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.

A Gravity-Triggered Liquid Metal Patch Antenna with Reconfigurable Frequency.

In this paper, a gravity-triggered liquid metal microstrip patch antenna with reconfigurable frequency is proposed with experimental verification. In this work, the substrate of the antenna is quickly obtained through three-dimensional (3D) printing technology. Non-toxic EGaIn alloy is filled into the resin substrate as a radiation patch, and the NaOH solution is used to remove the oxide film of EGaIn. In this configuration, the liquid metal inside the antenna can be flexibly flowed and deformed with different rotation angles due to the gravity to realize different working states. To validate the conception, the reflection coefficients and radiation patterns of the prototyped antenna are then measured, from which it can be observed that the measured results closely follow the simulations. The antenna can obtain a wide operating bandwidth of 3.69-4.95 GHz, which coverage over a range of frequencies suitable for various channels of the 5th generation (5G) mobile networks. The principle of gravitational driving can be applied to the design of reconfigurable antennas for other types of liquid metals.

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.

Fumigaclavine C activates PPARγ pathway and attenuates atherogenesis in ApoE-deficient mice.

OBJECTIVE: To develop alternative therapeutic strategy that reduces hypercholesterolemia, inflammation and atherosclerosis, we investigate if fumigaclavine C (FC), an indole alkaloid in structure, has anti-atherosclerosis function, and if so, what is the mechanism involved. METHODS AND RESULTS: We used ApoE-deficient (ApoE(-/-)) mice as an atherosclerosis model to examine if FC reduced aorta lesion size and improved serum lipid profiles. ApoE(-/-) mice at 6 weeks of age were fed on a western diet for 10 weeks before FC was administrated (5, 10 and 20 mg/kg) by gavage daily for additional 4 weeks. The mice were sacrificed at 20 weeks of age for examination. The atherosclerotic lesions were assessed with Oil Red O staining in the whole aorta and aortic sinus. Serum levels of triglycerides (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-c) and low density lipoprotein cholesterol (LDL-c) were determined enzymatically. Mouse macrophages were examined for lipid droplets inside cells. FC's effect on PPARγ and PPARγ signaling pathway were further investigated by western blot and luciferase assay. We found that FC decreased atherosclerotic lesion formation in ApoE(-/-) mice in a dose-dependent manner. Also FC improved lipid profiles in ApoE(-/-) mice and reduced the foam cell numbers of peritoneal macrophages. FC stimulated PPARγ signaling pathway proteins both in vitro and in vivo. FC enhanced PPARγ transactivation activity assayed by a PPRE reporter system. CONCLUSION: Our data indicated that FC activated PPARγ signaling pathway as well as its downstream proteins and had an effective role of anti-atherosclerosis.