Design, synthesis, and anticancer activity of three novel palbociclib derivatives.

Cancer is one of the most serious diseases threatening human health, so it is particularly important to develop effective tumor-targeting drugs. As the first CDK4/6 inhibitor, palbociclib effectively inhibits tumor proliferation by blocking the cell cycle to the G1 phase. 10-HCPT is a Topo I inhibitor; however, its clinical application has been greatly limited due to its high toxicity. Based on the successful development of double target inhibitors, three novel palbociclib derivatives (HP-1, HP-2, and HP-3) were designed and synthesized from Palbociclib and 10-HCPT, and their biological activities were investigated. At first, the possible binding sites of the three compounds to Topo I and CDK4/6 were predicted by molecular docking. Then, we evaluated the anti-proliferative effects of the three palbociclib derivatives. In general, human lung cancer cells were more sensitive to HP-1, HP-2, and HP-3, especially NCI-H460. In addition, cell cycle arrest and apoptosis induction were investigated by flow cytometry. The three palbociclib derivatives, especially HP-1, had obvious cell cycle arrest phenomenon on NCI-H460 cells and induced apoptosis of NCI-H460 cells significantly. In the end, it was proved that these three drugs had obvious cyclin-dependent kinase inhibitory activities. In short, all the data showed that HP-1, HP-2, and HP-3 could play anti-cancer roles by acting on dual targets and had the characteristics of high efficiencies and low toxicities, which opened up a new idea for the study of palbociclib derivatives.

The impact of age in acute type A aortic dissection: a retrospective study.

BACKGROUND: Acute type A aortic dissection (aTAAD) is a lethal disease and age is an important risk factor for outcomes. This retrospective study was to analyze the impact of age stratification in aTAAD, and to provide clues for surgeons when they make choices of therapy strategies. METHODS: From January 2011 to December 2019, 1092 aTAAD patients from Nanjing Drum Tower Hospital received surgical therapy. Patients were divided into 7 groups according to every ten-year interval (20-80 s). The differences between the groups were analyzed in terms of the baseline preoperative conditions, surgical methods and postoperative outcomes of patients of different age groups. During a median follow-up term of 17 months, the survival rates were compared among 7 groups through Kaplan-Meier analysis. RESULTS: The median age was 52.0 years old in whole cohort. The multiple comorbidities were more common in old age groups (60 s, 70 s, 80 s), while the 20 s group patients had the highest proportion of Marfan syndrome (28.1%). Preoperative hypotension was highest in 80 s (16.7%, P = 0.038). Young age groups (20-60 s) had a higher rate of root replacement and total arch replacement, which led to a longer duration of operation and hypothermic circulation arrest. The overall mortality was 14.1%, the tendency of mortality was increased with age except 20 s group (33.3% in 80 s, P = 0.016). The postoperative morbidity of gastrointestinal bleeding and bowel ischemia were 16.7% and 11.1% in 80 s group. CONCLUSIONS: Age is a major impact factor for aTAAD surgery. Old patients presented more comorbidities before surgery, the mortality and complications rate were significantly higher even with less invasive and conservative surgical therapy. But the favorable long-term survival indicated that the simple or less extensive arch repair is the preferred surgery for patients over 70 years old.

S­allyl­cysteine sulfoxide (alliin) alleviates myocardial infarction by modulating cardiomyocyte necroptosis and autophagy.

S­allyl­cysteine sulfoxide (alliin) is the main organosulfur component of garlic and its preparations. The present study aimed to examine the protective effect of alliin on cardiac function and the underlying mechanism in a mouse model of myocardial infarction (MI). Notably, alliin treatment preserved heart function, attenuated the area of infarction in the myocardium of mice and reduced lesions in the myocardium, including cardiomyocyte fibrosis and death. Further mechanistic experiments revealed that alliin inhibited necroptosis but promoted autophagy in vitro and in vivo. Cell viability assays showed that alliin dose­dependently reduced the necroptotic index and inhibited the expression of necroptosis­related receptor­interacting protein 1, receptor­interacting protein 3 and tumor necrosis factor receptor­associated factor 2, whereas the levels of Beclin 1 and microtubule­associated protein 1 light chain 3, which are associated with autophagy, exhibited an opposite trend upon treatment with alliin. In addition, the level of peroxisome proliferator­activated receptor γ was increased by alliin. Collectively, these findings demonstrate that alliin has the potential to protect cardiomyocytes from necroptosis following MI and that this protective effect occurs via the enhancement of autophagy.