Clinical characteristics and risk factors for fatal outcome of patients receiving Sun's procedure after previous cardiac surgery.

BACKGROUND: Cardiac reoperation has always been a difficult problem in clinical practice. Because of the difficulty of operation, the incidence of complications and mortality rate is high. Secondary aortic surgery, especially the reoperation involving arch, has higher risk and is more difficult for patients with renal failure. Sun's operation (total arch replacement + stent elephant nose) has achieved good results in the treatment of diseases involving aortic arch, and occupies an important position in the treatment of patients with secondary arch lesions after cardiac surgery. METHODS: A total of 395 patients with a history of cardiac surgery were recorded in our center from January 1, 2009 to December 31, 2017, among whom 118 (30.1%) patients underwent aortic reoperation via the original incision using Sun's aortic procedure owing to postoperative great vessel disease. We analyzed the clinical data and survival time, and used Cox regression to analyze the risk factors for 30-day mortality as well as long term mortality. RESULTS: The interval between the last operation and the present operation was 0.08-19 years. Sixteen patients died within 30 days after operation and the average mortality rate was 13.6%. During the follow-up period, 28 patients died, with the mortality rate of 23.7%. As of December 31, 2017, the longest survival time was 9.36 years, and the survival time of 70 patients was more than 3.05 years. The main risk factor associated with the 30-day survival was cardiopulmonary bypass (CPB) time. The longer the CPB time was, the greater the risk of death was. The main risk factors associated with the long-term survival were CPB time and 24-h bleeding volume. The longer the CPB time was, the more the 24-h bleeding volume was, the higher long-term mortality rate was. CONCLUSION: The second Sun's operation, as a surgical treatment after cardiac surgery, showed a high survival rate, with long survival time and good curative effect. CPB is the main risk factor for the 30-day survival state after operation, and CPB time and 24-h bleeding volume are the main risk factors for the long-term survival state after operation.

Tumor-targeting efficacy of a BF211 prodrug through hydrolysis by fibroblast activation protein-α.

BF211, a bufalin (BF) derivative, exhibits stronger anti-cancer activity than BF but with potential cardiotoxicity. Fibroblast activation protein-α (FAPα) is a membrane-bound protease specifically expressed by carcinoma-associated fibroblasts, thus has been used for the selective delivery of anticancer agents. In this study, we used a FAPα-based prodrug strategy to synthesize a dipeptide (Z-Gly-Pro)-conjugated BF211 prodrug named BF211-03. BF211-03 was hydrolyzed by recombinant human FAPα (rhFAPα) and cleaved by homogenates of human colon cancer HCT-116 or human gastric cancer MGC-803 xenografts. In contrast, BF211-03 showed good stability in plasma and in the homogenates of FAPα-negative normal tissues, such as heart and kidney. In HCT-116 and MGC-803 cells with low levels of FAPα expression, BF211-03 displayed a lower in vitro cytotoxicity than BF211 with approximately 30 to 40-fold larger IC50 values, whereas in human breast cancer MDA-MB-435 cells with high levels of FAPα expression, the IC50 value difference between BF211-03 and BF211 was small (approximately 4-fold). Although the cytotoxicity of BF211-03 against tumor cells was dramatically decreased by the chemical decoration, it was restored after cleavage of BF211-03 by rhFAPα or tumor homogenate. In HCT-116 tumor-bearing nude mice, doubling the dose of BF211-03, compared with BF211, caused less weight loss, but showing similar inhibitive effects on tumor growth. Our results suggest that BF211-03 is converted to active BF211 in tumor tissues and exhibits anti-tumor activities in tumor-bearing nude mice. FAPα-targeted BF211-03 displays tumor selectivity and may be useful as a targeting agent to improve the safety profile of cytotoxic natural products for use in cancer therapy.

LX2343 alleviates cognitive impairments in AD model rats by inhibiting oxidative stress-induced neuronal apoptosis and tauopathy.

Alzheimer's disease (AD) is a progressive neurodegenerative disease leading to the irreversible loss of brain neurons and cognitive abilities, and the vicious interplay between oxidative stress (OS) and tauopathy is believed to be one of the major players in AD development. Here, we demonstrated the capability of the small molecule N-(1,3-benzodioxol-5-yl)-2-[5-chloro-2-methoxy(phenylsulfonyl)anilino]acetamide (LX2343) to ameliorate the cognitive dysfunction of AD model rats by inhibiting OS-induced neuronal apoptosis and tauopathy. Streptozotocin (STZ) was used to induce OS in neuronal cells in vitro and in AD model rats that were made by intracerebroventricular injection of STZ (3 mg/kg, bilaterally), and Morris water maze test was used to evaluate the cognitive dysfunction in ICV-STZ rats. Treatment with LX2343 (5-20 µmol/L) significantly attenuated STZ-induced apoptosis in SH-SY5Y cells and mouse primary cortical neurons by alleviating OS and inhibiting the JNK/p38 and pro-apoptotic pathways. LX2343 was able to restore the integrity of mitochondrial function and morphology, increase ATP biosynthesis, and reduce ROS accumulation in the neuronal cells. In addition, LX2343 was found to be a non-ATP competitive GSK-3ß inhibitor with IC50 of 1.84±0.07 µmol/L, and it potently inhibited tau hyperphosphorylation in the neuronal cells. In ICV-STZ rats, administration of LX2343 (7, 21 mg·kg-1·d-1, ip, for 5 weeks) efficiently improved their cognitive deficits. LX2343 ameliorates the cognitive dysfunction in the AD model rats by suppressing OS-induced neuronal apoptosis and tauopathy, thus highlighting the potential of LX2343 for the treatment of AD.

Small molecule LX2343 ameliorates cognitive deficits in AD model mice by targeting both amyloid ß production and clearance.

AIM: Streptozotocin (STZ) is widely used to induce oxidative damage and to impair glucose metabolism, apoptosis, and tau/Aß pathology, eventually leading to cognitive deficits in both in vitro and in vivo models of Alzheimer's disease (AD). In this study, we constructed a cell-based platform using STZ to induce stress conditions mimicking the complicated pathologies of AD in vitro, and evaluated the anti-amyloid effects of a small molecule, N-(1,3-benzodioxol-5-yl)-2-[5-chloro-2-methoxy(phenylsulfonyl)anilino]acetamide (LX2343) in the amelioration of cognitive deficits in AD model mice. METHODS: Cell-based assays for screening anti-amyloid compounds were established by assessing Aß accumulation in HEK293-APPsw and CHO-APP cells, and Aß clearance in primary astrocytes and SH-SY5Y cells after the cells were treated with STZ in the presence of the test compounds. Autophagic flux was observed using confocal laser scanning microscopy. APP/PS1 transgenic mice were administered LX2343 (10 mg·kg-1·d-1, ip) for 100 d. After LX2343 administration, cognitive ability of the mice was evaluated using Morris water maze test, and senile plaques in the brains were detected using Thioflavine S staining. ELISA assay was used to evaluate Aß and sAPPß levels, while Western blot analysis was used to measure the signaling proteins in both cell and animal brains. RESULTS: LX2343 (5-20 µmol/L) dose-dependently decreased Aß accumulation in HEK293-APPsw and CHO-APP cells, and promoted Aß clearance in SH-SY5Y cells and primary astrocytes. The anti-amyloid effects of LX2343 were attributed to suppressing JNK-mediated APPThr668 phosphorylation, thus inhibiting APP cleavage on one hand, and inhibiting BACE1 enzymatic activity with an IC50 value of 11.43±0.36 µmol/L, on the other hand. Furthermore, LX2343 acted as a non-ATP competitive PI3K inhibitor to negatively regulate AKT/mTOR signaling, thus promoting autophagy, and increasing Aß clearance. Administration of LX2343 in APP/PS1 transgenic mice significantly ameliorated cognitive deficits and markedly ameliorated the Aß pathology in their brains. CONCLUSION: LX2343 ameliorates cognitive dysfunction in APP/PS1 transgenic mice via both Aß production inhibition and clearance promotion, which highlights the potential of LX2343 in the treatment of AD.