controversial. Some of those researches have proposed a supposed pathogenesis model that involves a post-traumatic inflammation, stem and progenitor cell transformation, and gliomagenesis. Other similar studies have involved transcription factors associated with TBI such as p53, hypoxia-inducible factor-1a (HIF-1a), and c-Myc. On the other hand, the possibility of a pre-existing tumor rather than a trauma-induced tumor is very possible in such cases

Functional and Mechanistic Consequences of Dual Oxidase 1 Suppression in Lung Cancer

The NADPH oxidase homolog, dual oxidase 1 (DUOX1), is an H2O2 producing transmembrane enzyme highly expressed in the airway epithelium. DUOX1-dependent redox signaling has been characterized to regulate many homeostatic processes in the lung epithelium, such as host defense, wound healing, and type II immune responses. Intriguingly, DUOX1 has been found to be suppressed in many epithelial cancers, including lung cancer, by hypermethylation of its promoter. Epigenetic silencing of DUOX1 in cancer is paradoxical to the understanding that tumors harbor elevated levels of reactive oxygen species (ROS), suggesting that DUOX1 may be a tumor suppressor. Since DUOX1 loss occurs in many forms of lung cancer, we aimed to characterize the functional importance of DUOX1 suppression. RNAi-mediated knockdown of DUOX1 in lung epithelial cells induced features of the epithelial-to-mesenchymal transition (EMT), a characteristic of aggressive or invasive tumor cells. Indeed, DUOX1 suppression promoted the acquisition of molecular signatures associated with EMT, such as the loss of E-cadherin, and induced expression of vimentin and smooth muscle actin. Additionally, we find that DUOX1 suppression promotes the acquisition of other EMT-related features, such as enhanced levels of cancer stem cell molecular markers, cellular invasiveness, and critically, resistance to epidermal growth factor receptor (EGFR) inhibition. Importantly, overexpression of DUOX1 in DUOX1-lacking lung cancer cells promoted the recovery of epithelial characteristics, pinning DUOX1 as a critical mediator of the epithelial phenotype. Based on prior studies demonstrating DUOX1 as an important regulator of EGFR signaling in the lung epithelium, we hypothesized that DUOX1 loss in lung cancer may impact EGFR regulation. EGFR belongs to a larger family of ErbB receptor tyrosine kinases, which are often overexpressed or mutated in many forms of lung cancer. Surprisingly, we find that lung cancer cells lacking DUOX1 have significantly altered EGFR redox regulation, specifically, kinetically enhanced cysteine oxidation-reduction dynamics. Additionally, our results demonstrate DUOX1-lacking cancer cells have altered intracellular EGFR trafficking with enhanced nuclear targeting. Indeed, we observe many oncogenic features of nuclear EGFR e.g. enhanced migratory capacity, resistance to EGFR blocking antibodies. Finally, we have uncovered that EGFR cysteine redox dynamics may regulate intracellular trafficking and/or nuclear transport, offering potentially novel avenues in the design of therapeutics. Proper DUOX1 localization and enzymatic function in the plasma membrane requires partnership with its maturation factor, dual oxidase maturation factor 1 (DUOXA1). Preliminary findings from a newly designed DUOX1-DUOXA1 co-expression system suggests that following enzymatic activation of DUOX1, DUOXA1 dissociates from DUOX1 and potentially translocates to the nucleus, a feature not previously described in lung epithelial or cancer cells. While these preliminary results require additional experimentation, this could be a unique regulatory feature of DUOX1 and a novel role for DUOXA1. Collectively, the research demonstrated in this dissertation characterizes the functional and mechanistic importance of DUOX1 suppression in cancer. Indeed, loss of DUOX1 expression may be an indicator of tumor aggressiveness and responsiveness to EGFR-targeted therapies, warranting its potential for use as a clinical biomarker in lung cancer

Inhibitory feedback control of NF-κB signalling in health and disease.

Cells must adapt to changes in their environment to maintain cell, tissue and organismal integrity in the face of mechanical, chemical or microbiological stress. Nuclear factor-κB (NF-κB) is one of the most important transcription factors that controls inducible gene expression as cells attempt to restore homeostasis. It plays critical roles in the immune system, from acute inflammation to the development of secondary lymphoid organs, and also has roles in cell survival, proliferation and differentiation. Given its role in such critical processes, NF-κB signalling must be subject to strict spatiotemporal control to ensure measured and context-specific cellular responses. Indeed, deregulation of NF-κB signalling can result in debilitating and even lethal inflammation and also underpins some forms of cancer. In this review, we describe the homeostatic feedback mechanisms that limit and 're-set' inducible activation of NF-κB. We first describe the key components of the signalling pathways leading to activation of NF-κB, including the prominent role of protein phosphorylation and protein ubiquitylation, before briefly introducing the key features of feedback control mechanisms. We then describe the array of negative feedback loops targeting different components of the NF-κB signalling cascade including controls at the receptor level, post-receptor signalosome complexes, direct regulation of the critical 'inhibitor of κB kinases' (IKKs) and inhibitory feedforward regulation of NF-κB-dependent transcriptional responses. We also review post-transcriptional feedback controls affecting RNA stability and translation. Finally, we describe the deregulation of these feedback controls in human disease and consider how feedback may be a challenge to the efficacy of inhibitors

Targeting STAT3 and STAT5 in Cancer

Every minute, 34 new patients are diagnosed with cancer globally. Although over the past 50 years treatments have improved and survival rates have increased dramatically for several types of cancers, many remain incurable. Several aggressive types of blood and solid cancers form when mutations occur in a critical cellular signaling pathway, the JAK-STAT pathway; (Janus Kinase-Signal Transducer and Activator of Transcription). Currently, there are no clinically available drugs that target the oncogenic STAT3/5 proteins in particular or their Gain of Function hyperactive mutant products. Here, we summarize targeting approaches on STAT3/5, as the field moves towards clinical applications as well as we illuminate on upstream or downstream JAK-STAT pathway interference with kinase inhibitors, heat shock protein blockers or changing nuclear import/export processes. We cover the design paradigms and medicinal chemistry approaches to illuminate progress and challenges in understanding the pleiotropic role of STAT3 and STAT5 in oncogenesis, the microenvironment, the immune system in particular, all culminating in a complex interplay towards cancer progression

Role of Protein Phosphatase-2A in Regulating Monocyte Activation by Soluble and Crystalline Uric Acid in Gout

Gout is a chronic inflammatory disease caused by the phagocytosis of monosodium urate monohydrate (MSU) crystals by monocytes/macrophages resulting in downstream expression and production of interleukin-1 beta (IL-1β) and chemokines. The activation of monocytes by MSU crystals involves the priming of monocytes with danger signals e.g. lipopolysaccharide (LPS) or soluble uric acid (UA), crystal phagocytosis and subsequent NLRP3 inflammasome activation and conversion of pro-IL-1β to active IL-1β. Protein-phosphatase-2A (PP2A) is a serine/threonine phosphatase that plays an important role in cell growth and inflammation. The prodrug Fingolimod (FTY720) and its phosphorylated active metabolite (p-FTY720) activate intracellular PP2A. We hypothesized that monocyte activation by MSU crystals is mediated by a reduction in intracellular PP2A activity and restoring PP2A activity reduces MSU-induced inflammation in monocytes. We aimed to investigate the role of PP2A in regulating monocyte priming and activation by MSU crystals and evaluate whether intracellular PP2A activation exerts an anti-inflammatory effect in MSU-stimulated monocytes. Human THP-1 monocytes were primed with a combination of UA and LPS. MSU stimulation was performed for 4-6 hours and MSU crystal phagocytosis, PP2A activity, IL-1β expression and production were studied in primed and unprimed monocytes. We performed PP2A knockdown in THP-1 monocytes and evaluated the impact of PP2A attenuation on IL-1β expression and production in unprimed THP-1 monocytes. Time-dependent intracellular PP2A activation in response to FTY720 or p-FTY720 treatments was studied and we evaluated the impact of p-FTY720 treatment on IL-1β expression and production in MSU stimulated human monocytes. Priming with UA+LPS increased MSU phagocytosis and IL-1β expression and production in monocytes. This effect was associated with a reduction in intracellular PP2A activity. PP2A knockdown increased IL-1β expression and production. FTY720 and p-FTY720 increased intracellular PP2A activity in monocytes. p-FTY720 treatment reduced IL-1β expression and production in UA+LPS pre-treated monocytes following MSU stimulation mediated by an increase in PP2A activity with no alteration in PP2A gene expression. In summary, UA and LPS enhanced MSU phagocytosis, expression and production of IL-1β via a reduction in PP2A activity. Pharmacological restoration of PP2A activity exerted an antiinflammatory effect. We conclude that PP2A is a novel therapeutic target for gout treatment