Synthesis and Biological Evaluation of 5-Fluoro-2-Oxindole Derivatives as Potential α-Glucosidase Inhibitors.

α-Glucosidase inhibitors are known to prevent the digestion of carbohydrates and reduce the impact of carbohydrates on blood glucose. To develop novel α-glucosidase inhibitors, a series of 5-fluoro-2-oxindole derivatives (3a ∼ 3v) were synthesized, and their α-glucosidase inhibitory activities were investigated. Biological assessment results showed that most synthesized compounds presented potential inhibition on α-glucosidase. Among them, compounds 3d, 3f, and 3i exhibited much better inhibitory activity with IC50 values of 49.89 ± 1.16 µM, 35.83 ± 0.98 µM, and 56.87 ± 0.42 µM, respectively, which were about 10 ∼ 15 folds higher than acarbose (IC50 = 569.43 ± 43.72 µM). A kinetic mechanism study revealed that compounds 3d, 3f, and 3i inhibited the α-glucosidase in a reversible and mixed manner. Molecular docking was carried out to simulate the affinity between the compound and α-glucosidase.

Association of Satellite Sign with Postoperative Rebleeding in Patients Undergoing Stereotactic Minimally Invasive Surgery for Hypertensive Intracerebral Haemorrhage.

There are few studies regarding imaging markers for predicting postoperative rebleeding after stereotactic minimally invasive surgery (MIS) for hypertensive intracerebral haemorrhage (ICH), and little is known about the relationship between satellite sign on computed tomography (CT) scans and postoperative rebleeding after MIS. This study aimed to determine the value of the CT satellite sign in predicting postoperative rebleeding in patients with hypertensive ICH who undergo stereotactic MIS. We retrospectively examined and analysed 105 patients with hypertensive ICH who underwent standard stereotactic MIS for hematoma evacuation within 72 h following admission. Postoperative rebleeding occurred in 14 of 65 (21.5%) patients with the satellite sign on baseline CT, and in 5 of the 40 (12.5%) patients without the satellite sign. This difference was statistically significant. Positive and negative values of the satellite sign for predicting postoperative rebleeding were 21.5% and 87.5%, respectively. Multivariate logistic regression analysis verified that baseline ICH volume and intraventricular rupture were independent predictors of postoperative rebleeding. In conclusion, the satellite sign on baseline CT scans may not predict postoperative rebleeding following stereotactic MIS for hypertensive ICH.

Synthesis and biological evaluation of coumarin derivatives as α-glucosidase inhibitors.

In this study, two series of coumarin derivatives 5a∼i and 6a∼i were synthesized, and their inhibitory activity against α-glucosidase was determined. The results indicated that most of the synthesized derivatives exhibited prominent inhibitory activities against α-glucosidase. Among them, compounds 5a and 5b showed the strongest inhibition with the IC50 values of 19.64 µM and 12.98 µM, respectively. Enzyme kinetic studies of compounds 5a and 5b proved that their inhibition was reversible and a mixed type. The KI and KIS values of compound 5a were calculated to be 27.39 µM and 13.02 µM, respectively, and the corresponding values for compound 5b being 27.02 µM and 13.65 µM, respectively. The docking studies showed that compound 5b could be inserted into the active pocket of α-glucosidase and form hydrogen bonds with LYS293 to enhance the binding affinity.

Probucol suppresses human glioma cell proliferation in vitro via ROS production and LKB1-AMPK activation.

AIM: Probucol, an anti-hyperlipidemic drug, has been reported to exert antitumor activities at various stages of tumor initiation, promotion and progression. In this study we examined whether the drug affected glioma cell growth in vitro and the underlying mechanisms. METHODS: Human glioma U87 and glioblastoma SF295 cell lines were used. Cell proliferation was accessed using the cell proliferation assay and BrdU incorporation. The phosphorylation of AMPK, liver kinase B1 (LKB1) and p27(Kip1) was detected by Western blot. The activity of 26S proteasome was assessed with an in situ fluorescent substrate. siRNAs were used to suppress the expression of the relevant signaling proteins. RESULTS: Treatment of U87 glioma cells with probucol (10-100 µmol/L) suppressed the cell proliferation in dose- and time dependent manners. Meanwhile, probucol markedly increased the ROS production, phosphorylation of AMPK at Thr172 and LKB1 at Ser428 in the cells. Furthermore, probucol significantly decreased 26S proteasome activity and increased p27(Kip1) protein level in the cells in an AMPK-dependent manner. Probucol-induced suppression of U87 cell proliferation could be reversed by pretreatment with tempol (a superoxide dismutase mimetic), MG132 (proteasome inhibitor) or compound C (AMPK inhibitor), or by gene silencing of LKB1, AMPK or p27(Kip1). Similar results were observed in probucol-treated SF295 cells. CONCLUSION: Probucol suppresses human glioma cell proliferation in vitro via ROS production and LKB1-AMPK activation, which reduces 26S proteasome-dependent degradation of p27(Kip1).

Intraclot recombinant tissue-type plasminogen activator reduces perihematomal edema and mortality in patients with spontaneous intracerebral hemorrhage.

The study aimed to investigate the impact of intraclot recombinant tissue-type plasminogen activator (rt-PA) on perihematomal edema (PHE) development in patients with intracerebral hemorrhage (ICH) treated with minimally invasive surgery (MIS) and the effects of intraclot rt-PA on the 30-day survival. We reviewed the medical records of ICH patients undergoing MIS between October 2011 and July 2013. A volumetric analysis was done to assess the change in PHE and ICH volumes at pre-MIS (T1), post-MIS (T2) and day 10-16 (T3) following diagnostic computed tomographic scans (T0). Forty-three patients aged 52.8±11.1 years with (n=30) or without rt-PA (n=13) were enrolled from our institutional ICH database. The median rt-PA dose was 1.5 (1) mg, with a maximum dose of 4.0 mg. The ratio of clot evacuation was significantly increased by intraclot rt-PA as compared with controls (77.9%±20.4% vs. 64%±15%; P=0.046). From T1 to T2, reduction in PHE volume was strongly associated with the percentage of clot evacuation (ρ=0.34; P=0.027). In addition, PHE volume was positively correlated with residual ICH volume at the same day (ρ ranging from 0.39-0.56, P<0.01). There was no correlation between the cumulative dose of rt-PA and early (T2) PHE volume (ρ=0.24; P=0.12) or delayed (T3) PHE volume (ρ=0.19; P=0.16). The 30-day mortality was zero in this cohort. In the selected cohort of ICH patients treated with MIS, intraclot rt-PA accelerated clot removal and had no effects on PHE formation. MIS aspiration and low dose of rt-PA seemed to be feasible to reduce the 30-day mortality in patients with severe ICH. A large, randomized study addressing dose titration and long-term outcome is needed.

αν and ß1 Integrins mediate Aß-induced neurotoxicity in hippocampal neurons via the FAK signaling pathway.

αν and ß1 integrins mediate Aß-induced neurotoxicity in primary hippocampal neurons. We treated hippocampal neurons with 2.5 µg/mL 17E6 and 5 µg/mL ab58524, which are specific αν and ß1 integrin antagonists, respectively, for 42 h prior to 10 µM Aß treatment. Next, we employed small interfering RNA (siRNA) to silence focal adhesion kinase (FAK), a downstream target gene of integrins. The siRNAs were designed with a target sequence, an MOI of 10 and the addition of 5 µg/mL polybrene. Under these conditions, the neurons were transfected and the apoptosis of different cell types was detected. Moreover, we used real-time PCR and Western blotting analyses to detect the expression of FAK and ρFAK genes in different cell types and investigated the underlying mechanism and signal pathway by which αν and ß1 integrins mediate Aß-induced neurotoxicity in hippocampal neurons. An MTT assay showed that both 17E6 and ab58524 significantly increased cell viability compared with the Aß-treated neurons (P<0.01 and P<0.05, respectively). However, this protective effect was markedly attenuated after transfection with silencing FAK (siFAK). Moreover, TUNEL immunostaining and flow cytometry indicated that both 17E6 and ab58524 significantly protected hippocampal neurons against apoptosis induced by Aß (P<0.05) compared with the Aß-treated cells. However, this protective effect was reversed with siFAK treatment. Both the gene and protein expression of FAK increased after Aß treatment. Interestingly, as the gene and protein levels of FAK decreased, the ρFAK protein expression markedly increased. Furthermore, both the gene and protein expression of FAK and ρFAK were significantly diminished. Thus, we concluded that both αν and ß1 integrins interfered with Aß-induced neurotoxicity in hippocampal neurons and that this mechanism partially contributes to the activation of the Integrin-FAK signaling pathway.