Discovery of potent and selective dual cholinesterases and ß-secretase inhibitors in pomegranate as a treatment for Alzheimer's disease.

Pomegranate (Punica granatum L.) extract has been reported to inhibit cholinesterase and the ß-site amyloid precursor protein cleaving enzyme 1 (BACE1); however, most of its constituents' potential inhibition of these enzymes remains unknown. Thus, we investigated the anti-Alzheimer's disease (anti-AD) potential of 16 ellagitannin and gallotannin, and nine anthocyanin derivatives' inhibition of BACE1, AChE, and BChE, and gallagic acid inhibited both the best. Further, a kinetic study identified different modes of inhibition, and a molecular docking simulation revealed that active compounds inhibited these three enzymes with low binding energy through hydrophilic and hydrophobic interactions in the active site cavities. Gallagic acid and castalagin decreased Aß peptides secretion from neuroblastoma cells that overexpressed human ß-amyloid precursor protein significantly by 10 µM. Further, treatment with gallagic acid and castalagin reduced BACE1 and APPsß expression levels significantly without affecting amyloid precursor protein (APP) levels in the amyloidogenic pathway. Co-incubation of Aß42 with gallagic acid reduced Aß42-induced intracellular reactive oxygen species (ROS) production significantly. Our results suggest that pomegranate constituents, specifically gallagic acid, may be useful in developing therapeutic treatment modalities for AD.

Ginsenoside derivatives inhibit advanced glycation end-product formation and glucose-fructose mediated protein glycation in vitro via a specific structure-activity relationship.

Ginseng (Panax ginseng and red ginseng) extract has been reported to inhibit the formation of advanced glycation end-products (AGEs); however, the potential inhibitory activity of its major constituents (ginsenosides) against AGE formation is still unknown. In the present study, we investigated the inhibitory effect of ginsenoside derivatives on AGE formation. Herein, we assessed the activity of 22 ginsenosides, most of which significantly inhibited fluorescent AGE formation. Notably, ginsenoside Rh2, ginsenoside Rh1, and compound K exhibited the most potent AGE inhibitory potential with IC50 values of 3.38, 8.42, and 10.85 µM, respectively. The structure- activity relationship revealed that the presence of sugar moieties, hydroxyl groups, and their linkages, and the stereostructure of the ginsenoside skeleton played an important role in the inhibition of AGE formation. Furthermore, the inhibitory activity of the most active ginsenoside Rh2 on fructose-glucose-mediated protein glycation and oxidation of bovine serum albumin (BSA) was explored. Rh2 (0.1-12.5 µM) inhibited the formation of fluorescent AGE and non-fluorescent AGE, as well as the level of fructosamine and prevented protein oxidation by decreasing protein carbonyl formation and protein thiol group modification. Rh2 also suppressed the formation of the ß-cross amyloid structure of BSA. Ginsenosides might be promising new anti-glycation agents for the prevention of diabetic complications via inhibition of AGE formation and oxidation-dependent protein damage.

Poncirin, an orally active flavonoid exerts antidiabetic complications and improves glucose uptake activating PI3K/Akt signaling pathway in insulin resistant C2C12 cells with anti-glycation capacities.

Poncirin, a natural flavanone glycoside present abundantly in many citrus fruits, contains an extensive range of biological activities. However, the antidiabetic mechanism of poncirin is unexplored yet. In this study, we examined the anti-diabetic prospective of poncirin by evaluating its ability to inhibit protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, human recombinant AR (HRAR), rat lens aldose reductase (RLAR), and advanced glycation end-product (AGE) formation (IC50 = 7.76 ± 0.21, 21.31 ± 1.26, 3.56 ± 0.33, 11.91 ± 0.21, and 3.23 ± 0.09 µM, respectively). Kinetics data and docking studies showed the lowest binding energy and highestaffinityforthemixed and competitivetypeof inhibitorsof poncirin. Moreover, the molecular mechanisms underlying the antidiabetic outcomes of poncirin in insulin resistant C2C12 skeletal muscle cells were explored, which significantly increased glucose uptake and decreased the expression of PTP1B in C2C12 cells. Consequently, poncirin increased GLUT-4 expression level by activating the IRS-1/PI3K/Akt/GSK-3 signaling pathway. Moreover, poncirin (0.5-50 µM) remarkably inhibited the formation of fluorescent AGE, nonfluorescent CML, fructosamine, and ß-cross amyloid structures in glucose-fructose-induced BSA glycation during 4 weeks of study. Poncirin also notably prevented protein oxidation demonstrated with decreasing the protein carbonyl and the consumption of protein thiol in the dose-dependent manner. The results clearly expressed the promising activity of poncirin for the therapy of diabetes and its related complications.

Anti-diabetic and anti-Alzheimer's disease activities of Angelica decursiva.

Diabetes mellitus (DM) and Alzheimer's disease (AD) constitute two global health issues. DM is an ever-increasing epidemic affecting millions of elderly people worldwide, causing major repercussions on patients' daily lives, mostly due to chronic complications. Complications from DM can affect the brain, thereby characterizing DM as a risk factor for AD. In the present study, we examined the inhibitory activity of methanol extracts of different parts of 12 Angelica species against α-glucosidase, protein tyrosine phosphatase 1B (PTP1B), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). The methanol extract of Angelica decursiva exhibited the highest inhibitory activities against α-glucosidase, PTP1B, AChE, and BChE and so was selected for further investigation. Repeated column chromatography based on bioactivity-guided fractionation yielded seven compounds (1-7). Among these compounds, nodakenin (1), nodakenetin (2), umbelliferone (3), cis-3'-acetyl-4'-angeloylkhellactone (4), 3'(R)-O-acetyl-4'(S)-O-tigloylkhellactone (5), isorutarine (6), and para-hydroxybenzoic acid (7) exhibited potent inhibitory activities against α-glucosidase, PTP1B, rat lens aldose reductase (RLAR), AChE, BChE, and ß-site amyloid precursor protein cleaving enzyme 1 (BACE1). Our results clearly indicate the potential inhibition of α-glucosidase, PTP1B, RLAR, AChE, BChE, and BACE1 by A. decursiva as well as its isolated constituents, which could be further explored to develop therapeutic modalities for the treatment of DM and AD.