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Metabolism is a major defense mechanism of the body against xenobiotic threats. Here we unravel a critical role of Bmal1 for circadian clock-controlled Cyp3a11 expression and xenobiotic metabolism. Bmal1 deficiency decreases the mRNA, protein and microsomal activity of Cyp3a11, and blunts their circadian rhythms in mice. A screen for Cyp3a11 regulators identifies two circadian genes Dbp and Hnf4α as potential regulatory mediators. Cell-based experiments confirm that Dbp and Hnf4α activate Cyp3a11 transcription by their binding to a D-box and a DR1 element in the Cyp3a11 promoter, respectively. Bmal1 binds to the P1 distal promoter to regulate Hnf4α transcriptionally. Cellular regulation of Cyp3a11 by Bmal1 is Dbp- and Hnf4α-dependent. Bmal1 deficiency sensitizes mice to toxicities of drugs such as aconitine and triptolide (and blunts circadian toxicity rhythmicities) due to elevated drug exposure. In summary, Bmal1 connects circadian clock and Cyp3a11 metabolism, thereby impacting drug detoxification as a function of daily time.

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Background: Many factors are associated with no-reflow (NRF) phenomenon in ST-segment elevation myocardial infarction (STEMI), including plasma glucose, age, and pre-percutaneous coronary intervention (PCI) thrombus score. Initial clinical assessment would benefit from accurate NRF prediction. This study aimed to develop a simple scoring system to predict the risk of NRF in patients undergoing primary PCI with STEMI. Methods: Baseline clinical and procedural variables were used for risk score development (the training dataset, n = 912) and validation (the test dataset, n = 864). Independent predictors of NRF from the multivariable model were assigned integer weights based on their coefficients and incorporated into a risk score. The discriminant ability of the score was tested by receiver operating characteristic analysis using the test dataset.Results: The final model included 7 significant variables, which were age, pain-to-PCI time, neutrophil count, admission plasma glucose level, pre-PCI thrombus score, collateral circulation, and Killip class. All these variables were then used to build a risk score in terms of the prediction of NRF. Receiver operating characteristic analysis demonstrated good risk prediction with a c statistic of 0.800 (95% confidence interval: 0.772-0.826) in the test dataset. Conclusions: In patients with STEMI treated by primary PCI, incidence of NRF phenomenon may be predicted with an acceptable accuracy based on a 7-item simplified risk score.

We uncover a cycling and NF-κB–driven lncRNA (named Lnc-UC) that epigenetically modifies transcription of circadian clock gene Rev-erbα, thereby linking circadian clock to colitis. Cycling expression of Lnc-UC is generated by the central clock protein Bmal1 via an E-box element. NF-κB activation in experimental colitis transcriptionally drives Lnc-UC through direct binding to two κB sites. Lnc-UC ablation disrupts colonic expressions of clock genes in mice; particularly, Rev-erbα is down-regulated and its diurnal rhythm is blunted. Consistently, Lnc-UC promotes expression of Rev-erbα (a known dual NF-κB/Nlrp3 repressor) to inactivate NF-κB signaling and Nlrp3 inflammasome in macrophages. Furthermore, Lnc-UC ablation sensitizes mice to experimental colitis and abolishes the diurnal rhythmicity in disease severity. Mechanistically, Lnc-UC physically interacts with Cbx1 protein to reduce its gene silencing activity via H3K9me3, thereby enhancing Rev-erbα transcription and expression. In addition, we identify a human Lnc-UC that has potential to promote Rev-erbα expression and restrain inflammations.

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