Background: The triglyceride-glucose (TyG) index could serve as a convenient substitute of insulin resistance (IR), but epidemiological evidence on its relationship with the long-term risk of mortality is limited.Methods: Participants from the National Health and Nutrition Examination Survey during 1999–2014 were grouped according to TyG index (<8, 8–9, 9–10, >10). Cox regression was conducted to compute the hazard ratios (HRs) and 95% confidence interval (CI). Restricted cubic spline and piecewise linear regression were performed to detect the shape of the relationship between TyG index and mortality.Results: A total of 19,420 participants (48.9% men) were included. On average, participants were followed-up for 98.2 months, and 2,238 (11.5%) and 445 (2.3%) cases of mortality due to all-cause or cardiovascular disease were observed. After adjusting for confounders, TyG index was independently associated with an elevated risk of all-cause (HR, 1.10; 95% CI, 1.00–1.20) and cardiovascular death (HR, 1.29; 95% CI, 1.05–1.57). Spline analyses showed that the relationship of TyG index with mortality was non-linear (All non-linear P < 0.001), and the threshold value were 9.36 for all-cause and 9.52 for cardiovascular death, respectively. The HRs above the threshold point were 1.50 (95% CI, 1.29–1.75) and 2.35 (95% CI, 1.73–3.19) for all-cause and cardiovascular death. No significant difference was found below the threshold points (All P > 0.05).Conclusion: Elevated TyG index reflected a more severe IR and was associated with mortality due to all-cause and cardiovascular disease in a non-linear manner.

Human dihydroorotate dehydrogenase (DHODH) is a flavin-dependent mitochondrial enzyme catalyzing the fourth step in the de novo pyrimidine synthesis pathway. It is originally a target for the treatment of the non-neoplastic diseases involving in rheumatoid arthritis and multiple sclerosis, and is re-emerging as a validated therapeutic target for cancer therapy. In this review, we mainly unravel the biological function of DHODH in tumor progression, including its crucial role in de novo pyrimidine synthesis and mitochondrial respiratory chain in cancer cells. Moreover, various DHODH inhibitors developing in the past decades are also been displayed, and the specific mechanism between DHODH and its additional effects are illustrated. Collectively, we detailly discuss the association between DHODH and tumors in recent years here, and believe it will provide significant evidences and potential strategies for utilizing DHODH as a potential target in preclinical and clinical cancer therapies.

Background & Aims Multidrug resistance–associated protein 2 (MRP2) excretes conjugated organic anions including bilirubin and bile acids. Malfunction of MRP2 leads to jaundice in patients. Studies in rodents indicate that Radixin plays a critical role in determining Mrp2 canalicular membrane expression. However, it is not known how human hepatic MRP2 expression is regulated in cholestasis. Methods We assessed liver MRP2 expression in patients with obstructive cholestasis caused by gallstone blockage of bile ducts, and investigated the regulatory mechanism in HepG2 cells. Results Western blot detected that liver MRP2 protein expression in obstructive cholestatic patients (n=30) was significantly reduced to 25% of the non-cholestatic controls (n=23). Immunoprecipitation identified Ezrin but not Radixin associating with MRP2 in human livers, and the increased amount of phospho-Ezrin Thr567 was positively correlated with the amount of co-precipitated MRP2 in cholestatic livers, whereas Ezrin and Radixin total protein levels were unchanged in cholestasis. Further detailed studies indicate that Ezrin Thr567 phosphorylation plays an important role in MRP2 internalization in HepG2 cells. Since increased expression of PKCα, δ and ε were detected in these cholestatic livers, we further confirmed that these PKCs stimulated Ezrin phosphorylation and reduced MRP2 membrane expression in HepG2 cells. Finally, we identified GP78 as the key ubiquitin ligase E3 involved in MRP2 proteasome degradation. Conclusions Activation of liver PKCs during cholestasis leads to Ezrin Thr567 phosphorylation resulting in MRP2 internalization and degradation where ubiquitin ligase E3 GP78 is involved. This process provides a mechanistic explanation for jaundice seen in patients with obstructive cholestasis.

Human dihydroorotate dehydrogenase (hDHODH) is an attractive target for cancer therapy. Based on its crystal structure, we designed and synthesized a focused compound library containing the structural moiety of 1,4-benzoquinone, which possesses reactive oxygen species (ROS) induction capacity. Compound 3s with a naphtho­[2,3-d]­[1,2,3]­triazole-4,9-dione scaffold exhibited inhibitory activity against hDHODH. Further optimization led to compounds 11k and 11l, which inhibited hDHODH activity with IC50 values of 9 and 4.5 nM, respectively. Protein–ligand cocrystal structures clearly depicted hydrogen bond and hydrophobic interactions of 11k and 11l with hDHODH. Compounds 11k and 11l significantly inhibited leukemia cell and solid tumor cell proliferation and induced ROS production, mitochondrial dysfunction, apoptosis, and cell cycle arrest. Nanocrystallization of compound 11l displayed significant in vivo antitumor effects in the Raji xenograft model. Overall, this study provides a novel bifunctional compound 11l with hDHODH inhibition and ROS induction efficacy, which represents a promising anticancer lead worthy of further exploration.