Xiaobin Zeng

The chemotherapeutic drug doxorubicin (DOX) has been demonstrated to trigger pyroptosis in tumor cells at exceptionally high concentrations. Nevertheless, the administration of DOX at suprapharmacological doses could cause acute off-target cytotoxicity and severe adverse effects. Herein, a biflavonoid derivative, F24, was found to improve the sensitivity of hepatocellular carcinoma (HCC) cells to low-dose DOX and reduce the adverse effects of DOX. We demonstrated that F24 synergized with low-dose DOX to increase pyroptosis and autophagy in HCC cells through dual-target CDK6 inhibition/p53 activation at a proper ratio. To achieve this synergistic effect, nanodiscs with large hydrophobic cavities were selected to codeliver the low-dose hydrophobic drugs DOX and F24 (DOX-F24@Nanodisc, DF@N), which improved the tumor accumulation of the two drugs and ensured precise drug ratio integrity within the tumor cells. DF@N can trigger gasdermin-E (GSDME)-based pyroptosis in tumor cells, accompanied by the cleavage of caspase-3. Strikingly, knocking out GSDME or caspase-3 redirected DF@N-driven cellular death from the pyroptosis pathway to the apoptotic pathway. Furthermore, DF@N administration suppressed tumor growth and activated pyroptosis in a Huh7 mouse xenograft tumor model. Overall, F24 was found to induce autophagy by targeting CDK6 and had a synergistic effect on DOX-induced pyroptosis. These results indicate that the pyroptosis-induced DF@N nanodisc system provides an effective and secure therapeutic strategy for treating HCC.

The aim of this study was to investigate the association between serum albumin to serum creatinine ratio (sACR) and the prognosis of heart failure (HF). In this single‐center prospective cohort study, a total of 2625 patients with HF were enrolled between March 2012 and June 2017. All patients were divided into three groups according to the tertiles of sACR. Of 2625 patients, the mean age was 57.0 ± 14.3 years. During a median follow‐up time of 23 months, 666 end point events occurred. Prognosis analysis indicated that the lowest sACR was significantly associated with higher mortality risk of HF (hazard ratio [HR] = 1.920, 95% confidence interval [CI] = 1.585–2.326, p < 0.001) when compared with the highest tertile. After adjusting for covariates including age, gender, diabetes, systolic blood pressure (SBP), diastolic blood pressure, heart rate, total cholesterol, triglycerides, HDL‐C, LDL‐C, white blood cell count, hemoglobin, glycosylated hemoglobin, and β‐blocker use, the HRs for mortality risk of HF was 1.513 (95% CI = 1.070–2.139, p = 0.019). Subgroup analysis indicated that the mortality risk of HF statistically significantly reduced with the rise in sACR in patients with no β‐blocker use, patients with serum creatine less than 97 μmol/L. However, stratification by age, sex, history of hypertension, diabetes, and smoking, level of glycosylated hemoglobin, and albumin have no obvious effect on the association between sACR and the prognosis of HF. Additionally, patients with lower sACR displayed reduced left ventricular ejection fraction and increased left ventricular end‐diastolic diameter. The discriminant power of sACR alone and in combination with age, gender, SBP, heart rate, and glycosylated hemoglobin were excellent with C statistic of 0.655 and 0.889, respectively. Lower sACR was an independent risk factor for mortality risk of HF.

We have purified a novel caffeoylquinic acid named 3,4-di-O-caffeoylquinic acid isobutyl ester from the flower buds of Lonicera japonica Thunb., Caprifoliaceae. However, the biological function of 3,4-di-O-caffeoylquinic acid isobutyl ester is still unknown. Here, we found that 3,4-di-O-caffeoylquinic acid isobutyl ester effectively inhibited the proliferation and migration of hepatocellular carcinoma cells, and it displayed less toxicity to a normal liver cell line. Mechanistic studies showed that 3,4-di-O-caffeoylquinic acid isobutyl ester diminished the expression of YAP at the mRNA level. Overexpression of YAP significantly rescued HepG2 cells from the 3,4-di-O-caffeoylquinic acid isobutyl ester–induced suppression of proliferation and migration. Furthermore, the YAP downstream target gene CTGF was significantly repressed upon 3,4-di-O-caffeoylquinic acid isobutyl ester treatment, which was ameliorated by YAP overexpression. In addition, 3,4-di-O-caffeoylquinic acid isobutyl ester decreased the expression of β-catenin as well as CDK4/6. Collectively, 3,4-di-O-caffeoylquinic acid isobutyl ester exerts antihepatocellular carcinoma activity by inhibiting the YAP-CTGF pathway which controls the proliferation and migration of hepatocellular carcinoma cells. The Wnt/β-catenin pathway might be another pathway by which 3,4-di-O-caffeoylquinic acid isobutyl ester exerts antihepatocellular carcinoma activity. As a novel natural compound, 3,4-di-O-caffeoylquinic acid isobutyl ester might be a promising agent for hepatocellular carcinoma therapy. Graphical Abstract