THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Catalytic receptors

Alexander, Stephen P.H.; Fabbro, Doriano; Kelly, Eamonn; Mathie, Alistair; Peters, John A.; Veale, Emma L.; Armstrong, Jane F.; Faccenda, Elena; Harding, Simon D; Pawson, Adam J.; Southan, Christopher; Davies, Jamie A.; Beuve, Annie; Brouckaert, Peter; Bryant, Clare E.; Burnett, John C.; Farndale, Richard W.; Friebe, Andreas; Garthwaite, John; Hobbs, Adrian J.; Jarvis, Gavin E.; Kühn, Michaela; MacEwan, David J.; Monie, Tom P.; Papapetropoulos, Andreas; Potter, Lincoln R.; Schmidt, Harald; Szabó, Csaba; Waldman, Scott A.

doi:10.1111/bph.15541

Cited by 166 publications

(151 citation statements)

References 55 publications

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“…Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org/ and are permanently archived in the Concise Guide to PHARMACOLOGY 2021/22 (Alexander et al, 2021a, 2021b).…”

Section: Methodsmentioning

confidence: 99%

Rhein regulates redox‐mediated activation of NLRP3 inflammasomes in intestinal inflammation through macrophage‐activated crosstalk

Zhou

Gao

Vong

et al. 2022

British J Pharmacology

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Background and Purpose: Macrophage infiltration and activation is a critical step during acute colitis. Redox-mediated activation of NLRP3 inflammasomes in macrophages plays a critical role in mediating colonic inflammatory responses. Rhein isolated from the rhizome of rhubarb exhibits anti-inflammatory effects in various diseases. However, its role in regulating acute colonic inflammation is unexplored.Here, we investigated the protective mechanisms of rhein during acute gut inflammation and its regulation of macrophage activation. Experimental Approach: Inhibitory effects of rhein on NLRP3 inflammasomes were evaluated in activated macrophages and a mouse model of colitis. Expression of inflammatory mediators, inflammasome complex and redox-related signalling were analysed by ELISA, Western blots, immunofluorescence staining, and qRT-PCR. The phenotype of macrophages was assessed by flow cytometry. Colonic inflammation was evaluated by histological analysis. Key Results: Rhein significantly decreased IL-1β secretion via NLRP3 inflammasomes by disturbing their assembly in macrophages. Rhein also activated the Nrf2-HO1-NQO1 pathway and inhibited expression of Nox2 subunits and translocation to regulate redox balance. Moreover, rhein attenuated inflammatory responses by mediating macrophage polarization from M1 to M2 phenotype. NF-κB, AP-1, and MAPK signalling were also involved in improving inflammatory conditions by rhein. In mice with acute intestinal inflammation, rhein treatment attenuated clinical features and reduced macrophage infiltration into damaged tissue to alleviate colonic inflammation. Conclusion and Implications:Rhein regulated redox-mediated NLRP3 inflammasome activation to protect against acute colitis, by interfering with macrophage accumulation and polarization. These findings provide a promising strategy of novel compounds for regulating mucosal inflammation in gastrointestinal disorders.Abbreviations: AIM2, absent in melanoma 2; AP1, activator protein 1; Arg1, arginase 1; ASC, apoptosis-associated speck-like protein containing a C-terminal caspase-activation and recruitment (CARD) domain; BMDMs, bone marrow-derived macrophages; Chil3, chitinase-like 3; cLPs, colonic lamina propria cells; DCFH-DA, 2 0 7 0 -dichlorodihydrofluorescein diacetate; DSS, dextran sulphate sodium; GEO, gene expression omnibus; HO-1, haem oxygenase-1; IBD, inflammatory bowel disease; MPO, myeloperoxidase; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NLRC4, NLR family CARD domain containing; NLRP3, NOD-like receptor family pyrin domain-containing 3; Nox, NADPH oxidase; NQO1, NAD(P)H dehydrogenase (quinone 1); Nrf2, nuclear factor-erythroid 2-related factor 2; PMA, phorbol 12-myristate 13-acetate.

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Section: Methodsmentioning

confidence: 99%

Rhein regulates redox‐mediated activation of NLRP3 inflammasomes in intestinal inflammation through macrophage‐activated crosstalk

Zhou

Gao

Vong

et al. 2022

British J Pharmacology

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“…Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org , and are permanently archived in the Concise Guide to PHARMACOLOGY 2021/22. 23 …”

Section: Methodsmentioning

confidence: 99%

Efficacy and safety of tocilizumab versus standard care/placebo in patients with COVID‐19; a systematic review and meta‐analysis of randomized clinical trials

Vela

Vela-Gaxha

Rexhepi

et al. 2021

Brit J Clinical Pharma

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Aims Tocilizumab has emerged as an important therapy in treating patients with coronavirus disease (COVID‐19). Our purpose was to evaluate the efficacy and safety of tocilizumab versus standard care/placebo in patients with COVID‐19. Methods We searched a variety of sources from 1 January 2020 to 5 May 2021. All randomized controlled trials that reported tocilizumab efficacy as a primary agent in COVID‐19 patients were considered. RCTs had to include mortality events, incidence of mechanical ventilation and serious adverse events. Two reviewers were independently responsible for data extraction. Assessment of bias and certainty of evidence was carried out using the Cochrane Risk of Bias Tool and GRADE methodology. RR for mortality events was evaluated using a fixed‐effects model. Results A total of 6837 patients were included from 10 RCTs, of which nine were peer‐reviewed. Pooled risk ratio (RR) for all‐cause mortality in patients with tocilizumab administration was RR = 0.88 (95% CI: 0.81–0.95, P = .0009). RR for incidence of mechanical ventilation at 28–30 days was 0.79 (95% CI: 0.71–0.88). Serious adverse events (SAE) with tocilizumab use were associated with lower RR (RR = 0.91, 95% CI: 0.76–1.09) but the certainty of evidence was downgraded to moderate due to serious risk of bias. Conclusion In COVID‐19 patients with moderate to critical COVID‐19, use of tocilizumab reduces all‐cause mortality and progression to mechanical ventilation. This efficacy was not associated with higher number of serious adverse events.

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“…Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org , the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY, 25 and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20. 26 , 27 …”

Section: Methodsmentioning

confidence: 99%

2‐Deoxy‐d‐glucose induces deglycosylation of proinflammatory cytokine receptors and strongly reduces immunological responses in mouse models of inflammation

Uehara

Kajita

Tanimura

et al. 2022

Pharmacology Res & Perspec

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Anti‐proinflammatory cytokine therapies against interleukin (IL)‐6, tumor necrosis factor (TNF)‐α, and IL‐1 are major advancements in treating inflammatory diseases, especially rheumatoid arthritis. Such therapies are mainly performed by injection of antibodies against cytokines or cytokine receptors. We initially found that the glycolytic inhibitor 2‐deoxy‐ d ‐glucose (2‐DG), a simple monosaccharide, attenuated cellular responses to IL‐6 by inhibiting N‐linked glycosylation of the IL‐6 receptor gp130. Aglycoforms of gp130 did not bind to IL‐6 or activate downstream intracellular signals that included Janus kinases. 2‐DG completely inhibited dextran sodium sulfate‐induced colitis, a mouse model for inflammatory bowel disease, and alleviated laminarin‐induced arthritis in the SKG mouse, an experimental model for human rheumatoid arthritis. These diseases have been shown to be partially dependent on IL‐6. We also found that 2‐DG inhibited signals for other proinflammatory cytokines such as TNF‐α, IL‐1β, and interferon ‐γ, and accordingly, prevented death by another inflammatory disease, lipopolysaccharide (LPS) shock. Furthermore, 2‐DG prevented LPS shock, a model for a cytokine storm, and LPS‐induced pulmonary inflammation, a model for acute respiratory distress syndrome of coronavirus disease 2019 (COVID‐19). These results suggest that targeted therapies that inhibit cytokine receptor glycosylation are effective for treatment of various inflammatory diseases.

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THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Catalytic receptors

Cited by 166 publications

References 55 publications

Rhein regulates redox‐mediated activation of NLRP3 inflammasomes in intestinal inflammation through macrophage‐activated crosstalk

Rhein regulates redox‐mediated activation of NLRP3 inflammasomes in intestinal inflammation through macrophage‐activated crosstalk

Efficacy and safety of tocilizumab versus standard care/placebo in patients with COVID‐19; a systematic review and meta‐analysis of randomized clinical trials

2‐Deoxy‐d‐glucose induces deglycosylation of proinflammatory cytokine receptors and strongly reduces immunological responses in mouse models of inflammation

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