The NLRP3 inhibitor Mcc950 attenuates acute allograft damage in rat kidney transplants

Zou, Xun-feng; Gu, Jianhua; Duan, Jihui; Hu, Zhandong; Z, Cui

doi:10.1016/j.trim.2020.101293

Cited by 12 publications

(3 citation statements)

References 36 publications

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“…Previous studies demonstrated that the high expression of Caspase‐1 and GSDMD was an indicator of pyroptosis 23,24 . The inhibition caused by small molecule is more efficient than single blockade of other components (ASC, Caspase‐1) or its downstream IL‐1β, suggesting that NLRP3 is a central molecule in the NLRP3‐Caspase‐1‐IL1β pathway 25 . NLRP3 recruits and activates Caspase‐1 after the identification of pathogen molecular pattern, cleaves Gasdermin D (GSDMD) to form GSDMD‐N and induces cell membrane perforation, cell rupture, release of contents, causing pyroptosis 26,27 .…”

Section: Discussionmentioning

confidence: 99%

Protective effect of Aster tataricus extract on NLRP3‐mediated pyroptosis of bladder urothelial cells

Wang

Yin

Zhou

et al. 2020

J Cellular Molecular Medi

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Aster tataricus L.f. is a traditional Eastern Asian herbal medicine used for the relief of uroschesis‐related illnesses and has been demonstrated clinically to exert satisfied effects. However, the mechanism of its therapeutic action remains unclear. The present study aimed to evaluate the protective mechanism of Aster tataricus extract (ATE) on CYP or LPS + ATP‐induced interstitial cystitis (IC), we successfully constructed the induced IC Sprague‐Dawley (SD) rat model and IC human urothelium cell (SV‐HUC‐1) model. The main compounds of ATE were determined by LC‐MS. After intervention, the changes on the bladder wall morphology and inflammation were observed in each group. SV‐HUC1 cell viability was measured by MTT and double stained with Hoechst 33342 and propidium iodide (PI). The expression levels of NLRP3, Pro‐caspase‐1, Caspsae‐1 p20, GSDMD, GSDMD‐N and Cleave‐IL‐1β in vivo and in vitro in different groups were detected by Western blotting. ATE significantly alleviated oedema and haemorrhage and reduced the inflammation index and histopathological score in SD rat bladder. The results of cell revealed that ATE could improve cell viability and decrease pyroptosis ratio. The expression of NLRP3 and other pyroptosis‐related protein was remarkably decreased by ATE both in vivo and in vitro. ATE may be used as an inhibitor of NLRP3 in treating IC. The discovery of NLRP3/Caspase‐1/GSDMD‐N as a new protective pathway provides a new direction for protecting cell against IC.

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Section: Discussionmentioning

confidence: 99%

Protective effect of Aster tataricus extract on NLRP3‐mediated pyroptosis of bladder urothelial cells

Wang

Yin

Zhou

et al. 2020

J Cellular Molecular Medi

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“…Early post-transplant administration of MCC950 (50 mg/kg, i.p), a specific NLRP3 inhibitor that blocks inflammasome oligomerization, reduced the activation of caspase-1 and the release of IL-1β in allograft of mice that underwent IRI and ameliorated the post-transplant functional recovery of these organs (79).…”

Section: Inflammasomes In Ischemia/ Reperfusion Injury During Kidney ...mentioning

confidence: 99%

Inflammasome pathway in kidney transplantation

Granata,

La Russa,

Stallone

et al. 2023

Front. Med.

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Kidney transplantation is the best available renal replacement therapy for patients with end-stage kidney disease and is associated with better quality of life and patient survival compared with dialysis. However, despite the significant technical and pharmaceutical advances in this field, kidney transplant recipients are still characterized by reduced long-term graft survival. In fact, almost half of the patients lose their allograft after 15–20 years. Most of the conditions leading to graft loss are triggered by the activation of a large immune-inflammatory machinery. In this context, several inflammatory markers have been identified, and the deregulation of the inflammasome (NLRP3, NLRP1, NLRC4, AIM2), a multiprotein complex activated by either whole pathogens (including fungi, bacteria, and viruses) or host-derived molecules, seems to play a pivotal pathogenetic role. However, the biological mechanisms leading to inflammasome activation in patients developing post-transplant complications (including, ischemia-reperfusion injury, rejections, infections) are still largely unrecognized, and only a few research reports, reviewed in this manuscript, have addressed the association between abnormal activation of this pathway and the onset/development of major clinical effects. Finally, the regulation of the inflammasome machinery could represent in future a valuable therapeutic target in kidney transplantation.

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“…Mcc950 (IUPAC: N-[[(1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) amino]carbonyl]-4-(1-hydroxy-1-methylethyl)-2-furansulfonamide sodium; Shorthand name: C 20 H 23 N 2 NaO 5 S; Molecular weight: 426.46), as a novel and selective inhibitor of NLRP3-inflammasome (10), interrupts the NLRP3-mediated ASC oligomerization, thereby preventing the activation of NLRP3 inflammasome. Recent studies demonstrated that mcc950 could significantly alleviate liver and kidney IRI during organ transplantation (11,12). Mcc950, which is a novel inhibitor of the NLRP3 inflammasome, can be applied to treat various kinds of cardiovascular diseases, such as atherosclerosis and myocardial infarction (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Normothermic ex vivo heart perfusion with NLRP3 inflammasome inhibitor Mcc950 treatment improves cardiac function of circulatory death hearts after transplantation

Zeng

Niu

et al. 2023

Front. Cardiovasc. Med.

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BackgroundThe utilization of donation after circulatory death (DCD) hearts can enlarge the donor pool. However, DCD hearts suffer from serious ischemia/reperfusion injury (IRI). Recent studies found that the activation of NLRP3 inflammasome could play a significant role in organ IRI. Mcc950, which is a novel inhibitor of the NLRP3 inflammasome, can be applied to treat various kinds of cardiovascular diseases. Therefore, we hypothesized that the treatment of mcc950 could protect DCD hearts preserved with normothermic ex vivo heart perfusion (EVHP) against myocardial IRI via inhibiting NLRP3 inflammasome in a rat heart transplantation model of DCD.MethodsDonor-heart rats were randomly divided into four groups: Control group; Vehicle group; MP-mcc950 group; and MP + PO-mcc950 group. Mcc950 was added into the perfusate of normothermic EVHP in the MP-mcc950 and MP + PO-mcc950 groups, and was injected into the left external jugular vein after heart transplantation in the MP + PO-mcc950 group. Cardiac functional assessment was performed. The level of oxidative stress, inflammatory response, apoptosis, and NLRP3 inflammasome-associated protein of donor hearts were evaluated.ResultsThe treatment with mcc950 significantly increased the developed pressure (DP), dP/dtmax, and dP/dtmin of the left ventricular of DCD hearts at 90 min after heart transplantation in both MP-mcc950 and MP + PO-mcc950 groups. Furthermore, mcc950 added into perfusate and injected after transplantation in both MP-mcc950 and MP + PO-mcc950 groups significantly attenuated the level of oxidative stress, inflammatory response, apoptosis, and NLRP3 inflammasome compared with the vehicle group.ConclusionsNormothermic EVHP combined with mcc950 treatment can be a promising and novel DCD heart preservation strategy, which can alleviate myocardial IRI via inhibiting NLRP3 inflammasome.

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The NLRP3 inhibitor Mcc950 attenuates acute allograft damage in rat kidney transplants

Cited by 12 publications

References 36 publications

Protective effect of Aster tataricus extract on NLRP3‐mediated pyroptosis of bladder urothelial cells

Protective effect of Aster tataricus extract on NLRP3‐mediated pyroptosis of bladder urothelial cells

Inflammasome pathway in kidney transplantation

Normothermic ex vivo heart perfusion with NLRP3 inflammasome inhibitor Mcc950 treatment improves cardiac function of circulatory death hearts after transplantation

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