Anti-Diabetic Effects of Gynura Bicolor Aqueous Extract in Mice.

The effects of Gynura bicolor aqueous extract (GAE) upon glycemic control, coagulation disorder, lipid accumulation, and glycative, oxidative, and inflammatory stresses in diabetic mice were investigated. Mice were treated with streptozotocin to induce type 1 diabetes. Diabetic mice were divided into four groups, consumed GAE at 0%, 0.25%, 0.5%, or 1%. Normal group consumed standard mouse basal diet. After 8-week treatments, mice were sacrificed after overnight fasting. Results showed that GAE supplement at 0.5% and 1% decreased plasma glucose level and increased plasma insulin level. Diabetes lowered plasma level of protein C and anti-thrombin III; and raised plasminogen activator inhibitor-1 activity and fibrinogen level in plasma. GAE supplement at 0.5% and 1% reversed these alterations. Histological data, assayed by Oil Red O stain, indicated that GAE supplement decreased lipid accumulation in liver. GAE supplement at 0.5% and 1% reduced aldose reductase activity in heart and kidney; and lowered the levels of carboxymethyllysine and pentosidine in plasma and two organs. Diabetes decreased glutathione content, and increased reactive oxygen species, interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α production in heart and kidney. GAE supplement at three test doses reversed these changes. Diabetes upregulated the mRNA expression of p38 and nuclear factor kappa (NF-κ)B in heart and kidney. GAE supplement suppressed the mRNA expression of both p38 and NF-κB. These novel findings suggest that Gynura bicolor is a potent functional food for diabetic prevention or alleviation.

Synthesis and biological evaluation of genistein-O-alkylamine derivatives as potential multifunctional anti-Alzheimer agents.

A series of genistein derivatives were synthesized and evaluated as multifunctional anti-Alzheimer agents. The results showed that these derivatives had significant acetylcholinesterase (AChE) inhibitory activity; compound 5a exhibited the strongest inhibition to AChE with an IC50 value (0.034 µM) much lower than that of rivastigmine (6.53 µM). A Lineweaver-Burk plot and molecular modeling study showed that compound 5a targeted both the catalytic active site and the peripheral anionic site of AChE. These compounds also showed potent peroxy scavenging activity and metal-chelating ability. The compounds did not show obvious effect on HepG2 and PC12 cell viability at the concentration of 100 µM. Therefore, these genistein derivatives can be utilized as multifunctional agents for the treatment of AD.

Discovery of the Polyamine Conjugate with Benzo[ cd]indol-2(1 H)-one as a Lysosome-Targeted Antimetastatic Agent.

Polyamine derivatives have a promising prospect in dealing with disseminated tumor cells, a major obstacle in cancer therapy. To develop a bifunctional polyamine derivative that can serve as a fluorescent probe and an antimetastatic agent, three kinds of polyamine conjugates with benzo[ cd]indol-2(1 H)-one as a scaffold were designed and synthesized. Compound 5e was selected as a lead by in vitro screening. Two animal models demonstrated that 5e inhibited pulmonary metastasis and tumor growth. As a fluorescent probe, 5e might partially enter cells via a polyamine transporter and subsequently localize in the lysosome. Mechanistic investigations demonstrated the interdependence of 5e-triggered apoptosis and autophagy. Compound 5e modulated the expression of LC3-II, p62, cathepsins, and the expression of capases 3, caspase 8, Bcl-2, and p53. The SSAT-mediated Akt/ß-catenin pathways were also inhibited by 5e. The dual features of 5e make it a worthwhile lead compound for further structural optimization.

Development of tacrine-bifendate conjugates with improved cholinesterase inhibitory and pro-cognitive efficacy and reduced hepatotoxicity.

A novel series of tacrine-bifendate (THA-DDB) conjugates (7a-e) were synthesized and evaluated as potential anti-Alzheimer's agents. These compounds showed potent cholinesterase and self-induced ß-amyloid (Aß) aggregation inhibitory activities. A Lineweaver-Burk plot and molecular modeling study showed that these compounds can target both catalytic active site (CAS) and peripheral anionic site (PAS) of acetylcholinesterase (AChE). The cytotoxicity of the conjugate 7d against PC12 and HepG2 cells and hepatotoxicity against human hepatocyte cell line (HL-7702) were found to be considerably less compared to THA. Moreover, treatment with 7d did not exhibit significant hepatotoxicity in mice. Finally, in vivo studies confirmed that 7d significantly ameliorates the cognitive performances of scopolamine-treated ICR mice. Therefore, 7d has high potential for the treatment of Alzheimer's disease and warrants further investigation.

Design, synthesis and evaluation of novel 7-aminoalkyl-substituted flavonoid derivatives with improved cholinesterase inhibitory activities.

A novel series of 7-aminoalkyl-substituted flavonoid derivatives 5a-5r were designed, synthesized and evaluated as potential cholinesterase inhibitors. The results showed that most of the synthesized compounds exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities at the micromolar range. Compound 2-(naphthalen-1-yl)-7-(8-(pyrrolidin-1-yl)octyloxy)-4H-chromen-4-one (5q) showed the best inhibitory activity (IC50, 0.64µM for AChE and 0.42µM for BChE) which were better than our previously reported compounds and the commercially available cholinergic agent Rivastigmine. The results from a Lineweaver-Burk plot indicated a mixed-type inhibition for compound 5q with AChE and BChE. Furthermore, molecular modeling study showed that 5q targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds (5a-5r) did not affect PC12 and HepG2 cell viability at the concentration of 10µM. Consequently, these flavonoid derivatives should be further investigated as multipotent agents for the treatment of Alzheimer's disease.