scholarly journals Молекулярные и клеточные механизмы воспаления при подагре

2019 ◽  
Author(s):  
I.Yu. Malyshev ◽  
A.E. Pihlak ◽  
O.P. Budanova
Keyword(s):  
Inflammatory Response ◽  
New Technologies ◽  
Therapeutic Potential ◽  
Main Role ◽  
Crystal Deposition ◽  
Inflammation Resolution ◽  
Two Stages ◽  
Nlrp3 Inflammasomes ◽  
Kinase Signaling Pathway

В обзоре проанализированы механизмы подагрического воспаления и разрешения острого воспаления при подагре, и то, как их понимание способствует созданию новых технологий лечения подагры. В первой части обзора анализируется кристалл-индуцированное воспаление при подагре, которое связано с активацией инфламмасомы NLRP3 в макрофагах, состоящее из двух этапов: 1) синтез компонентов инфламмасомы; и 2) сборка инфламмасомы. Проанализированы сигналы, активирующие синтез компонентов инфламмасомы, которые генерируются при взаимодействии кристаллов урата мононатрия с макрофагами. Описаны этапы инициации воспаления при подагре: синтез компонентов инфламмасомы, про-каспаз и про-IL-1β. IL-1β - основной эффекторный цитокин, который запускает не только воспалительный ответ, но и вызывает вазодилатацию сосудов, привлечение нейтрофилов к месту отложения кристаллов и еще большее усиление острого воспалительного эпизода через TLR-зависимую активацию NF-κB (фактор транскрипции). Рассматривается роль растворимой мочевой кислоты в активации инфламмасомы NLRP3. Подчёркнуто, что в разрешении острого воспаления при подагре основную роль играют те же клетки, что и в развитии классической воспалительной реакции: макрофаги и нейтрофилы. В обзоре рассмотрены сигнальные пути, которые переключают воспалительный ответ на разрешение и завершение воспаления: AMPK- (AMP-активируемая киназа) зависимый путь; антивоспалительные цитокины TGFβ1, IL-10 и IL-1Ra; белок аннексин А1 (AnxA1) и α1-антитрипсин (ААТ). Описаны способы терапевтического блокирования воспаления при подагре с помощью ингибиторов инфламмасомы и ингибиторов IL-1β. Изучение механизмов подагрического воспаления и его разрешения привело к идее о разработке методов репрограммирования иммунных клеток и адаптивной иммунотерапии подагры, методов, которые при других заболеваниях, таких как рак, уже показали выдающиеся возможности лечения больных.The review analyzes mechanisms of gouty inflammation and resolution of acute inflammation in gout and shows how their understanding contributes to creation of new technologies for the treatment of gout. The first part of the review addresses crystal-induced inflammation in gout, which is associated with activation of the NLRP3 inflammasome in macrophages. The crystal-induced inflammation consists of two stages, 1) synthesis of inflammasome components and 2) inflammasome assembly. The review analyzes signals activating the synthesis of inflammasome components, which are generated by the interaction of MSU (monosodium urate crystals) and macrophages. Stages of inflammation initiation are described, including the synthesis of inflammasome components, pro-caspases and pro-IL-1β. IL-1β is the main effector cytokine of gouty inflammation, which not only triggers the inflammatory response but also induces vasodilation, attraction of neutrophils to the place of crystal deposition, and even a greater potentiation of the acute inflammatory episode via the TLR-dependent activation of NF-κB (transcription factor). The role of soluble uric acid in the activation of NLRP3 inflammasomes is addressed. The main role in resolving acute gouty inflammation belongs to the same cells, macrophages and neutrophils, that contribute to the development of inflammation. The review focuses on signaling pathways switching the inflammatory response to inflammation resolution and termination, including the AMPK (AMP-activated kinase) signaling pathway, the TGFβ1, IL-10 and IL-1Ra anti-inflammatory cytokines, the protein annexin A1 (AnxA1), and α1-antitrypsin (AAT). The authors described in detail the techniques for therapeutic suppression of inflammation in gout using inflammasome and IL-1β inhibitors. Studying the mechanisms of gouty inflammation and its resolution has resulted in development of methods for reprogramming immune cells and adaptive immunotherapy of gout. These methods have already shown outstanding therapeutic potential for patients with other diseases such as cancer.

scholarly journals The Role of the Immune Response in the Pathogenesis of Bronchiectasis

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Paul T. King
Keyword(s):  
Immune Response ◽  
Inflammatory Response ◽  
Respiratory Tract ◽  
Lower Respiratory Tract ◽  
Therapeutic Potential ◽  
Small Airways ◽  
Upper Respiratory Tract ◽  
Causative Factors ◽  
Triggering Factor

Bronchiectasis is a prevalent respiratory condition characterised by permanent and abnormal dilation of the lung airways (bronchi). There are a large variety of causative factors that have been identified for bronchiectasis; all of these compromise the function of the immune response to fight infection. A triggering factor may lead to the establishment of chronic infection in the lower respiratory tract. The bacteria responsible for the lower respiratory tract infection are usually found as commensals in the upper respiratory tract microbiome. The consequent inflammatory response to infection is largely responsible for the pathology of this condition. Both innate and adaptive immune responses are activated. The literature has highlighted the central role of neutrophils in the pathogenesis of bronchiectasis. Proteases produced in the lung by the inflammatory response damage the airways and lead to the pathological dilation that is the pathognomonic feature of bronchiectasis. The small airways demonstrate infiltration with lymphoid follicles that may contribute to localised small airway obstruction. Despite aggressive treatment, most patients will have persistent disease. Manipulating the immune response in bronchiectasis may potentially have therapeutic potential.

scholarly journals MARTs and MARylation in the Cytosol: Biological Functions, Mechanisms of Action, and Therapeutic Potential

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 313
Author(s):  
Sridevi Challa ◽  
MiKayla S. Stokes ◽  
W. Lee Kraus
Keyword(s):  
Stress Responses ◽  
Molecular Mechanisms ◽  
Neuronal Development ◽  
New Technologies ◽  
Therapeutic Potential ◽  
Structural Features ◽  
Cellular Transport ◽  
Biological Functions ◽  
Post Translational Modification

Mono(ADP-ribosyl)ation (MARylation) is a regulatory post-translational modification of proteins that controls their functions through a variety of mechanisms. MARylation is catalyzed by mono(ADP-ribosyl) transferase (MART) enzymes, a subclass of the poly(ADP-ribosyl) polymerase (PARP) family of enzymes. Although the role of PARPs and poly(ADP-ribosyl)ation (PARylation) in cellular pathways, such as DNA repair and transcription, is well studied, the role of MARylation and MARTs (i.e., the PARP ‘monoenzymes’) are not well understood. Moreover, compared to PARPs, the development of MART-targeted therapeutics is in its infancy. Recent studies are beginning to shed light on the structural features, catalytic targets, and biological functions of MARTs. The development of new technologies to study MARTs have uncovered essential roles for these enzymes in the regulation of cellular processes, such as RNA metabolism, cellular transport, focal adhesion, and stress responses. These insights have increased our understanding of the biological functions of MARTs in cancers, neuronal development, and immune responses. Furthermore, several novel inhibitors of MARTs have been developed and are nearing clinical utility. In this review, we summarize the biological functions and molecular mechanisms of MARTs and MARylation, as well as recent advances in technology that have enabled detection and inhibition of their activity. We emphasize PARP-7, which is at the forefront of the MART subfamily with respect to understanding its biological roles and the development of therapeutically useful inhibitors. Collectively, the available studies reveal a growing understanding of the biochemistry, chemical biology, physiology, and pathology of MARTs.

The role of microRNAs in arterial remodelling

2012 ◽  
Vol 107 (04) ◽  
pp. 611-618 ◽  
Author(s):  
Maliheh Nazari-Jahantigh ◽  
Yuanyuan Wei ◽  
Andreas Schober
Keyword(s):  
Endothelial Cells ◽  
Inflammatory Response ◽  
Vessel Wall ◽  
Structural Changes ◽  
Therapeutic Potential ◽  
Density Lipoprotein ◽  
Protective Role ◽  
Vascular Remodelling

SummaryAdaptive alterations of the vessel wall architecture, called vascular remodelling, can be found in arterial hypertension, during the formation of aneurysms, in restenosis after vascular interventions, and in atherosclerosis. MicroRNAs (miR) critically affect the main cellular players in arterial remodelling and may either promote or inhibit the structural changes in the vessel wall. They regulate the phenotype of smooth muscle cells (SMCs) and control the inflammatory response in endothelial cells and macrophages. In SMCs, different sets of miRs induce either a synthetic or contractile phenotype, respectively. The conversion into a synthetic SMC phenotype is a crucial event in arterial remodelling. Therefore, reprogramming of the SMC phenotype by miR targeting can modulate the remodelling process. Furthermore, the effects of stimuli that induce remodelling, such as shear stress, angiotensin II, oxidised low-density lipoprotein, or apoptosis, on endothelial cells are mediated by miRs. The endothelial cell-specific miR-126, for example, is transferred in microvesicles from apoptotic endothelial cells and plays a protective role in atherogenesis. The inflammatory response of the innate immune system, especially through macrophages, promotes arterial remodelling. miR-155 induces the expression of inflammatory cytokines, whereas miR-146a and miR-147 are involved in the resolution phase of inflammation. However, in vivo data on the role of miRs in vascular remodelling are still scarce, which are required to test the therapeutic potential of the available, highly effective miR inhibitors.

scholarly journals The role of Interleukin-1 receptor antagonist as a treatment option in calcium pyrophosphate crystal deposition disease

2021 ◽  
Author(s):  
Alberto Altomare ◽  
Addolorata Corrado ◽  
Nicola Maruotti ◽  
Daniela Cici ◽  
Francesco Paolo Cantatore
Keyword(s):  
Articular Cartilage ◽  
Inflammatory Response ◽  
Interleukin 1 ◽  
Calcium Pyrophosphate ◽  
Therapeutic Strategies ◽  
Crystal Deposition ◽  
Traditional Treatment ◽  
X Ray ◽  
Crystal Arthritis

AbstractCalcium Pyrophosphate Crystal Deposition (CPPD) disease is characterized by the deposition of calcium pyrophosphate crystals in the cartilage. In most cases, it can manifest as a subclinical condition named chondrocalcinosis, often revealed by joint x-ray examination. In other cases, deposition can cause flares of arthritis, known as acute CPP crystal arthritis. In the last few years, many pathogenic pathways have been discovered. Interleukin-1 (IL-1) plays a key role in the pathogenesis of CPPD disease, both as a mediator of inflammatory response to crystals and as a promoter of damage to articular cartilage. In this review, we investigated the role of IL-1R inhibitor, such as Anakinra, as an alternative to the various therapeutic strategies for CPPD disease, especially among patients resistant to traditional treatment with NSAIDs, corticosteroids and colchicine.

Role of the immune response in the pathogenesis of Alzheimer’s disease and possibilities of anti-inflammatory therapy

2021 ◽  
Vol LII (3) ◽  
pp. 55-62
Author(s):  
Sergey V. Vorobev ◽  
Andrey Yu. Emelin ◽  
Raisa N. Kuznetsova ◽  
Igor V. Kudryavtsev
Keyword(s):  
Inflammatory Cytokines ◽  
Therapeutic Potential ◽  
Main Role ◽  
Markers Of Inflammation ◽  
Alternative Hypotheses ◽  
The Central Nervous System ◽  
Anti Inflammatory ◽  
T Helpers ◽  
Pro Inflammatory Cytokines

In modern scientific society several alternative hypotheses for the formation of Alzheimers disease are considered, proposed on the basis of data obtained as a result of research. In almost any of them, the development of an immuno-inflammatory response is discussed as one of the main pathogenic mechanisms of the disease. It was found that the development of neurodegeneration is accompanied by the accumulation of pro-inflammatory cytokines and other markers of inflammation in the peripheral blood and brain tissues. At the same time, the obtained results suggest that the main role in pathogenesis may be played by T-helpers of the Th17 population that can penetrate the blood-brain barrier. In addition, microglia, which is the main immune-presenting component of the central nervous system, and astrocytes, which are capable of excessive production of pro- inflammatory cytokines and regulation of -amyloid clearance, are considered as key components in these reactions. Based on these data, attempts are being made to develop drugs that have an anti-inflammatory effect and can positively influence the dynamics of the disease. The initial results obtained in some cases demonstrate a certain positive effect, which suggests that there is a therapeutic potential for this type of therapy.

Therapeutic Potential of Probiotics: A Ray of Hope or Nightmare?

2019 ◽  
Vol 6 (1) ◽  
pp. 18-33 ◽  
Author(s):  
Malika Arora ◽  
Navdeep Kaur ◽  
Parveen Bansal ◽  
Ashish Baldi
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Oral Health ◽  
Mode Of Action ◽  
New Technologies ◽  
Therapeutic Potential ◽  
Safety And Efficacy ◽  
Regulatory Guidelines ◽  
Health And Disease

Background:The role of various probiotic microorganisms with a particular emphasis on their therapeutic use in human health and disease has been highlighted by diverse scientific research reports. Due to improvement and introduction of new technologies useful to understand the functionality and mode of action of probiotics with respect to nutritional as well as health perspectives, the research on probiotics has recently grabbed the attention of manufacturers, regulators as well as researchers. Currently there are clinical trial based evidences to support the effectiveness of probiotic interventions in various types of diarrheal diseases, chronic gastrointestinal inflammatory disorders, hypercholesterolemia, hypertension, diabetes, oral health etc. However, due to inadequate awareness about risks associated with the probiotics amongst physicians, regulatory authorities, consumers and manufacturers many attributes like quality, safety and efficacy require urgent attention. At the same time regulatory guidelines for these products face ambiguity. So, it is of utmost importance to evaluate the true status of probiotic products available in market with respect to all above mentioned parameters and to formulate harmonized regulatory guidelines for the manufacturing of probiotic products.Conclusion:The present compilation aims to highlight the progression of probiotic research related to therapeutic potentials of probiotics, clinical trials on probiotics, risks and regulatory concerns associated with probiotics and their use.

Role of spectrin in membrane fusion and in shape change of human erythrocyte ghost

1978 ◽  
Vol 36 (2) ◽  
pp. 328-329
Author(s):  
Hideo Hayashi ◽  
Yoshikazu Hirai ◽  
John T. Penniston
Keyword(s):  
Conformational Changes ◽  
Human Erythrocyte ◽  
Shape Change ◽  
Membrane Surface ◽  
Slight Modification ◽  
Active Role ◽  
Main Role ◽  
Bank Blood ◽  
Human Erythrocyte Ghost

Spectrin is a membrane associated protein most of which properties have been tentatively elucidated. A main role of the protein has been assumed to give a supporting structure to inside of the membrane. As reported previously, however, the isolated spectrin molecule underwent self assemble to form such as fibrous, meshwork, dispersed or aggregated arrangements depending upon the buffer suspended and was suggested to play an active role in the membrane conformational changes. In this study, the role of spectrin and actin was examined in terms of the molecular arrangements on the erythrocyte membrane surface with correlation to the functional states of the ghosts.Human erythrocyte ghosts were prepared from either freshly drawn or stocked bank blood by the method of Dodge et al with a slight modification as described before. Anti-spectrin antibody was raised against rabbit by injection of purified spectrin and partially purified.

Mesophyll conductance: the leaf corridors for photosynthesis

2020 ◽  
Vol 48 (2) ◽  
pp. 429-439 ◽  
Author(s):  
Jorge Gago ◽  
Danilo M. Daloso ◽  
Marc Carriquí ◽  
Miquel Nadal ◽  
Melanie Morales ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Main Role ◽  
Mesophyll Conductance ◽  
Future Studies ◽  
Cell Structures ◽  
Leaf Tissues ◽  
Change Framework ◽  
Chloroplast Stroma

Besides stomata, the photosynthetic CO2 pathway also involves the transport of CO2 from the sub-stomatal air spaces inside to the carboxylation sites in the chloroplast stroma, where Rubisco is located. This pathway is far to be a simple and direct way, formed by series of consecutive barriers that the CO2 should cross to be finally assimilated in photosynthesis, known as the mesophyll conductance (gm). Therefore, the gm reflects the pathway through different air, water and biophysical barriers within the leaf tissues and cell structures. Currently, it is known that gm can impose the same level of limitation (or even higher depending of the conditions) to photosynthesis than the wider known stomata or biochemistry. In this mini-review, we are focused on each of the gm determinants to summarize the current knowledge on the mechanisms driving gm from anatomical to metabolic and biochemical perspectives. Special attention deserve the latest studies demonstrating the importance of the molecular mechanisms driving anatomical traits as cell wall and the chloroplast surface exposed to the mesophyll airspaces (Sc/S) that significantly constrain gm. However, even considering these recent discoveries, still is poorly understood the mechanisms about signaling pathways linking the environment a/biotic stressors with gm responses. Thus, considering the main role of gm as a major driver of the CO2 availability at the carboxylation sites, future studies into these aspects will help us to understand photosynthesis responses in a global change framework.

Meiotic CENP-C is a shepherd: bridging the space between the centromere and the kinetochore in time and space

2020 ◽  
Vol 64 (2) ◽  
pp. 251-261
Author(s):  
Jessica E. Fellmeth ◽  
Kim S. McKim
Keyword(s):  
Chromosome Segregation ◽  
New Technologies ◽  
Early Prophase ◽  
Unique Role ◽  
Kinetochore Assembly ◽  
M Phase ◽  
In Vivo Analysis ◽  
Meiosis I

Abstract While many of the proteins involved in the mitotic centromere and kinetochore are conserved in meiosis, they often gain a novel function due to the unique needs of homolog segregation during meiosis I (MI). CENP-C is a critical component of the centromere for kinetochore assembly in mitosis. Recent work, however, has highlighted the unique features of meiotic CENP-C. Centromere establishment and stability require CENP-C loading at the centromere for CENP-A function. Pre-meiotic loading of proteins necessary for homolog recombination as well as cohesion also rely on CENP-C, as do the main scaffolding components of the kinetochore. Much of this work relies on new technologies that enable in vivo analysis of meiosis like never before. Here, we strive to highlight the unique role of this highly conserved centromere protein that loads on to centromeres prior to M-phase onset, but continues to perform critical functions through chromosome segregation. CENP-C is not merely a structural link between the centromere and the kinetochore, but also a functional one joining the processes of early prophase homolog synapsis to late metaphase kinetochore assembly and signaling.

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