STING
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Neadaptivní imunitní systém je první obranou organismu při jeho napadení patogenem. Signalizační cesta cGAS -cGAMP -STING je součástí tohoto systému a je zcela klíčová při obraně proti DNA virům a retrovirům Zároveň je chronické vybuzení této kaskády pravděpodobnou příčinou některých autoimunitních onemocnění. Studium této signalizační cesty je klíčové pro vývoj terapeutik virových a autoimunitních onemocnění.
The innate immune system is the first line of defence of organism against pathogens. As a part of innate immune system, cGAS -cGAMP- -STING signaling pathway takes a crucial part in immune response to DNA viruses and retroviruses. In contrast, chronic activation of this pathway is probably cause of some autoimmune diseases. Studium of this signaling pathway is crucial for new antiviral and immunosupresive drugs development.
- Klíčová slova
- cGAS-cGAMP-STING,
- MeSH
- DNA viry * imunologie MeSH
- DNA genetika chemie imunologie MeSH
- fosforylace MeSH
- interferon typ I * metabolismus MeSH
- lidé MeSH
- přirozená imunita * MeSH
- receptor interferonu alfa-beta * MeSH
- receptory rozpoznávající vzory MeSH
- Retroviridae * imunologie MeSH
- signální transdukce * MeSH
- ubikvitiny metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Tento článek se zaměřuje na roli strukturní biologie ve vývoji malých molekul, sloužících jako ligandy proteinů, které by mohly být v budoucnosti využity jako léky. Pro získávání strukturních informací o proteinech jsou využívány experimentální metody, které následně umožňují virtuální screening rozsáhlých knihoven látek. Nalezené ligandy jsou dále experimentálně ověřovány, přičemž strukturní biologie hraje klíčovou roli v jejich dalším zdokonalení. Cílem je vyvinout ligand s vysokou afinitou a specifitou, který by se mohl stát účinným léčivem. Následuje optimalizace těchto látek z hlediska chemie a farmakologie. Celý tento proces je ilustrován na příkladech z nedávné minulosti, jako jsou kinasy lipidů, stimulátor interferonových genů (STING) a virové methyltransferasy.
This article focuses on the role of structural biology in the development of small molecules that serve as protein ligands, which could potentially be used as drugs in the future. Experimental methods are utilized to obtain structural information about proteins, which then allow for virtual screening of extensive libraries of substances. The discovered ligands are further experimentally verified, with structural biology playing a crucial role in their refinement. The goal is to develop a ligand with high affinity and specificity, which could become an effective medicine. This is followed by the optimization of these substances from a chemical and pharmacological standpoint. The entire process is illustrated with examples from the recent past, such as lipid kinases, the stimulator of interferon genes (STING), and viral methyltransferases.
Provedli jsme expoziční test se včelím jedem u 17 pacientů, kteří byli léčeni subkutánně podávanou alergenovou imunoterapií po dobu minimálně 3 let. Expoziční test odhalil přetrvávající klinickou senzitivitu u 3 pacientů (17,6 % testovaných pacientů). Nalezli jsme vazbu citlivosti v kožním testu (prahová citlivost) a výsledku expozičního testu, nebyl nalezen vztah mezi expozičním testem a hodnotou IgE a IgG4 protilátky specifické pro daný alergen.
We performed deliberate bee sting challenge test in 17 patients. All of them were previously treated by subcutaneously administrated allergen immunotherapy at least 3 years. Sting challenge test found out persistent clinical sensitivity in 3 patients, (17,6 % of all patients tested). A correlation of skin test sensitivity (threshold positivity) and the result of the challenge test has been found, there were no significant relationship between the challenge test and the level of allergen specific IgE and IgG4 antibody.
Expoziční test jedem hmyzu je základní pomůckou v diagnostice alergie na jed blanokřídlého hmyzu (Hymenopter). Současná kritéria pro odhadnutí klinické senzibilizace, zejména během nebo po alergenové imunoterapii, mohou být doplněna tímto testem. V článku je popsána indikace, rizika a etické aspekty, autoři popisují protokol expozičního testu.
Deliberate insect sting challenge is the basic tool in the Hymenoptera venom allergy diagnostics. Current criteria for clinical sensitivity assesment, particullary during or after immunotherapy, can be supplement by the sting challenge. Current indication, risk and ethical consideration are reviewed, authors describe their protocol of the challenge.
Druhově specifické rozdíly mezi jednotlivými medúzami mohou bránit ve volbě adekvátní lokální terapie a správnému poskytnutí první pomoci. Dodnes neexistuje univerzální protokol aplikabilní pro všechna poranění způsobená těmito živočichy. Přijetí bezpečných a účinných opatření a zásad první pomoci při žáhnutí medúzou je také komplikováno šířením celé řady neoficiálních zpráv a nedostatkem důkazů ve vědecké literatuře. Jedinou možností, jak z této situace uniknout, je postupná publikace kazuistik nebo sérií kazuistik s jednotícím léčebným konceptem tak, aby mohla být následně realizována klinická doporučení pro lokální terapii podložená dostatečným množství robustních dat.
Species-specific differences between individual jellyfish can prevent the choice of adequate local therapy and the correct provision of first aid. To date, there is no universal protocol applicable to all injuries caused by these marine animals. Adoption of safe and effective first aid measures for jellyfish stings is also complicated by a wide variety of unofficial reports and a lack of evidence in the scientific literature. The only way out of this situation is the gradual publication of case reports or a series of case reports with a unifying treatment concept so that clinical recommendations for local therapy supported by a sufficient amount of robust data can subsequently be implemented.
- MeSH
- dospělí MeSH
- jedy žahavců škodlivé účinky toxicita MeSH
- kousnutí a bodnutí komplikace ošetřování MeSH
- lidé MeSH
- nematocysta zranění MeSH
- přecitlivělost na hmyzí jed * komplikace ošetřování prevence a kontrola MeSH
- Scyphozoa * MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
The cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) pathway plays a crucial role in inducing an antiviral and antitumor immune response. We studied the effects of synthetic STING agonists on several immune populations and related cytokine production. In comparison with the toll-like receptor 7 (TLR7) agonist, STING agonists induced secretion of a broader proinflammatory cytokine spectrum. Unlike the TLR7 agonist, the structurally diverse STING agonists partially depleted B and NK cells and completely depleted CD14+ monocytes via induction of apoptosis. The TANK-binding kinase 1 inhibitor efficiently prevented interferon alpha (IFNα) secretion and cell depletion, suggesting their possible dependence on the cGAS-STING pathway activation. Finally, IFNα, tumor necrosis factor alpha, interleukin 6, and interleukin 1 beta secretion and CD14+ monocyte apoptosis were primary responses to STING agonists, whereas IFNγ was secreted secondarily. These findings bring new insights into the cGAS-STING pathway immunomodulation that is of future therapeutic importance.
Cyclic dinucleotides (CDNs) trigger the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which plays a key role in cytosolic DNA sensing and thus in immunomodulation against infections, cell damage and cancer. However, cancer immunotherapy trials with CDNs have shown immune activation, but not complete tumor regression. Nevertheless, we designed a novel class of CDNs containing vinylphosphonate based on a STING-affinity screening assay. In vitro, acyloxymethyl phosphate/phosphonate prodrugs of these vinylphosphonate CDNs were up to 1000-fold more potent than the clinical candidate ADU-S100. In vivo, the lead prodrug induced tumor-specific T cell priming and facilitated tumor regression in the 4T1 syngeneic mouse model of breast cancer. Moreover, we solved the crystal structure of this ligand bound to the STING protein. Therefore, our findings not only validate the therapeutic potential of vinylphosphonate CDNs but also open up opportunities for drug development in cancer immunotherapy bridging innate and adaptive immunity.
- MeSH
- DNA MeSH
- imunoterapie MeSH
- myši MeSH
- nádory * farmakoterapie MeSH
- nukleotidy cyklické * farmakologie metabolismus MeSH
- přirozená imunita MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
To explore the mechanism whereby cGAS-STING pathway regulates the pyroptosis of cryptorchidism cells, with a view to finding a new strategy for clinically treating cryptorchidism-induced infertility. Spermatogonial GC-1 cells were heat stimulated to simulate the heat hurt microenvironment of cryptorchidism. The cell viability was assayed by CCK-8, and cellular DNA damage was detected by gamma-H2AX immunofluo-rescence assay. Flow cytometry was employed to assess pyroptosis index, while western blot, ELISA and PCR were used to examine the expressions of pyroptosis-related proteins (Caspase-1, IL-1beta, NLRP3) and cGAS-STING pathway proteins (cGAS, STING). After STING silencing by siRNA, the expressions of pyroptosis-related proteins were determined. Pyroptosis occurred after heat stimulation of cells. Morphological detection found cell swelling and karyopyknosis. According to the gamma-H2AX immunofluorescence (IFA) assay, the endonuclear green fluorescence was significantly enhanced, the gamma-H2AX content markedly increased, and the endonuclear DNA was damaged. Flow cytometry revealed a significant increase in pyroptosis index. Western blot and PCR assays showed that the expressions of intracellular pyrogenic proteins like Caspase-1, NLRP3 and GSDMD were elevated. The increased STING protein and gene expressions in cGAS-STING pathway suggested that the pathway was intracellularly activated. Silencing STING protein in cGAS-STING pathway led to significantly inhibited pyroptosis. These results indicate that cGAS-STING pathway plays an important role in heat stress-induced pyroptosis of spermatogonial cells. After heat stimulation of spermatogonial GC-1 cells, pyroptosis was induced and cGAS-STING pathway was activated. This study can further enrich and improve the molecular mechanism of cryptorchidism.
