Polyphenolic Biflavonoids Inhibit Amyloid-Beta Fibrillation and Disaggregate Preformed Amyloid-Beta Fibrils

Alzheimer’s disease (AD) is a devastating neurodegenerative disease and a major cause of dementia in elderly individuals world-wide. Increased deposition of insoluble amyloid β (Aβ) fibrils in the brain is thought be a key neuropathological hallmark of AD. Many recent studies show that natural products such as polyphenolic flavonoids inhibit the formation of insoluble Aβ fibrils and/or destabilize β-sheet-rich Aβ fibrils to form non-cytotoxic aggregates. In the present study, we explored the structure-activity relationship of naturally-occurring biflavonoids on Aβ amyloidogenesis utilizing an in vitro thioflavin T assay with Aβ1–42 peptide which is prone to aggregate more rapidly to fibrils than Aβ1–40 peptide. Among the biflavonoids we tested, we found amentoflavone revealed the most potent effects on inhibiting Aβ1–42 fibrillization (IC50: 0.26 μM), as well as on disassembling preformed Aβ1–42 fibrils (EC50: 0.59 μM). Our structure-activity relationship study suggests that the hydroxyl groups of biflavonoid compounds play an essential role in their molecular interaction with the dynamic process of Aβ1–42 fibrillization. Our atomic force microscopic imaging analysis demonstrates that amentoflavone directly disrupts the fibrillar structure of preformed Aβ1–42 fibrils, resulting in conversion of those fibrils to amorphous Aβ1–42 aggregates. These results indicate that amentoflavone affords the most potent anti-amyloidogenic effects on both inhibition of Aβ1–42 fibrillization and disaggregation of preformed mature Aβ1–42 fibrils.

Ethanolic Extract of the Seed of Zizyphus jujuba var. spinosa Ameliorates Cognitive Impairment Induced by Cholinergic Blockade in Mice

In the present study, we investigated the effect of ethanolic extract of the seed of Zizyphus jujuba var. spinosa (EEZS) on cholinergic blockade-induced memory impairment in mice. Male ICR mice were treated with EEZS. The behavioral tests were conducted using the passive avoidance, the Y-maze, and the Morris water maze tasks. EEZS (100 or 200 mg/kg, p.o.) significantly ameliorated the scopolamine-induced cognitive impairment in our present behavioral tasks without changes of locomotor activity. The ameliorating effect of EEZS on scopolamine-induced memory impairment was significantly reversed by a sub-effective dose of MK-801 (0.0125 mg/kg, s.c.). In addition, single administration of EEZS in normal naive mouse enhanced latency time in the passive avoidance task. Western blot analysis was employed to confirm the mechanism of memory-ameliorating effect of EEZS. Administration of EEZS (200 mg/kg) increased the level of memory-related signaling molecules, including phosphorylation of extracellular signal-regulated kinase or cAMP response element-binding protein in the hippocampal region. Also, the time-dependent expression level of brain-derived neurotrophic factor by the administration of EEZS was markedly increased from 3 to 9 h. These results suggest that EEZS has memory-ameliorating effect on scopolamine-induced cognitive impairment, which is mediated by the enhancement of the cholinergic neurotransmitter system, in part, via NMDA receptor signaling, and that EEZS would be useful agent against cognitive dysfunction such as Alzheimer's disease.

Inhibition of Adenosine Triphosphate-stimulated Mucin Secretion from Airway Epithelial Cells by Schizandrin

Schizandrae Fructus has been used for controlling respiratory allergic or inflammatory diseases in folk medicine and their components, schizandrin, schizandrin-A and gomisin-A were reported to have diverse biological effects. In this study, we investigated whether schizandrin, schizandrin-A and gomisin-A affect adenosine triphosphate (ATP)-induced mucin secretion from cultured airway epithelial cells. Confluent primary hamster tracheal surface epithelial (HTSE) cells were metabolically radiolabeled using 3H-glucosamine for 24 h and chased for 30 min in the presence of varying concentrations of each agent to assess the effects on 3H-mucin secretion. The results were as follows: 1) schizandrin significantly inhibited ATP-induced mucin secretion; 2) However, schizandrin-A and gomisin-A did not affect ATP-induced mucin secretion, significantly. We conclude that schizandrin can inhibit ATP-induced mucin secretion by directly acting on airway mucin-secreting cells. Therefore, schizandrin should further be investigated for the possible use as mucoregulators in the treatment of inflammatory airway diseases.

Glycyrrhizin and Morroniside Stimulate Mucin Secretion from Cultured Airway Epithelial Cells

In this study, we investigated whether glycyrrhizin, prunetin and morroniside affect mucin secretion from cultured airway epithelial cells and compared the possible activities of these agents with the inhibitory action on mucin secretion by poly-L-lysine (PLL) and the stimulatory action by adenosine triphosphate (ATP). Confluent primary hamster tracheal surface epithelial (HTSE) cells were metabolically radiolabeled using (3)H-glucosamine for 24 h and chased for 30 min in the presence of varying concentrations of each agent to assess the effects on (3)H-mucin secretion. The results were as follows: 1) glycyrrhizin and morroniside increased basal mucin secretion from airway; 2) prunetin did not affect basal mucin secretion; 3) glycyrrhizin did not inhibit ATP-induced mucin secretion. We conclude that glycyrrhizin and morroniside can increase basal mucin secretion, by directly acting on airway mucin-secreting cells and suggest that two compounds be further investigated for the possible use as mild expectorants during the treatment of inflammatory airway diseases.

Synthesis and Biodistribution of Flumazenil Derivative F-18(3-(2-Fluoro) flumazenil for Imaging Benzodiazepine Receptor / 대한핵의학회잡지

PURPOSE: Radiotracers that bind to the central benzodiazepine receptor are useful for the investigation of various neurological and psychiatric diseases. [C-11]Flumazenil, a benzodiazepine antagonist, is the most widely used radioligand for central benzodiazepine receptor imaging by PET. We synthesized 3-(2-[F- 18]fluoro)flumazenil, a new fluorine-18 (t1/2=110 min) labeled analogue of benzodiazepine receptor imaging agent, and evaluated in vivo for biodistribution in mice. MATERIALS AND METHODS: Flumazenil (Ro 15-1788) was synthesized by a modification of the reported method. Precursor of 3-(2-[F-18]fluoro)flumazenil, the tosylated flumazenil derivative was prepared by the tosylation of the ethyl ester by ditosylethane. [F-18] labeling of tosyl substitued flumazenil precursor was performed by adding F-18 ion at 85 degree C in the hot cell for 20 min. The reaction mixture was trapped by C18 cartridge, washed with 10% ethanol, and eluted by 40% ethanol. Bidistribution in mice was determined after intravenous injection. RESULTS: The total chemical yield of tosylated flumazenil derivative was ~40%. The efficiency of labeling 3-(2-[F-18]fluoro)flumazenil was 66% with a total synthesis time of 50 min. Brain uptakes of 3-(2-[F-18]fluoro)flumazenil at 10, 30, 60 min after injection, were 2.5+/-0.37, 2.2+/-0.26, 2.1+/-0.11 and blood activities were 3.7+/-0.43, 3.3+/-0.07, 3.3+/-0.09%ID/g, respectively. CONCLUSION: We synthesized a tosylated flumazenil derivative which was successfully labeled with no-carrier-added F-18 by nucleophilic substitution.

A Case of Acute Renal Failure and Other Symptoms Associated with Phytolacca Radix Poisoning / 대한신장학회잡지

Phytolaccae had been used as a pharmaceutical drug or food But nowadays, due to its toxicity, Phytolaccae is rarely used and cases of patients poisoned with it are seldom reported. The case presented here was of 43 year-old male who after ingesting extract of Phytolacca esculenta suffered from abdominal pain, diarrhea, nausea, vomiting, tachycardia, hypotension, pruritus, paresthesia, oliguria and azotemia. Kidney biopsy revealed tubular necrosis and some protein casts in tubular lumens. These findings suggested that acute renal failure was mainly caused by nephrotoxicity of Phytolacca extracts. Through continuous arteriovenous hemofiltration and two times of hemodialysis, he was completely recovered from acute renal failure. Other symptoms also disappeared by symptomatic management, but paresthesia of both lower extremities still remained. So we reported this case with a brief review of literature.