The relationship among amyloid-ß deposition, sphingomyelin level, and the expression and function of P-glycoprotein in Alzheimer's disease pathological process.

In Alzheimer's disease, the transporter P-glycoprotein is responsible for the clearance of amyloid-ß in the brain. Amyloid-ß correlates with the sphingomyelin metabolism, and sphingomyelin participates in the regulation of P-glycoprotein. The amyloid cascade hypothesis describes amyloid-ß as the central cause of Alzheimer's disease neuropathology. Better understanding of the change of P-glycoprotein and sphingomyelin along with amyloid-ß and their potential association in the pathological process of Alzheimer's disease is critical. Herein, we found that the expression of P-glycoprotein in APP/PS1 mice tended to increase with age and was significantly higher at 9 and 12 months of age than that in wild-type mice at comparable age. The functionality of P-glycoprotein of APP/PS1 mice did not change with age but was significantly lower than that of wild-type mice at 12 months of age. Decreased sphingomyelin levels, increased ceramide levels, and the increased expression and activity of neutral sphingomyelinase 1 were observed in APP/PS1 mice at 9 and 12 months of age compared with the levels in wild-type mice. Similar results were observed in the Alzheimer's disease mouse model induced by intracerebroventricular injection of amyloid-ß1-42 and human cerebral microvascular endothelial cells treated with amyloid-ß1-42. In human cerebral microvascular endothelial cells, neutral sphingomyelinase 1 inhibitor interfered with the changes of sphingomyelin metabolism and P-glycoprotein expression and functionality caused by amyloid-ß1-42 treatment. Neutral sphingomyelinase 1 regulated the expression and functionality of P-glycoprotein and the levels of sphingomyelin and ceramide. Together, these findings indicate that neutral sphingomyelinase 1 regulates the expression and function of P-glycoprotein via the sphingomyelin/ceramide pathway. These studies may serve as new pursuits for the development of anti-Alzheimer's disease drugs.

[A preliminary study of the inhibitive efficacy of iodized linoleic acid and its fluorodeoxyuridine ester in hepatocellular cancer].

OBJECTIVE: To explore the potential of iodized linoleic acid (ILA) and its 5-fluoro-deoxyuridine ester (IFU) to inhibit hepatocellular carcinoma (HCC) cells in vitro and tumors in vivo. METHODS: ILA and its constituent component IFU were chemically synthesized, purified, and confirmed by 1H-NMR. The HCC cell lines, QGY-7703 (5-fluorouracil (5-FU) treatment sensitive) and SMMC-7721 (5-FU resistant), were treated with ILA, IFU, 5-FU, or traditional lipiodol for 72 hours. Survival rates of the treated cells were assessed by the methyl thiazolyl tetrazolium method, and used to calculate the IC50 and IC90. In addition, thirty nude mice were subcutaneously inoculated with SMMC-7721 cells and randomly divided two weeks later into four treatment groups (n = 6 each) for intra-tumoral injection of ILA, IFU, 5-FU, lipiodol or DMSO (controls). The rate of tumor inhibition (RTI) was calculated for each group at week 4 after treatment. RESULTS: For the cultured SMMC-7721 cells, the inhibitory concentrations for ILA, IFU, and 5-FU were: IC50: 134.38 mumol/L, 17.55 mumol/L, and 7.38 mumol/L; IC90: 192.88 mumol/L, 97.63 mumol/L, and more than 200 mumol/L. For the cultured QGY-7703 cells, the inhibitory concentrations for ILA, IFU, and 5-FU were: IC50: 109.55 mumol/L, 44.79 mumol/L, and 98.06 mumol/L; IC90: all, more than 200 mumol/L. In both cell types, the IC50 of lipiodol was more than 400 mumol/L. Compared with the RTI of the control mice (100%), the RTI of ILA-treated mice was 31.9% (t = 2.37, P less than 0.05), of IFU-treated mice was 56.9% (t = 4.91, P less than 0.01), and of 5-FU-treated mice was 31.0% (t = 2.59, P less than 0.05). The RTI of IFU was significantly stronger than that of either ILA or 5-FU (P less than 0.05). The lipiodol treatment showed no inhibition effect on tumors (P more than 0.05). CONCLUSION: ILA and IFU can effectively inhibit the growth of HCC cells in vitro and tumors in vivo. Furthermore, IFU outperforms ILA in inhibiting HCC growth.

Oren-gedoku-to and its constituents with therapeutic potential in Alzheimer's disease inhibit indoleamine 2, 3-dioxygenase activity in vitro.

A well-known traditional Chinese medicinal prescription, Oren-gedoku-to (OGT), has been used in clinical therapies for many types of dementia in China and Japan. Additionally, it ameliorates the age-related deterioration of learning and memory in an Alzheimer's disease (AD) rat model. Indoleamine 2, 3-dioxygenase (IDO-1) is the first and rate-limiting enzyme in the kynurenine pathway of tryptophan catabolism, which ultimately leads to the production of the excitotoxin quinolinic acid (QUIN). IDO-1 has recently been established as one of the key players involved in the pathogenesis of AD. OGT is indicated to prevent cholinergic dysfunction and reduce oxidative stress; however, the exact mechanism underlying its ability to improve cognitive ability remains elusive. Here we present a novel mechanism of OGT's therapeutic potential in AD. We demonstrated that OGT significantly inhibited recombinant human IDO-1 (rhIDO-1) activity in vitro, and its four main constituents (i.e., berberine, palmatine, jatrorrhizine, and baicalein) were potent IDO-1 inhibitors. IC50 values, obtained from a cell-based assay, of HEK 293 cells and an enzymatic assay were much lower than the most commonly used IDO-1 inhibitor, 1-methyl tryptophan (1-MT). Berberine was the best inhibitor and had IC50 values of 7 µM (cell-based assay) and 9.3 µM (enzymatic assay). Jatrorrhizine and palmatine exhibited irreversible inhibition of rhIDO-1, whereas berberine and baicalein behaved as uncompetitive, reversible inhibitors with Ki values of 8 µM and 215 µM, respectively. In conclusion, constituents of OGT show strong IDO-1 inhibitory activity and may have significant therapeutic potential for AD.