Qian, Chenchen

AbstractTargeting NLRP3 inflammasome has been recognized as a promising therapeutic strategy for the treatment of numerous common diseases. UK5099, a long‐established inhibitor of mitochondrial pyruvate carrier (MPC), is previously found to inhibit macrophage inflammatory responses independent of MPC expression. However, the mechanisms by which UK5099 inhibit inflammatory responses remain unclear. Here, it is shown that UK5099 is a potent inhibitor of the NLRP3 inflammasome in both mouse and human primary macrophages. UK5099 selectively suppresses the activation of the NLRP3 but not the NLRC4 or AIM2 inflammasomes. Of note, UK5099 retains activities on NLRP3 in macrophages devoid of MPC expression, indicating this inhibitory effect is MPC‐independent. Mechanistically, UK5099 abrogates mitochondria‐NLRP3 interaction and in turn inhibits the assembly of the NLRP3 inflammasome. Further, a single dose of UK5099 persistently reduces IL‐1β production in an endotoxemia mouse model. Importantly, structure modification reveals that the inhibitory activities of UK5099 on NLRP3 are unrelated to the existence of the activated double bond within the UK5099 molecule. Thus, this study uncovers a previously unknown molecular target for UK5099, which not only offers a new candidate for the treatment of NLRP3‐driven diseases but also confounds its use as an MPC inhibitor in immunometabolism studies.

Intestinal fibrosis is considered an inevitable complication of Crohn’s disease (CD) that results in symptoms of obstruction and stricture formation. Endoscopic or surgical treatment is required to treat the majority of patients. Progress in the management of stricturing CD is hampered by the lack of effective antifibrotic therapy; however, this situation is likely to change because of recent advances in other fibrotic diseases of the lung, liver, and skin. In this review, we summarize data from randomized controlled trials (RCTs) of antifibrotic therapies in these conditions. Multiple compounds have been tested for antifibrotic effects in other organs. According to their mechanisms, they were categorized into growth factor modulators, inflammation modulators, 5-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, intracellular enzymes and kinases, renin-angiotensin system (RAS) modulators, and others. From our review of the results from the clinical trials and discussion of their implications in the gastrointestinal tract, we have identified several molecular candidates that could serve as potential therapies for intestinal fibrosis in CD.

Acute kidney injury (AKI) is a complication of COVID-19. However, the incidence of AKI in COVID-19 varies among studies. Thus, we aimed to evaluate the pooled incidence of AKI and its association with mortality in patients with COVID-19 using a meta-analysis. We search Ovid MEDLINE, EMBASE, and the Cochrane Library for eligible publications reporting the clinical characteristics of patients with COVID-19 without language restriction. Incidence of AKI and mortality were reported. Meta-regression was used to describe the association between outcomes. From 26 studies (n=5497), the pooled incidence of AKI in patients with COVID-19 was 8.4% (95% CI 6.0% to 11.7%) with a pooled incidence of renal replacement therapy of 3.6% (95% CI 1.8% to 7.1%). The incidence of AKI was higher in critically ill patients (19.9%) compared with hospitalized patients (7.3%). The pooled estimated odds ratio for mortality from AKI was 13.33 (95% CI 4.05 to 43.91). No potential publication bias was detected. By using meta-regression analyses, the incidence of AKI was positively associated with mortality after adjusted for age and sex (Q=26.18; p=0.02). Moreover, age (p<0.01), diabetes (p=0.02), hypertension (p<0.01) and baseline serum creatinine levels (p=0.04) were positively associated with AKI incidence in adjusted models. In conclusion, AKI is present in 8.3% of overall patients with COVID-19 and in 19.9% of critically ill patients with COVID-19. Presence of AKI is associated with 13-fold increased risk of mortality. Age, diabetes, hypertension, and baseline serum creatinine levels are associated with increased AKI incidence.