Inhibition of CYP2E1 attenuates myocardial dysfunction in a murine model of insulin resistance through NLRP3-mediated regulation of mitophagy.

Insulin resistance leads to myocardial contractile dysfunction and deranged autophagy although the underlying mechanism or targeted therapeutic strategy is still lacking. This study was designed to examine the impact of inhibition of the cytochrome P450 2E1 (CYP2E1) enzyme on myocardial function and mitochondrial autophagy (mitophagy) in an Akt2 knockout model of insulin resistance. Adult wild-type (WT) and Akt2-/- mice were treated with the CYP2E1 inhibitor diallyl sulfide (100 mg/kg/d, i.p.) for 4 weeks. Cardiac geometry and function were assessed using echocardiographic and IonOptix systems. Western blot analysis was used to evaluate autophagy, mitophagy, inducible NOS (iNOS), and the NLRP3 inflammasome, a multi-protein intracellular pattern recognition receptor complex. Akt2 deletion triggered insulin resistance, compromised cardiac contractile and intracellular Ca2+ property, mitochondrial ultrastructural damage, elevated O2- production, as well as suppressed autophagy and mitophagy, accompanied with elevated levels of NLRP3 and iNOS, the effects of which were significantly attenuated or ablated by diallyl sulfide. In vitro studies revealed that the NLRP3 activator nigericin nullified diallyl sulfide-offered benefit against Akt2 knockout on cardiomyocyte mechanical function and mitophagy (using Western blot and colocalization of GFP-LC3 and MitoTracker Red). Moreover, inhibition of iNOS but not mitochondrial ROS production attenuated Akt2 deletion-induced activation of NLRP3, substantiating a role for iNOS-mediated NLRP3 in insulin resistance-induced changes in mitophagy and cardiac dysfunction. In conclusion, these data depict that insulin resistance through CYP2E1 may contribute to the pathogenesis of myopathic changes including myocardial contractile dysfunction, oxidative stress and mitochondrial injury, possibly through activation of iNOS and NLRP3 signaling.

Obesity increases the risk of failure of noninvasive prenatal screening regardless of gestational age.

BACKGROUND: Noninvasive prenatal screening has become an increasingly prevalent choice for women who desire aneuploidy screening. Although the test characteristics are impressive, some women are at increased risk for noninvasive prenatal screen failure. The risk of test failure increases with maternal weight; thus, obese women may be at elevated risk for failure. This risk of failure may be mitigated by the addition of a paternal cheek swab and screening at a later gestational age. OBJECTIVE: The purpose of this study was to evaluate the association among obesity, gestational age, and paternal cheek swab in the prevention of screening failure. STUDY DESIGN: A retrospective cohort study was performed for women who were ≥35 years old at delivery who underwent screening at NorthShore University HealthSystem, Evanston, IL. Maternal weight, body mass index, gestational age, and a paternal cheek swab were evaluated in univariate and multivariable logistic regression analyses to assess the association with failed screening. RESULTS: Five hundred sixty-five women met inclusion criteria for our study. The mean body mass index was 25.9 ± 5.1 kg/m(2); 111 women (20%) were obese (body mass index, ≥30 kg/m(2)). Forty-four women (7.8%) had a failed screen. Obese women had a failure rate of 24.3% compared with 3.8% in nonobese women (P < .01). Gestational age was not associated with failure rate (mean ± standard deviation, 13 ± 3 weeks for both screen failure and nonfailure; P = .76). The addition of a paternal cheek swab reduced the failure rate from 10.2% in women with no swab to 3.8% in women with a swab (P < .01). In multivariable analysis, obesity and lack of a paternal cheek swab were independent predictors of screen failure (odds ratio, 9.75; 95% confidence interval, 4.85-19.61; P < .01; and odds ratio, 3.61; 95% confidence interval, 1.56-8.33; P < .01, respectively). CONCLUSION: The addition of a paternal cheek swab significantly improved noninvasive prenatal screen success rates in obese women. However, delaying testing to a later gestational age did not.